Propylene glycol

by Health Jade Team on August 10, 2018

What is propylene glycol

Propylene glycol (1,2-dihydroxypropane or 1,2-propanediol or methyl glycol or trimethyl glycol) is a water soluble alcohol and it is a clear liquid used in antifreeze and deicing solutions for cars, airplanes, and boats; to make polyester compounds; and as solvent in the paint and plastics industries. Propylene glycol is a clear, colorless, slightly syrupy liquids at room temperature. It may exist in air in the vapor form, although propylene glycol must be heated or briskly shaken to produce a vapor. Propylene glycol is practically odorless and tasteless. Propylene glycol is also used to create artificial smoke or fog used in fire-fighting training and in theatrical productions.

Propylene glycol is used in pharmaceuticals, as a drug vehicle (for example as a U.S. Food and Drug Administration (FDA)-approved solvent for intravenous diazepam) and preservative. Propylene glycol is also used in personal lubricants, in semi-moist pet food and as a humectant for tobacco. Propylene glycol is currently authorized as a food additive (E 1520). In the food industry propylene glycol (E 1520) is used as a solvent for food colors and flavors, as a humectant, preservative and emulsifier ¹. Propylene glycol is used to absorb extra water and maintain moisture in certain medicines, cosmetics, or food products. The U.S. Food and Drug Administration (FDA) has classified propylene glycol as an additive that is “generally recognized as safe” for use in food, which means that it is acceptable for use in flavorings, drugs, and cosmetics, and as a direct food additive.

The Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) established an acceptable dietary intake of propylene glycol is 0 to 25 mg of propylene glycol for every kilogram (kg) of body weight for propylene glycol, which the European Food Safety Authority Panel on Contaminants in the Food Chain (CONTAM) endorses ². The lowest oral LD50 (lethal dose 50 is a dose where 50% of the test subjects die) values range between 18 and 23.9 grams (5 different species) and the reported dermal LD50 is 20.8 grams ³. Propylene glycol is not genotoxic. Its use as previous cargo would not give rise to any concerns regarding possible irritancy or allergenicity. There are no reactions of concern with edible fats and oils, nor are any anticipated impurities likely to be present at levels of toxicological relevance.

Propylene glycol can enter your bloodstream if you breathe air containing mists or vapors from this compound. Propylene glycol can also enter your bloodstream through your skin if you come in direct contact with it and do not wash it off. If you eat products that contain propylene glycol, it may enter your bloodstream. Exposure of the general population to propylene glycol is likely since many foods, drugs, and cosmetics contain it.

Propylene glycol breaks down in the body in about 48 hours. However, studies of people and animals show that if you have repeated eye, skin, nasal, or oral exposures to propylene glycol for a short time, you may develop some irritation.

Propylene glycol increases the amount of acid in your body. However, large amounts of propylene glycol are needed to cause this effect.

Propylene glycol breaks down at the same rate as ethylene glycol, although it does not form harmful crystals when it breaks down. Frequent skin exposure to propylene glycol can sometimes irritate the skin.

Propylene glycol induces remarkably fewer adverse effects in both humans and animals than does ethylene glycol ⁴. Data describing either human or animal effects after exposure to propylene glycol were not as prevalent as those found for ethylene glycol. Human data came from case reports of clinical studies, adverse reactions to medical treatment, or accidental exposure. Animal data generally support those effects, or lack thereof, observed in humans.

Propylene glycol is essentially nonirritating to the skin and mildly irritating to the eyes. Numerous studies support that propylene glycol is not a skin sensitizer. Repeated exposures of rats to propylene glycol in drinking water or feed did not result in adverse effects at levels up to 10% in water (estimated at about 10 g/kg body weight/day) or 5% in feed (dosage reported as 2.5 g/kg body weight/day) for periods up to 2 years. In cats, two studies of at least 90 days duration show that a species-specific effect of increased Heinz bodies was observed (NOAEL = 80 mg/kg body weight/day; LOAEL = 443 mg/kg body weight/day), with other hematological effects (decrease in number of erythrocytes and erythrocyte survival) reported at higher doses (6-12% in diet, or 3.7-10.1 g/cat/day). No Observed Adverse Effect Level (NOAEL) is the highest dose at which there was not an observed toxic or adverse effect. The Lowest Observed Adverse Effect Level (LOAEL) is the lowest dose at which there was an observed toxic or adverse effect. Propylene glycol did not cause fetal or developmental toxicity in rats, mice, rabbits, or hamsters (NOAELs range from 1.2 to 1.6 g/kg body weight/day in four species). No reproductive effects were found when propylene glycol was administered at up to 5% in the drinking water (reported as 10.1 g/kg body weight/day) of mice. Propylene glycol was not a genetic toxicant as demonstrated by a battery of in vivo (micronucleus, dominant lethal, chromosome aberration) and in vitro (bacterial and mammalian cells and cultures) studies. No increase in tumors was found in all tissues examined when propylene glycol was administered in the diet of rats (2.5 g/kg body weight/day for 2 years), or applied to the skin of female rats (100% propylene glycol; total dose not reported; 14 months) or mice (mouse dose estimated at about 2 g/kg body weight/week; lifetime). These data support a lack of carcinogenicity for propylene glycol.

Propylene glycol allergy

There is evidence from clinical studies that propylene glycol is a weak irritant and skin sensitizer (challenge with 2 % solution or stronger), and may increase the reaction to some contact allergens (i.e. adjuvant-like effect), if there is co-exposure, for example when propylene glycol is used as a vehicle ⁵. Oral or IV administration of propylene glycol may exacerbate dermatitis in some individuals ⁶. Taking into account that the worst case residue levels of propylene glycol in the oils and fats is considered to be 100 mg/kg, and additionally that propylene glycol is only a weak or very weak irritant, allergen or adjuvant, the European Food Safety Authority Panel on Contaminants in the Food Chain (CONTAM) Panel considers that there would be no significant risk for adverse reactions due to irritancy or allergy from the use of propylene glycol.

Retrospective analysis of cross-sectional data compiled by the North American Contact Dermatitis Group ⁷ from 1996 to 2006 /was examined/. RESULTS: Of 23,359 patients, 810 (3.5%) had allergic patch-test reactions to 30% propylene glycol, 12.8% of the reactions were of definite clinical relevance (positive reaction to a personal product containing propylene glycol), 88.3% were considered to be currently relevant (definite, probable, or possible relevance), and 4.2% of reactions were occupation related, most commonly to mechanical and motor vehicle occupations. Common sources of propylene glycol were personal care products (creams, lotions, and cosmetics, 53.8%), topical corticosteroids (18.3%), and other topical medicaments (10.1%). In patients positive only to PG (n = 135), the face was most commonly affected (25.9%), followed by a scattered or generalized pattern (23.7%).

To characterize relevant allergens and irritants associated with food in patients referred to the North American Contact Dermatitis Group ⁸ for patch testing retrospective analysis of cross-sectional data from the North American Contact Dermatitis Group from 2001 to 2004 was performed. Of 10,061 patch-tested patients, 109 (1.1%) had a total of 122 reactions associated with food. Approximately two-thirds of patients (66%) were female, and one-third (36%) were atopic. The hands were the most common sites of dermatitis (36.7%). There were 78 currently relevant (definite, probable, or possible) allergic reactions to North American Contact Dermatitis Group standard series allergens with a food source; the most common allergen was nickel (48.7%), followed by Myroxilon pereirae (balsam of Peru) (20.6%) and propylene glycol (6.4%) ⁸.

Contact dermatitis has been reported from propylene glycol exposure in a wide variety of topical preparations and ingestion of propylene glycol in sensitized individuals has produced flares of dermatitis ⁹. Skin irritation resulting from topical exposure is manifest as erythematous reactions restricted to sites of exposure. The irritation potential is enhanced after prolonged dermal exposure, under dermal occlusion, and in combination with triethanolamine-stearate, a cosmetic emulsifier. The nature of the skin reaction of propylene glycol-sensitive patients has been a matter of controversy. In one study primary irritant reactions to the skin and type IV delayed hypersensitivity reactions were observed following oral ingestion or topical application of propylene glycol. However, in most cases, the skin reaction was due to a primary irritation, not to an allergic reaction ⁹.

Results from human patch testing show no sensitization potential of propylene glycol after semi-occlusive or occlusive epicutaneous application to the skin of volunteers (in excess of 300 subjects in total). These studies demonstrate that propylene glycol is not irritating to skin or eye, nor does it cause sensitization by skin contact ¹⁰.

Patch-test in humans, 15 uL 100% propylene glycol/test chamber for 48 hr. Results: not irritating ¹¹.

In 6 human volunteers, pads containing /propylene glycol/ test substance were fixed to the forearm for 2 hr, observation time: 7 days. Results: not irritating ¹¹.

Cream containing 12% propylene glycol was tested on 204 persons. Results: not sensitizing ¹².

The irritant effects of propylene glycol was studied in humans (number of test subjects not indicated) using laser Doppler flowmetry ¹³. Propylene glycol was applied using three different methods: single open exposures to 1.0 mL propylene glycol on the ventral aspect of the thigh with and without occlusive patches for 5-15 min and repeated open exposure to 1.0 mL propylene glycol on the skin for 12 days. Blood flow at the test site was measured and used as an indication of irritation. propylene glycol, when administered under occlusive patches, caused weak erythema at the test site; the maximum reaction was measured 26 hr after exposure. Single open applications and repeated open exposure to propylene glycol did not cause any irritation reactions in this test ¹³.

A total of 866 patients with various dermatological conditions were patch tested (closed or covered patches) with 100% propylene glycol from April 1951 to April 1952 ¹³. The patches were applied to clinically normal skin, and test sites were examined 48 hr after patch application. Positive reactions were observed in 138 (15.7%) patients. Reactions ranged from simple erythema (+) to erythema with induration and vesiculations (++++). 89 of the 138 patients with positive reactions suffered from dermatitis venenata. A seasonal fluctuation in the incidence of positive reactions was also noted. The incidence was at a minimum when the climate was hot and humid (July, August, and September 1951 in New York City) and significantly greater during the cooler and less humid seasons. Of the 84 patients involved with simultaneous testing with several samples of propylene glycol from different sources, positive reactions were observed in 15. There were no differences in patient responses to different brands of propylene glycol 23 of the 138 patients with positive reactions to 100% propylene glycol were patch tested with aqueous propylene glycol. There were only 5 positive responses to 10% propylene glycol, and the application of 2.5% propylene glycol in water to 3 of the 23 patients resulted in one positive reaction. Additionally, 16 of the patients with positive reactions to 100% propylene glycol were also tested by simple inunction of the test substance. There was no evidence of an inflammatory response to the the rubbing of propylene glycol into the skin either shortly after application or 48 hr later ¹³.

When 1,556 patients were patch tested with 100% propylene glycol, positive reactions were observed in 194 subjects ¹³. 4 patients had “true allergy” and the remainder had irritant reactions. Three groups of 42 patients with positive reactions to 100% propylene glycol were later tested with 3.2, 10, and 32 % propylene glycol, respectively, and the results were as follows: 3.2% propylene glycol (9 positive reactions), 10% propylene glycol (12 positive reactions), and 32% propylene glycol (20 positive reactions) ¹³.

Is propylene glycol safe?

The Scientific Committee on Food evaluated propylene glycol in 1996 and considered this substance as acceptable, noting that propylene glycol was a food additive with an ADI previously established by the Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) of 0-25 mg/kg body weight per day ¹⁴. In the 2003 Scientific Committee on Food evaluation of acceptable previous cargoes, propylene glycol was not further evaluated as it was already considered acceptable ¹⁵.

In 1993, the Scientific Committee on Food had also evaluated propylene glycol as a food additive, and concluded that “the uncertainty with regard to potential mutagenic effects at the germ cell level, the fact that most studies at the chromosomal level used limited protocols, that there is no in vitro assay for gene mutation in cultured mammalian cells as well as the absence of a carcinogenicity study in a second species leads the Committee to change the established full ADI into a temporary ADI of 25 mg/kg b.w.” ¹⁶. Propylene glycol is currently authorized as a food additive (E 1520).

The Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) at its 17th meeting in 1973 established an “Estimate of acceptable daily intake for man” of 0 to 25 mg/kg body weight for propylene glycol ¹⁷, following several previous evaluations, and specifications were also prepared ¹⁸. JECFA also evaluated propylene glycol as a flavoring substance in 2001. The evaluation was not finalised as further information was required whether propylene glycol is currently in use as a flavoring agent ¹⁹.

Propylene glycol was evaluated by the Scientific Committee on Food in 1978 as a substance intended for use in the manufacture of regenerated cellulose films ²⁰. The Committee considered the substance toxicologically acceptable for the use intended on the basis of the Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) acceptable daily intake of 0-25 mg/kg body weight per day. In 1984, propylene glycol was evaluated by the Scientific Committee on Food as a substance intended for use in materials in contact with food and considered acceptable on the basis of the JECFA acceptable daily intake.

The US Agency for Toxic Substances and Disease Registry (ATSDR) has prepared a toxicological profile on propylene glycol ²¹. There was insufficient information to establish an oral reference value.

Absorption, distribution, metabolism and elimination

According to JECFA ¹⁷, propylene glycol is rapidly absorbed after oral administration and appears in the blood-stream. After a dose of 8 mL/kg body weight (equivalent to 8,284 mg/kg body weight) had been administered to dogs approximately 24 hours were required for complete elimination from the blood-stream. Conversion to lactic acid has been shown to be the normal metabolic pathway, via two biochemical pathways ¹⁹. Phosphorylated propylene glycol can be converted to acetolphosphate, lactaldehyde phosphate, lactyl phosphate, and then lactic acid. Non-phosphorylated propylene glycol is successively oxidized to lactaldehyde, methylgloyoxal, and lactic acid ¹⁹. High doses are likely to be excreted largely unchanged in the urine ¹⁹.

Acute toxicity

As reported by JECFA, acute toxicity studies on propylene glycol have been carried out in rats, mice, rabbits and guinea pigs, providing LD50 (lethal dose 50 where 50% of the test subjects die) values of greater than 19,000 mg/kg body weight in all these species ¹⁷.

Subacute, subchronic toxicity studies

Short-term oral toxicity studies of propylene glycol in rats, rabbits and dogs have shown no adverse effects at levels approximating 10 % in the diet ¹⁶. Hematological effects have been seen at high dose levels in some species, notably cats. Cats appear to be uniquely sensitive to hematological effects of ingested propylene glycol, manifest as an increase of Heinz bodies in circulating erythrocytes ²².

Genotoxicity

Propylene glycol has been extensively evaluated in a range of genetic toxicity test systems. The existing studies provide convincing evidence that it is not genotoxic ¹⁹. Chronic toxicity studies and carcinogenicity as cited by JECFA ¹⁹, in a study in which rats were given propylene glycol in the diet at a concentration of 2.45 % or 4.9 % (equivalent to 900 and 1,800 mg/kg body weight per day) for 2 years no treatment-related adverse effects were found on growth, and histological examination revealed no treatment-related effects ²³. As cited by JECFA ¹⁹, in a study in which rats received propylene glycol in the diet at a concentration of 0, 310, 630, 1,300 or 2,500 mg/kg body weight per day for 2 years no treatment-related adverse effects on body weight gain, hematological, urinary, or clinical chemical end-points, or organ weights were found. The NOAEL was 1,300 mg/kg body weight per day ²⁴. No Observed Adverse Effect Level (NOAEL) is the highest dose at which there was not an observed toxic or adverse effect. As cited by JECFA ¹⁹, in a study in which dogs received propylene glycol in the diet at a concentration of 0, 2000, or 5000 mg/kg body weight per day for 2 years increased erythrocyte destruction was found at 5,000 mg/kg body weight per day. No significant treatment-related effects on hematological, clinical chemical, or urinary end-points, or on gross or histological appearance were found ²⁵.

Developmental and reproductive toxicity

In rats and mice, no adverse effects on reproductive performance were observed after oral treatment at doses as high as 10,000 mg/kg body weight per day during gestation of 1 generation or for multiple litters and 2 generations of mice ²⁶ or inhalation exposure to 112 ppm for 18 months ²⁷. Agency for Toxic Substances and Disease Registry (ATSDR) considered that further evaluation of the reproductive toxicity of propylene glycol was not necessary ²². As reported by JECFA, in a study to examine the potential of di(2-ethylhexyl)phthalate and its metabolites to cause testicular damage in rats after oral administration, a control group of six male Sprague Dawley rats were given propylene glycol orally at a dose of 2,000 mg/kg body weight per day for 5 days. Histopathological examination of testis, prostate and liver was done following
sacrifice on day 6. The testes of animals given propylene glycol were reported to contain occasional degenerated cells, most of which were in early meiotic prophase or undergoing meiotic division ²⁸. In another study cited by JECFA ²⁹, in which the effects of 15 chemicals, including propylene glycol, on differential ovarian follicle counts and reproductive performance were compared, propylene glycol was reported to have no effect on reproductive function ³⁰.

How might I be exposed to propylene glycol?

You can be exposed to propylene glycol by eating food products, using cosmetics, or taking medicine that contains it.
If you work in an industry that uses propylene glycol or products containing propylene glycol, you could be exposed by breathing or touching these substances.

Propylene glycol has been approved for use at certain levels in food (food additive E 1520), cosmetics, and pharmaceutical products. If you eat food products, use cosmetics, or take medicines that contain it, you will be exposed to propylene glycol, but these amounts are not generally considered harmful. People who work in industries that use propylene glycol may be exposed by touching these products or inhaling mists from spraying them. These exposures tend to be at low levels, however. Propylene glycol is used to make artificial smoke and mists for fire safety training, theatrical performances, and rock concerts. These artificial smoke products may also be used by private citizens. These products are frequently used in enclosed spaces, where exposure may be more intense.

Is there a medical test to determine whether I have been exposed to propylene glycol?

Propylene glycol is generally considered to be a safe chemical, and is not routinely tested for, unless specific exposure, such as to a medicine or cosmetic, can be linked with symptoms.

Since propylene glycol breaks down very quickly in the body, it is very difficult to detect, even though symptoms may be present.

How likely is propylene glycol to cause cancer?

The Department of Health and Human Services, the International Agency for Research on Cancer (IARC), and the EPA have not classified propylene glycol for carcinogenicity. Animal studies have not shown propylene glycol to be carcinogen.

No increase in tumors was observed after twice weekly applications of propylene glycol to the skin of Swiss mice for 120 weeks, at doses up to 2 mg ³¹. Based on this information, its long history of use in consumer products, and structural activity considerations, it is extremely unlikely that exposure to levels of propylene glycol near hazardous waste sites would influence the incidence of cancer in the population living in the vicinity.

Propylene glycol in medicinal products for children

Clinically, the weak evidence and the reliance on predominantly non-comparative data and case reports, severely limit the robustness of any recommendation regarding safe propylene glycol exposure levels in children. A variety of relevant aspects are to be considered when considering a safe dose of propylene glycol. These include patient characteristics such as (developmental) age, weight, health status, concomitant medication, administration route, pattern and duration of use.

In pre-term infants where metabolism and secretion mechanisms are yet immature, accumulation of propylene glycol can occur more easily, thus leading to an increased potential toxicity ³². Propylene glycol is used as excipient for a variety of medicinal products frequently applied in an intensive care unit (ICU) setting, where the patient collective will arguably display a variety of severe health conditions that could accentuate but also mask any adverse effects due to propylene glycol. In this regard, studies considered for this review have been conducted in an ICU setting. Finally, the hardly quantifiable impact of co-medication and its excipients (e.g. mannitol) or sources of propylene glycol other than those investigated could potentially distort the clinical picture and the interpretation of data, accordingly.

The current regulatory recommendations concerning propylene glycol have been made for oral intake via food products (FAO/WHO) or focus on the alcohol effect of propylene glycol only (European Medicines Agency – EMA).

Attempts to define a safety threshold for propylene glycol administration have not been utterly conclusive so far. For children, it was concluded that “a median propylene glycol exposure of 34 mg/kg/24h seems well tolerated and does not affect normal postnatal maturational changes in renal, metabolic and hepatic function” ³³. Determining a safe upper limit of propylene glycol exposure of 34 mg/kg/day might be a possible, rather conservative, approach. Importantly however, study specifics limit the generalizability of the proposed threshold: mainly (pre-term) infants in an ICU setting, short-term exposure (48h), use of historical controls, and assessment of selected endpoints only.

Based on the limited overall quality, non-clinical and clinical data available, the European Medicines Agency Committee considered that ³²:

No recommendation on a safe dose for propylene glycol can be made based on the current available data;
Correlations between propylene glycol exposure, patient characteristics and reported adverse events are not established;
While there is a trend of increasing safety concerns with propylene glycol doses in excess of several hundred mg /kg/day in infants, the limitations of the available data do not allow for a definite conclusion;

The European Medicines Agency Committee therefore concluded that well designed clinical trials investigating the safety of propylene glycol exposure and reflective of common clinical use in terms of duration and quantity are needed to allow a better understanding of propylene glycol safety in children. Additional information from non-clinical juvenile studies assessing the toxicity and toxicokinetics of propylene glycol following repeated administration in the relevant species and age groups may be considered useful to assess the safety risks (particularly central nervous system toxicity) inherent to the formulation.

Propylene glycol uses

Propylene glycol (1,2-dihydroxypropane or 1,2-propanediol or methyl glycol or trimethyl glycol) is a clear liquid used in antifreeze and deicing solutions for cars, airplanes, and boats; to make polyester compounds; and as solvent in the paint and plastics industries. Propylene glycol is also used to create artificial smoke or fog used in fire-fighting training and in theatrical productions.

Uses of propylene glycol, with percent of demand, are:

Unsaturated polyester resins, 26 percent;
Antifreeze and de-icing fluids, 22 percent;
Food, drug and cosmetics uses, 18 percent;
Liquid detergents, 11 percent;
Functional fluids (inks, specialty anti-freeze, de-icing lubricants), 4 percent;
Pet foods, 3 percent;
Paints and coatings, 5 percent;
Tobacco, 3 percent;
Miscellaneous, including plasticizer use, 8 percent.

Propylene glycol is a synthetic liquid substance that absorbs water. Propylene glycol is used by the chemical, food, and pharmaceutical industries as an antifreeze when leakage might lead to contact with food. The Food and Drug Administration (FDA) has classified propylene glycol as an additive that is “generally recognized as safe” for use in food. It is used to absorb extra water and maintain moisture in certain medicines, cosmetics, or food products. It is a solvent for food colors and flavors, and in the paint and plastics industries.

Propylene glycol toxicity

Below are symptoms of propylene glycol antifreeze poisoning in different parts of the body.

Airways and lungs

Rapid breathing
No breathing

Bladder and kidneys

Blood in urine
No urine output or decreased urine output

Eyes, Ears, Nose, and Throat

Blurred vision
Blindness

Heart and blood

Rapid heartbeat
Low blood pressure

Muscles and joints

Leg cramps

Nervous system

Coma
Convulsions
Dizziness
Fatigue
Headache
Slurred speech
Stupor (lack of alertness)
Unconsciousness
Unsteady walk
Weakness

Skin

Blue lips and fingernails

Stomach and gastrointestinal tract

Nausea and vomiting

Home Care

Seek medical help right away. DO NOT make a person throw up unless poison control or a health care provider tells you to.

Use standard first aid and CPR for signs of shock or no heartbeat (cardiac arrest). Call your local poison control center or your local emergency services number for more help. You can call for any reason, 24 hours a day, 7 days a week.

Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere in the United States. They will give you further instructions.

This is a free and confidential service. All local poison control centers in the United States use this national number. You should call if you have any questions about poisoning or poison prevention. It does NOT need to be an emergency.

What to Expect at the Emergency Room

Take the container with you to the hospital, if possible.

The healthcare provider will measure and monitor the person’s vital signs, including temperature, pulse, breathing rate, and blood pressure. The person may receive:

Blood and urine tests
Breathing support, including oxygen, tube through the mouth into the throat, and breathing machine
Chest x-ray
CT scan (advanced brain imaging)
ECG (electrocardiogram or heart tracing)
Intravenous fluids (through a vein)
Medicines to reverse the effects of the poison
Tube placed down the nose and into the stomach (sometimes)

Dialysis (kidney machine) treatment may be needed during recovery. This need may be permanent if kidney damage is severe.

Propylene glycol side effects

Non-asthmatic volunteers (n=27) were exposed to propylene glycol (propylene glycol) mist over 1 minute, during realistic training conditions ³⁴. Geometric mean concentration of propylene glycol was 309 mg/m³ (range 176-851 mg/³), with the highest concentrations in the afternoon. The medical investigation was performed both before and after the exposure (within 15 minutes). It included an estimate of tear film stability break up time, nasal patency by acoustic rhinometry, dynamic spirometry, and a doctor’s administered questionnaire on symptoms. After exposure to propylene glycol mist for 1 minute tear film stability decreased, ocular and throat symptoms increased, forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) was slightly reduced, and self rated severity of dyspnea was slightly increased. No effect was found for nasal patency, vital capacity (VC), FVC, nasal symptoms, dermal symptoms, smell of solvent, or any systemic symptoms. Those exposed to the higher concentrations in the afternoon had a more pronounced increase of throat symptoms, and a more pronounced decrease of tear film stability. In four subjects who reported development of irritative cough during exposure to propylene glycol, FEV1 was decreased by 5%, but FEV1 was unchanged among those who did not develop a cough. Those who developed a cough also had an increased perception of mild dyspnea. Short exposure to propylene glycol mist from artificial smoke generators in discotheques, theaters, and aviation emergency training may cause acute ocular and upper airway irritation in non-asthmatic subjects. A few may also react with cough and slight airway obstruction.

Propylene glycol is estimated to be one-third as intoxicating as ethanol, with administration of large volumes being associated with adverse effects most commonly on the central nervous system, especially in neonates and children. Other adverse reactions reported, though generally isolated, include: ototoxicity; cardiovascular effects; seizures; and hyperosmolarity and lactic acidosis, both of which occur most frequently in patients with consumption of large quantities of propylene glycol or on administration to neonates, children under 4 years of age, pregnant women, and patients with hepatic or renal failure. Adverse effects may also occur in patients treated with disulfiram or metronidazole ³⁵.

There are numerous reports of propylene glycol-induced serum hyperosmolarity following the topical administration of silver sulfadiazine. Systemic absorption of propylene glycol resulting in hyperosmolarity occurred with topical application of silver sulfadiazine cream in 15 burn patients with burns over more than 35% of their body surface area ³⁶.

References

Scientific Opinion on the evaluation of the substances currently on the list in the Annex to Commission Directive 96/3/EC as acceptable previous cargoes for edible fats and oils – Part I of III. EFSA Journal 2011;9(12):2482. https://doi.org/10.2903/j.efsa.2011.2482
Scientific Opinion on the evaluation of the substances currently on the list in the Annex to Commission Directive 96/3/EC as acceptable previous cargoes for edible fats and oils – Part I of III. https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2011.2482
Propylene Glycol. https://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=1122&tid=240
PROPYLENE GLYCOL. Health Effects. https://www.atsdr.cdc.gov/toxprofiles/tp189-c2.pdf
Andersen FA, ed. 1994. Final report on the safety assessment of Propylene Glycol and Polypropylene Glycols. Journal of the American College of Toxicology, 13, 437-491.
Monograph on the Potential Human Reproductive and Developmental Effects of Propylene Glycol (March 2004) NIH Pub No. 04-4482 p.II-44
Positive patch-test reactions to propylene glycol: a retrospective cross-sectional analysis from the North American Contact Dermatitis Group, 1996 to 2006. Dermatitis. 2009 Jan-Feb;20(1):14-20. https://www.ncbi.nlm.nih.gov/pubmed/19321115
Contact dermatitis associated with food: retrospective cross-sectional analysis of North American Contact Dermatitis Group data, 2001-2004. Dermatitis. 2008 Sep-Oct;19(5):252-60. https://www.ncbi.nlm.nih.gov/pubmed/18845115
Monograph on the Potential Human Reproductive and Developmental Effects of Propylene Glycol (March 2004) NIH Pub No. 04-4482 pp.II-28-29
Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.17, 2001
Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.56, 2001
Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.60, 2001
Cosmetic Ingredient Review Expert Panel; J Am Coll Toxicol 13 (6): 437-91; 1994
SCF (Scientific Committee on Food), 1997. Opinion on the potential risk to human health arising from the transport in ships’ tanks of oils and fats from substances proposed as acceptable previous cargoes (expressed on 20 September 1996). Annex VII to Document III/5693/96. DG III, European Commission, Brussels.
SCF (Scientific Committee on Food), 2003. Updated opinion of the Scientific Committee on Food on the potential risk to human health arising from the transport in ships’ tanks of oils and fats from substances proposed as acceptable previous cargoes (expressed on 4 April 2003). Health and Consumer Protection Directorate-General, European Commission, Brussels.
SCF (Scientific Committee on Food), 1996. Reports of the Scientific Committee for Food. Thirty-fifth Series. Opinions on the Scientific Committee for Food on: Propylene glycol. European Commission, Luxemburg.
JECFA (Joint FAO/WHO Expert Committee on Food Additives), 1974. WHO Food Additives Series No. 5. Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents. Seventeenth Report of the Joint FAO/WHO Expert Committee on Food Additives. WHO, Geneva, Switzerland.
JECFA (Joint FAO/WHO Expert Committee on Food Additives), 2006. Propylene glycol. Specifications. Prepared at the 49th JECFA (1997).
JECFA (Joint FAO/WHO Expert Committee on Food Additives), 2001. WHO Food Additives Series No 48. Safety evaluation of certain food additives and contaminants, Aliphatic acyclic diols, triols, and related substances. WHO, Geneva, Switzerland.
SCF (Scientific Committee on Food), 1978. Reports of the Scientific Committee for Food. Sixth series. Report of the Scientific Committee for Food on the positive list of substances to be authorized in the manufacture of regenerated cellulose films intended to come into contact with foodstuffs (Opinion expressed 28 September 1978). European Commission. Brussels-Luxemburg.
Propylene Glycol. https://www.atsdr.cdc.gov/substances/toxsubstance.asp?toxid=240
ATSRD (US Agency for Toxic Substances and Disease Registry), 1997. Toxicological profile for propylene glycol. September 1997.
Morris HJ, Nelson AA and Calvery HO, 1942. Journal of Pharmacology and Experimental Therapeutics, 74, 266. As cited in JECFA (2001).
Gaunt IF, Carpanini FMB, Grasso P and Lansdown ABG, 1972. Long-term toxicity of propylene glycol in rats. Food and Cosmetics Toxicology, 10, 151-162. As cited by JECFA (2001).
Weil CS, Woodside MD, Smyth MF and Carpenter CP, 1971. Results of feeding propylene glycol in the diet to dogs for two years. Food and Cosmetic Toxicology, 9, 479. As cited in JECFA (2001).
Kavlock RJ, Short RD and Chemoff N, 1987. Further evaluation of and in vivo teratology screen. Teratogensis, Carcinogenisi and Mutagenesis, 7, 7-16. As cited by ATSDR (1997).
Robertson OH, Loosli CG and Puck TT, 1947. Test for chronic toxicity of propylene glycol and triethylene glycol on monkeys and rats by vapor inhalation and oral administration. Journal of Pharmacology and Experimental Therapeutics, 91, 52-76. As Cited by ATSDR (1997).
Sjoberg R, Bondesson U, Gray TJB and Ploen L, 1986. Effects of di-(2-ethylhexyl) phthalate and five of its metabolites on rat testis in vivo and in vitro. Acta Pharmacologica et Toxicologica, 58, 225-233.
JECFA (Joint FAO/WHO Expert Committee on Food Additives), 2001. WHO Food Additives Series No 48. Safety evaluation of certain food additives and contaminants, Aliphatic acyclic diols, triols, and related substances. WHO, Geneva, Switzerland
Bolon B, Bucci TJ, Warbritton AR, Chen JJ, Mattison DR and Heindel JJ, 1997. Differential Follicle Counts as a Screen for Chemically Induced Ovarian Toxicity in Mice: Results from Continuous Breeding Bioassays. Fundamental and Applied Toxicology, 39, 1-10. As cited by JECFA (2001).
Stenback F, Shubik P. 1974. Lack of toxicity and carcinogenicity of some commonly used cutaneous agents. Toxicol Appl Pharmacol 30:7-13.
Propylene glycol in medicinal products for children. European Medicines Agency Assessment Report. Article 5(3) of Regulation (EC) No 726/2004. http://www.ema.europa.eu/docs/en_GB/document_library/Report/2014/03/WC500163989.pdf
Kulo et al., 2012. Biochemical tolerance during low dose propylene glycol exposure in neonates: A formulation-controlled evaluation
Wieslander G et al; Occup Environ Med 58 (10): 649-55; 2001 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1740047/pdf/v058p00649.pdf
Rowe, R.C., Sheskey, P.J., Quinn, M.E.; (Eds.), Handbook of Pharmaceutical Excipients 6th edition Pharmaceutical Press, London, England 2009, p. 593
Goldfrank LR et al; Goldfrank’s Toxicologic Emergencies 7th Ed., McGraw-Hill, New York, N.Y. p.842; 2002

Drugs Drugs & Supplements

Calcium gluconate

by Health Jade Team on August 10, 2018

What is calcium gluconate

Calcium gluconate also called D-gluconic acid calcium salt, is the calcium salt of gluconic acid or gluconate salt of calcium. Calcium gluconate is used to prevent or to treat calcium deficiencies. Calcium gluconate exists in both an anhydrous form (empirical formula C₁₂H₂₂O₁₄Ca) and as a monohydrate (empirical formula C₁₂H₂₂O₁₄CaH₂O). Each form is an odorless, white, free-flowing powder that is soluble in water, insoluble in alcohol and most organic solvents, and stable in air. Calcium gluconate has a variety of uses, including its use as a calcium replenisher in hypocalcemic states. Calcium as the gluconate salt helps to maintain calcium balance and prevent bone loss when taken orally. Calcium gluconate use in food in general as a source of calcium and the U.S. Food and Drug Administration (FDA) consider calcium gluconate as Generally Recognized as Safe (GRAS) ¹.

Calcium, the most abundant mineral in the body, is found in some foods, added to others, available as a dietary supplement, and present in some medicines (such as antacids). Calcium is required for vascular contraction and vasodilation, muscle function, nerve transmission, intracellular signaling and hormonal secretion, though less than 1% of total body calcium is needed to support these critical metabolic functions ². Serum calcium is very tightly regulated and does not fluctuate with changes in dietary intakes; the body uses bone tissue as a reservoir for, and source of calcium, to maintain constant concentrations of calcium in blood, muscle, and intercellular fluids ².

The remaining 99% of the body’s calcium supply is stored in the bones and teeth as calcium hydroxyapatite, where it supports their structure and function ². Bone itself undergoes continuous remodeling, with constant resorption and deposition of calcium into new bone. The balance between bone resorption and deposition changes with age. Bone formation exceeds resorption in periods of growth in children and adolescents, whereas in early and middle adulthood both processes are relatively equal. In aging adults, particularly among postmenopausal women, bone breakdown exceeds formation, resulting in bone loss that increases the risk of osteoporosis over time ².

Intestinal calcium absorption occurs through both an active, saturable, transcellular process and a non-saturable, passive process. Active transport is controlled by 1,25-dihydroxyvitamin D [1,25(OH)2D] or calcitriol, and passive transport is paracellular. Calcium absorption varies considerably throughout the lifespan, being higher during periods of rapid growth and lower in old age. Calcium absorption is affected by vitamin D status; it has been shown to be low in patients with vitamin D deficiency, but there is uncertainty about the serum concentration of 25-hydroxyvitamin D [25(OH)D] or calcidiol, that is required for optimal calcium absorption. Unabsorbed dietary calcium is lost in the feces. The main routes of obligatory (endogenous) calcium loss are urine, feces, and skin and sweat (dermal losses).

Table 1: Recommended Dietary Allowances (RDAs) for Calcium

Age	Male	Female	Pregnant	Lactating
0–6 months*	200 mg	200 mg
7–12 months*	260 mg	260 mg
1–3 years	700 mg	700 mg
4–8 years	1,000 mg	1,000 mg
9–13 years	1,300 mg	1,300 mg
14–18 years	1,300 mg	1,300 mg	1,300 mg	1,300 mg
19–50 years	1,000 mg	1,000 mg	1,000 mg	1,000 mg
51–70 years	1,000 mg	1,200 mg
71+ years	1,200 mg	1,200 mg

Footnotes:

Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.

* Adequate Intake (AI)

[Source ³]

National Academy of Sciences has recommended 1000 – 1300 mg per day as an adequate intake for adults, with an “upper limit” of 2500 mg per day to limit the potential for adverse effects that can be associated with excessive consumption of calcium, such as kidney stones, hypercalcemia, renal insufficiency, and the possibility of reduced absorption of other minerals.

If the dietary supply of calcium is insufficient to meet physiological requirements, calcium is resorbed from the skeleton to maintain blood concentrations within the range required for normal cellular and tissue functions. This causes a reduction in bone mass, which leads to osteopenia and osteoporosis, and an associated increased risk of fracture.

Excessively high levels of calcium in the blood known as hypercalcemia is defined by serum calcium concentrations > 2.75 mmol/L (11 mg/dL). Although very high calcium intakes have the potential to cause hypercalcemia ⁴, it is unlikely to occur with high intake of calcium from the diet alone but can be caused by high-dose calcium supplements, especially when accompanied by vitamin D supplements, as these can increase calcium absorption and hypercalcemia is most commonly associated with primary hyperparathyroidism or malignancy ².

Excessively high levels of calcium in the blood (hypercalcemia) can cause renal insufficiency, vascular and soft tissue calcification, hypercalciuria (high levels of calcium in the urine) and kidney stones ².

High calcium intake can cause constipation. It might also interfere with the absorption of iron and zinc, though this effect is not well established ². High intake of calcium from supplements, but not foods, has been associated with increased risk of kidney stones ². Some evidence links higher calcium intake with increased risk of prostate cancer, but this effect is not well understood, in part because it is challenging to separate the potential effect of dairy products from that of calcium ². Some studies also link high calcium intake, particularly from supplements, with increased risk of cardiovascular disease ⁴.

Milk, yogurt, and cheese are rich natural sources of calcium and are the major food contributors of this nutrient to people in the United States ². Nondairy sources include vegetables, such as Chinese cabbage, kale, and broccoli. Spinach provides calcium, but its bioavailability is poor. Most grains do not have high amounts of calcium unless they are fortified; however, they contribute calcium to the diet because they contain small amounts of calcium and people consume them frequently. Foods fortified with calcium include many fruit juices and drinks, tofu, and cereals. Selected food sources of calcium are listed in Table 2.

Table 2: Selected Food Sources of Calcium

Food	Milligrams (mg) per serving	Percent DV*
Yogurt, plain, low fat, 8 ounces	415	42
Mozzarella, part skim, 1.5 ounces	333	33
Sardines, canned in oil, with bones, 3 ounces	325	33
Yogurt, fruit, low fat, 8 ounces	313–384	31–38
Cheddar cheese, 1.5 ounces	307	31
Milk, nonfat, 8 ounces**	299	30
Soymilk, calcium-fortified, 8 ounces	299	30
Milk, reduced-fat (2% milk fat), 8 ounces	293	29
Milk, buttermilk, lowfat, 8 ounces	284	28
Milk, whole (3.25% milk fat), 8 ounces	276	28
Orange juice, calcium-fortified, 6 ounces	261	26
Tofu, firm, made with calcium sulfate, ½ cup***	253	25
Salmon, pink, canned, solids with bone, 3 ounces	181	18
Cottage cheese, 1% milk fat, 1 cup	138	14
Tofu, soft, made with calcium sulfate, ½ cup***	138	14
Ready-to-eat cereal, calcium-fortified, 1 cup	100–1,000	10–100
Frozen yogurt, vanilla, soft serve, ½ cup	103	10
Turnip greens, fresh, boiled, ½ cup	99	10
Kale, fresh, cooked, 1 cup	94	9
Ice cream, vanilla, ½ cup	84	8
Chinese cabbage, bok choi, raw, shredded, 1 cup	74	7
Bread, white, 1 slice	73	7
Pudding, chocolate, ready to eat, refrigerated, 4 ounces	55	6
Tortilla, corn, ready-to-bake/fry, one 6” diameter	46	5
Tortilla, flour, ready-to-bake/fry, one 6” diameter	32	3
Sour cream, reduced fat, cultured, 2 tablespoons	31	3
Bread, whole-wheat, 1 slice	30	3
Kale, raw, chopped, 1 cup	24	2
Broccoli, raw, ½ cup	21	2
Cheese, cream, regular, 1 tablespoon	14	1

Footnotes:

* DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient contents among products within the context of a total daily diet. The DV for calcium is 1,000 mg for adults and children aged 4 years and older. Foods providing 20% of more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet. The U.S. Department of Agriculture’s (USDA’s) Nutrient Database site lists the nutrient content of many foods and provides comprehensive list of foods containing calcium arranged by nutrient content (https://ods.od.nih.gov/pubs/usdandb/Calcium-Content.pdf) and by food name (https://ods.od.nih.gov/pubs/usdandb/Calcium-Food.pdf).

** Calcium content varies slightly by fat content; the more fat, the less calcium the food contains.
*** Calcium content is for tofu processed with a calcium salt. Tofu processed with other salts does not provide significant amounts of calcium.

[Source ³]

Calcium and Health

Many claims are made about calcium’s potential benefits in health promotion and disease prevention and treatment.

Bone health and osteoporosis

Bones increase in size and mass during periods of growth in childhood and adolescence, reaching peak bone mass around age 30. The greater the peak bone mass, the longer one can delay serious bone loss with increasing age. Everyone should therefore consume adequate amounts of calcium and vitamin D throughout childhood, adolescence, and early adulthood. Osteoporosis, a disorder characterized by porous and fragile bones, is a serious public health problem for more than 10 million U.S. adults, 80% of whom are women. Another 34 million have osteopenia, or low bone mass, which precedes osteoporosis. Osteoporosis is most associated with fractures of the hip, vertebrae, wrist, pelvis, ribs, and other bones ⁵. An estimated 1.5 million fractures occur each year in the United States due to osteoporosis ⁶.

When calcium intake is low or ingested calcium is poorly absorbed, bone breakdown occurs as the body uses its stored calcium to maintain normal biological functions. Bone loss also occurs as part of the normal aging process, particularly in postmenopausal women due to decreased amounts of estrogen. Many factors increase the risk of developing osteoporosis, including being female, thin, inactive, or of advanced age; smoking cigarettes; drinking excessive amounts of alcohol; and having a family history of osteoporosis ⁷.

Various bone mineral density (BMD) tests are available. The T-score from these tests compares an individual’s bone mineral density to an optimal bone mineral density (that of a healthy 30-year old adult). A T-score of -1.0 or above indicates normal bone density, -1.0 to -2.5 indicates low bone mass (osteopenia), and lower than -2.5 indicates osteoporosis ⁸. Although osteoporosis affects individuals of all races, ethnicities, and both genders, women are at highest risk because their skeletons are smaller than those of men and because of the accelerated bone loss that accompanies menopause. Regular exercise and adequate intakes of calcium and vitamin D are critical to the development and maintenance of healthy bones throughout the life cycle. Both weight-bearing exercises (such as walking, running, and activities where one’s feet leave and hit the ground and work against gravity) and resistance exercises (such as calisthenics and that involve weights) support bone health.

Supplementation with calcium plus vitamin D has been shown to be effective in reducing fractures and falls (which can cause fractures) in institutionalized older adults ⁹. However, among community-dwelling older adults over age 50, the benefits of supplementation with these nutrients on fracture resistance are much less clear. A recent systematic review of 26 randomized controlled trials found that calcium supplements, with or without vitamin D, modestly but significantly reduced the risk of total and vertebral fractures, but not fractures of the hip or forearm ¹⁰. But the four trials with the lowest risk of bias, involving a total of 44,505 individuals, showed no effect of supplementation on risk of fracture at any site. A related meta-analysis of calcium intake on bone mineral density found that calcium supplementation produced only a small, initial, and non-progressive increase in bone mineral density that was unlikely to result in a clinically significant reduction in the risk of bone fractures ¹¹. The U.S. Preventive Services Task Force concluded that the current evidence is insufficient to assess the balance of benefits and harms of combined vitamin D and calcium supplementation to prevent bone fractures in premenopausal women or in men ¹². For non-institutionalized postmenopausal women, the U.S. Preventive Services Task Force concluded that while current evidence was insufficient to assess the balance of benefits and harms of combined supplementation with vitamin D (at more than 400 IU/day) and calcium (at more than 1,000 mg/day) to prevent bone fractures, there was clearly no benefit in supplementing with smaller doses of these nutrients for this purpose.

In 1993, the U.S. Food and Drug Administration authorized a health claim related to calcium and osteoporosis for foods and supplements. In January 2010, this health claim was expanded to include vitamin D. Model health claims include the following: “Adequate calcium throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis” and “Adequate calcium and vitamin D as part of a healthful diet, along with physical activity, may reduce the risk of osteoporosis in later life” ¹³.

Cancer of the colon and rectum

Data from observational and experimental studies on the potential role of calcium in preventing colorectal cancer, though somewhat inconsistent, are highly suggestive of a protective effect ². Several studies have found that higher intakes of calcium from foods (low-fat dairy sources) and/or supplements are associated with a decreased risk of colon cancer ¹⁴. In a follow-up study to the Calcium Polyp Prevention Study, supplementation with calcium carbonate led to reductions in the risk of adenoma (a nonmalignant tumor) in the colon, a precursor to cancer ¹⁵, even as long as 5 years after the subjects stopped taking the supplement ¹⁶. In two large prospective epidemiological trials, men and women who consumed 700–800 mg per day of calcium had a 40%–50% lower risk of developing left-side colon cancer ¹⁷. But other observational studies have found the associations to be inconclusive ¹⁸.

In the Women’s Health Initiative, a clinical trial involving 36,282 postmenopausal women, daily supplementation with 1,000 mg of calcium and 400 International Units (IU) of vitamin D3 for 7 years produced no significant differences in the risk of invasive colorectal cancer compared to placebo ¹⁹. The authors of a Cochrane systematic review concluded that calcium supplementation might moderately help prevent colorectal adenomas, but there is not enough evidence to recommend routine use of calcium supplements to prevent colorectal cancer ²⁰. Given the long latency period for colon cancer development, long-term studies are needed to fully understand whether calcium intakes affect colorectal cancer risk.

Cancer of the prostate

Several epidemiological studies have found an association between high intakes of calcium, dairy foods or both and an increased risk of developing prostate cancer ²¹. However, others have found only a weak relationship, no relationship, or a negative association between calcium intake and prostate cancer risk ²². The authors of a meta-analysis of prospective studies concluded that high intakes of dairy products and calcium might slightly increase prostate cancer risk ²³.

Interpretation of the available evidence is complicated by the difficulty in separating the effects of dairy products from that of calcium. But overall, results from observational studies suggest that total calcium intakes >1,500 mg/day or >2,000 mg/day may be associated with increased prostate cancer risk (particularly advanced and metastatic cancer) compared with lower amounts of calcium (500–1,000 mg/day ²⁴. Additional research is needed to clarify the effects of calcium and/or dairy products on prostate cancer risk and elucidate potential biological mechanisms.

Cardiovascular disease

Calcium has been proposed to help reduce cardiovascular disease risk by decreasing intestinal absorption of lipids, increasing lipid excretion, lowering cholesterol levels in the blood, and promoting calcium influx into cells ². However, data from prospective studies of calcium’s effects on cardiovascular disease risk are inconsistent, and whether dietary calcium has different effects on the cardiovascular system than supplemental calcium is not clear. In the Iowa Women’s Health Study, higher calcium intake from diet and/or supplements was associated with reduced ischemic heart disease mortality in postmenopausal women ²⁵. Conversely, in a cohort of older Swedish women, both total and dietary calcium intakes of 1,400 mg/day and higher were associated with higher rates of death from cardiovascular disease and ischemic heart disease than intakes of 600–1,000 mg/day [85]. Other prospective studies have shown no significant associations between calcium intake and cardiac events or cardiovascular mortality ²⁶. Data for stroke are mixed, with some studies linking higher calcium intakes to lower risk of stroke, and others finding no associations or trends in the opposite direction ²⁶, ⁴.

Several studies have raised concerns that calcium from supplements might increase the risk of cardiovascular disease, including myocardial infarction and coronary heart disease ²⁷. For example, Xiao and colleagues ²⁸ reported that men who took more than 1,000 mg/day supplemental calcium had a 20% higher risk of total cardiovascular disease death than men who did not take supplemental calcium, but supplemental calcium intake in women was unrelated to cardiovascular disease mortality. A reanalysis of data from the Women’s Health Initiative found that calcium supplements (1,000 mg/day) taken with or without vitamin D (400 IU/day) increased the risk of cardiovascular events in women who were not taking calcium supplements when they entered the study ²⁹. While there is no established biological mechanism to support an association between calcium and cardiovascular disease, some scientists hypothesize that excessively high calcium intakes from supplements might override normal homeostatic controls of serum calcium levels and produce a temporary hypercalcemia ²⁹. Hypercalcemia is associated with increased blood coagulation, vascular calcification, and arterial stiffness, all of which raise cardiovascular disease risk ²⁹.

Many scientists question the strength of the available evidence linking supplemental calcium intake with cardiovascular disease risk, noting that no clinical trials were designed primarily to evaluate this potential relationship, so researchers have only considered cardiovascular disease outcomes in secondary analyses of trial data ³⁰. Based on a 2016 systematic review and meta-analysis of 4 randomized trials and 27 observational studies ³¹, the American Society for Preventive Cardiology and the National Osteoporosis Foundation concluded that there is “moderate-quality evidence” that calcium with or without vitamin D (from supplements or foods) “has no relationship (beneficial or harmful) with the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults” ³². They added that based on the evidence to date, “calcium intake from food and supplements that does not exceed the [UL] should be considered safe from a cardiovascular standpoint.”

Blood pressure and hypertension

Several clinical trials have demonstrated a relationship between increased calcium intakes and both lower blood pressure and risk of hypertension ³³, although the reductions are inconsistent. In the Women’s Health Study, calcium intake was inversely associated with risk of hypertension in middle-aged and older women ³⁴. However, other studies have found no association between calcium intake and incidence of hypertension ²⁶. The authors of a systematic review of the effects of calcium supplements for hypertension found any link to be weak at best, largely due to the poor quality of most studies and differences in methodologies ³⁵.

Calcium’s effects on blood pressure might depend upon the population being studied. In hypertensive subjects, calcium supplementation appears to lower systolic blood pressure by 2–4 mmHg, whereas in normotensive subjects, calcium appears to have no significant effect on systolic or diastolic blood pressure ²⁶.

Other observational and experimental studies suggest that individuals who eat a vegetarian diet high in minerals (such as calcium, magnesium, and potassium) and fiber and low in fat tend to have lower blood pressure ³⁶. The Dietary Approaches to Stop Hypertension (DASH) study was conducted to test the effects of three different eating patterns on blood pressure: a control “typical” American diet; one high in fruits and vegetables; and a third diet high in fruits, vegetables, and low-fat dairy products. The diet containing dairy products resulted in the greatest decrease in blood pressure ³⁷, although the contribution of calcium to this effect was not evaluated.

Preeclampsia

Preeclampsia is a serious medical condition in which a pregnant woman develops hypertension and proteinuria, usually after 20 weeks’ gestation ³⁸. It is a leading cause of maternal and neonatal morbidity and mortality, affecting about 5–8% of pregnancies in the United States and up to 14% of pregnancies worldwide ³⁸.

Studies suggest that calcium supplementation during pregnancy reduces the risk of preeclampsia, but the benefits may apply only to populations with inadequate calcium intakes ³⁹. For example, in a randomized clinical trial among 524 healthy women in India with mean baseline calcium intakes of only 314 mg/day, daily supplementation with 2,000 mg calcium starting between 12 and 25 weeks’ gestation and continuing until delivery significantly reduced the risk of preeclampsia, as well as preterm birth, compared to placebo ⁴⁰. Conversely, in a randomized trial of 4,589 healthy women in the United States, daily supplementation with 2,000 mg calcium from 13–21 weeks’ gestation through the remainder of pregnancy did not reduce the incidence of preeclampsia, pregnancy-induced hypertension, or other adverse perinatal outcomes compared to placebo [112]. The mean baseline calcium intake among these women, however, was about 1,100 mg/day. The authors of a 2014 Cochrane review of 13 clinical trials concluded that daily supplementation with 1,000 mg or more of calcium during pregnancy reduced the risk of preeclampsia by 55% ⁴¹. The reduction in risk was greatest for women at high risk of preeclampsia and those with low baseline calcium intakes (less than about 900 mg/day). For women with higher dietary calcium intakes, however, the reduction in preeclampsia risk was not statistically significant.

Several professional organizations recommend calcium supplements during pregnancy for women with low calcium intakes to reduce the risk of preeclampsia. For example, the American College of Obstetrics and Gynecology (ACOG) states that daily supplementation with 1,500–2,000 mg calcium may reduce the severity of preeclampsia in pregnant women who have calcium intakes less than 600 mg/day ⁴². Similarly, the World Health Organization (WHO) recommends 1,500–2,000 mg calcium for pregnant women with low dietary calcium intakes, particularly those at higher risk of gestational hypertension ³⁹. The WHO recommends dividing the total daily dose into three doses, preferably to be taken at mealtimes, and taking the supplements from 20 weeks’ gestation until delivery. The WHO also recommends separating calcium and prenatal iron supplements by several hours to minimize the inhibitory effects of calcium on iron absorption. But some researchers argue that this interaction has minimal clinical significance and suggest that providers not counsel patients to separate the supplements to simplify the supplement regimen and facilitate adherence ⁴³. The Canadian Hypertensive Disorders of Pregnancy Working Group ⁴⁴, the International Society for the Study of Hypertension in Pregnancy ⁴⁵, and the Society of Obstetric Medicine of Australia and New Zealand ⁴⁶ have all issued similar recommendations to ACOG and the WHO.

Kidney stones

Kidney stones in the urinary tract are most commonly composed of calcium oxalate. Some, but not all, studies suggest a positive association between supplemental calcium intake and the risk of kidney stones, and these findings were used as the basis for setting the calcium upper limit intake in adults ². In the Women’s Health Initiative, postmenopausal women who consumed 1,000 mg of supplemental calcium and 400 IU of vitamin D per day for 7 years had a 17% higher risk of kidney stones than subjects taking a placebo ⁴⁷. The Nurses’ Health Study also showed a positive association between supplemental calcium intake and kidney stone formation ⁴⁶. High intakes of dietary calcium, on the other hand, do not appear to cause kidney stones and may actually protect against developing them ⁴⁸. For most individuals, other risk factors for kidney stones, such as high intakes of oxalates from food and low intakes of fluid, probably play a bigger role than calcium intake ⁴⁹.

Weight management

Several studies have linked higher calcium intakes to lower body weight or less weight gain over time ⁵⁰. Two explanations have been proposed. First, high calcium intakes might reduce calcium concentrations in fat cells by decreasing the production of parathyroid hormone and the active form of vitamin D. Decreased intracellular calcium concentrations in turn increase fat breakdown and discourage fat accumulation in these cells ⁵¹. Secondly, calcium from food or supplements might bind to small amounts of dietary fat in the digestive tract and prevent its absorption ⁵¹. Dairy products, in particular, might contain additional components that have even greater effects on body weight than their calcium content alone would suggest ⁵².

Despite these findings, the results from clinical trials have been largely negative. For example, dietary supplementation with 1,500 mg/day of calcium (from calcium carbonate) for 2 years was found to have no clinically significant effects on weight in 340 overweight and obese adults as compared with placebo ⁵³. Three reviews of published studies on calcium from supplements or dairy products on weight management came to similar conclusions ⁵⁴. A meta-analysis of 13 randomized controlled trials published in 2006 concluded that neither calcium supplementation nor increased dairy product consumption had a statistically significant effect on weight reduction [136]. More recently, a 2009 evidence report from the Agency for Healthcare Research and Quality concluded that, overall, clinical trial results do not support an effect of calcium supplementation on weight loss ²⁶. Also, a 2012 meta-analysis of 29 randomized controlled trials found no benefit of an increased consumption of dairy products on body weight and fat loss in long-term studies ⁵⁴. Overall, the results from clinical trials do not support a link between higher calcium intakes and lower body weight or weight loss.

Calcium gluconate vs calcium chloride

10% Calcium Chloride injection is indicated for the treatment of hypocalcemia and conditions secondary to hypocalcemia (eg, tetany, seizures, arrhythmias); emergent treatment of severe hypermagnesemia, requiring a prompt increase in plasma calcium levels. Calcium chloride in water dissociates to provide calcium (Ca++) and chloride (Cl−) ions. They are normal constituents of the body fluids and are dependent on various physiological mechanisms for maintenance of balance between intake and output.

Based on the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care ⁵⁵, calcium chloride is an effective and recommended treatment to stabilize the myocardial cell membrane in patients with severe hyperkalemia (K+ >6.5 mEq/L with toxic ECG changes).

Based on the American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care ⁵⁵, calcium chloride is effective and recommended for the treatment of malignant arrhythmias (including cardiac arrest) in patients with hypermagnesemia.

Based on the American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care ⁵⁵ and the American Academy of Pediatrics Committee on Drugs, calcium chloride, although based on limited evidence, is an effective and recommended treatment in the setting of beta-blocker overdose (refractory to glucagon and high-dose inotropes/vasopressors).

Calcium chloride injection also contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Calcium chloride is contraindications

Calcium chloride is contraindicated for cardiac resuscitation in the presence of ventricular fibrillation or in patients with the risk of existing digitalis toxicity.

Calcium chloride is not recommended in the treatment of asystole and electromechanical dissociation.

Calcium chloride dosage

10% Calcium Chloride injection consists of 1 gram of calcium chloride in a 10 mL vial, or 100 mg/mL. This concentration represents 27 mg or 1.4 mEq of elemental calcium per mL. Thus, one 10 mL syringe provides 270 mg of elemental calcium. The dosage recommendation in various references is given either as amount of calcium chloride or amount of elemental calcium, and often it is not specified. Ionized calcium concentrations should be measured, to assist in dosage adjustment.

10% Calcium Chloride injection is administered only by slow intravenous injection (not to exceed 1 mL/min), preferably in a central or deep vein.

The usual precautions for intravenous therapy should be observed. If time permits, the solution should be warmed to body temperature. The injection should be halted if the patient complains of any discomfort; it may be resumed when symptoms disappear. Following injection, the patient should remain recumbent for a short time.

The usual adult dosage in hypocalcemic disorders ranges from 200 mg to 1 g (2 to 10 mL) at intervals of 1 to 3 days depending on the response of the patient and/or results of serum ionized calcium determinations. Repeated injections may be required because of rapid excretion of calcium.

The pediatric dosage in hypocalcemic disorders ranges from 2.7 to 5.0 mg/kg hydrated Calcium Chloride (or 0.136 to 0.252 mEq elemental calcium per kg, or 0.027 to 0.05 mL of 10% Calcium Chloride injection per kg). No data from clinical trials is available about repeated dosages, though textbook references recommend repeat dosages q 4 to 6 hours.

Calcium gluconate uses

Parenteral calcium salts (ie, chloride, glubionate, gluceptate, and gluconate) are indicated in the treatment of hypocalcemia in conditions that require a rapid increase in serum calcium-ion concentration, such as in neonatal hypocalcemia due to “hungry bones” syndrome (remineralization hypocalcemia) following surgery for hyperparathyroidis, vitamin D deficiency; and alkalosis. Calcium gluconate have been used as adjunctive therapy for insect bites or stings, such as Black Widow Spider bites, and sensitivity reactions, especially when characterized by urticaria; and as an aid in the management of acute symptoms of lead colic, overdose of magnesium or certain heart medicines, and rickets. Calcium gluconate is also used for life support and life-threatening heart conditions. Parenteral calcuim gluconate and calcium gluceptate are also used for the prevention of hypocalcemia during exchange transfusions ⁵⁶.

Calcium gluconate is also used in sewage purification, industrial cleaning, metal surface treatment, textile bleach stabilizing, aluminum processing, and as a chelating agent in cement set retarding, cleaning products, personal care products, pharmaceuticals, coffee processing (anti-caking agent), and food and drugs (sequestering, buffering, and gelling agent). Calcium gluconate also has veterinary use for hypocalcemic conditions.

Calcium gluconate precautions and warnings

Calcium Gluconate Injection Contraindications

Calcium Gluconate Injection is contraindicated in:

Hypercalcemia
Neonates (28 days of age or younger) receiving ceftriaxone

Arrhythmias with concomitant cardiac glycoside use

Cardiac arrhythmias may occur if calcium and cardiac glycosides are administered together. Hypercalcemia increases the risk of digoxin toxicity. Administration of Calcium Gluconate Injection should be avoided in patients receiving cardiac glycosides. If concomitant therapy is necessary, Calcium Gluconate Injection should be given slowly in small amounts and with close ECG monitoring.

End-Organ damage due to intravascular ceftriaxone-calcium precipitates

Concomitant use of ceftriaxone and Calcium Gluconate Injection is contraindicated in neonates (28 days of age or younger) due to cases of fatal outcomes in neonates in which a crystalline material was observed in the lungs and kidneys at autopsy after ceftriaxone and calcium were administrated simultaneously through the same intravenous line. Concomitant administration can lead to the formation of ceftriaxone-calcium precipitates that may act as emboli, resulting in vascular spasm or infarction.

In patients older than 28 days of age, ceftriaxone and Calcium Gluconate Injection may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with a compatible fluid. Do not administer Ceftriaxone simultaneously with Calcium Gluconate Injection via a Y-site in any age group.

Tissue Necrosis and Calcinosis

Intravenous administration of Calcium Gluconate Injection and local trauma may result in calcinosis cutis due to transient increase in local calcium concentration. Calcinosis cutis can occur with or without extravasation of Calcium Gluconate Injection, is characterized by abnormal dermal deposits of calcium salts, and clinically manifests as papules, plaques, or nodules that may be associated with erythema, swelling, or induration. Tissue necrosis, ulceration, and secondary infection are the most serious complications.

A case report on an infant with severe asphyxia and persistent pulmonary hypertension as a newborn. The baby received prolonged intravenous calcium gluconate therapy for hypocalcemia ⁵⁷. At 5 weeks of age, multiple firm, indurated areas (armor-like lesions) were palpable in the subcutaneous tissues of the trunk, arms, legs, and face, particularly in skin folds. Roentgenographic study showed generalized soft-tissue calcifications throughout the body, extremities, and face. Calcinosis cutis occurs through a variety of pathogenetic mechanisms. Case reports on calcinosis cutis in infants are uncommon, and the calcifications are mostly localized. In this patient, they are generalized ⁵⁷.

If extravasation occurs or clinical manifestations of calcinosis cutis are noted, immediately discontinue intravenous administration at that site and treat as needed.

Hypotension, bradycardia, and cardiac arrhythmias with rapid administration

Rapid injection of Calcium Gluconate Injection may cause vasodilation, decreased blood pressure, bradycardia, cardiac arrhythmias, syncope and cardiac arrest. To avoid adverse reactions that may follow rapid intravenous administration, Calcium Gluconate Injection should be diluted with 5% dextrose or normal saline and infused slowly. If rapid intravenous bolus of Calcium Gluconate Injection is required, the rate of intravenous administration should not exceed 200 mg/minute in adults and 100 mg/minute in pediatric patients and ECG monitoring during administration is recommended

Aluminum Toxicity

Calcium Gluconate Injection contains aluminum, up to 400 mcg per liter, that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 mcg/kg/day to 5 mcg/kg/day accumulate aluminum levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Drug Incompatibilities

Do not mix Calcium Gluconate Injection with ceftriaxone. Concurrent use of intravenous ceftriaxone and Calcium Gluconate Injection can lead to the formation of ceftriaxone-calcium precipitates. Concomitant use of ceftriaxone and intravenous calcium-containing products is contraindicated in neonates (28 days of age or younger). In patients older than 28 days of age, ceftriaxone and calcium-containing products may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with a compatible fluid. Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions via a Y-site in any age group.
Do not mix Calcium Gluconate Injection with fluids containing bicarbonate or phosphate. Calcium Gluconate Injection is not physically compatible with fluids containing phosphate or bicarbonate. Precipitation may result if mixed.
Do not mix Calcium Gluconate Injection with minocycline injection. Calcium complexes minocycline rendering it inactive.
Vitamin D, vitamin A, thiazide diuretics, estrogen, calcipotriene and teriparatide administration may cause hypercalcemia. Monitor plasma calcium concentrations in patients taking these drugs concurrently.

Calcium gluconate in pregnancy

FDA Pregnancy Risk Category C: Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk ⁵⁸.

Risk summary

Limited available data with Calcium Gluconate Injection use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. There are risks to the mother and the fetus associated with hypocalcemia in pregnancy.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal risk: Maternal hypocalcemia can result in an increased rate of spontaneous abortion, premature and dysfunctional labor, and possibly preeclampsia.

Fetal/Neonatal adverse reactions: Infants born to mothers with hypocalcemia can have associated fetal and neonatal hyperparathyroidism, which in turn can cause fetal and neonatal skeletal demineralization, subperiosteal bone resorption, osteitis fibrosa cystica and neonatal seizures. Infants born to mothers with hypocalcemia should be carefully monitored for signs of hypocalcemia or hypercalcemia, including neuromuscular irritability, apnea, cyanosis and cardiac rhythm disorders.

Calcium gluconate in breastfeeding

Risk summary

Calcium is present in human milk as a natural component of human milk. It is not known whether intravenous administration of Calcium Gluconate Injection can alter calcium concentration in human milk. There are no data on the effects of Calcium Gluconate Injection on the breastfed infant, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Calcium Gluconate Injection and any potential adverse effects on the breastfed child from Calcium Gluconate Injection or from the underlying maternal condition.

Calcium gluconate for pediatric use

The safety and effectiveness of Calcium Gluconate Injection have been established in pediatric patients for the treatment of acute, symptomatic hypocalcemia.

Pediatric approval for Calcium Gluconate Injection, including doses, is not based on adequate and well-controlled clinical studies. Safety and dosing recommendations in pediatric patients are based on published literature and clinical experience.

Concomitant use of ceftriaxone and Calcium Gluconate Injection is contraindicated in neonates (28 days of age or younger) due to reports of fatal outcomes associated with the presence of lung and kidney ceftriaxone-calcium precipitates. In patients older than 28 days of age, ceftriaxone and Calcium Gluconate Injection may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with a compatible fluid. Calcium Gluconate Injection contains up to 400 mcg/L aluminum which may be toxic, particularly for premature neonates due to immature renal function. Parenteral administration of aluminum greater than 4 to 5 mcg/kg/day is associated with central nervous system and bone toxicity.

Calcium gluconate for geriatric use

In general dose selection for an elderly patient should start at the lowest dose of the recommended dose range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Calcium gluconate in people with kidney impairment

For patients with renal impairment, initiate Calcium Gluconate Injection at the lowest dose of the recommended dose ranges across all age groups. Monitor serum calcium levels every 4 hours.

Calcium Gluconate in people with liver impairment

Hepatic function does not impact the availability of ionized calcium after calcium gluconate intravenous administration. Dose adjustment in hepatically impaired patients may not be necessary.

Calcium gluconate dose

Calcium gluconate is contraindicated in patients with hypercalcemia, ventricular fibrillation, and in digitalized patients. Some medicines can affect how calcium gluconate works. Tell your doctor if you are taking digoxin or antibiotics.

Calcium gluconate injection contains aluminum which may be toxic. Patients with impaired renal function, undergoing prolonged parenteral administration of calcium gluconate, should be monitored for clinical signs of aluminum toxicity. Clinicians should be aware these patients may achieve a level of aluminum accumulation capable of causing central nervous system and bone toxicity, as well as, tissue loading.

Ask a doctor or pharmacist if it is safe for you to take calcium gluconate if you have ever had:

kidney disease;
kidney stones;
cancer;
a parathyroid gland disorder; or
high levels of calcium in your blood.

Ask a doctor before using calcium gluconate if you are pregnant or breast-feeding. Your dose needs may be different during pregnancy or while you are nursing.

Calcium can make it harder for your body to absorb certain medicines. If you take other medications, take them at least 2 hours before or 4 or 6 hours after you take calcium gluconate.

Other drugs may interact with calcium gluconate, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

Calcium Gluconate Injection Dosage and Administration

Your doctor will prescribe your dose and schedule. This medicine is given through a needle placed in a vein.
A nurse or other health provider will give you this medicine.

Calcium Gluconate Injection USP is a clear, colorless to slightly yellow, solution available in the following:

Single dose vial: 1,000 mg per 10 mL (100 mg per mL)
Single dose vial: 5,000 mg per 50 mL (100 mg per mL)
Pharmacy bulk package: 10,000 mg per 100 mL (100 mg per mL)

Each mL of Calcium Gluconate Injection USP contains 9.3 mg (0.465 mEq) of elemental calcium.

Important Administration Instructions

Calcium Gluconate Injection contains 100 mg of calcium gluconate per mL which contains 9.3 mg (i.e., 0.465 mEq) of elemental calcium.
Dilute Calcium Gluconate Injection prior to use in 5% dextrose or normal saline and assess for potential drug or IV fluid incompatibilities.
Inspect Calcium Gluconate Injection visually prior to administration. The solution should appear clear and colorless to slightly yellow. Do not administer if there is particulate matter or discoloration.
Use the diluted solution immediately after preparation.
Administer Calcium Gluconate Injection intravenously via a secure intravenous line to avoid calcinosis cutis and tissue necrosis.
Administer Calcium Gluconate Injection by bolus administration or continuous infusion:

For bolus intravenous administration:

Dilute the dose of Calcium Gluconate Injection in 5% dextrose or normal saline to a concentration of 10-50 mg/mL prior to administration. Administer the dose slowly and DO NOT exceed an infusion rate of 200 mg/minute in adults or 100 mg/minute in pediatric patients, including neonates. Monitor patients, vitals and electrocardiograph (ECG) during administration.

For continuous intravenous infusion:

Dilute Calcium Gluconate Injection in 5% dextrose or normal saline to a concentration of 5.8-10 mg/mL prior to administration. Administer at the rate recommended in Table 3 and monitor patients, vitals, calcium and ECG during the infusion.
Calcium Gluconate Injection is supplied in single-dose vials and pharmacy bulk packages.

Table 3. Dosing Recommendations in mg of Calcium Gluconate for Neonate, Pediatric, and Adult Patients

Patient Population	Initial Dose	Subsequent Doses (if needed)
Patient Population	Initial Dose	Bolus	Continuous Infusion
Neonate (≤ 1 month)	100 – 200 mg/kg	100 – 200 mg/kg every 6 hours	Initiate at 17-33 mg/kg/hour
Pediatric (> 1 month to < 17 years)	29 – 60 mg/kg	29 – 60 mg/kg every 6 hours	Initiate at 8-13 mg/kg/hour
Adult	1000 – 2000 mg	1000 – 2000 mg every 6 hours	Initiate at 5.4 – 21.5 mg/kg/hour
For bolus administration, DO NOT exceed an infusion rate of: 200 mg/minute in adult patients 100 mg/minute in pediatric patients For continuous infusions, adjust rate as needed based on serum calcium levels

Serum Calcium Monitoring

Measure serum calcium every 4 to 6 hours during intermittent infusions with Calcium Gluconate Injection and measure serum calcium every 1 to 4 hours during continuous infusion.

Dosage in Renal Impairment

For patients with renal impairment, initiate Calcium Gluconate Injection at the lowest dose of the recommended dose ranges for all age groups and monitor serum calcium levels every 4 hours.

Adult dose for hypocalcemia

Calcium gluconate intravenous:

500 to 2000 mg (5 to 20 mL) IV one time at a rate not to exceed 0.5 to 2 mL/min. The dose may be increased as needed. The usual daily dosage ranges from 1000 to 15,000 mg (10 to 150 mL) in divided doses or as a continuous infusion. Doses may be repeated every 1 to 3 days as needed and tolerated to normalize the serum calcium level.

Calcium gluconate oral:

500 to 2000 mg orally 2 to 4 times a day.

Adult dose for hypermagnesemia

1000 to 2000 mg (10 to 20 mL) IV one time at a rate not to exceed 0.5 to 2 mL/min. This dose may be repeated as necessary in severe cases of hypermagnesemia (where discontinuation of exogenous magnesium is inadequate) to temporarily reverse many of the toxic effects of magnesium in the central nervous system.

Adult dose for hyperkalemia

500 to 3000 mg (5 to 30 mL) IV one time at a rate not to exceed 0.5 to 2 mL/min. This dose may be repeated as necessary in cases of extreme hyperkalemia cardiotoxicity when P waves are absent, the QRS complexes are widened, and when continuous ECG monitoring is available. The use of calcium does not reduce the serum potassium level, but counteracts the effects of hyperkalemia on cardiac excitability.

Adult dose for exchange transfusion

300 mg (3 mL) IV one time with each 100 mL of citrated blood at a rate not to exceed 0.5 to 2 mL/min.

Adult dose for osteoporosis

1000 to 1500 mg/day orally in divided doses.

Pediatric dose for hypocalcemia

Neonatal:

Recommended daily allowance (RDA): (Dosage is in terms of elemental calcium):

Oral: 400 mg/day
Daily maintenance calcium:
IV: 3 to 4 mEq/kg/day

Cardiac arrest in the presence of hyperkalemia or hypocalcemia, magnesium toxicity, or calcium antagonist toxicity: Dosage expressed in mg of calcium gluconate:

IV or intraosseous IO:

60 to 100 mg/kg/dose; may repeat in 10 minutes if necessary. If effective, consider IV infusion.

Hypocalcemia (dose depends on clinical condition and serum calcium level):

IV: (Dose expressed in mg of calcium gluconate): 200 to 800 mg/kg/day as a continuous infusion or in 4 divided doses
Oral: (Dosage expressed in mg of elemental calcium): 50 to 150 mg/kg/day in 4 to 6 divided doses
Do not exceed 1 g/day

Dose expressed in mg of calcium gluconate:

500 to 1500 mg/kg/day in 4 to 6 divided doses

Hypocalcemia secondary to citrated blood infusion:

IV: Give 0.45 mEq elemental calcium for each 100 mL citrated blood infused

Tetany: (Dose expressed in mg of calcium gluconate):

IV: 100 to 200 mg/kg/dose over 5 to 10 minutes; may repeat after 6 hours or follow with an infusion with a maximum dose of 500 mg/kg/day

Dosing: Usual

Adequate intake (AI): (Dosage is in terms of elemental calcium):

Oral:

1 to 6 months: 210 mg/day
7 to 12 months: 270 mg/day
1 to 3 years: 500 mg/day
4 to 8 years: 800 mg/day
9 to 18 years: 1300 mg/day

Recommended daily allowance (RDA): (Dosage is in terms of elemental calcium):

Oral:

1 to 6 months: 400 mg/day
6 to 12 months: 600 mg/day
1 to 10 years: 800 mg/day
11 to 24 years: 1200 mg/day

Hypocalcemia (dose depends on clinical condition and serum calcium level):

Oral: (Dose expressed in mg of elemental calcium):

Children: 45 to 65 mg/kg/day in 4 divided doses
Dose expressed in mg of calcium gluconate: Infants and Children: 500 to 725 mg/kg/day in 3 to 4 divided doses

Hypocalcemia (dose depends on clinical condition and serum calcium level):

IV: (Dose expressed in mg of calcium gluconate):

Infants and Children: 200 to 500 mg/kg/day as a continuous infusion or in 4 divided doses

Cardiac arrest in the presence of hyperkalemia or hypocalcemia, magnesium toxicity, or calcium antagonist toxicity:

IV, IO: (Dosage expressed in mg of calcium gluconate):

Infants and Children: 60 to 100 mg/kg/dose (maximum: 3 g/dose); may repeat in 10 minutes if necessary; if effective, consider IV infusion.

Hypocalcemia secondary to citrated blood infusion:

IV: Give 0.45 mEq elemental calcium for each 100 mL citrated blood infused

Tetany:

IV: (Dose expressed in mg of calcium gluconate): Infants and Children: 100 to 200 mg/kg/dose; over 5 to 10 minutes; may repeat after 6 hours or follow with an infusion with a maximum dose of 500 mg/kg/day.

Daily maintenance calcium:

IV:

Infants and Children 25 kg and less: 1 to 2 mEq/kg/day
Children 25 to 45 kg: 0.5 to 1.5 mEq/kg/day
Children greater than 45 kg: 0.2 to 0.3 mEq/kg/day or 10 to 20 mEq/day

Renal dose adjustments

Patients with renal dysfunction have an increased risk of hypercalcemia. Periodically checking the serum calcium level, especially if signs or symptoms of hypercalcemia are detected, is recommended.

Liver dose adjustments

Data not available

Dialysis

Calcium is removed by hemodialysis. To ensure a positive net calcium flux into the patient during dialysis, a dialysate calcium concentration of 3.0 to 3.5 mEq/L is usually required. Mid-dialysis hypercalcemia is not uncommon when this concentration is used.

Calcium is removed by peritoneal dialysis. The standard peritoneal dialysate contains 3.5 mEq/L of calcium (in 1.5% dextrose) to maintain a positive calcium balance and to prevent calcium losses. When higher concentrations of dextrose are used, the net calcium balance may be negative because of a greater convective removal of calcium during ultrafiltration, which counterbalances the diffusion of calcium from the dialysate to the patient.

Calcium gluconate side effects

Do not use calcium gluconate if you had an allergic reaction to calcium gluconate.

Call your doctor right away if you notice any of these side effects:

Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat, chest tightness, trouble breathing
Feeling of warmth, tingling, or confusion
Lightheadedness or fainting
Slow or irregular heartbeat
Little or no urinating
Swelling, rapid weight gain
High levels of calcium in your blood–nausea, vomiting, constipation, increased thirst or urination, muscle weakness, bone pain, confusion, lack of energy, or feeling tired.

If you notice these less serious side effects, talk with your doctor:

Constipation, loss of appetite, nausea, vomiting, stomach pain
Dry mouth, thirst, chalky taste in your mouth
Increase in how much or how often you urinate
Redness, swelling, irritation, or infection on the skin where the injection is given

Common side effects may include:

upset stomach, gas; or
constipation.

If you notice other side effects that you think are caused by calcium gluconate, tell your doctor.

Call your doctor for medical advice about side effects.

Calcium gluconate injection contains aluminum, up to 400 mcg per liter, that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 mcg/kg/day to 5 mcg/kg/day accumulate aluminum levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Psychiatric

Psychiatric side effects have been reported rarely. They have included a single case of mania possibly associated with changes in cerebrospinal fluid and serum calcium following calcium gluconate administration.

A 35-year-old woman with an organic mental disorder associated with hypocalcemia and hypomagnesemia (secondary to short bowel syndrome) became noncompliant with her intramuscular injections of magnesium (Mg). Upon evaluation for progressive confusion and dysphoria, her serum Mg and calcium were found to be 0.3 mEq/L and 7.1 mg/dl, respectively. Intravenous Mg sulfate and calcium gluconate (6,000 mg) were given, with subsequent clearing of her sensorium. Within 12 hours the patient became manic and grandiose; associated Mg and calcium levels were 1.4 mEq/L and 8.2 mg/L, respectively. The symptoms of mania resolved without psychotropic medications and with discontinuation of calcium gluconate. This case report and other limited data suggest that mania can be precipitated by the rapid intravenous administration of calcium gluconate, particularly in persons who are predisposed to affective disorders.

Genitourinary

Genitourinary side effects have rarely included calcium nephrolithiasis. This effect has been reported more commonly with coadministration of loop diuretics.

Cardiovascular

A 51-year-old man with no history of cardiac disease was referred for calcium gluconate/pentagastrin testing for early detection of medullary thyroid carcinoma. He became pulseless and hypotensive within 15 seconds after receiving calcium gluconate 2 mg/kg and pentagastrin 0.5 mcg/kg. Atrial fibrillation and a ventricular rate response of 110/min ensued after a precordial thump. A complete evaluation for the cause of his atrial fibrillation was negative.

Cardiovascular side effects have included peripheral vasodilation, hypotension, syncope, vasospastic angina, serious cardiac arrhythmias, AV dissociation, and shock. Extreme caution is advised when parenteral calcium is given to a patient who has received digitalis since calcium may unmask digitalis intoxication. A single case of new atrial fibrillation has been reported.

Renal

Renal side effects have included significant increases in renal plasma flow, glomerular filtration rate, diuresis, natriuresis, and prostaglandin E2 and F1-alpha levels. However, the renal side effects do not appear to be clinically significant.

The renal effects of calcium gluconate include significant increases in renal plasma flow, glomerular filtration rate, diuresis, natriuresis, and prostaglandin E2 and F1-alpha levels. Data indicate that calcium gluconate infusions at subpressor doses have renal vasodilating, diuretic and natriuretic properties that appear to be facilitated by an increase in the renal production of prostaglandins.

Nervous system

Nervous system side effects have included tingling sensations, a “chalky” taste and a sense of oppression or “heat wave.”

Calcium gluconate antidote

There is no specific antidote for calcium salts poisoning. Calcium is rapidly cleared by hemodialysis. However, dialysis is rarely indicated unless the patient has renal failure.

A serum calcium concentration exceeding 2.6 mmol per liter (10.5 mg per 100 mL) is considered a hypercalcemic condition. Withholding additional administration of calcium and any other medications that may cause hypercalcemia usually resolves mild hypercalcemia in asymptomatic patients, when patient renal function is adequate ⁵⁹.

Most cases of hypercalcemia can be treated with saline hydration. Gastrointestinal or skin irritation is usually self-limited and does not require specific treatment beyond decontamination. There is no role for bisphosphonates or calcitonin in the treatment of hypercalcemia due to calcium salt exposure.

Management of severe toxicity

Most cases of hypercalcemia will resolve with hydration in patients with normal renal function. Hemodialysis can be used if emergent clearance is required of if the patient’s renal function is impaired. There is no role for bisphosphonates or calcitonin in the treatment of hypercalcemia due to calcium salt exposure.

When serum calcium concentration are greater than 2.9 mmol per liter (12 mg per 100 mL), immediate measures may be required with possible use of the following: Hydrating with intravenous 0.9% sodium chloride injection ⁵⁹. Forcing diuresis with furosemide or ethacrynic acid may be used to rapidly increase calcium and sodium excretion when saline overload occurs. Monitoring of potassium and magnesium serum concentrations and starting replacement early to prevent complications of therapy. ECG monitoring and the possible use of beta-adrenergic blocking agents to protect the heart against serious arrhythmias. Possibly including hemodialysis, calcitonin, and adrenocorticoids in the treatment. Determining serum calcium concentration at frequent intervals to guide therapy adjustments ⁵⁹.

References

Calcium gluconate. GRN No. 136 https://www.accessdata.fda.gov/scripts/fdcc/?set=GRASNotices&id=136
Committee to Review Dietary Reference Intakes for Vitamin D and Calcium, Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.
Calcium. https://ods.od.nih.gov/factsheets/Calcium-HealthProfessional/
Michaelsson K, Melhus H, Warensjo Lemming E, Wold A, Byberg L. Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study. BMJ 2013;12;346:f228
National Institutes of Health. Osteoporosis prevention, diagnosis, and therapy. NIH Consensus Statement Online 2000:1-45
Riggs BL, Melton L. The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 1995;17:505S-11S.
National Osteoporosis Foundation. https://www.nof.org/interdisciplinary-symposium-on-osteoporosis/
National Osteoporosis Foundation. https://www.nof.org/patients/diagnosis-information/
Cranney A, Horsley T, O’Donnell S, Weiler HA, Puil L, Ooi DS, Atkinson SA, Ward LM, Moher D, Hanley DA, Fang M, Yazdi F, Garritty C, Sampson M, Barrowman N, Tsertsvadze A, Mamaladze V. Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment No. 158 (Prepared by the University of Ottawa Evidence-based Practice Center (UO-EPC) under Contract No. 290-02-0021. AHRQ Publication No. 07-E013. Rockville, MD: Agency for Healthcare Research and Quality. August 2007.
Bolland MJ, Leung W, Tai V, Bastin S, Gamble GD, Grey A, Reid IR. Calcium intake and risk of fracture: systematic review. BMJ 2015;351:h4580 doi: 10.1136/bmj.h4580.
Tai V, Leung W, Grey A, Reid IR, Bolland MJ. Calcium intake and bone mineral density: systematic review and meta-analysis. BMJ 2015;351:h4183 doi: 10.1136/bmj.h4183.
Moyer VA. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2013;158:691-6.
Guidance for Industry: Health Claims on Calcium and Osteoporosis; and Calcium, Vitamin D, and Osteoporosis. https://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/ucm152626.htm
Biasco G, Paganelli M. European trials on dietary supplementation for cancer prevention. Ann N Y Acad Sci 1999;889:152-6.
Bonithon-Kopp C, Kronborg O, Giacosa A, Rath U, Faivre J. Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial. European Cancer Prevention Organisation Study Group. Lancet. 2000;356:1300-6.
Grau MV, Baron JA, Sandler RS, Wallace K, Haile RW, Church TR, et al. Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial. J Natl Cancer Inst 2007;99:129-36.
Wu K, Willett WC, Fuchs CS, Colditz GA, Giovannucci EL. Calcium intake and risk of colon cancer in women and men. J Natl Cancer Inst 2002;94:437-46.
Cascinu S, Del Ferro E, Cioccolini P. Effects of calcium and vitamin supplementation on colon cancer cell proliferation in colorectal cancer. Cancer Invest 2000;18:411-6.
Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-96
Weingarten MA, Zalmanovici A, Yaphe J. Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003548
Mitrou PN, Albanes D, Weinstein SJ, Pietinen P, Taylor PR, Virtamo J, et al. A prospective study of dietary calcium, dairy products and prostate cancer risk (Finland). Int J Cancer 2007;120:2466-73.
Chan JM, Pietinen P, Virtanen M, Chan JM, Pietinen P, Virtanen M, et al. Diet and prostate cancer risk in a cohort of smokers, with a specific focus on calcium and phosphorus (Finland). Cancer Causes Control 2000;11:859-67.
Gao X, LaValley MP, Tucker KL. Prospective studies of dairy product and calcium intakes and prostate cancer risk: a meta-analysis. J Natl Cancer Inst 2005;97:1768-77.
Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, Lichtenstein A, Patel K, Raman G, Tatsioni A, Terasawa T, Trikalinos TA. Vitamin D and Calcium: Systematic Review of Health Outcomes. Evidence Report/Technology Assessment No. 183. (Prepared by Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I). AHRQ Publication No. 09-E015, Rockville, MD: Agency for Healthcare Research and Quality. August 2009
Bostick RM, Kushi LH, Wu Y, Meyer KA, Sellers TA, Folsom AR. Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol. 1999 Jan 15;149(2):151-61.
Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, Lichtenstein A, Patel K, Raman G, Tatsioni A, Terasawa T, Trikalinos TA. Vitamin D and Calcium: Systematic Review of Health Outcomes. Evidence Report/Technology Assessment No. 183. (Prepared by Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I). AHRQ Publication No. 09-E015, Rockville, MD: Agency for Healthcare Research and Quality. August 2009.
Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, Reid IR.Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010 Jul 29;341:c3691
Xiao Q, Murphy RA, Houston DK, Harris TB, Chow WH, Park Y. Dietary and Supplemental Calcium Intake and Cardiovascular Disease Mortality: The National Institutes of Health-AARP Diet and Health Study. JAMA Intern Med. 2013 Feb 4:1-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756477/
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ. 2011 Apr 19;342:d2040 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079822/
Wang L, Manson JE, Sesso HD. Calcium intake and risk of cardiovascular disease: a review of prospective studies and randomized clinical trials. Am J Cardiovasc Drugs 2012;12:105-16
Chung M, Tang AM, Fu Z, Wang DD, Newberry SJ. Calcium intake and cardiovascular disease risk: An updated systematic review and meta-analysis. Ann Intern Med. Published online ahead of print on October 25, 2016.
Kopecky SL, Bauer DC, Giulati M, Nieves JW, Singer AJ, Toth PP, UInderberg JA, Wallace TC, Weaver C. Lack of evidence linking calcium with or without vitamin D supplementation to cardiovascular disease in generally healthy adults: A clinical guideline from the National Osteoporosis Foundation and the American Society for Preventive Cardiology. Ann Intern Med. Published online ahead of print on October 25, 2016.
McCarron D, Reusser M. Finding consensus in the dietary calcium-blood pressure debate. J Am Coll Nutr 1999;18:398S-405S.
Wang L, Manson JE, Buring JE, Lee IM, Sesso HD. Dietary intake of dairy products, calcium, and vitamin D and the risk of hypertension in middle-aged and older women. Hypertension. 2008 Apr;51(4):1073-9.
Dickinson HO, Nicolson DJ, Cook JV, Campbell F, Beyer FR, Ford GA, et al. Calcium supplementation for the management of primary hypertension in adults. Cochrane Database Syst Rev 2006;(2):CD004639
Berkow SE, Barnard ND. Blood pressure regulation and vegetarian diets. Nutr Rev 2005;63:1-8.
Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997;336:1117-24
Cudihy D, Lee RV. The pathophysiology of pre-eclampsia: current clinical concepts. J Obstet Gynaecol. 2009;29:576-82.
World Health Organization. Guideline: Calcium supplementation in pregnant women. http://apps.who.int/iris/bitstream/handle/10665/85120/9789241505376_eng.pdf
Kumar A, Devi SG, Batra S, Singh C, Shukla DK. Calcium supplementation for the prevention of pre-eclampsia. Int J Gynaecol Obstet. 2009;104:32-6.
Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM, Morris CD, et al. Trial of calcium to prevent preeclampsia. N Engl J Med. 1997;337:69-76.
ACOG Task Force on Hypertension in Pregnancy. Hypertension in Pregnancy. https://www.acog.org/Clinical-Guidance-and-Publications/Task-Force-and-Work-Group-Reports/Hypertension-in-Pregnancy
Omotayo MO, Dickin KL, O’Brien KO, Neufeld LM, De Regil LM, Stoltzfus RJ. Calcium supplementation to prevent preeclampsia: translating guidelines into practice in low-income countries. Adv Nutr. 2016;7:275-8.
Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P; Canadian Hypertensive Disorders of Pregnancy Working Group. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. J Obstet Gynaecol Can. 2014;36:416-41.
Tranquilli AL, Dekker G, Magee L, Roberts J, Sibai BM, Steyn W, et al. The classification, diagnosis and management of the hypertensive disorders of pregnancy: A revised statement from the ISSHP. Pregnancy Hypertens. 2014;4:97-104.
Lowe SA, Bowyer L, Lust K, McMahon LP, Morton M, North RA, et al. SOMANZ guidelines for the management of hypertensive disorders of pregnancy 2014. Aust N Z J Obstet Gynaecol. 2015;55:e1-29
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-83.
Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997 Apr 1;126(7):497-504.
Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 2002;346:77-84.
Davies KM, Heaney RP, Recker RR, Lappe JM, Barger-Lux MJ, Rafferty K, et al. Calcium intake and body weight. J Clin Endocrinol Metab 2000;85:4635-8.
Parikh SJ, Yanovski JA. Calcium intake and adiposity. Am J Clin Nutr 2003;77:281-7
Zemel MB, Shi H, Greer B, DiRienzo D, Zemel P. Regulation of adiposity by dietary calcium. FASEB J 2000;14:1132-8.
Zemel MB, Richards J, Mathis S, Milstead A, Gebhardt L, Silva E. Dairy augmentation of total and central fat loss in obese subjects. Int J Obes 2005;29:391-7.
Chen M, Pan A, Malik VS, Hu FB. Effects of dairy intake on body weight and fat: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2012;96:735-747.
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. https://www.ahajournals.org/doi/pdf/10.1161/circulationaha.110.971069
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 741
Puvabanditsin S et al; Pediatric Radiology 35 (5): 539-42, 2005 https://www.ncbi.nlm.nih.gov/pubmed/15565339
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 742
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 746

Drugs Drugs & Supplements

Magnesium oxide

by Health Jade Team on August 9, 2018

What is magnesium oxide

Magnesium is an abundant mineral in the body and magnesium is naturally present in many foods, added to other food products, available as a dietary supplement, and present in some medicines (such as antacids and laxatives). Magnesium oxide may be used for different reasons with some people using it as an antacid to relieve heartburn, sour stomach, or acid indigestion. Magnesium oxide also may be used as a laxative for short-term, rapid emptying of the bowel (before surgery, for example). Magnesium oxide should not be used repeatedly. Magnesium oxide also is used as a dietary supplement when the amount of magnesium in the diet is not enough. Magnesium oxide is available without a prescription.

Magnesium is a cofactor in more than 300 enzyme systems that regulate diverse biochemical reactions in the body, including protein synthesis, muscle and nerve function, blood glucose control, and blood pressure regulation ¹. Magnesium is required for energy production, oxidative phosphorylation, and glycolysis. Magnesium contributes to the structural development of bone and is required for the synthesis of DNA, RNA, and the antioxidant glutathione. Magnesium also plays a role in the active transport of calcium and potassium ions across cell membranes, a process that is important to nerve impulse conduction, muscle contraction, and normal heart rhythm ¹.

The total magnesium content of the human body is reported to be ~20 mmol/kg of fat-free tissue. In other words, total magnesium in the average 70 kg adult with 20% (w/w) fat is ~1000 to 1120 mmol or approximately 25 g magnesium, with 50% to 60% present in the bones and most of the rest in soft tissues ². About 99% of total body magnesium is located in bone, muscles and non-muscular soft tissue. Less than 1% of total magnesium is in blood serum, and these levels are kept under tight control. Magnesium excretion is mainly regulated by the kidney. About 100 mmol/L magnesium is filtered daily ³. Normal serum magnesium concentrations range between 0.75 and 0.95 millimoles (mmol)/L ⁴. Hypomagnesemia is defined as a serum magnesium level less than 0.75 mmol/L ⁵. Magnesium homeostasis is largely controlled by the kidney, which typically excretes about 120 mg magnesium into the urine each day ⁶. Urinary excretion is reduced when magnesium status is low ⁷.

Magnesium is widely distributed in plant and animal foods and in beverages (see Table 2). Green leafy vegetables, such as spinach, legumes, nuts, seeds, and whole grains, are good sources ¹. Water accounts for ~10% of daily magnesium intake ⁸, chlorophyll (and thus green vegetables such as spinach) is the major source of magnesium. Nuts, seeds and unprocessed cereals are also rich in magnesium. Legumes, fruit, fish and meat have an intermediate magnesium concentration. Some types of food processing, such as refining grains in ways that remove the nutrient-rich germ and bran, lower magnesium content substantially. Low magnesium concentrations are found in dairy products, except milk ⁹. In general, foods containing dietary fiber provide magnesium. Magnesium is also added to some breakfast cereals and other fortified foods. Some types of food processing, such as refining grains in ways that remove the nutrient-rich germ and bran, lower magnesium content substantially ⁷. Selected food sources of magnesium are listed in Table 2.

Tap, mineral, and bottled waters can also be sources of magnesium, but the amount of magnesium in water varies by source and brand (ranging from 1 mg/L to more than 120 mg/L) ¹⁰.

Approximately 30% to 40% of the dietary magnesium consumed is typically absorbed by the body ⁶.

Assessing magnesium status is difficult because most magnesium is inside cells or in bone ¹. The most commonly used and readily available method for assessing magnesium status is measurement of serum magnesium concentration, even though serum levels have little correlation with total body magnesium levels or concentrations in specific tissues ⁵. Other methods for assessing magnesium status include measuring magnesium concentrations in erythrocytes, saliva, and urine; measuring ionized magnesium concentrations in blood, plasma, or serum; and conducting a magnesium-loading (or “tolerance”) test. No single method is considered satisfactory ¹¹. Some experts ² but not others ¹ consider the tolerance test (in which urinary magnesium is measured after parenteral infusion of a dose of magnesium) to be the best method to assess magnesium status in adults. To comprehensively evaluate magnesium status, both laboratory tests and a clinical assessment might be required ⁵.

Table 1: Recommended Dietary Allowances (RDAs) for Magnesium

Age	Male	Female	Pregnancy	Lactation
Birth to 6 months	30 mg*	30 mg*
7–12 months	75 mg*	75 mg*
1–3 years	80 mg	80 mg
4–8 years	130 mg	130 mg
9–13 years	240 mg	240 mg
14–18 years	410 mg	360 mg	400 mg	360 mg
19–30 years	400 mg	310 mg	350 mg	310 mg
31–50 years	420 mg	320 mg	360 mg	320 mg
51+ years	420 mg	320 mg

Footnote: *Adequate Intake (AI) = Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an Recommended Dietary Allowance (average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.).

[Source ¹²]

Table 2: Selected food sources of magnesium

Food	Milligrams (mg) per serving	Percent DV*
Almonds, dry roasted, 1 ounce	80	20
Spinach, boiled, ½ cup	78	20
Cashews, dry roasted, 1 ounce	74	19
Peanuts, oil roasted, ¼ cup	63	16
Cereal, shredded wheat, 2 large biscuits	61	15
Soymilk, plain or vanilla, 1 cup	61	15
Black beans, cooked, ½ cup	60	15
Edamame, shelled, cooked, ½ cup	50	13
Peanut butter, smooth, 2 tablespoons	49	12
Bread, whole wheat, 2 slices	46	12
Avocado, cubed, 1 cup	44	11
Potato, baked with skin, 3.5 ounces	43	11
Rice, brown, cooked, ½ cup	42	11
Yogurt, plain, low fat, 8 ounces	42	11
Breakfast cereals, fortified with 10% of the DV for magnesium	40	10
Oatmeal, instant, 1 packet	36	9
Kidney beans, canned, ½ cup	35	9
Banana, 1 medium	32	8
Salmon, Atlantic, farmed, cooked, 3 ounces	26	7
Milk, 1 cup	24–27	6–7
Halibut, cooked, 3 ounces	24	6
Raisins, ½ cup	23	6
Chicken breast, roasted, 3 ounces	22	6
Beef, ground, 90% lean, pan broiled, 3 ounces	20	5
Broccoli, chopped and cooked, ½ cup	12	3
Rice, white, cooked, ½ cup	10	3
Apple, 1 medium	9	2
Carrot, raw, 1 medium	7	2

Footnotes: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for magnesium is 400 mg for adults and children aged 4 and older. However, the FDA does not require food labels to list magnesium content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

[Source ¹²]

Magnesium oxide supplement

Magnesium oxide supplement is available in a variety of forms, including magnesium oxide, magnesium citrate, and magnesium chloride ¹. The Supplement Facts panel on a dietary supplement label declares the amount of elemental magnesium in the product, not the weight of the entire magnesium-containing compound.

Absorption of magnesium from different kinds of magnesium supplements varies. Forms of magnesium that dissolve well in liquid are more completely absorbed in the gut than less soluble forms ⁶. Small studies have found that magnesium in the aspartate, citrate, lactate, and chloride forms is absorbed more completely and is more bioavailable than magnesium oxide and magnesium sulfate ¹³. One study found that very high doses of zinc from supplements (142 mg/day) can interfere with magnesium absorption and disrupt the magnesium balance in the body ¹⁴.

Magnesium oxide vs Magnesium citrate

Small studies have found that magnesium in the aspartate, citrate, lactate, and chloride forms is absorbed more completely and is more bioavailable than magnesium oxide and magnesium sulfate ¹³. Just like magnesium oxide, magnesium citrate is also used to treats constipation, and empties the bowel before surgery or other medical procedures. Magnesium citrate is a low-volume osmotic laxative that is effective in small-volume bowel preparation. The 8-oz (237 mL) magnesium citrate solution consisted of magnesium carbonate (31%), citric acid (65%), and potassium citrate (3%), yielding 18.0 g of magnesium citrate (e.g., LoSo Prep; E-Z-Em).

Magnesium oxide uses

What is magnesium oxide used for

Magnesium oxide is used to treat or prevent low magnesium levels.
Magnesium oxide is used to treat heartburn and upset stomach.
Magnesium oxide is used as laxative to relieve occasional constipation.

You should not use magnesium oxide if you are allergic to it.

Ask a doctor or pharmacist if it is safe for you to use magnesium oxide if you have other medical conditions, especially:

kidney disease;
heart disease;
nausea, vomiting;
a blockage in your intestines;
low levels of calcium in your blood; or
a sudden change in bowel habits for 2 weeks or longer.

It is not known whether magnesium oxide will harm an unborn baby. Ask a doctor before using this medicine if you are pregnant.

It is not known whether magnesium oxide passes into breast milk or if it could affect a nursing baby. Ask a doctor before using this medicine if you are breast-feeding.

Do not give this medicine to a child without medical advice.

Magnesium oxide should not be given to a child younger than 6 years old.

Magnesium benefits

Magnesium for ADHD

Attention deficit hyperactivity disorder (ADHD) is the most common psychiatric disorder in clinical samples of children and adolescents referring to child psychiatric clinics. Dietary factors can play a significant role in the etiology of attention deficit hyperactivity disorder (ADHD). Several studies reported that the magnesium level in children with ADHD is decreased in serum and erythrocytes and the Mg2+-ATPase activity is reduced ¹⁵. Treatment of magnesium deficiency can help in revealing hyperactivity in children [126,127,128,129,130]. Current treatments for ADHD, such as atomoxetine and stimulants, act through adrenergic and dopaminergic receptors. Magnesium interacts with the ADHD-related neurotransmitters (e.g., dopamine, serotonin) and inhibits N-methyl-d-aspartate (NMDA)-induced norepinephrine release. The results of several studies are promising that magnesium supplementation (e.g. 6 mg/kg BW per day) may be helpful in the treatment of ADHD ¹⁶. Unfortunately, until now there is still no double-blind randomized controlled clinical trial investigating the efficacy and safety of magnesium for treating ADHD.

Magnesium for osteoporosis

Magnesium is involved in bone formation and influences the activities of osteoblasts and osteoclasts ¹⁷. Magnesium also affects the concentrations of both parathyroid hormone and the active form of vitamin D, which are major regulators of bone homeostasis. Several population-based studies have found positive associations between magnesium intake and bone mineral density in both men and women ¹⁸. Other research has found that women with osteoporosis have lower serum magnesium levels than women with osteopenia and those who do not have osteoporosis or osteopenia ¹⁹. These and other findings indicate that magnesium deficiency might be a risk factor for osteoporosis ¹⁷.

Although limited in number, studies suggest that increasing magnesium intakes from food or supplements might increase bone mineral density in postmenopausal and elderly women ⁷. For example, one short-term study found that 290 mg/day elemental magnesium (as magnesium citrate) for 30 days in 20 postmenopausal women with osteoporosis suppressed bone turnover compared with placebo, suggesting that bone loss decreased ²⁰.

Diets that provide recommended levels of magnesium enhance bone health, but further research is needed to elucidate the role of magnesium in the prevention and management of osteoporosis.

Magnesium for migraines and headaches

Magnesium deficiency is related to factors that promote headaches, including neurotransmitter release and vasoconstriction ²¹. People who experience migraine headaches have lower levels of serum and tissue magnesium than those who do not.

However, research on the use of magnesium supplements to prevent or reduce symptoms of migraine headaches is limited. Three of four small, short-term, placebo-controlled trials found modest reductions in the frequency of migraines in patients given up to 600 mg/day magnesium ²¹. The authors of a review on migraine prophylaxis ²² suggested that taking 300 mg magnesium twice a day, either alone or in combination with medication, can prevent migraines.

In their evidence-based guideline update, the American Academy of Neurology and the American Headache Society concluded that magnesium therapy is “probably effective” for migraine prevention ²³. Because the typical dose of magnesium used for migraine prevention exceeds the Tolerable Upper Intake Level (maximum daily intake unlikely to cause adverse health effects), this treatment should be used only under the direction and supervision of a healthcare provider.

Magnesium for hypertension and cardiovascular disease

Hypertension is a major risk factor for heart disease and stroke. Studies to date, however, have found that magnesium supplementation lowers blood pressure, at best, to only a small extent. A meta-analysis of 12 clinical trials found that magnesium supplementation for 8–26 weeks in 545 hypertensive participants resulted in only a small reduction (2.2 mmHg) in diastolic blood pressure ²⁴. The dose of magnesium ranged from approximately 243 to 973 mg/day. The authors of another meta-analysis of 22 studies with 1,173 normotensive and hypertensive adults concluded that magnesium supplementation for 3–24 weeks decreased systolic blood pressure by 3–4 mmHg and diastolic blood pressure by 2–3 mmHg ²⁵. The effects were somewhat larger when supplemental magnesium intakes of the participants in the nine crossover-design trials exceeded 370 mg/day. A diet containing more magnesium because of added fruits and vegetables, more low-fat or non-fat dairy products, and less fat overall was shown to lower systolic and diastolic blood pressure by an average of 5.5 and 3.0 mmHg, respectively ²⁶. However, this Dietary Approaches to Stop Hypertension (DASH) diet also increases intakes of other nutrients, such as potassium and calcium, that are associated with reductions in blood pressure, so any independent contribution of magnesium cannot be determined.

Several prospective studies have examined associations between magnesium intakes and heart disease. The Atherosclerosis Risk in Communities study assessed heart disease risk factors and levels of serum magnesium in a cohort of 14,232 white and African-American men and women aged 45 to 64 years at baseline ²⁷. Over an average of 12 years of follow-up, individuals in the highest quartile of the normal physiologic range of serum magnesium (at least 0.88 mmol/L) had a 38% reduced risk of sudden cardiac death compared with individuals in the lowest quartile (0.75 mmol/L or less). However, dietary magnesium intakes had no association with risk of sudden cardiac death. Another prospective study tracked 88,375 female nurses in the United States to determine whether serum magnesium levels measured early in the study and magnesium intakes from food and supplements assessed every 2 to 4 years were associated with sudden cardiac death over 26 years of follow-up ²⁸. Women in the highest compared with the lowest quartile of ingested and plasma magnesium concentrations had a 34% and 77% lower risk of sudden cardiac death, respectively. Another prospective population study of 7,664 adults aged 20 to 75 years in the Netherlands who did not have cardiovascular disease found that low urinary magnesium excretion levels (a marker for low dietary magnesium intake) were associated with a higher risk of ischemic heart disease over a median follow-up period of 10.5 years. Plasma magnesium concentrations were not associated with risk of ischemic heart disease ²⁹. A systematic review and meta-analysis of prospective studies found that higher serum levels of magnesium were significantly associated with a lower risk of cardiovascular disease, and higher dietary magnesium intakes (up to approximately 250 mg/day) were associated with a significantly lower risk of ischemic heart disease caused by a reduced blood supply to the heart muscle ³⁰.

Higher magnesium intakes might reduce the risk of stroke. In a meta-analysis of 7 prospective trials with a total of 241,378 participants, an additional 100 mg/day magnesium in the diet was associated with an 8% decreased risk of total stroke, especially ischemic rather than hemorrhagic stroke ³¹. One limitation of such observational studies, however, is the possibility of confounding with other nutrients or dietary components that could also affect the risk of stroke.

A large, well-designed clinical trial is needed to better understand the contributions of magnesium from food and dietary supplements to heart health and the primary prevention of cardiovascular disease ³².

Magnesium for type 2 diabetes

Diets with higher amounts of magnesium are associated with a significantly lower risk of diabetes, possibly because of the important role of magnesium in glucose metabolism ³³. Hypomagnesemia might worsen insulin resistance, a condition that often precedes diabetes, or it might be a consequence of insulin resistance ³⁴. Diabetes leads to increased urinary losses of magnesium, and the subsequent magnesium inadequacy might impair insulin secretion and action, thereby worsening diabetes control ¹.

Most investigations of magnesium intake and risk of type 2 diabetes have been prospective cohort studies. A meta-analysis of 7 of these studies, which included 286,668 patients and 10,912 cases of diabetes over 6 to 17 years of follow-up, found that a 100 mg/day increase in total magnesium intake decreased the risk of diabetes by a statistically significant 15% ³⁵. Another meta-analysis of 8 prospective cohort studies that followed 271,869 men and women over 4 to 18 years found a significant inverse association between magnesium intake from food and risk of type 2 diabetes; the relative risk reduction was 23% when the highest to lowest intakes were compared ³⁶.

A 2011 meta-analysis of prospective cohort studies of the association between magnesium intake and risk of type 2 diabetes included 13 studies with a total of 536,318 participants and 24,516 cases of diabetes ³⁷. The mean length of follow-up ranged from 4 to 20 years. Investigators found an inverse association between magnesium intake and risk of type 2 diabetes in a dose-responsive fashion, but this association achieved statistical significance only in overweight (body mass index [BMI] 25 or higher) but not normal-weight individuals (BMI less than 25). Again, a limitation of these observational studies is the possibility of confounding with other dietary components or lifestyle or environmental variables that are correlated with magnesium intake.

Only a few small, short-term clinical trials have examined the potential effects of supplemental magnesium on control of type 2 diabetes and the results are conflicting ³⁸. For example, 128 patients with poorly controlled diabetes in a Brazilian clinical trial received a placebo or a supplement containing either 500 mg/day or 1,000 mg/day magnesium oxide (providing 300 or 600 mg elemental magnesium, respectively) ³⁹. After 30 days of supplementation, plasma, cellular, and urine magnesium levels increased in participants receiving the larger dose of the supplement, and their glycemic control improved. In another small trial in Mexico, participants with type 2 diabetes and hypomagnesemia who received a liquid supplement of magnesium chloride (providing 300 mg/day elemental magnesium) for 16 weeks showed significant reductions in fasting glucose and glycosylated hemoglobin concentrations compared with participants receiving a placebo, and their serum magnesium levels became normal ⁴⁰. In contrast, neither a supplement of magnesium aspartate (providing 369 mg/day elemental magnesium) nor a placebo taken for 3 months had any effect on glycemic control in 50 patients with type 2 diabetes who were taking insulin ⁴¹.

The American Diabetes Association states that there is insufficient evidence to support the routine use of magnesium to improve glycemic control in people with diabetes ³⁸. It further notes that there is no clear scientific evidence that vitamin and mineral supplementation benefits people with diabetes who do not have underlying nutritional deficiencies.

Magnesium oxide dosage

Use magnesium oxide exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Take magnesium oxide with a full glass of water.

When using magnesium oxide as a laxative, it may be best to take your dose at bedtime.

Magnesium oxide may be taken with food if it upsets your stomach.

Call your doctor if your symptoms do not improve after 7 days of treatment, or if symptoms get worse.

Store at room temperature away from moisture and heat.

Magnesium oxide can make it harder for your body to absorb other medicines you take by mouth. Avoid taking other medicines within 2 hours before or 2 hours after you take magnesium oxide. You may need to wait 4 hours to take your other medicines after taking magnesium oxide. Ask your doctor how to best schedule your medications.

Adult dose for dyspepsia

Uses: Acid indigestion, upset stomach

400 mg tablets: 1 tablet orally twice a day
Maximum dose: 2 tablets per 24 hour period
Duration of therapy: Up to 2 weeks

Comments:

May have a laxative effect.

Adult dose for constipation

Oral: Caplets (500 mg): 2 to 4 caplets orally daily with a full 8 ounce glass of liquid.
Caplets may be taken all at bedtime or separately throughout the day.

Adult dose for vitamin/mineral supplementation during pregnancy/lactation

Recommended dietary intake:

Women 19 to 30 years: 508 mg magnesium oxide (310 mg elemental magnesium) orally daily
Women 31 years and older: 525 mg magnesium oxide (320 mg elemental magnesium) orally daily
Men 19 to 30 years: 656 mg magnesium oxide (400 mg elemental magnesium) orally daily
Men 31 years and older: 689 mg magnesium oxide (420 mg elemental) orally daily

Maximum magnesium oxide supplement dose: 574 mg magnesium oxide (350 mg elemental magnesium)

Pediatric dose for constipation

500 mg caplets:

12 years and older: 2 to 4 caplets orally daily, as a single dose or divided dose
Maximum dose: 4 caplets per day
Duration of therapy: 7 days or less

Comments:

-Bedtime is the preferred administration time for a single dose.
-Take with a full glass of water.

Pediatric dose for vitamin/mineral supplementation

Recommended dietary intakes:

14 to 18 years:
Males: 672 mg magnesium oxide (410 mg elemental magnesium) per day
Females: 590 mg magnesium oxide (360 mg elemental magnesium) per day

Maximum magnesium oxide supplement dose (both sexes): 574 mg magnesium oxide (350 mg elemental magnesium) per day

9 to 13 years: 394 mg magnesium oxide (240 mg elemental) per day

Maximum magnesium oxide supplement dose: 574 mg magnesium oxide (350 mg elemental magnesium) per day

4 to 8 years: 213 mg magnesium oxide (130 mg elemental magnesium) per day

Maximum magnesium oxide supplement dose: 180 mg magnesium oxide (110 mg elemental magnesium) per day

1 to 3 years: 131 mg magnesium oxide (80 mg elemental) per day

Maximum magnesium oxide supplement dose: 107 mg magnesium oxide (65 mg elemental magnesium) per day

7 to 12 months: 123 mg magnesium oxide (75 mg elemental magnesium) per day

Birth to 6 months: 49 mg magnesium oxide (30 mg elemental magnesium) per day

Magnesium oxide side effects

Too much magnesium from food does not pose a health risk in healthy individuals because the kidneys eliminate excess amounts in the urine ⁴². However, high doses of magnesium from dietary supplements or medications often result in diarrhea that can be accompanied by nausea and abdominal cramping ⁷. Forms of magnesium most commonly reported to cause diarrhea include magnesium carbonate, chloride, gluconate, and oxide ⁴³. The diarrhea and laxative effects of magnesium salts are due to the osmotic activity of unabsorbed salts in the intestine and colon and the stimulation of gastric motility.

Very large doses of magnesium-containing laxatives and antacids (typically providing more than 5,000 mg/day magnesium) have been associated with magnesium toxicity ⁴⁴, including fatal hypermagnesemia in a 28-month-old boy ⁴⁵ and an elderly man ⁴⁶. Symptoms of magnesium toxicity, which usually develop after serum concentrations exceed 1.74–2.61 mmol/L, can include hypotension, nausea, vomiting, facial flushing, retention of urine, ileus, depression, and lethargy before progressing to muscle weakness, difficulty breathing, extreme hypotension, irregular heartbeat, and cardiac arrest ⁴⁷. The risk of magnesium toxicity increases with impaired renal function or kidney failure because the ability to remove excess magnesium is reduced or lost ⁴⁷.

Magnesium oxide may cause side effects. To avoid unpleasant taste, take the tablet with citrus fruit juice or carbonated citrus drink. Tell your doctor if either of these symptoms are severe or do not go away:

cramping
diarrhea

If you experience any of the following symptoms, call your doctor immediately:

rash or hives
itching
dizziness or lightheadedness
mood or mental changes
unusual tiredness
weakness
nausea
vomiting

Interactions with Medications

Several types of medications have the potential to interact with magnesium supplements or affect magnesium status. A few examples are provided below. People taking these and other medications on a regular basis should discuss their magnesium intakes with their healthcare providers.

Bisphosphonates

Magnesium-rich supplements or medications can decrease the absorption of oral bisphosphonates, such as alendronate (Fosamax®), used to treat osteoporosis ⁴⁸. Use of magnesium-rich supplements or medications and oral bisphosphonates should be separated by at least 2 hours.

Antibiotics

Magnesium can form insoluble complexes with tetracyclines, such as demeclocycline (Declomycin®) and doxycycline (Vibramycin®), as well as quinolone antibiotics, such as ciprofloxacin (Cipro®) and levofloxacin (Levaquin®). These antibiotics should be taken at least 2 hours before or 4–6 hours after a magnesium-containing supplement ⁴⁹.

Diuretics

Chronic treatment with loop diuretics, such as furosemide (Lasix®) and bumetanide (Bumex®), and thiazide diuretics, such as hydrochlorothiazide (Aquazide H®) and ethacrynic acid (Edecrin®), can increase the loss of magnesium in urine and lead to magnesium depletion ⁵⁰. In contrast, potassium-sparing diuretics, such as amiloride (Midamor®) and spironolactone (Aldactone®), reduce magnesium excretion ⁵⁰.

Proton pump inhibitors

Prescription proton pump inhibitor (PPI) drugs, such as esomeprazole magnesium (Nexium®) and lansoprazole (Prevacid®), when taken for prolonged periods (typically more than a year) can cause hypomagnesemia. In cases that FDA reviewed, magnesium supplements often raised the low serum magnesium levels caused by PPIs. However, in 25% of the cases, supplements did not raise magnesium levels and the patients had to discontinue the PPI. FDA advises healthcare professionals to consider measuring patients’ serum magnesium levels prior to initiating long-term PPI treatment and to check magnesium levels in these patients periodically.

References

Rude RK. Magnesium. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed. Baltimore, Mass: Lippincott Williams & Wilkins; 2012:159-75.
Volpe SL. Magnesium. In: Erdman JW, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Ames, Iowa; John Wiley & Sons, 2012:459-74.
The clinical importance of magnesium. 2. The indications for supplementation and therapy. Classen HG, Nowitzki S. Fortschr Med. 1990 Apr 10; 108(10):198-200.
Elin RJ. Assessment of magnesium status for diagnosis and therapy. Magnes Res 2010;23:1-5.
Gibson, RS. Principles of Nutritional Assessment, 2nd ed. New York, NY: Oxford University Press, 2005.
Rude RK. Magnesium. In: Coates PM, Betz JM, Blackman MR, Cragg GM, Levine M, Moss J, White JD, eds. Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare; 2010:527-37.
Institute of Medicine (IOM). Food and Nutrition Board. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Washington, DC: National Academy Press, 1997.
Magnesium in drinking water and ischemic heart disease. Marx A, Neutra RR. Epidemiol Rev. 1997; 19(2):258-72.
Introduction: importance of Mg in physiology and medicine and the need for ion selective electrodes. Altura BM. Scand J Clin Lab Invest Suppl. 1994; 217():5-9.
Azoulay A, Garzon P, Eisenberg MJ. Comparison of the mineral content of tap water and bottled waters. J Gen Intern Med 2001;16:168-75.
Witkowski M, Hubert J, Mazur A. Methods of assessment of magnesium status in humans: a systematic review. Magnesium Res 2011;24:163-80.
Magnesium. https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/
Walker AF, Marakis G, Christie S, Byng M. Mg citrate found more bioavailable than other Mg preparations in a randomized, double-blind study. Mag Res 2003;16:183-91.
Spencer H, Norris C, Williams D. Inhibitory effects of zinc on magnesium balance and magnesium absorption in man. J Am Coll Nutr 1994;13:479-84.
Nogovitsina O.R., Levitina E.V. Diagnostic value of examination of the magnesium homeostasis in children with attention deficit syndrome with hyperactivity. Klin. Lab. Diagn. 2005;5:17–19.
Nogovitsina O.R., Levitina E.V. Effect of MAGNE-B6 on the clinical and biochemical manifestations of the syndrome of attention deficit and hyperactivity in children. Eksp. Klin. Farmakol. 2006;69:74–77.
Rude RK, Singer FR, Gruber HE. Skeletal and hormonal effects of magnesium deficiency. J Am Coll Nutr 2009;28:131–41.
Tucker KL. Osteoporosis prevention and nutrition. Curr Osteoporos Rep 2009;7:111-7.
Mutlu M, Argun M, Kilic E, Saraymen R, Yazar S. Magnesium, zinc and copper status in osteoporotic, osteopenic and normal post-menopausal women. J Int Med Res 2007;35:692-5.
Aydin H, Deyneli O, Yavuz D, Gözü H, Mutlu N, Kaygusuz I, Akalin S. Short-term oral magnesium supplementation suppresses bone turnover in postmenopausal osteoporotic women. Biol Trace Elem Res 2010;133:136-43.
Sun-Edelstein C, Mauskop A. Role of magnesium in the pathogenesis and treatment of migraine. Expert Rev Neurother 2009;9:369–79 https://doi.org/10.1586/14737175.9.3.369
Schürks M, Diener H-C, Goadsby P. Update on the prophylaxis of migraine. Cur Treat Options Neurol 2008;10:20–9. https://www.ncbi.nlm.nih.gov/pubmed/18325296
Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults. Neurology 2012;78:1346-53. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335449/
Dickinson HO, Nicolson D, Campbell F, Cook JV, Beyer FR, Ford GA, Mason J. Magnesium supplementation for the management of primary hypertension in adults. Cochrane Database of Systematic Reviews 2006: CD004640.
Kass L, Weekes J, Carpenter L. Effect of magnesium supplementation on blood pressure: a meta-analysis. Eur J Clin Nutr 2012;66:411-8.
Champagne CM. Dietary interventions on blood pressure: the Dietary Approaches to Stop Hypertension (DASH) trials. Nutr Rev 2006;64:S53-6.
Peacock JM, Ohira T, Post W, Sotoodehnia N, Rosamond W, Folsom AR. Serum magnesium and risk of sudden cardiac death in the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J 2010;160:464-70
Chiuve SE, Korngold EC, Januzzi Jr JL, Gantzer ML, Albert CM. Plasma and dietary magnesium and risk of sudden cardiac death in women. Am J Clin Nutr 2011;93:253-60
Joosten MM, Gansevoort RT, Mukamal KJ, van der Harst P, Geleijnse JM, Feskens EJM, Navis G, Bakker SJL. Urinary and plasma magnesium and risk of ischemic heart disease. Am J Clin Nutr 2013;97:1299-306.
Del Gobbo LC, Imamura F, Wu JHY, Otto MCdO, Chiuve SE, Mozaffarian D. Circulating and dietary magnesium and risk of cardiovascular disease: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr 2013;98:160-73.
Larsson SC, Orsini N, Wolk A. Dietary magnesium intake and risk of stroke: a meta-analysis of prospective studies. Am J Clin Nutr 2012;95:362-6.
Song Y, Liu S. Magnesium for cardiovascular health: time for intervention. Am J Clin Nutr 2012;95:269-70.
Rodriguez-Moran M, Simental Mendia LE, Zambrano Galvan G, Guerrero-Romero F. The role of magnesium in type 2 diabetes: a brief based-clinical review. Magnes Res 2011;24:156-62.
Simmons D, Joshi S, Shaw J. Hypomagnesaemia is associated with diabetes: not pre-diabetes, obesity or the metabolic syndrome. Diabetes Res Clin Pract 2010;87:261-6
Larsson SC, Wolk A. Magnesium intake and risk of type 2 diabetes: a meta-analysis. J Intern Med 2007;262:208-14.
Schulze MB, Schulz M, Heidemann C, Schienkiewitz A, Hoffmann K, Boeing H. Fiber and magnesium intake and incidence of type 2 diabetes: a prospective study and meta-analysis. Arch Intern Med 2007;167:956–65.
Dong J-Y, Xun P, He K, Qin L-Q. Magnesium intake and risk of type 2 diabetes: meta-analysis of prospective cohort studies. Diabetes Care 2011;34:2116-22.
Evert AB, Boucher JL, Cypress M, Dunbar SA, Franz MJ, Mayer-Davis EJ, Neumiller JJ, Nwankwo R, Verdi CL, Urbanski P, Yancy WS Jr. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care 2013;36:3821-42.
Lima MDL, Cruz T, Pousada JC, Rodrigues LE, Barbosa K, Canguco V. The effect of magnesium supplementation in increasing doses on the control of type 2 diabetes. Diabetes Care 1998;21:682-6.
Rodriquez-Moran M, Guerrero-Romero F. Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care 2003;26:1147-52.
de Valk HW, Verkaaik R, van Rijn HJ, Geerdink RA, Struyvenberg A. Oral magnesium supplementation in insulin-requiring Type 2 diabetic patients. Diabet Med 1998;15:503-7
Musso CG Magnesium metabolism in health and disease. Int Urol Nephrol 2009;41:357-62. https://www.ncbi.nlm.nih.gov/pubmed/19274487
Ranade VV, Somberg JC. Bioavailability and pharmacokinetics of magnesium after administration of magnesium salts to humans. Am J Ther 2001;8:345-57.
Kutsal E, Aydemir C, Eldes N, Demirel F, Polat R, Taspnar O, Kulah E. Severe hypermagnesemia as a result of excessive cathartic ingestion in a child without renal failure. Pediatr Emerg Care 2007;23:570-2.
McGuire JK, Kulkarni MS, Baden HP. Fatal hypermagnesemia in a child treated with megavitamin/megamineral therapy. Pediatrics 2000;105:E18.
Onishi S, Yoshino S. Cathartic-induced fatal hypermagnesemia in the elderly. Intern Med 2006;45:207-10.
Musso CG Magnesium metabolism in health and disease. Int Urol Nephrol 2009;41:357-62.
Dunn CJ, Goa KL. Risedronate: A review of its pharmacological properties and clinical use in resorptive bone disease. Drugs 2001;61:685-712.
Arayne MS, Sultana N, Hussain F. Interactions between ciprofloxacin and antacids–dissolution and adsorption studies. Drug Metabol Drug Interact 2005;21:117-29
Sarafidis PA, Georgianos PI, Lasaridis AN. Diuretics in clinical practice. Part II: electrolyte and acid-base disorders complicating diuretic therapy. Expert Opin Drug Saf 2010;9:259-73.

Drugs Drugs & Supplements

Potassium chloride

by Health Jade Team on August 8, 2018

What is potassium chloride

Potassium is a mineral that is found in many foods and potassium is also an electrolyte that is vital to cell metabolism and is needed for several functions of your body, especially the beating of your heart. Potassium chloride is a mineral used to replenish potassium within your body. Potassium chloride (KCl) is used to prevent or to treat low blood levels of potassium (hypokalemia). Potassium levels can be low as a result of a disease or from taking certain medicines e.g. when thiazide diuretics or corticosteroids, or after a prolonged illness with diarrhea or vomiting or diets poor in potassium. Potassium chloride supplement may irritate your stomach and other side effects generally only occur with higher dosages. Acute oral potassium chloride toxicity is rare because large single doses induce nausea and vomiting, and because potassium chloride is rapidly excreted in the absence of any pre-existing kidney damage. Symptoms of acute poisoning after ingestion of potassium chloride are usually mild. Potassium chloride oral overdoses manifests in neuromuscular signs in the form of hyperkalemia, general muscular weakness and ascending paralysis, listlessness, vertigo, mental confusion, hypotension, acute cardiovascular changes with ECG abnormalities, and heart block. Gastrointestinal symptoms manifest as nausea, vomiting, paralytic ileus, and local mucosal necrosis, which may lead to perforation. There are several case reports of accidental IV (intravenous) or intraperitoneal administrations of potassium chloride. Symptoms of acute poisoning after parenteral administration are similar to symptoms after oral exposure but can appear more promptly and be more severe. A case report of a subcutaneous injection of potassium chloride reports chemical burns and skin lesions.

Potassium chloride (KCl) consists of odorless white crystals or crystalline powder or white granular powder or colorless crystals, with a strong saline taste.

Potassium chloride (KCl) is also used in the treatment of cumulative digitalis poisoning; and as a component of lethal injections. Potassium chloride is also used in the fertilizer industry as potash and in buffer solutions for photography. Potassium chloride has been identified as being used in hydraulic fracturing as a clay stabilizer.

You get most of the potassium you need from the foods that you eat, the usual dietary intake of potassium is 50 to 100 millimole (mmol) per day and most people have an adequate intake of potassium. Your body uses what it requires and your kidneys eliminate the rest in the urine. Your body tries to keep the blood potassium level within a very narrow range. Levels are mainly controlled by aldosterone, a hormone produced by the adrenal glands in the kidneys.

Potassium is absorbed via passive diffusion, primarily in the small intestine ¹. About 90% of ingested potassium is absorbed and used to maintain its normal intracellular and extracellular concentrations ². Potassium is excreted primarily in the urine, some is excreted in the stool, and a very small amount is lost in sweat. The kidneys control potassium excretion in response to changes in dietary intakes, and potassium excretion increases rapidly in healthy people after potassium consumption, unless body stores are depleted ³. The kidneys can adapt to variable potassium intakes in healthy individuals, but a minimum of 5 mmol (about 195 mg) potassium is excreted daily in urine ⁴. This, combined with other obligatory losses, suggests that potassium balance cannot be achieved with intakes less than about 400–800 mg/day.

The total amount of potassium in the adult body is about 45 millimole (mmol)/kg body weight (about 140 g for a 175 pound adult; 1 mmol = 1 milliequivalent [mEq] or 39.1 mg potassium) ⁴. Most potassium resides intracellularly, and a small amount is in extracellular fluid ¹. The intracellular concentration of potassium is about 30 times higher than the extracellular concentration, and this difference forms a transmembrane electrochemical gradient that is maintained via the sodium-potassium (Na+/K+) ATPase transporter ¹. In addition to maintaining cellular tonicity, this gradient is required for proper nerve transmission, muscle contraction, and kidney function.

The intracellular concentration of potassium is approximately 150 to 160 millimole (mmol) per liter. The normal adult plasma concentration is 3.6 to 5.0 mmol per liter. An active ion transport system maintains this gradient across the plasma membrane.

Because the blood concentration of potassium is so small, minor changes can have significant consequences. If potassium levels are too low or too high, there can be serious health consequences; a person may be at risk for developing shock, respiratory failure, or heart rhythm disturbances. An abnormal potassium level can alter the function of the nerves and muscles; for example, the heart muscle may lose its ability to contract.

Potassium helps transport nutrients into cells and removes waste products out of cells. Potassium is also important in muscle function, helping to transmit messages between nerves and muscles.

Potassium, along with other electrolytes such as sodium, chloride, and bicarbonate (total CO2), helps regulate the amount of fluid in your body and maintains a stable acid-base balance. Potassium is present in all body fluids, but most potassium is found within the cells. Only a small amount is present in fluids outside the cells and in the liquid part of the blood (called serum or plasma).

A potassium test is used to detect abnormal concentrations of potassium, including high potassium (hyperkalemia) and low potassium (hypokalemia). It is often used as part of an electrolyte panel or basic metabolic panel for a routine physical.

Potassium urine concentrations must be evaluated in association with blood levels. The body normally eliminates excess potassium, so the concentration in the urine may be elevated because it is elevated in the blood. It may also be elevated in the urine when the body is losing too much potassium; in this case, the blood level would be normal to low. If blood potassium levels are low due to insufficient intake, then urine concentrations will also be low.

Decreased urinary potassium levels may be due to certain drugs such as NSAIDs, beta blockers, and lithium or due to the adrenal glands producing too little of the hormone aldosterone.
Increased urinary potassium levels may be due to kidney disease, eating disorders such as anorexia, or muscle damage.

High potassium levels (hyperkalemia) may be seen in conditions such as:

Kidney disease
Addison disease
Injury to tissue
Infection
Diabetes
Dehydration
Consuming too much potassium (for example, fruits are particularly high in potassium, so excessive intake of fruits or juices may contribute to high potassium)
In patients on intravenous (IV) fluids, excessive IV potassium
Certain drugs can also cause high potassium in a small percent of people; among them are non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors, beta blockers (such as propanolol and atenolol), angiotensin-converting enzyme inhibitors (such as captopril, enalapril, and lisinopril), and potassium-sparing diuretics (such as triamterene, amiloride, and spironolactone).

Low potassium levels (hypokalemia) may be seen in conditions such as:

Diarrhea and vomiting
Conn syndrome (hyperaldosteronism)
A complication of acetaminophen overdose
In diabetes, the potassium level may fall after someone takes insulin, particularly if the person has not managed his or her diabetes well.
Low potassium is commonly due to “water pills” (potassium-wasting diuretics); if someone is taking these, their healthcare provider will check their potassium level regularly.
Additionally, certain drugs such as corticosteroids, beta-adrenergic agonists such as isoproterenol, alpha-adrenergic antagonists such as clonidine, antibiotics such as gentamicin and carbenicillin, and the antifungal agent amphotericin B can cause loss of potassium.

The usual dietary intake of potassium by the average adult is 50 mEq to 100 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 mEq or more mEq of potassium from the total body store.

Potassium depletion will occur whenever the rate of potassium loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of potassium intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of potassium in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Potassium depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis.

Potassium depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If potassium depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, e.g., where the patient requires long-term diuretic therapy, supplemental potassium in the form of high-potassium food or Potassium Chloride may be able to restore normal potassium levels.

In rare circumstances (e.g., patients with renal tubular acidosis) potassium depletion may be associated with metabolic acidosis and hyperchloremia. In such patients potassium replacement should be accomplished with potassium salts other than the chloride, such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

Treatment for low potassium may include the use of potassium chloride supplements and increasing the amount of potassium-rich foods in the diet, such as bananas, beef or spinach. Treatment for high potassium may include the use of diuretics, kidney dialysis, or insulin injections.

Potassium chloride medication

You should NOT use potassium chloride if you are allergic to it, or if:

you have high levels of potassium in your blood (hyperkalemia); or
you take a “potassium-sparing” diuretic (water pill) such as amiloride, spironolactone, or triamterene.

To make sure potassium chloride medicine is safe for you, tell your doctor if you have ever had:

kidney disease;
cirrhosis or other liver disease;
an adrenal gland disorder;
a large tissue injury such as a severe burn;
severe dehydration;
diabetes;
heart disease or high blood pressure;
stomach or intestinal bleeding;
a blockage in your stomach or intestines; or
chronic diarrhea (such as ulcerative colitis, Crohn’s disease).

It is not known whether potassium chloride medicine will harm an unborn baby. Your dose needs may be different during pregnancy. Tell your doctor if you are pregnant or breast-feeding.

Do not give this medicine to a child without medical advice.

How should I take potassium chloride?

Take potassium chloride exactly as prescribed by your doctor. Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose.

Read and carefully follow any Instructions for Use provided with your medicine. Ask your doctor or pharmacist if you do not understand these instructions.

Take potassium chloride with a full glass of water. Take the medicine with food or just after a meal.

Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

Do not crush, chew, or suck on a tablet or capsule. Sucking on the pill could irritate your mouth or throat.

Call your doctor if you have trouble swallowing a potassium chloride capsule or tablet. You may be able to dissolve the tablet in water, or mix the medicine from a capsule with soft food. Carefully follow your doctor’s instructions.

Mix the powder form of this medicine with at least 4 ounces (one-half cup) of cold water or fruit juice before taking. Drink the mixture slowly, over 5 to 10 minutes in all. To make sure you get the entire dose, add a little more water to the same glass, swirl gently and drink right away.

To be sure this medicine is helping your condition, you may need frequent blood tests. You may not notice any change in your symptoms, but your blood work will help your doctor determine how long to treat you with potassium chloride. Your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG). Even if you have no symptoms, tests can help your doctor determine if this medicine is effective.

Your treatment may include a special diet. Follow the diet plan created for you by your doctor or nutrition counselor. Get familiar with the list of foods you should eat or avoid to help control your condition.

Potassium-rich foods include: squash, baked potatoes (skin on), spinach, lentils, broccoli, Brussels sprouts, zucchini, kidney or navy beans, raisins, watermelon, orange juice, bananas, cantaloupe, and low-fat milk or yogurt. Consume only the daily amounts recommended by your doctor or nutrition counselor.

Some tablets are made with a shell that is not absorbed or melted in the body. Part of this shell may appear in your stool. This is normal and will not make the medicine less effective.

Store at room temperature away from moisture and heat. Keep the medication in a closed container.

Potassium in food

Description	Potassium, K (mg) Value Per 100 gram
Beverages, tea, instant, unsweetened, powder	6040
Beverages, coffee, instant, decaffeinated, powder	3501
Spices, tarragon, dried	3020
Peppers, pasilla, dried	2222
Whey, sweet, dried	2080
Spices, turmeric, ground	2080
Apricots, dehydrated (low-moisture), sulfured, uncooked	1850
Milk, dry, nonfat, regular, without added vitamin A and vitamin D	1794
Beverages, chocolate powder, no sugar added	1705
Snacks, potato chips, fat free, salted	1628
Onions, dehydrated flakes	1622
Milk, buttermilk, dried	1592
Kanpyo, (dried gourd strips)	1582
Spices, marjoram, dried	1522
Beans, black, mature seeds, raw	1483
Beans, pink, mature seeds, raw	1464
Spices, anise seed	1441
Salami, pork, beef, less sodium	1372
Seeds, lotus seeds, dried	1368
Spices, caraway seed	1351
Spices, ginger, ground	1320
Beans, adzuki, mature seeds, raw	1254
Snacks, potato sticks	1237
Snacks, potato chips, barbecue-flavor	1186
Spices, curry powder	1170
Snacks, potato chips, fat-free, made with olestra	1160
Potatoes, mashed, dehydrated, flakes without milk, dry form	1098
Spices, savory, ground	1051
Beverages, Protein powder soy based	933
Snacks, potato chips, made from dried potatoes, fat-free, made with olestra	931
Arrowhead, cooked, boiled, drained, without salt	881
Beverages, Whey protein powder isolate	872
Spices, thyme, dried	814
Seeds, pumpkin and squash seed kernels, roasted, with salt added	788
Currants, zante, dried	777
Beet greens, raw	762
Beans, pinto, immature seeds, frozen, unprepared	756
Nuts, almond butter, plain, with salt added	748
Egg substitute, powder	744
Spices, mustard seed, ground	738
Dill weed, fresh	738
Nuts, almonds, dry roasted, without salt added	713
Nuts, hazelnuts or filberts	680
Milk, dry, nonfat, calcium reduced	680
Longans, dried	658
Snacks, trail mix, regular, with chocolate chips, unsalted nuts and seeds	648
Amaranth leaves, cooked, boiled, drained, without salt	641
Peanuts, all types, dry-roasted, without salt	634
Nuts, mixed nuts, oil roasted, with peanuts, lightly salted	632
Orange juice, frozen concentrate, unsweetened, undiluted	629
Taro, tahitian, cooked, without salt	623
Soybeans, green, raw	620
Peanuts, valencia, oil-roasted, without salt	612
Cress, garden, raw	606
Parmesan cheese topping, fat free	600
Potatoes, baked, skin, without salt	573
Lima beans, immature seeds, cooked, boiled, drained, without salt	570
Candies, chocolate, dark, NFS (45-59% cacao solids 90%; 60-69% cacao solids 5%; 70-85% cacao solids 5%)	568
Chocolate, dark, 60-69% cacao solids	567
Luncheon meat, pork, ham, and chicken, minced, canned, reduced sodium, added ascorbic acid, includes SPAM, 25% less sodium	564
Fish, lingcod, cooked, dry heat	560
Spinach, raw	558
Nuts, coconut meat, dried (desiccated), toasted	554
Peaches, dehydrated (low-moisture), sulfured, stewed	554
Fish, salmon, chum, cooked, dry heat	550
Potatoes, Russet, flesh and skin, baked	550
Jute, potherb, cooked, boiled, drained, without salt	550
Infant formula, ABBOTT NUTRITION, SIMILAC, For Spit Up, powder, with ARA and DHA	550
Nuts, coconut meat, dried (desiccated), not sweetened	543
Cereals ready-to-eat, granola, homemade	539
Soybeans, green, cooked, boiled, drained, without salt	539
Fish, yellowtail, mixed species, cooked, dry heat	538
Fish, mahimahi, cooked, dry heat	533
Bamboo shoots, raw	533
Spices, bay leaf	529
Fish, cod, Atlantic, canned, solids and liquid	528
Pork, fresh, enhanced, loin, tenderloin, separable lean only, raw	527
Fish, tuna, skipjack, fresh, cooked, dry heat	522
Pork, fresh, loin, tenderloin, separable lean and fat, with added solution, raw	519
Fish, burbot, cooked, dry heat	518
Nuts, chestnuts, european, raw, unpeeled	518
Mushrooms, Chanterelle, raw	506
Candies, confectioner’s coating, peanut butter	505
Cereals ready-to-eat, NATURE’S PATH, Organic FLAX PLUS flakes	501
Fish, swordfish, cooked, dry heat	499
Mountain yam, hawaii, cooked, steamed, without salt	495
Purslane, raw	494
Seeds, sunflower seed kernels, toasted, without salt	491
Breadfruit, raw	490
Purslane, cooked, boiled, drained, without salt	488
Plantains, yellow, raw	487
Grapefruit juice, white, frozen concentrate, unsweetened, undiluted	484
Seeds, sunflower seed kernels, oil roasted, without salt	483
Fish, grouper, mixed species, raw	483
Edamame, frozen, unprepared	482
Lima beans, immature seeds, frozen, fordhook, unprepared	478
Fish, bluefish, cooked, dry heat	477
Plantains, yellow, baked	477
Fish, grouper, mixed species, cooked, dry heat	475
Sweet potato, cooked, baked in skin, flesh, with salt	475
Beverages, Orange drink, breakfast type, with juice and pulp, frozen concentrate	465
Spices, mace, ground	463
Fish, trout, mixed species, cooked, dry heat	463
Drumstick pods, raw	461
Biscuits, mixed grain, refrigerated dough	456
Fish, salmon, coho, wild, cooked, moist heat	455
Cowpeas, leafy tips, raw	455
Cheese substitute, mozzarella	455
Crackers, rye, wafers, seasoned	454
Lima beans, immature seeds, frozen, baby, unprepared	452
Potatoes, roasted, salt added in processing, frozen, unprepared	450
Fish, trout, rainbow, farmed, cooked, dry heat	450
Hormel Pillow Pak Sliced Turkey Pepperoni	449
Beef, shank crosscuts, separable lean only, trimmed to 1/4″ fat, choice, cooked, simmered	447
Fish, mackerel, spanish, raw	446
Tomato products, canned, puree, without salt added	439
Pork, fresh, loin, blade (roasts), boneless, separable lean and fat, cooked, roasted	439
Tomato products, canned, puree, with salt added	439
Fish, seatrout, mixed species, cooked, dry heat	437
Mushrooms, portabella, grilled	437
Beef, round, top round, steak, separable lean and fat, trimmed to 1/8″ fat, prime, cooked, broiled	436
Pasta, whole-wheat, dry (Includes foods for USDA’s Food Distribution Program)	434
Beans, black turtle, mature seeds, cooked, boiled, without salt	433
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, all grades, cooked, grilled	433
Cowpeas (blackeyes), immature seeds, raw	431
Spices, cinnamon, ground	431
Pork, fresh, loin, blade (chops), boneless, separable lean only, boneless, cooked, broiled	430
Snacks, pretzels, hard, whole-wheat including both salted and unsalted	430
Crackers, standard snack-type, sandwich, with cheese filling	429
Candies, NESTLE, BUTTERFINGER Crisp	429
Pork, ground, 96% lean / 4% fat, cooked, crumbles	428
Beef, round, top round steak, boneless, separable lean and fat, trimmed to 0″ fat, choice, cooked, grilled	426
Beef, loin, top sirloin petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	426
Potatoes, flesh and skin, raw	425
Pork, fresh, loin, whole, separable lean and fat, cooked, broiled	423
Fish, herring, Pacific, raw	423
Nuts, butternuts, dried	421
Mountain yam, hawaii, raw	418
Cowpeas (blackeyes), immature seeds, cooked, boiled, drained, without salt	418
Ginger root, raw	415
Tomato products, canned, sauce, with onions	413
Apricots, dried, sulfured, stewed, without added sugar	411
Lima beans, immature seeds, frozen, baby, cooked, boiled, drained, without salt	411
Chocolate-flavored hazelnut spread	407
Garlic, raw	401
Cardoon, raw	400
Pork, Leg sirloin tip roast, boneless, separable lean and fat, raw	399
Tomato products, canned, sauce, with onions, green peppers, and celery	398
Game meat, deer, loin, separable lean only, 1″ steak, cooked, broiled	398
Seeds, sesame flour, low-fat	397

What is potassium chloride used for?

Potassium chloride (KCl) is used as prevention and treatment of potassium deficiency, e.g. when thiazide diuretics or corticosteroids are used in case of excessive vomiting or diarrhea, or diets poor in potassium; in the treatment of cumulative digitalis poisoning; and as a component of lethal injections. Potassium chloride (KCl) is also used in the fertilizer industry as potash and in buffer solutions for photography. Potassium chloride has been identified as being used in hydraulic fracturing as a clay stabilizer.

Potassium chloride tablets replace potassium in your body. Potassium chloride tablets are used to prevent and treat low blood levels of potassium (this is also called hypokalemia). Potassium levels can become low if you have had a prolonged bout of either diarrhea or vomiting, have been taking diuretics (water pills), or with some diseases.

For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.
For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, e.g., digitalized patients or patients with significant cardiac arrhythmias.

The use of potassium salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum potassium should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with potassium salts may be indicated.

Potassium chloride tablets should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation.

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

Break the tablet in half, and take each half separately with a glass of water.
Prepare an aqueous (water) suspension as follows:
1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
3. Stir for about half a minute after the tablet(s) has disintegrated.
4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
5. Add another 1 fluid ounce of water, swirl, and consume immediately.
6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of potassium chloride that is not taken immediately should be discarded. The use of other liquids for suspending potassium chloride tablets, is not recommended.

Potassium chloride dosage

You should NOT use potassium chloride if you have high levels of potassium in your blood (hyperkalemia), or if you also take a “potassium-sparing” diuretic.

Contraindicated in renal failure. May cause potassium intoxication and life-threatening hyperkalemia in patients with renal insufficiency.
Never give injectable potassium chloride undiluted.
Do not infuse rapidly.
Administer oral potassium with or after food to minimize gastric irritation.
Take oral potassium with meals and a full glass of water or other liquids.
TTake this medication as prescribed.
Check with your physician at once if tarry stools or other signs of gastrointestinal bleeding are noticed.

To be sure potassium chloride is helping your condition, your blood may need to be tested often. Your heart rate may also be checked using an electrocardiograph or ECG (sometimes called an EKG) to measure electrical activity of the heart. This test will help your doctor determine how long to treat you with potassium. Do not miss any scheduled appointments.

Serious side effects of potassium include uneven heartbeat, muscle weakness or limp feeling, severe stomach pain, and numbness or tingling in your hands, feet, or mouth.

Do not stop taking this medicine without first talking to your doctor. If you stop taking this medicine suddenly, your condition may become worse.

Do not crush, chew, break, or suck on an extended-release tablet or capsule. Swallow the pill whole. Breaking or crushing the pill may cause too much of the drug to be released at one time. Sucking on a tablet can irritate your mouth or throat. Take potassium chloride with food or just after a meal.

Usual Adult Dose for Hypokalemia (low blood potassium)

Oral:

40 to 100 mEq per day, orally, in 2 to 5 divided doses
Maximum single dose: 20 mEq per dose
Maximum daily dose: 200 mEq

Parenteral (must be diluted prior to administration):

Dose and rate of administration are dependent on patient condition

If serum potassium is 2.5 mEq/L or higher, rate should not exceed 10 mEq/hour, and manufacturers recommend that concentration not exceed 40 mEq/L

Maximum daily dose: 200 mEq

If treatment is urgent (serum potassium less than 2 mEq/L and electrocardiographic changes and/or muscle paralysis), infuse cautiously at up to 40 mEq/hour with continuous cardiac monitoring

Maximum daily dose: 400 mEq

-In critical situations, may administer in saline rather than dextrose (dextrose may lower serum potassium)

Comments:

Never give injectable potassium chloride undiluted.
The usual adult dietary intake is 50 to 100 mEq potassium per day.
Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 mEq or more of the total body stores of potassium.

Usual Adult Dose for Prevention of Hypokalemia (low blood potassium)

Oral:

Typical dose: 20 mEq, orally, daily

Individualize dose based on serum potassium levels
Divide dose if more than 20 mEq per day is used

Parenteral (must be diluted prior to administration):

Dose and rate of administration are dependent on patient condition

If serum potassium is 2.5 mEq/L or higher, rate should not exceed 10 mEq/hour, and manufacturers recommend that concentration not exceed 40 mEq/L

Maximum daily dose: 200 mEq

Comments:

Never give injectable potassium chloride undiluted
The usual adult dietary intake is 50 to 100 mEq potassium per day.

Usual Pediatric Dose for Hypokalemia (low blood potassium)

Birth to 16 years:

Oral solution:

Initial dose: 2 to 4 mEq/kg/day, orally, in divided doses
Limit to 1 mEq/kg or 40 mEq per dose, whichever is lower

Maximum daily dose: 100 mEq

Parenteral (must be diluted prior to administration):

Dose and rate of administration are dependent on patient condition

If serum potassium is 2.5 mEq/L or higher, rate should not exceed 10 mEq/hour, and manufacturers recommend that concentration not exceed 40 mEq/L

Maximum daily dose: 200 mEq

If treatment is urgent (serum potassium less than 2 mEq/L and electrocardiographic changes and/or muscle paralysis), infuse cautiously at up to 40 mEq/hour with continuous cardiac monitoring

Maximum daily dose: 400 mEq

In critical situations, may administer in saline rather than dextrose (dextrose may lower serum potassium)

Comments:

Never give injectable potassium chloride undiluted

Usual Pediatric Dose for Prevention of Hypokalemia (low blood potassium)

Birth to 16 years:

Oral solution:

Initial dose: 1 mEq/kg/day, orally
Maximum daily dose: 3 mEq/kg/day

Intravenous (must be diluted prior to administration):

Dose and rate of administration are dependent on patient condition

If serum potassium is 2.5 mEq/L or higher, rate should not exceed 10 mEq/hour, and manufacturers recommend that concentration not exceed 40 mEq/L

Maximum daily dose: 200 mEq

Comments:

Never give injectable potassium chloride undiluted

Potassium chloride side effects

If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:

Diarrhea, stomach pain, muscle weakness, numbness or tingling in the hands, feet, or mouth, uneven heartbeat. Side effects are more likely if high dosages of potassium chloride are being taken.
May not be suitable for some people including those with kidney failure, Addison’s disease, severe burns, or severe wounds.
Should also not be taken by a person who is dehydrated or has high levels of potassium in their blood.
May interact with several other medicines including digoxin, quinidine, ACE inhibitors, and several diuretics.
Signs of a high potassium level (hyperkalemia): cardiac arrhythmias, cardiac arrest, slow heartbeat and heart block; listlessness, mental confusion; feeling weak (muscle weakness), lightheaded, or dizzy; feel like passing out; numbness or tingling (paresthesia) of the extremities; or shortness of breath; flaccid paralysis, cold skin, grey pallor, peripheral vascular collapse, fall in blood pressure and paralysis. Electrocardiogram (ECG) abnormalities include disappearance of the P-wave, widening and slurring of QRS complex, changes of the S-T segment, tall peaked T-waves. At extremely high concentrations (8 to 11 mmol/L) may cause death from cardiac depression, arrhythmias, or arrest.
Chest pain or pressure.
Signs of bowel problems like black, tarry, or bloody stools; fever; mucus in the stools; throwing up blood or throw up that looks like coffee grounds; very bad belly pain; or very bad hard stools (constipation) or loose stools (diarrhea).
Very upset stomach or throwing up.
Gastrointestinal ulceration may be caused by enteric-coated potassium chloride tablets.
Delayed intestinal transit
Nausea, vomiting, flatulence, abdominal pain/discomfort, diarrhea, obstruction, bleeding, ulceration, perforation, gastrointestinal hemorrhage, local irritation of the mucosa
Swelling of belly.
Local pain and inflammation may develop from intravenous or subcutaneous administration.
Skin rash, urticaria and pruritus
Neuromuscular symptoms may occur.

Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Potassium chloride overdose

Cardiac and related effects are the most important risks of potassium chloride overdose.

The administration of oral potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if potassium is administered too rapidly intravenously, potentially fatal hyperkalemia can result.

It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration (6.5 mEq to 8 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval).

Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9 mEq to 12 mEq/L).

Treatment measures for hyperkalemia include the following:

Basic life support measures are essential in severely poisoned patients:

establish IV-line, obtain blood sample for electrolytes, BUN, glucose and arterial blood gas analysis;
continuous ECG monitoring should be started for arrhythmias and electrolyte changes;
cardiac dysrhythmias should be controlled with an appropriate drug regimen;
emesis or gastric lavage should be performed as soon as possible.

Reduce the plasma concentration of potassium by infusion of sodium bicarbonate, glucose plus insulin, or dialysis. These regimes shift potassium into cells; they do not increase its elimination. Infusion of calcium salts may be necessary to correct ECG changes. Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be noted that in patients who have been stabilized on digitalis, too rapid a lowering of the serum potassium concentration can produce digitalis toxicity.

The extended-release potassium chloride feature means that absorption and toxic effects may be delayed for hours. Consider standard measures to remove any unabsorbed drug.

References

Hinderling PH. The pharmacokinetics of potassium in humans is unusual. J Clin Pharmacol 2016;56:1212-20.
Bailey JL, Sands JM, Franch HA. Water, electrolytes, and acid-based metabolism. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2014:102-32.
Stone MS, Martyn L, Weaver CM. Potassium intake, bioavailability, hypertension, and glucose control. Nutrients 2016;8.
Preuss HG, Clouatre DL. Sodium, chloride, and potassium. In: Erdman JW, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Washington, DC: Wiley-Blackwell; 2012:475-92.

Drugs Drugs & Supplements

Kaolin

by Health Jade Team on August 8, 2018

What is kaolin

Kaolin is also called bentone, China clay, porcelain clay or white bole, is a mixture of different minerals. The name “kaolin” is derived from the word Kau-Ling, or high ridge, the name given to a hill near Jau-chau Fu, China, where kaolin was first mined ¹. Kaolin, commonly referred to as China clay, is a clay that contains 10–95% of the mineral kaolinite and usually consists mainly of kaolinite (85–95%). In addition to kaolinite, kaolin usually contains quartz and mica and also, less frequently, feldspar, illite, montmorillonite, ilmenite, anastase, haematite, bauxite, zircon, rutile, kyanite, silliminate, graphite, attapulgite, and halloysite ². The structure of kaolinite is a tetrahedral silica sheet alternating with an octahedral alumina sheet. Kaolinite, the main constituent of kaolin, is formed by rock weathering. It is white, greyish-white, or slightly colored. It is made up of tiny, thin, pseudohexagonal, flexible sheets of triclinic crystal with a diameter of 0.2–12 µm. It has a density of 2.1–2.6 g/cm³. Kaolinite adsorbs small molecular substances such as lecithin, quinoline, paraquat, and diquat, but also proteins, polyacrylonitrile, bacteria, and viruses ³.

Kaolin is used in paper production, in paints, rubber, plastic, ceramic, chemical, pharmaceutical and cosmetic industries ⁴. Some clays used for purposes similar to those for which kaolin is used may contain substantial amounts of quartz: “kaolin-like” clays used in South African pottery contained 23–58% quartz and, as the other major constituent, 20–36% kaolinite ⁵.

Kaolin is a natural component in soil and found in ambient air. Kaolin and other clays are natural components of the soil and occur widely in ambient air as floating dust. Accordingly, exposure of the general population to them must be universal, albeit at low concentrations. In the vicinity of mines and industrial projects, kaolinite is likely to be present at high concentrations in air; however, no data are available. Stobbe et al. ⁶ analysed mine dusts of West Virginia, USA. Respirable dust samples collected in three locations in the mines contained 64% illite, 21% calcite, 8.5% kaolinite, and 6.7% quartz on average. Kaolin mining and refining involve considerable exposure and significant exposure is expected in paper, rubber and plastics production ⁴. Long term exposure to kaolin causes the development of radiologically diagnosed pneumoconiosis known as kaolinosis in an exposure related fashion ⁴. Occupationally inhaled kaolin produced chronic pulmonary fibrosis. Reduced lung function and related symptoms been reported. Kaolin contains quartz and exposure to quartz is casually related to silicosis and lung cancer ⁴. Significant increases in the incidence of mortality from chronic bronchitis and pulmonary emphysema have been reported after exposure to quartz ⁴.

No report on local or systemic adverse effects has been identified from the extensive use of kaolin in cosmetics.

A study reported in detail on six workers who had been working in the drying and bagging of kaolin from Cornwall mines, in England ⁷. Medical and radiological examinations /were performed/ of those occupationally exposed to kaolin. All had radiological pneumoconiosis, and two were further studied in autopsy. In one case, characteristic silicotic-type nodulation together with progressive tuberculosis were found. Large quantities of kaolinite and amorphous quartz were found in the lung. In another case, large quantities of pure kaolinite (as much as 20-40 g) were found in the lung without tuberculosis but with severe fibrosis. The disease was like the pneumoconiosis of coal miners and differed from classic silicosis. In the upper part of the lung, greyish or blue-greyish massive confluent lesions were described, which were not as hard on palpation as the silicotic conglomerates.

In animal studies, Kaolin instilled intratracheally (into the trachea) produces storage foci, foreign body reaction and diffuse exudative reaction. After high doses of kaolin containing 8-65% quartz, fibrosis was noted. Kaolin has a low toxicity to aquatic species. Intratracheal instillation of kaolin to a guinea pig, stopped lung collagen production after a long exposure period. Nonsignificant LDH, protein or phospholipid leakage to the supernatant fraction observed in bronchioalveolar fluid 15-60 days after intratracheal instillation of kaolin in rats. Rats given ip administration of kaolin developed after 1-3 months reticulin fibers. Kaolin intratracheal administration has provided data indicating rats and guinea pigs were more susceptible to bacterial infections.

Kaolin and Pectin

Pectin is a complex polysaccharide found in the cell walls of a variety of vegetables and fruits, which is mainly composed of d-galacturonic acid (GalA) with α-(1-4) glycosidic linkages ⁸. Pectin is a structurally complex polymer with at least 17 different monosaccharides interconnected through more than 20 different linkages ⁹. Pectin exists particularly in the middle lamella and the primary cell walls of dicotyledonous plants, where it plays a fundamental role in cell growth ¹⁰, mechanical strength ¹¹ and defence mechanisms ¹². In industrial extraction processes pectin is mainly derived from citrus peel.

Pectin is used as a gelling, thickening and emulsifying agent in a wide range of applications, from food to pharmaceutical products ¹³. Pectin is also used as a complex dietary fiber and a prebiotic ¹⁴. Pectin when eaten is completely degraded by the gut microbiota at 6, 12, and 18 hours, and Lachnospira and Faecalibacterium, which can utilize pectin, were increased. Pectin-induced changes in the gut microbiota increased the formation of associated short chain fatty acids from 6 hours on, when pectin was decomposed.

Current industrial pectin extraction processes are based on fruit peel, a waste product from the juicing industry, in which thousands of tons of citrus (orange, lemon and lime) are processed worldwide every year. As a pre-treatment before pectin extraction, washing and drying of the peel provides necessary preservation for storage and/or transport. Afterwards, commercial pectin is extracted at high temperature by acid hydrolysis. The final product has a wide range of applications related to its 1,4-linked-α-d-galacturonic acid and neutral sugar content, the degree and pattern of methylesterification, molecular weight and intrinsic viscosity. The length of homogalacturonan and the proportions of homogalacturonan, Rhamnogalacturonan I and Rhamnogalacturonan II in the molecule may also influence pectin properties ¹⁵.

Kaolin and pectin preparations have essentially no adverse effects ¹⁶. Constipation may occur but is usually mild and transient; however, constipation may rarely lead to fecal impaction, especially in infants or debilitated geriatric patients.

Kaolin uses

Use of kaolin dates back to the third century BC in China. Today it is mined and used in significant quantities for numerous industrial uses. Its most important use is in paper production, where it is used as a coating material. In addition, it is used in great quantities in the paint, rubber, plastic, ceramic, chemical, pharmaceutical, and cosmetics industries.

Kaolin is an important industrial mineral that has an enormous variety of uses. Uses of kaolin mined in the USA for the years 1995, 1999, and 2002 are summarized in Table 1.

Use of kaolin as a coating for paper accounted for almost half of the total domestic consumption and for roughly 80% of the exported kaolin. Widespread use of kaolin-coated papers in the manufacture of cigarettes ¹⁷ may expose smokers to kaolinite particles by inhalation. Other important uses of kaolin were as a filler in the production of paint, paper, and rubber, as a component of fibreglass and mineral wool, as a landfill liner, and as a catalyst in oil and gas refining. The usage historically associated with kaolin, manufacture of porcelain and chinaware, accounted for less than 1% of the domestic consumption in the USA. In China, 80–85% of the total production in 2003 was used for ceramics, 5% for paper, 3% for rubber, and 2% for paint. In India, 290 000 tonnes were used for ceramics, 84 000 tonnes for paints, 68 000 tonnes for paper/paperboard, 29 000 tonnes for detergents, and 27 500 tonnes for rubber ¹⁸.

Kaolinite has a number of properties relevant to medicine. It is an excellent adsorbent and will adsorb not only lipids and proteins ¹⁹ but also viruses and bacteria ³. Kaolinite can be used to induce aggregation of platelets ²⁰, to initiate coagulation of plasma by activation of factor XII ²¹, and to remove non-specific hemaglutinin inhibitors from serum ²². Kaolin is used in medical therapy as a local and gastrointestinal adsorbent (Kaopectate, bolus alba).

Table 1. Kaolin sold or used by producers in the USA, by use

Use	Amount sold or used (kilotonnes)^b,c
	1995	1999	2002
Domestic
Ceramics
– Catalyst (oil and gas refining)	93.2	208	210
– Electrical porcelain	7.6	12.7	8.3
– Fine china and dinnerware	26.4	23.5	27.4
– Floor and wall tile	38.3	39.8	63.1
– Pottery	20.6	11.2	13.4
– Roofing granules	24.9	43.2	36.5
– Sanitary ware	67.9	75.6	85.2
– Miscellaneous	152	26.3	W
Chemical manufacture	130	23.2	31.6
Civil engineering	W	W	W
Fibreglass, mineral wool	402	329	288
Fillers, extenders, binders
– Adhesive	71.6	81.5	67.4
– Fertilizer	W	W	3.55
– Medical, pharmaceutical, cosmetic	W	W	0.754
– Paint	270	288	298
– Paper coating	2800	3000	2540
– Paper filling	853	791	450
– Pesticide	11.2	13.1	W
– Plastic	39.5	39.7	49.7
– Rubber	194	222	177
– Miscellaneous	156	115	107
Heavy clay products
– Brick, common and face	230	126	70.9
– Portland cement	W	54.2	W
Refractories			904^d
– Firebrick, block and shapes	26.8	13.8
– Grogs and calcines	190	135
– High-alumina brick and specialties, kiln furniture	885	W
– Foundry sand, mortar, cement, miscellaneous refractories	145	621
Miscellaneous applications	138	430	91.6
Total	6970	6720	5520
Exports
Ceramics	187	210	203
Paint	67.7	88.1	85
Paper coating	2040	1970	2040
Paper filling	145	110	93.9
Rubber	36.3	45.7	50.7
Miscellaneous^e	165.9	23.8	19
Total	2510	2440	2490
Grand total	9480	9160	8010

Footnotes:

b: Data are rounded to no more than three significant digits and may not add to the totals shown.

c: W = Withheld to avoid disclosing company proprietary data; included with “Miscellaneous” or “Miscellaneous applications.”

d: Includes firebrick (blocks and shapes), grogs and calcines, high-alumina brick and specialties, kiln furniture, and miscellaneous refractories.

e: Includes 145 000 tonnes of foundry sand, mortar, cement, and miscellaneous refractories in 1995.

[Source ²³]

Kaolin for skin and cosmetics

Kaolin is used in a large number of different cosmetic products, such as eyeshadows, blushers, face powders, “powders,” mascaras, foundations, makeup bases, and others. In 1998, kaolin was reported to be used in 509 different cosmetics in the USA, usually at concentrations between 5% and 30%, but reaching 84% in some paste masks ²⁴. Medical, pharmaceutical, and cosmetic uses, however, accounted for roughly 0.01% of the total US consumption of kaolin (see Table 1).

Kaolin effects on laboratory mammals and in vitro tests

In the landmark paper in which intratracheal instillation as a means of studying the effects of dust on lungs was described, no collagen production was detected in the lung of a guinea-pig 336 days after the administration (whereas fibrosis was observed after similar injection of quartz) ²⁵. Similarly, intratracheal instillation of kaolin from South Wales or untreated or ignited Cornish kaolin did not induce fibrosis in rats ²⁶ (see Table 2).

After the instillation of a single dose of commercial acid-washed kaolin containing 8% hydrated free silica and 12% mica, grade 2–3 fibrosis was observed in rats after 8 months (grade 1 = minimal reticulin fibrosis, grade 4 = maximal fibrosis, as induced by quartz) ²⁷ (Table 2).

Following intratracheal dust treatment in rats, the histological reaction was found to depend on the composition of the dust ²⁸. Foreign body reaction as an effect of kaolinite was observed in all cases where the crystalline quartz content of the dust was less than or equal to 30%. The sample containing 65% quartz and 35% kaolinite caused progressive fibrosis. In addition to the composition, particle size also played a role in the development of the tissue reaction. Kaolin samples containing particles less than 2 µm caused storage foci ²⁹, while the kaolin samples containing bigger particles (particle size between 2 and 5 µm) caused mainly storage foci but also, to a smaller extent, foreign body reaction (Table 2).

Goldstein & Rendall ³⁰ observed cellular reaction with minimal fibrosis: some loose reticulin with either no collagen in some animals or a few collagen fibres in other rats 4 months after an intratracheal instillation of kaolin (Table 2).

Martin et al. ³¹ observed an increase in the collagen content in the lungs of rats 3 months after an intratracheal instillation of non-specified kaolin; the reaction was considerably weaker than after a similar treatment with quartz (Table 2).

Sahu et al. ³² described the development of grade 2 fibrosis in mice after 7 months of exposure to non-specified kaolin (Table 2).

Rosmanith et al. ³³ compared the fibrogenicity of four kaolinite samples with that of quartz in rats using intratracheal instillation. The fibrogenicity of kaolinites, as measured by the increase in hydroxyproline content in relation to the amount of dust retained, was approximately 1/10 that of quartz, but the inflammatory reaction was considerably less (Table 2).

No significant LDH, protein, or phospholipid leakage to the supernate fraction was observed in bronchoalveolar fluid 15–60 days after an intratracheal instillation of kaolin to rats. In this system, effects of quartz became apparent towards the end of the observation period ³⁴ (Table 2).

Table 2. Effects of intratracheal instillation of kaolin and illite on the respiratory tract

Species/gender^a / number	Treatment	Findings
Guinea-pig /2	Intratracheal instillation of an unstated amount of kaolin, follow-up for 14 and 336 days	No collagen production in 336 days; in animals treated similarly with quartz, fibrosis observed.
Rat/12	Intratracheal instillation of a single dose of commercial acid-washed kaolin containing 8% hydrated free silica and 12% mica; two animals killed between days 3 and 6; the rest kept for life (up until 8 months)	Grade 2-3 fibrosis observed in rats after 8 months (grade 1 = minimal reticulin fibrosis, 4 = maximal fibrosis, as induced by quartz).
Rat / 6 or 10 per group	A single intratracheal instillation (50-60 mg) of washed South Wales kaolin, untreated Cornish kaolin, ignited Cornish kaolin, quartz; follow-up up to 6 months	South Wales kaolin (10 rats): Up to 60 days, no fibrous reaction; thereafter, local reticulinosis, no fibrosis or emphysema.
		Cornish kaolin (10): Eight animals died within 10 days; the remaining two showed no fibrous reaction.
		Ignited Cornish kaolin (6): Only four rats available for study; their survival was 14, 28, 73, and 140 days; in the last-mentioned, there was local reticulinosis.
		Quartz (6): Severe nodular silicosis in all five animals available for study; survival 68, 121, 130, 207, and 240 days.
Rat	Intratracheal administration of kaolin, kaolin baked for 1 h at 900 or 1200 °C	Active phagocytosis, local storage of the dust without reticular fibres, and nodules were observed. In the case of heat-treated kaolin samples, the reaction was somewhat stronger, although fibrosis reached grade 1 in only a few cases (Belt-King scale). Histological signs resembling silicosis did not develop.
Rat / 25 per group	A single intratracheal administration of kaolin containing kaolinite and quartz in ratios 82/18, 70/30, or 35/65; follow-up to 1 year	Foreign body reaction with the two samples containing 82 or 70% kaolinite, productive fibrosis with the sample containing 65% quartz.
Rat/10-15 per group	Single intratracheal instillation of kaolin (sericite and quartz as main impurities, 1 % quartz), particle size <5 µm; histological analysis of lungs after 4 months	Cellular lesions, some loose reticulin, with either no collagen or a few collagen fibres.
Rat/10 per group	Intratracheal instillation of 50 mg non-specified kaolin, 3-month follow-up	Amount of collagen / amount of dust in lung after kaolin exposure 3 times higher than in titanium dioxide-treated control and 2.4 times more than in coal-treated animals, but only 15% of that in the quartz-treated animals.
Rat, strain not specified / number and gender not specified	40 mg of illite clay F, nominal composition 100% illite (diameter <2 or 2-5 µm), kaolin S (82% kaolinite, 18% quartz; diameter <3 µm), or kaolin Sz (95% kaolinite, 5% quartz; diameter <2 or 2-5 µm), instilled to rats; animals killed after 5, 15, 40, and 365 days and histological analysis performed	Illite F and kaolin Sz <2 µm caused “storage foci,” kaolin S, “foreign body” reaction, and kaolin Sz 2-5 µm, mainly storage foci, rarely foreign body reaction.
Rat, strain not specified /10	60 mg of illite (not described) instilled intratracheally and followed for 6 months; lung weight, lipid, phospholipid, and hydroxyproline were analysed, and histological and histochemical studies on collagen performed	“Storage foci” observed in lungs of illite-treated rats.
Rat, Sprague-Dawley / female /10 per group	30 or 50^b mg non-specified kaolin or illite clay injected intratracheally, followed for 3 and 12 months	Kaolin increased the lung weight 9 and 4 mg and collagen formed <26 and <7 mg/mg of injected dust at 3 and 12 months (all normalized to quartz = 100).
Rat, Sprague-Dawley / female /10 per group		Illite clay induced alveolar proteinosis and thus increased the lung weight 17 and 6 mg, and collagen formed <26 and 11 mg/mg of injected dust at 3 and 12 months (all normalized to quartz = 100).
Rat, Sprague-Dawley / female /10 per group	30 or 50^b mg non-specified kaolin or illite clay injected intratracheally, followed for 3 and 12 months	Correlation to haemolysis (rat erythrocytes) and release of LDH^c and alkaline phosphatase from rabbit alveolar macrophages (see Table 17) weak.
Rat, Fischer F344 / 10 per group	5 mg kaolin (non-specified), MMAD^d 2.1 µm, instilled intratracheally, killed 1 day, 3 days, 7 days, 3 months, and 6 months later	Acute inflammatory reaction on day 1; thereafter, a slight interstitial cell thickening. At 3 and 6 months, lungs were normal.
Rat / male / 5 per group	Intratracheal injection of 10 mg of a kaolin containing 67% kaolinite and 23% quartz; bronchopulmonary lavage after 15 days, LDH activity and protein content and, after 15, 30, and 60 days, phospholipid content of supernatant measured	Kaolin did not induce significant LDH, protein, or phospholipid leakage to the supernate fraction. No change in the LDH or protein leakage was observed after similar exposure to eight other minerals, including two quartz samples. The quartz samples, however, increased the phospholipid content at 30 and 60 days.
Rat, SD/male	Intratracheal injection of 10 mg of a kaolin containing 86% kaolinite, 4% quartz, 5% illite, and 5% amorphous silica; bronchopulmonary lavage after 14, 30, and 90 days, number of cells, activities, LDH activity, protein and phospholipid content of supernatant measured	Kaolinite caused a statistically significant increase in the protein content at 14 days, which returned to control level thereafter. No changes were observed in the other parameters studied.
Mouse / 70 per group	Intratracheal instillation of 5 mg of kaolin, 91% >3.62 µm in diameter; follow-up 210 days	Fibroblast reaction from 60 days post-exposure, prominent from day 120. Grade 2 fibrosis by day 210 (Belt-King scale).
Rat, Wistar/female/ 20 per group	Kaolinite 1 (K1) contained 2% muscovite; K2, 1% quartz and 9% muscovite; K3, <1% quartz and anatase and 1 % muscovite; and K4, 1 % quartz and anatase and 2% muscovite; mean value for volume distribution was 3.6 and 2.6 µm for K3 and K4, not analysed for K1 or K2; instilled once intratracheally at 50 mg/kg of body weight; autopsy after 7 months; lung weight, histology, amount of dust, hydroxyproline, and total lipid content analysed; two samples of quartz also investigated, dose given 5 mg/kg of body weight	All kaolinite samples fibrogenic. Absolute amount of hydroxyproline roughly similar after exposure to kaolinites and quartz, hydroxyproline / retained dust in kaolinite-treated animals 1/10 that in quartz-treated animals. Absolute increase of lung weight one-sixth and of total lipids roughly 10% of that in quartz-treated animals.
Rats, SD(SD)BR/ male / 6 per group	Exposed by intratracheal instillation to 50 mg dust from the town Mexicali (see above), mean diameter 3.2 µm; lung analysis after 30 days	Multifocal interstitial lung disease. Mononuclear cell accumulation and presence of collagen fibres.

Footnotes:

a Where available.

b Composition or particle size not given.

c LDH = lactate dehydrogenase.

d MMAD = mass median aerodynamic diameter.

[Source ²³]

Table 3. Toxicity of kaolin and illite clay in vitro

System / species / gender	Dose (mg/ml)/ treatment^a	Findings^a
Peritoneal macrophages
Rat (Sprague-Dawley CFY)	Two types of kaolin (90% kaolinite, 4% quartz; or 93% kaolinite, 4% quartz; diameter not given) incubated with cells for 24 h either as such or after dry milling for 32 h	Dry milling decreased the methylene blue adsorption to a third and the inhibition of TTC reduction by one-half to two-thirds.
Mouse (Swiss T.O.)	Kaolin (non-specified), 100 µg/ml, incubation for 18 h	Approximately 25% release of LDH and beta-glucuronidase release with native kaolin; one-half to two-thirds of the activity lost upon calcination.
Rat (Sprague-Dawley CFY), male	Six different kaolins, kaolinite content 51-95%, quartz content 5-20%; 1.0 mg/ml (<5 µm diameter, median 1-2 µm) incubated in cell suspension for 1 h	All samples considered cytotoxic based on TTC reduction, except one (30%), which had 71% kaolinite and 22% quartz. All considered inert based on small LDH release, except the one with the highest quartz concentration (29%); the kaolinite concentration in this specimen was 67%.
	One sample of an illite clay (28% illite, 28% quartz); 1.0 mg/ml (<5 µm diameter, median 1-2 µm) incubated in cell suspension for 1 h	Cytotoxic based on TTC reduction, but not cytotoxic based on small LDH release.
Rat (Sprague-Dawley CFY), male	Four different kaolins (from Hungary, silica content 4, 5, 18, and 30%, <5 µm diameter, otherwise not specified) incubated in cell suspension for 24 h; similar experiment with a non-specified illite clay	Three out of four kaolins and illite considered cytotoxic based on TTC reduction; no relationship between quartz concentration and cytotoxicity. The clays studied did not induce release of LDH, but illite decreased intracellular LDH activity.
Mouse (T.O.), female	Culture of unstimulated macrophages with Cornwall kaolinite (not specified) for 18 h	Kaolinite induced LDH release from macrophages; this was prevented by polyvinylpyridine-N-oxide.
Mouse (T.O.), female	Cornwall kaolin (98% kaolinite, 2% mica), 98% <5 µm in diameter, incubated with cells at 40 µg/ml for 18 h	Kaolinite induced a 70% LDH release to the medium; the release was partly prevented by treatment of kaolin with polyvinylpyridine-N-oxide and fully prevented by additional treatment with polyacrylicacid.
Rat (Wistar, SPF), both sexes	Kaolin (composition not specified, diameter 0.2-25 µm), 0.5 mg/10⁶ cells incubated for 2h	Of all cells with particles, 0.6% and 1.6% dead cells with particles at 1 and 2 h (lowest toxicity group of three).
Mouse	Fifteen respirable dust samples from kaolin drying and calcining plants in England (kaolinite content 84-96%, mica 3-6%, quartz 1 %, feldspar 0-7%), a sample of Cornish kaolin (K1, 98% kaolinite, no quartz or feldspar, 2% mica), and a sample of Georgia kaolin (K2, 99% kaolinite, no quartz, mica, or feldspar, and reference quartz DQ12, mica, gibbsite, and titanium dioxide as controls; incubation for 18 h with macrophages, LDH release measured	All dust samples were cytotoxic. The quartz content could not explain the cytotoxicity. The kaolinite samples showed a dose-dependent cytotoxicity, which could not be explained by their content of ancillary materials.
		Polyacrylic acid treatment of kaolin has only a small effect on its cytotoxicity, indicating that the positive charge at the edge of the mineral (blocked by acrylic acid) is not a major determinant of the toxicity.
Alveolar macrophages
Rat (Wistar, SPF), both sexes	Kaolin (composition not specified, diameter 0.2-25 µm), 0.5 mg/10⁶ cells incubated for 2h	Of all cells with particles, 3.7% and 4.2% dead cells with particles at 1 and 2 h (lowest toxicity group of three).
Rabbit (New Zealand)	Kaolinite (>99% pure), >99% respirable size, incubated with cells at 0.25-2.5 mg/ml	Kaolinite caused an inhibition of amino acid incorporation into protein in a dose-dependent manner, 65% inhibition at 1 mg/ml. Inhibition reversed by addition of serum.
Guinea-pig	Kaolin (non-specified), 100 µg/ml, incubation for 18 h	Approximately 30% release of LDH and beta-glucuronidase release with native kaolin; >90% of the activity lost upon calcination.
Rabbit (New Zealand)	Kaolin (unspecified) and illite clay (unspecified) (<5 µm diameter), 0.5 mg/ml incubated in cell suspension for 24 h	Kaolin induced a 15.3% release of LDH and a 7% release of alkaline phosphatase. Illite clay induced a 2% release of LDH and a 1.3% release of alkaline phosphatase. For quartz, the figures were 51 % and 16%.
Rat (Sprague-Dawley), male	Georgia kaolin (>96% kaolinite, no quartz, >95% >5 µm in diameter), incubated with cells for 1 h at 0.1-1 mg/litre	Kaolin induced a dose-dependent release of LDH, beta-glucuronidase, and beta–N-acetylglucosaminidase of 60-80%. The effect was largely (9-15% release) abolished by lecithin.
Rat (strain not specified)	Kaolin, 1.0 mg/ml (<5 µm diameter, MMAD 2.1 µm) incubated in cell suspension for 2 h	Kaolin induced an 80% release of LDH and a 60% release of beta-glucuronidase and beta–N-acetylglucosaminidase, being most cytotoxic of all minerals studied, quartz included.
Rat (Wistar), male	Alveolar macrophages incubated with Mexicali dust (see Table 13); LDH release measured	Concentration- and time-dependent release of LDH, which reacted 50% at 0.5 mg/ml and was much more pronounced than with quartz.
Leukocytes
Human phagocytic cells from one donor	Well crystallized standard kaolinite KGa-1, no quartz, cristobalite, or mica, particle size 3.2 µm median volume diameter	Kaolinite at concentrations of approximately 1 mg/ml induced luminol-dependent chemilumi-nescence as an expression of generation of reactive oxygen species in both monocytes and neutrophils when opsonized and when not opsonized.
Erythrocytes
Human washed erythrocytes	Erythrocytes incubated with Hungarian water-cleaned kaolin (composition not indicated; <5 µm in diameter), as such or after heat treatment at 290-900 °C for 90 min	Kaolin was strongly haemolytic; heating for 90 min to 200 or 350 °C increased, but heating to 500 or 650 °C practically abolished, the haemolytic potency. Kaolin heated at 800 or 950 °C was at least as potent a haemolyser as non-treated kaolin.
Sheep, plasma-free erythrocytes	Kaolin (source and composition unspecified), <5 µm in diameter, incubated with cells at 1 mg/ml for 2 h	Kaolin caused 40% haemolysis; acid and alkali treatments of the clay decreased its haemolytic potency.
Rat (strain not specified)	Kaolin (unspecified) and illite clay (unspecified) (<5 µm in diameter) 1.0 mg/ml incubated in cell suspension for 1 h	Kaolin caused 98% haemolysis, illite 24% (quartz 48%).
Rabbit	Kaolin (non-specified), incubation for 50 min	Twenty per cent haemolysis caused by 1.3 mg kaolin in a total volume of 4 ml; 11.6 mg of calcined kaolin was needed for the same effect.
Sheep (citrated blood)	Kaolin (median volume diameter 4.7 µm) incubated in cell suspension	Haemolysis 60% in 30 min; haemolytic potency similar to that of quartz.
Sheep	Kaolin, 1.0 mg/ml (<5 µm diameter, MMAD 2.1 µm) at five concentrations, 0.1-1 mg/ ml, incubated in cell suspension for 50 min	Linear, dose-dependent haemolysis; about 20% haemolysis with 0.5 mg/ml; 35% with 1 mg/ml; approximately 2 times as potent as quartz.
Sheep (citrated blood, single donor)	Kaolinite 90% <2 µm in diameter at six concentrations, 0.005-0.25 mg/ml, incubated in cell suspension for 1 h	More haemolytic per mg than silica or talc; 20% haemolysis with 0.25 mg/ml; 95% with 25 mg/ml.
Sheep	Georgia kaolin (>96% kaolinite, no quartz, >95% >5 µm in diameter), incubated with cells for 1 h	Kaolin induced a dose-dependent haemolysis, which reached 42% at 1 mg/ml. The effect was completely abolished by lecithin.
Bovine erythrocytes washed with buffered saline	South Carolina kaolinite (composition not specified) incubated in cell suspension for 1 h	A concentration of 0.6 mg/ml induced 50% haemolysis of erythrocytes. Polyvinylpyridine-N-oxide, a hydrogen-bonding material, partly inhibited the haemolysis.
Bovine erythrocytes washed with buffered saline	South Carolina kaolinite (composition not specified) at several concentrations of different particle sizes incubated in cell suspension for 1 h	A concentration of 0.6 mg/ml induced 50% haemolysis of erythrocytes. Of the minerals studied, kaolinite was least haemolytic, the potency being 1/20 that of silica. Particles of 0.2-2 µm diameter were most active; particles <0.2 µm or >20 diameter had no or little haemolytic activity; reduction of surface charge and cation exchange capacity by coating particles with an aluminium-hydroxy polymer largely eliminated haemolytic capacity.
Human (citrated blood)	Six different kaolins, kaolinite content 51-95%, quartz content 5-20%; 1.0 mg/ml (<5 µm diameter, median 1-2 µm) incubated in cell suspension for 1 h	Haemolysis 60-90% for all samples except one (30%), which had 71% kaolinite and 22% quartz.
	One sample of an illite clay (28% illite, 28% quartz); 1.0 mg/ml (<5 µm diameter, median 1-2 µm) incubated in cell suspension for 1 h	Haemolysis 95%.
Human	One “bentonite,” containing 50% illite, 25% montmorillonite, 25% quartz; two undefined illite clays, one kaolinite with dickite and nakrite as main components and quartz as a minor component, one kaolin with kaolinite as the main component, and two unspecified kaolins ground in a ball mill to diameter <5 µm, incubated in cell suspension for 1 h	Fifty per cent haemolysis caused by 1.5-4 mg/ml kaolinites (0.06-0.115 m²/ml); and 1.0-4.0 mg/ml (0.039-0.12 m²/ml) illites. Haemolytic activity roughly proportionate to surface area of mineral powder; haemolytic activity largely lost after heating to over 500 °C.
Human red blood cells from normal donors	Dust from the town Mexicali (see Table 14)	Concentration of 2 mg/ml produced a 95 ± 3% haemolysis in 1 h; the haemolysis was stronger than with quartz.
Neural cells
Neuroblastoma (N1E-115) cells with differentiation induced by dimethylsulfoxide	Standard kaolinite KGa-1 0.1-1.0 mg/ml incubated in cell suspension	Within minutes, resting potential depolarized and ability to maintain action potentials in response to stimulation was lost; within 30 min, severe morphological deterioration of cells.
Neuroblastoma (N1E-115) cells and oligodendroglial (ROC-1) cells	South Carolina kaolinite (non-specified, mainly 1-2 µm diameter) incubated at 0.1 mg/ml in cell suspension for 24 h	No alteration of LDH activity in medium for either cell type; no decrease of the viability (assessed by trypan blue exclusion) of N1E-115 cells after 24 h.
*Other cell types and in vitro* systems**
Tracheal epithelial (cloned cell line from Syrian hamster, strain 87.20) in log growth phase in monolayer	Kaolinite 90% <2 µm in diameter at four concentrations, 0.003-0.1 mg/ml, incubated in cell suspension for 24 h	Cells phagocytized clay particles; dose-dependent damage to plasma membrane as evidenced by loss of ⁵¹Cr from cells; loss of ⁵¹Cr after 24 h approximately 40% with 0.1 mg/ml, twice that of quartz.
Human umbilical vein endothelial cells	South Carolina kaolinite (non-specified, mainly 1-2 µm diameter) incubated at 0.1 mg/ml in cell suspension for 24 h	Kaolinite induced a statistically significant 50% increase in LDH activity in the medium and killed 90% of the cells in 24 h.
Macrophage-like cell line P338D₁	Three kaolinites, 1 with “high crystallinity,” 1 with “medium crystallinity,” and 1 with “low crystallinity,” diameter <5 µm, incubated at 80 µg/ml for 48 h	Kaolinites caused a 78-91 % decrease in the viability of the cells and induced leakage of LDH and beta–N-acetylglucosaminidase. Adsorption of nitrous oxide on the minerals slightly decreased the effect on viability.
V79-4 Chinese hamster lung cell line	Non-specified kaolin incubated with the cells for 6-7 days	LD₅₀ 20 mg/ml for kaolin, which was the most toxic of the 21 particulate and fibrous materials tested.
Macrophage-like cell line P338D₁	Thirty respirable dust specimens from coal mines in United Kingdom; cytotoxicity index developed from effects on trypan blue exclusion, release of LDH, glucos-aminidase, and lactic acid production	A positive correlation between ash content and cytotoxicity of the dusts. In dusts with >90% coal, there was also a correlation between kaolin + mica content and cytotoxicity.
Macrophage-like cell line P338D₁	Two kaolinites (KGa-1, KGa-2) from Source Clays repository, particle sizes 3.2 and 3.9 µm, with no cristobalite or quartz, incubated for 48 h	Cell viability not changed at 20 µg/ml, and 60-70% at 80 µg/ml.
Isolated human leukocyte elastase	Cornwall kaolinite and four different illite clays (composition and particle size not specified), 5 µg/ml or 20 µg/ml	Kaolinite (5 µg/ml) caused 90% inhibition of the enzyme, illites (20 µg/ml), 10-53% inhibition.
Artificial organelles
Liposomes (artificial phospholipid membrane vesicles^b 0.1-2 µm diameter) entrapping dissolved chromate (CrO₄^2-)	Kaolinite, 90% <2 µm in diameter, at five concentrations, 0.1-10 mg/ml, incubated in cell suspension for 1 h	Dose-dependent loss of chromate from vesicles; loss of chromate after 1 h (in excess of spontaneous rate) approximately 20% with 10 mg/ml; spontaneous rate was 4-6%.

Footnotes:

a: LD50 = median lethal dose; LDH = lactate dehydrogenase; MMAD = mass median aerodynamic diameter; TTC = 2,3,5-triphenyltetrazolium chloride.

b: Prepared from dipalmitoyl phosphatidylcholine, sphingomyelin, cholesterol, and dicetylphosphate.

[Source ²³]

Kaolin parenteral administration

Policard & Collet ³⁵ demonstrated the development of reticulin fibres in rats 1–3 months after intraperitoneal administration of kaolin (90% <2 µm in diameter). The dust sample contained 1.2% free silica, an amount that the authors considered not to cause the effects observed.

Intraperitoneal administration of kaolinite (<3 µm or ~10 µm particle size; no quartz detectable with X-ray analysis) was fibrogenic in mice; the smaller particle size was just as active as quartz and led to fibrosis in 35 days, whereas fibrosis became evident only after 200 days for the larger size particles ³⁶.

Intraperitoneally instilled kaolin and kaolin baked for 1 h at 900 or 1200 °C caused marked fibrosis. The degree of the reaction was only slightly smaller than that caused by quartz ³⁷.

In a study of a large number of organic and inorganic particulates, kaolin (composition not specified, particle size 0.25–25 µm) injected intraperitoneally into rats produced a granulomatous reaction at 1 and 3 months, but no fibrosis. In vitro, it had low toxicity: it killed less than 2% of peritoneal macrophages and approximately 4% of alveolar macrophages ³⁸. For the group of some 20 particulate materials, the authors considered that there was a good correlation between toxicity to macrophages and fibrogenicity after intraperitoneal injection.

Kaolin by inhalation

Carleton ³⁹ studied the effects of kaolin by inhalation in guinea-pigs. Until 3 months after the exposure, mild alveolar proliferation only was observed. Thereafter, patchy bronchopneumonia occurred, with massive eosinophil infiltration. By 6 months, plaque formation and capillary bronchitis were observed.

Wagner and co-workers (1987) studied the carcinogenicity of palygorskite and attapulgite in an inhalation study and used “coating grade” kaolin as a negative control: 20 male and 20 female Fischer rats were exposed by inhalation (10 mg/m3, 91.4% of the particles <4.6 µm in diameter) for 6 h/day, 5 days/week, until they died. However, at 3, 6, and 12 months, four rats were killed from each group for ancillary studies (leaving only 28 animals for the carcinogenicity study). At the end of the study, full autopsy and microscopic analysis of the lungs, liver, kidney, spleen, and other organs were performed. In two kaolin-exposed rats, bronchoalveolar hyperplasia but no benign or malignant tumours of the lungs or pleura were observed. However, the number of tumours in the positive control group (crocidolite treatment at the same exposure level) was also low (one adenocarcinoma only). The mean fibrosis grading in the rats at interim sacrifices and at the end of the experiment was between 2.1 and 2.8 on a scale of 1–8 (1 being normal; 2, dust in macrophages; 3, early interstitial reaction; 4, first signs of fibrosis; 5, 6, 7, increasing fibrosis; 8, severe fibrosis).

As another part of the study on the carcinogenicity of mineral fibres, Wagner et al. ⁴⁰ injected a single dose (amount not given) of kaolin intrapleurally into 20 male and 20 female Fischer rats and followed the animals until moribund or dead (survival of animals in different groups not given). None of the kaolin-treated rats developed mesothelioma, whereas 34 of 40 of those given crocidolite did.

Mossman & Craighead ⁴¹ treated cultured tracheas from hamsters with Georgia kaolin (composition not indicated; diameter 3–5 µm) and kaolin coated with 3-methylcholanthrene, implanted the tracheas after 4 weeks into syngeneic hamsters, and followed the animals until moribund at 105–110 weeks. Animals treated with kaolin did not develop tumours, but a high incidence of pulmonary tumours, often fatal, was observed in animals treated with kaolin coated with 3-methylcholanthrene. Animals treated with 3-methylcholanthrene-coated haematite or carbon particles also developed a similar spectrum of tumors (carcinomas, sarcomas, undifferentiated tumors).

Kaolin reproductive effects

In a study that provided limited details, Sprague-Dawley rats were administered calcium or sodium montmorillonite orally on pregnancy days 1–15. No effects were observed on the litter weight, implantation rates, or resorptions ⁴².

Thirty-six Sprague-Dawley rats were fed a control diet, 20% kaolin (air-floated Georgia kaolin) diet, and iron-supplemented 20% kaolin diet 37–117 days before mating and during pregnancy ⁴³. Dams receiving kaolin diet developed anaemia, whereas anaemia was not observed in dams receiving iron supplementation. The birth weight of the pups of the dams receiving kaolin was 9% smaller than that of the control dams; again, iron supplementation prevented this decrease. There was no effect on the litter size or macroscopic malformations.

Kaolin and quartz

Schmidt & Lüchtrath ³⁷ studied the effects of intratracheal administration of a 2:3 mixture of kaolin and quartz. Kaolin alone did not cause significant reaction in the lung. The mixture of kaolin and quartz caused significant changes in the lung; after 9 months, the fibrosis was grade 5. (Using pure quartz, the development of silicosis was somewhat quicker, but after 9 months, the difference compared with the kaolin–quartz mixture was insignificant.)

Kaolin effects on humans

Many case reports and case series have suggested that exposure to kaolin causes pneumoconiosis ⁴⁴. In several cases, however, it was not clear whether kaolinite and quartz or quartz alone was responsible for the resulting pneumoconiosis ⁴⁵.

Kaolin workers, United Kingdom

In England, a number of papers have dealt with the effects of kaolin originating from Cornwall mines (Table 4). Hale et al. ⁴⁶ performed medical and radiological examinations of those occupationally exposed to kaolin and reported in detail on six workers who had been working in the drying and bagging of kaolin. All had radiological pneumoconiosis, and two were further studied in autopsy. In one case, characteristic silicotic-type nodulation together with progressive tuberculosis were found. Large quantities of kaolinite and amorphous quartz were found in the lung. In another case, large quantities of pure kaolinite (as much as 20–40 g) were found in the lung without tuberculosis but with severe fibrosis. The disease was like the pneumoconiosis of coal miners and differed from classic silicosis. In the upper part of the lung, greyish or blue-greyish massive confluent lesions were described, which were not as hard on palpation as the silicotic conglomerates. Hale and co-workers ⁴⁶ also studied the lung of a kaolin worker from Georgia, USA, and observed that the dust in the lungs consisted entirely of kaolinite; no trace of quartz could be seen.

Kaolin workers, USA

Kaolin workers in Georgia have been studied extensively (Table 4). Edenfield ⁴⁷ found pneumoconiosis in 44 (3.9%) of 1130 persons working with kaolin. All these had worked for a number of years in the loading area or some other area of the plant that in earlier years had been very dusty. Only 2 had worked in the kaolin industry less than 10 years, and 19 had been employed for more than 20 years. All of those classed as having severe pneumoconiosis (stage III) had worked more than 20 years, and all had worked in heavy dust in the car loading and bagging areas. Thirty-one of the 44 had a stage I pneumoconiosis; they had no symptoms or signs of respiratory dysfunction. Similarly, the seven workers with stage II pneumoconiosis exhibited no respiratory symptoms. The six cases with stage III pneumoconiosis also had emphysema, had complaints of cough and dyspnoea, and had been placed in jobs requiring minimal activity.

Lapenas & Gale ⁴⁸ found diffuse reticulonodular lung infiltration and a nodule in the upper lung lobe in a 35-year-old worker of a Georgia kaolin processing factory who had been occupationally exposed to kaolin aerosol for 17 years. Exploratory thoracotomy revealed an 8 × 12 × 10 cm conglomerate pneumoconiotic lesion containing large amounts of kaolinite. Quartz could not be demonstrated by scanning electron microscopy or X-ray diffraction.

Lapenas et al. ⁴⁹ performed a pathological study on biopsy or autopsy specimens from five patients admitted to the Medical Center Hospital of central Georgia between 1976 and 1981, who were estimated to represent some of the most advanced cases of kaolin pneumoconiosis seen in that hospital. Respiratory failure was a contributing factor to death in two of the three autopsy cases. Chest X-ray demonstrated small irregular shadows and large obscure patches typical of kaolin pneumoconiosis. Histological examinations revealed significant kaolinite deposits and peribronchial nodules. The nodules differed from those in silicotic patients and consisted mainly of kaolinite aggregates traversed by fibrous tissue trabecules. The presence of kaolinite in the lungs was confirmed by mineralogical examinations, while quartz could not be demonstrated.

Sepulveda et al. ¹ examined 39 current and 16 ex-workers of a Georgia kaolin mine and mill. Average respirable dust levels were approximately 0.2 mg/m3 in the mine and between 1 and 2 mg/m3 for other work stations. Samples of respirable dust contained 96% kaolinite, 4% titanium dioxide, and no silica. Pneumoconiosis was found in 15% of the workers and ex-workers with 5 years or more of exposure. Kaolin workers had a decreased forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and mean adjusted peak flow when the values were adjusted for age, height, race, and pack-years of smoking.

Kennedy et al. ⁵⁰ examined 459 kaolinite workers from central Georgia with a mean duration of employment of 12 years. Pneumoconiosis occurred in 9.2% of the workers and, among employees older than 54 years, was associated with high dust exposure. Among black workers with “complicated pneumoconiosis,” the FVC was 81.6%, indicating borderline restriction, and the FEV1/FVC was significantly lowered. The raw material from the mine contained 0.25% free crystalline silica. At the time of the study, the airborne concentrations of kaolin dust were below 5 mg/m3 and the dust contained less than 1% free silica, but dust concentrations up to 377 mg/m3 had been recorded in the past.

In a cross-sectional study of a Georgia kaolin mine and processing plant, Altekruse et al. ⁵¹ examined the pulmonary function and lung radiography of all 65 employees. The respirable dust concentration at the time of the study was 0.14 mg/m3 in the mine area and 1.74 mg/m3 in the kaolinite processing area, but had been higher earlier (see Table 9). About 94–98% of the particles were kaolinite and 2–6% anastase (titanium dioxide). Asbestiform fibres and crystalline silica were not present in the samples. Five workers, all of whom worked in the kaolinite processing area with highest exposure, showed radiological evidence of pneumoconiosis; they had worked for the company for 7–36 years. There was a slight, exposure duration-dependent decrease in the FVC and FEV1 among the workers, those with radiological pneumoconiosis having lower lung function than the others.

In a cross-sectional study of pulmonary function and radiology among workers of 12 kaolin companies in Georgia ⁵², an increased prevalence of pneumoconiosis and decreased lung function (FEV1, but not FVC) were observed among the workers working with calcined clay. Among workers with more than a 3-year tenure, the adjusted prevalence of simple and complicated pneumoconiosis was 3.2% and 0.63%, respectively. Smoking did not explain the presence of decreased FEV, nor was there a relationship between pneumoconiosis and lung function. The authors stated that the workers were not exposed to quartz ⁵².

Kaolin workers, other countries

Warraki & Herant ⁵³ examined radiologically 914 china clay workers of Ayyat, United Arab Republic; 264 of them had been exposed for less than 10 years, 133 for 10–15 years, 326 for 15– 20 years, and 191 for more than 20 years. Pneumoconiosis was diagnosed in six workers, all with exposures longer than 15 years. In two cases, confluent masses were found in the lungs; during a 2.5-year follow-up, one of these died with cor pulmonale. No measurements of dust were reported; a sample of airborne dust contained 1–2% free silica (Table 4).

Uragoda & Fernando ⁵⁴ examined workers in kaolinite processing in Sri Lanka. No individuals working with wet clay were examined because their risk of disease from dust exposure was considered low. Among the 11 persons working with dry materials (sacking and weighing), X-rays showed no sign of disease. The most frequent complaints were skin irritation and dermatitis, probably due to the tropical climate (high temperature and humidity). Lack of pneumoconiosis was to be expected because of the short exposure time (average 6 years, range 3–9 years).

Table 4. Effects of occupational exposure to kaolin and other clays on health

Study design, studied population	Exposure measurement	Exposure	Findings^a	References
Cross-sectional; 533 Cornish china clay workers	Occupational history from records for everyone. Millers, baggers, loaders considered to be continuously exposed, kiln workers and drymen intermittently exposed	Exposure to china clay; industrial hygiene expertise used to group occupations based on the intensity of exposure; no quantitative data or qualitative assessment of the dust	Exposure time-dependent increase in the prevalence of radiologically diagnosed kaolinosis, from 4% in those with less than 15 years of exposure to 19% among those with more than 25 years of exposure. Among 526 workers with less than 5 years of exposure, no kaolinosis was observed. Among the workers who were more heavily exposed (milling and bagging), the prevalence was 6% for those with a work history of 5-15 years and 23% for those with an exposure of >15 years. Confluent lesions were found in 12 workers, and 30 workers had ILO categories 2-3 lesions. There was little evidence of disability related to kaolinosis; only one worker with massive fibrosis had become disabled and changed to a lighter job.	⁵⁵
Cross-sectional; 1728 Cornish china clay workers in 1977	Occupational group and history of work in each group for all workers	Exposure to china clay; industrial hygiene expertise used to group occupations based on the intensity of exposure; no quantitative data or qualitative assessment of the dust	77.4% of workers in pneumoconiosis category 0, 17.9% in category 1, 4.7% in category 2 or 3. Advanced pneumoconiosis in 19 workers. Every dusty job contributed to the amount of simple pneumoconiosis. Smoking unrelated to radiographic appearance. Vital capacity deteriorated with advancing pneumoconiosis; for “FEV,” the association was not statistically significant. Subjective symptoms not related to past exposure as assessed by years worked in different jobs.	⁵⁶
Cross-sectional; 3831 employees and 336 pensioners in china clay industry in United Kingdom in 1985	Analysis by job classification	Average exposures at the time of the study 0.5-2.7 mg/m³ (see Table 9)	3374 workers in pneumoconiosis category 0, 271 in category 1, 39 in category 2, and 5 in category 3. Employment in mills had strongest effect on pneumoconiosis category, followed by dryers (in keeping with the exposure levels). In kilns, the exposure was also high, but pneumoconiosis was not equally prevalent; kaolin there is no longer crystalline. Work in mills or as dryer before 1971 had twice the effect on pneumoconiosis prevalence as work there after 1971. Ventilatory capacity related to radiological status, no consistent independent relation with occupational history was observed. Respiratory symptoms were related to ventilatory function.	⁵⁷
Cross-sectional; 4401 current and retired china clay workers in United Kingdom in 1990	Dust measurements from 1978, estimated exposure before 1978; detailed occupational history for each participant	Average respirable dust exposure 1.2-4.7 mg/m³ (see Table 9)	Small opacity profusion related to work dustiness and total occupational dust dose; to reach category 1 by age 60, the estimated total dose for non-smokers was 85 mg/m³years, for smokers, 65 mg/m³years. The major determinant of respiratory symptoms was smoking; total dust exposure had a minor effect.	⁵⁸
Cross-sectional; 4401 current and retired china clay workers in United Kingdom in 1990	Dust measurements from 1978, estimated exposure before 1978; detailed occupational history for each participant	Average respirable dust exposure 1.2-4.7 mg/m³ (see Table 9)	Univariate analysis showed relationships between lung function and age, X-ray score, smoking class, occupational history, and total occupational dust dose. In multiple regression analysis, when the effects of age, X-ray score, and smoking class had been accounted for, there was no independent additional effect from total occupational dust dose or occupational history.	⁵⁹
Cross-sectional; 39 current and 16 ex-kaolin workers at a kaolin mine and mill in Georgia, USA	Respirable and total dust analysed at the time of study (see Table 9)	Dust composed of 96% kaolinite, 4% titanium dioxide, no free silica, no asbestiform fibres; average respirable dust in all job categories <2 mg/m³	Of current and ex-workers with >5 years of exposure (n = 55), 4 had simple pneumoconiosis and 4 complicated pneumoconiosis. Mean adjusted FVC, FEV₁, peak flow lower (P < 0.05) among kaolin workers than among 189 non-kaolin-exposed referents.	¹
Cross-sectional; 459 workers in three Georgia kaolin mining and processing facilities with >1 year work history; mean duration of employment 12 years	Details on measurements not given	At the time of study, US Mine Safety and Health Administration documented exposure to kaolin dust <5 mg/m³ with less than 1% free silica; survey in one of the plants in 1951 and 1960 showed kaolin dust concentrations of 377 and 361 mg/m³; in 1951, the raw material had 0.25% free silica	417 workers had pneumoconiosis category 0, 29 category 1, 8 category 2, and 5 category 3. Of the blacks, 13.6%, and of the whites, 7.6% had pneumoconiosis. Pneumoconiosis was significantly related to age, >15 years of exposure, and greatest dust exposure. Complicated pneumoconiosis (large opacities) related to decreased respiratory function, but otherwise there was no correlation between pneumoconiosis and respiratory function.	⁵⁰
Cross-sectional; all 65 men employed in a Georgia kaolin mine studied	During 5-year period, 157 measurements of respirable dust (see Table 9)	Dust composed of 94-98% kaolinite and 2-6% anastase (TiO₂); no asbestiform fibres of crystalline silica; mean respirable dust in processing area 1.74 mg/m³, 0.14 mg/m³ in the mine	Five of the workers had radiological pneumoconiosis. All had worked in the processing area. For the whole group, FVC and FEV₁ were within the normal range, but they were lower for the workers with pneumoconiosis. FVC and FEV₁ decreased with years of employment in the processing area. Pneumoconiosis was not related to smoking.	⁵¹
Cross-sectional; 2379 current kaolin workers in Georgia, USA	No measurements; occupational title as proxy	The authors state that the free silica exposure is negligible because of washing out of impurities in the process	4.4% prevalence of category >1 simple pneumoconiosis, 0.89% prevalence of complicated pneumoconiosis; 7.1% of white and 19% of black dry processors and 4.1% of white and 9.1% of white wet processors had pneumoconiosis. FEV₁ was <80% of the expected among 7.5, 12.8, and 33.3% and FVC was <80% among 8.0, 10.5, and 33.3% of those with normal chest radiograph and those with simple and complicated pneumoconiosis. Similarly, among lifelong non-smokers, the frequency of lowered FEV₁ and FVC was elevated among those with complicated pneumoconiosis.	⁵²
Cross-sectional: workers of two Georgia, USA, kaolin plants	Reanalysis of data from two of the three plants studied by Kennedy et al. (1983); no measurements		19/162 and 21/223 workers in the two plants had pneumoconiosis. The adjusted prevalence of pneumoconiosis increased 1.1 % for each year in production. Workers in plant 1 had a 2.7 times higher prevalence than workers in plant 2. In plant 1, 15-20% of production had been calcined kaolin, while plant 2 had produced hydrous clay only.	⁶⁰
Cross-sectional; 914 workers in earthenware industry, United Arab Republic	No quantitative measurements	83-86% of respirable dust potassium aluminium silicate, 1-2% free silica	264 workers has worked for <10 years, 133 for 10-15 years; no pneumoconiosis cases were observed in these groups. 326 workers had worked 15-20 years and included 4 cases with pneumoconiosis, and 191 workers had worked >20 years and included 2 with pneumoconiosis. 2 of the pneumoconiosis cases were classified as progressive massive fibrosis; 4 had dyspnoea on exertion.	⁵³
Cross-sectional, 11 workers in the bagging section of a kaolin refinery in Sri Lanka, average age 35.2 years, duration of employment 3-9 years (average 6 years)	No measurements available	Kaolinite content of kaolin >99%, 76.8% <3 µm in diameter	No radiological abnormalities observed. The absence of pneumoconiosis most likely due to short duration of employment and young age of the workers studied.	⁵⁴
Cross-sectional; 18 factories in heavy clay industry in United Kingdom; 1934 current employees	1465 personal dust samples collected at the time of the study and analysed for respirable dust and quartz	Cumulative exposure <40 mg/m³years respirable dust for 94% and <4 mg/m³years quartz for 93%; for details, see Table 10	1.4% had radiographic small opacities in ILO category >1/0, 0.4% had small opacities in ILO category >2/1. Risk dependent on lifetime exposure to quartz and respirable dust. Anamnestic chronic bronchitis, wheezing, and breathlessness related to dust exposure. Dust and quartz exposure strongly correlated.	⁶¹
Cross-sectional; 268 current brick workers in South Africa	97 respirable, 78 total dust, and 29 silica analyses from three of the five participating factories at the time of the study	Mean respirable dust and total dust exposure 2.22 and 15.6 mg/m³; mean free silica 2.1%; for exposure in different groups, see Table 10	4.2% had profusion score >1/0; profusion score significantly related to cumulative respirable dust exposure. Anamnestic respiratory symptoms and FVC and FEV₁ significantly related to exposure to respirable dust.	⁶²

Footnotes:

a: FEV = forced expiratory volume; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; ILO = International Labour Organization.

[Source ²³] References

Sepulveda MJ, Vallyathan V, Attfield MD, Piacitelli L, & Tucker JH (1983) Pneumoconiosis and lung function in a group of kaolin workers. Am Rev Respir Dis, 127: 231–235.
BENTONITE, KAOLIN, AND SELECTED CLAY MINERALS. http://www.inchem.org/documents/ehc/ehc/ehc231.htm
Lipson SM & Stotzky G (1983) Adsorption of reovirus to clay minerals: Effects of cation-exchange capacity, cation saturation, and surface area. Appl Environ Microbiol, 46: 673–682.
World Health Organization/International Programme on Chemical Safety; Environmental Health Criteria 231 Bentonite, Kaolin, and Selected Clay Minerals. pp. 1-5, 2005
Rees D, Cronje R, & du Toir RSJ (1992) Dust exposure and pneumoconiosis in a South African pottery. 1. Study objectives and dust exposure. Br J Ind Med, 49: 459–464.
Stobbe TJ, Plummer RW, Kim H, & Dower JM (1986) Characterisation of coal mine dust. Ann Am Conf Gov Ind Hyg, 14: 689–696.
IPCS INCHEM; Environmental Health Criteria (EHC) Monographs. Bentonite, kaolin, and selected clay minerals (EHC 231). http://www.inchem.org/documents/ehc/ehc/ehc231.htm
Sriamornsak P. Chemistry of pectin and its pharmaceutical uses: a review. Silpakorn Univ Int J. 2003;3(1–2):206–228.
Pectins: structure, biosynthesis, and oligogalacturonide-related signaling. Ridley BL, O’Neill MA, Mohnen D. Phytochemistry. 2001 Jul; 57(6):929-67.
The role of pectin in plant morphogenesis. Palin R, Geitmann A. Biosystems. 2012 Sep; 109(3):397-402.
Homogalacturonan methyl-esterification and plant development. Wolf S, Mouille G, Pelloux J. Mol Plant. 2009 Sep; 2(5):851-60.
Methyl esterification of pectin plays a role during plant-pathogen interactions and affects plant resistance to diseases. Lionetti V, Cervone F, Bellincampi D. J Plant Physiol. 2012 Nov 1; 169(16):1623-30.
Kaya M, Sousa AG, Crépeau M-J, Sørensen SO, Ralet M-C. Characterization of citrus pectin samples extracted under different conditions: influence of acid type and pH of extraction. Annals of Botany. 2014;114(6):1319-1326. doi:10.1093/aob/mcu150. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195561/
Woods MN, Gorbach SL. Influences of fibers on the ecology of the intestinal flora. In: Spiller GA, editor. Handbook of dietary fibre in human nutrition. New York: CRC; 2001. pp. 257–270.
Characterisation of pectin subunits released by an optimised combination of enzymes. Bonnin E, Dolo E, Le Goff A, Thibault JF. Carbohydr Res. 2002 Oct 8; 337(18):1687-96.
McEvoy, G.K. (ed.). American Hospital Formulary Service–Drug Information 94. Bethesda, MD: American Society of Hospital Pharmacists, Inc. 1994 (Plus Supplements)., p. 1879
Wynder EL & Hoffman D (1967) Tobacco and tobacco smoke: Studies in experimental carcinogenesis. New York, Academic Press, 730 pp.
Moore P (2003) Kaolin — white gold or white dirt? Ind Miner, 430: 14–35.
Adamis Z & Timár M (1980) Investigations of the effects of quartz, aluminium silicates and colliery dusts on peritoneal macrophages. In: Brown RC, Gormley IP, Chamberlain M, & Davies R ed. The in vitro effects of mineral dusts. London, Academic Press, pp 13–18.
Cronberg S & Caen JP (1971) Release reaction in washed platelet suspensions induced by kaolin and other particles. Scand J Haematol, 8: 151–160.
Walsh PN (1972) The effects of collagen and kaolin on the intrinsic coagulant activity of platelets. Evidence for an alternative pathway in intrinsic coagulation not requiring factor XII. Br J Haematol, 22: 393–405.
Haukenes G & Aasen J (1972) Heterogeneity in the reactivity of antibodies with kaolin. Acta Pathol Microbiol Scand B, 80: 251–256.
http://www.inchem.org/documents/ehc/ehc/ehc231.htm
CIREP (2003) Final report [by the Cosmetic Ingredient Review Panel] on the safety of aluminium silicate, calcium silicate, magnesium aluminium silicate, magnesium silicate, magnesium trisilicate, sodium magnesium silicate, zirconium silicate, attapulgite, bentonite, Fuller’s earth, hectorite, kaolin, lithium magnesium silicate, lithium magnesium sodium silicate, montmorillonite, pyrophyllite, and zeolite. Int J Toxicol, 22(Suppl 1): 37–122.
Kettle EH & Hilton R (1932) The technique of experimental pneumoconiosis. Lancet, 222: 1190–1192.
King EJ, Harrison CV, & Nagelschmidt G (1948) The effects of kaolin on the lungs of rats. J Pathol Bacteriol, 60: 435–440.
Belt TH & King EJ (1945) Chronic pulmonary disease in South Wales coal miners. III. Experimental studies. D. Tissue reactions produced experimentally by selected dusts from South Wales coal mines. Med Res Counc Spec Rep Ser, 250: 29–68.
Timár M, Kendrey G, & Juhasz Z (1966) Experimental observations concerning the effects of mineral dust to pulmonary tissue. Med Lav, 57: 1–9.
Timár M, Adamis Z, & Ungváry G (1979) Biological effects of mineral dusts. In vitro and in vivo studies. Arch Hig Rada Toksikol, 30(Suppl): 871–874.
Goldstein B & Rendall RE (1969) The relative toxicities of the main classes of minerals. In: Shapiro HA ed. Pneumoconiosis. Proceedings of the international conference, Johannesburg. Capetown, Oxford University Press, pp 429–434.
Martin JC, Danile H, & Le Bouffant L (1977) Short- and long-term experimental study of the toxicity of coal-mine dust and some of its constituents. In: Walton WH & McGovern B ed. Inhaled particles. IV. Oxford, Pergamon Press, pp 361–370.
Sahu AP, Shanker R, & Zaidi SH (1978) Pulmonary response to kaolin, mica and talc in mice. Exp Pathol (Jena), 16: 276–282.
Rosmanith J, Hilscher W, Hessling B, Schyma SB, & Ehm W (1989) The fibrogenic action of kaolinite, muscovite and feldspar. In: Results of studies on dust suppression and silicosis prevention in hard coal mining, Vol 17. Essen, Steinkohlenbergbauverein, pp 305–321.
Adamis Z & Krass BK (1991) Studies on the cytotoxicity of ceramic respirable dusts using in vitro and in vivo test systems. Ann Occup Hyg, 35: 469–483.
Policard A & Collet A (1954) [Experimental study on pathological effect of kaolin.] Schweiz Z Pathol Bakteriol, 17: 320–325 in German.
Rüttner JR, Bovet P, Weber R, & Willy W (1952) Neue Ergebnisse tierexperimenteller Silikoseforschung. Naturwissenschaften, 39: 332.
Schmidt KG & Lüchtrath H (1958) [Effect of fresh and burned kaolin on the lungs and peritoneum of rats.] Beitr Silikoseforsch, 119: 3–37 in German.
Styles JA & Wilson J (1973) Comparison between in vitro toxicity of polymer and mineral dusts and their fibrogenicity. Ann Occup Hyg, 16: 241–250.
Carleton HM (1924) The pulmonary lesions produced by the inhalation of dust in guinea-pigs. A report to the Medical Research Council. J Hyg, 22: 438–478.
Wagner JC, Griffiths DM, & Munday DE (1987) Experimental studies with palygorskite dusts. Br J Ind Med, 44: 749–763.
Mossman BT & Craighead JE (1982) Comparative cocarcinogenic effects of crocidolite asbestos, hematite, kaolin and carbon in implanted tracheal organ cultures. Ann Occup Hyg, 26: 553–567.
Wiles M, Huebner H, Afriyie-Gyawu E, Taylor R, Bratton G, & Phillips T (2004) Toxicological evaluation and metal bioavailability in pregnant rats following exposure to clay minerals in the diet. J Toxicol Environ Health A, 67(11): 863–874.
Patterson EC & Staszak DJ (1977) Effects of geophagia (kaolin ingestion) on the maternal blood and embryonic development in the pregnant rat. J Nutr, 107: 2020–2025.
Levin JL, Frank AL, Williams MG, McConnel W, Suzuki Y, & Dodson R (1996) Kaolinosis in a cotton mill worker. Am J Ind Med, 29: 215–221.
Gudjonsson SV & Jacobsen CJ (1934) A fatal case of silicosis. J Hyg, 34: 166–171.
Hale LW, Gough J, King EJ, & Nagelschmidt G (1956) Pneumoconiosis of kaolin workers. Br J Ind Med, 13: 251–259.
Edenfield RW (1960) A clinical and roentgenological study of kaolin workers. Arch Environ Health, 1: 392–403.
Lapenas DJ & Gale PN (1983) Kaolin pneumoconiosis. A case report. Arch Pathol Lab Med, 107: 650–653.
Lapenas D, Gale P, Kennedy T, Rawlings W Jr, & Dietrich P (1984) Kaolin pneumoconiosis. Radiologic, pathologic, and mineralogic findings. Am Rev Respir Dis, 130: 282–288.
Kennedy T, Rawlings W Jr, Baser M, & Tockman M (1983) Pneumoconiosis in Georgia kaolin workers. Am Rev Respir Dis, 127: 215–220.
Altekruse EB, Chaudhary BA, Pearson MG, & Morgan WK (1984) Kaolin dust concentrations and pneumoconiosis at a kaolin mine. Thorax, 39: 436–441.
Morgan WK, Donner A, Higgins ITT, Perason MG, & Rawlings W Jr (1988) The effects of kaolin on the lung. Am Rev Respir Dis, 138: 813–820.
Warraki S & Herant Y (1963) Pneumoconiosis in china-clay workers. Br J Ind Med, 20: 226– 230.
Uragoda CG & Fernando BND (1974) An investigation into the health of kaolin workers in Sri Lanka. Ceylon Med J, 19: 77–79.
Sheers G (1964) Prevalence of pneumoconiosis in Cornish kaolin workers. Br J Ind Med, 21: 218–225.
Oldham PD (1983) Pneumoconiosis in Cornish china clay workers. Br J Ind Med, 40: 131– 137.
Ogle CJ, Rundle EM, & Sugar ET (1989) China clay workers in the south west of England: analysis of chest radiograph readings, ventilatory capacity, and respiratory symptoms in relation to type and duration of occupation. Br J Ind Med, 46: 261–270.
Rundle EM, Sugar ET, & Ogle CJ (1993) Analyses of the 1990 chest health survey of china clay workers. Br J Ind Med, 50: 913–919.
Comyns RA, Ogle CJ, Rundle EM, Cockroft A, & Rossiter CE (1994) Dose–response for kaolin: The effect of kaolin on workers’ health. Ann Occup Hyg, 38(Suppl 1): 825–831.
Baser ME, Kennedy TP, Dodson R, Rawlings W Jr, Rao NV, & Hoidal JR (1989) Differences in lung function and prevalence of pneumoconiosis between two kaolin plants. Br J Ind Med, 46: 773–776.
Love RG, Waclawski ER, Maclaren WM, Wetherill GZ, Groat SK, Porteous RH, & Soutar CA (1999) Risks of respiratory disease in the heavy clay industry. Occup Environ Med, 56: 124– 133.
Myers JE & Cornell JE (1989) Respiratory health of brickworkers in Cape Town, South Africa. Symptoms, signs and pulmonary function abnormalities. Scand J Work Environ Health, 15: 188–194.

Drugs

Magnesium hydroxide

by Health Jade Team on August 7, 2018

What is magnesium hydroxide

Magnesium hydroxide Mg(OH)₂ also called milk of magnesia or magnesia magma, is most commonly used an antacid for heartburn/indigestion or a laxative in either an oral liquid suspension or chewable tablet form. Magnesium hydroxide promotes bowel evacuation by causing osmotic retention of fluid which distends the colon with increased peristaltic activity; reacts with hydrochloric acid in stomach to form magnesium chloride. Magnesium hydroxide is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. Additionally, magnesium hydroxide has smoke supressing and flame retardant properties and is thus used commercially as a fire retardant. Magnesium hydroxide can also be used topically as an antiperspirant underarm deodorant or for relief of canker sores (aphthous ulcers).

Magnesium hydroxide is also used as a residual fuel-oil additive, an alkali drying agent in food, a color-retention agent, an ingredient of toothpaste and frozen desserts, a clarifier in sugar refining, and a neutralizing agent in the chemical industry ¹. Magnesium hydroxide Mg(OH)₂ is categorized by the U.S. Food and Drug Administration (FDA) as a GRAS (generally recognized as safe) food ingredient and is approved for use as a nutritional supplement and a pH-control agent in foods ².

Mg(OH)₂ is used as an flame retardant in commercial furniture applications in the United States and in commercial and residential furniture in the United Kingdom ³. The stability of magnesium hydroxide at temperatures above 300°C allows it to be incorporated into several polymers ⁴. Market-volume data published in 1993 suggest increasing the use of magnesium hydroxide as a flame retardant. About 2,000 and 3,000 tons of magnesium hydroxide were marketed as an Fire Retardant in the United States in 1986 and 1993, respectively ⁴.

Figure 1. Magnesium hydroxide

When administered orally, magnesium hydroxide Mg(OH)₂ dissociates in stomach acids to magnesium (Mg²⁺) cations. About 5–15% of the dissociated magnesium (Mg²⁺) cations are absorbed ⁵ through the epithelial lining of the small intestine (Sutton and Dirks 1986; Elin 1987). Absorption of magnesium (Mg²⁺) can be affected by the presence of food or other substances that readily complex with magnesium (Mg²⁺) cations. Magnesium hydroxide Mg(OH)₂ and magnesium oxide (MgO), which have relatively low solubilities at neutral and alkaline pH, are less completely absorbed than the more water-soluble Mg²⁺compounds-magnesium chloride (MgCl₂), magnesium citrate, and magnesium lactate ⁶. Determination of increased plasma or urinary Mg²⁺ cations after oral administration of Mg(OH)₂ is not possible, because of rapid homeostasis of exogenous Mg²⁺ in humans ⁶.

A single study in human volunteers measured the oral absorption of magnesium (Mg²⁺) cations ⁶. In that study, six healthy males were administered a single oral dose of 360 mg of ²⁶Mg²⁺ as magnesium lactate or citrate and absorption of magnesium (Mg²⁺) over 5 days was found to be 34.5%±18.8% and 39.8%± 24.3% based on urinary excretion. Absorption of magnesium (Mg²⁺) was 25.6% ±34.5%; this estimate was based on fecal excretion.

Magnesium hydroxide in pregnancy

There are no studies in humans that evaluated reproductive or developmental effects associated with the ingestion of magnesium hydroxide.

Magnesium crosses the placenta; serum concentrations in the fetus are similar to those in the mother. The American Gastroenterological Association considers the use of magnesium containing antacids to be low risk in pregnancy.

Other magnesium salts (such as magnesium sulfate) have been used extensively during pregnancy in large doses with no reports of congenital defects. Magnesium hydroxide should only be given in pregnancy when benefit outweighs risk.

Oral administration of MgCl₂ solution caused no toxic signs in pregnant Wistar rats and no increases in the incidences of fetal malformations that were given doses of 0, 200, 400, or 800 mg/kg per day (Mg²⁺ at 0, 24, 47, and 96 mg/kg-d) on day 6 through 15 of pregnancy ⁷. Pregnant dams were killed on day 20 of pregnancy and all fetuses underwent pathological examination for skeletal and visceral malformations. No malformations were observed at any dose tested. The authors concluded that the No-observed-adverse-effect level (NOAEL) for developmental and maternal toxicity was over 800 mg/kg per day (equivalent to 96 mg Mg²⁺/kg per day) in this study ⁷.

Twenty-seven hypertensive women were treated with magnesium hydroxide during the third trimester of pregnancy; no effect was noted on the newborns, except a slight increase in body weight in the children born to the treated mothers vs. controls ⁸. Cord serum levels of magnesium were reported to be 70-100% of the maternal levels after maternal therapy. In such cases, neurological depression may occur in the neonate, characterized by respiratory depression, muscle weakness, and decreased reflexes ⁸. No decrease in Apgar scores was noted in infants of females treated for pregnancy-induced hypertension, although the magnesium levels in the infants reflected hypermagnesiumemia (high blood magnesium levels). Prolonged magnesium treatment during pregnancy may be associated with maternal and fetal hypocalcemia (low blood calcium levels) and adverse effects on fetal bone mineralization ⁸.

Magnesium hydroxide and breastfeeding

A study on the use of magnesium hydroxide during breastfeeding found no adverse reactions in breastfed infants. Intravenous magnesium increases milk magnesium concentrations only slightly. Oral absorption of magnesium by the infant is poor, so maternal magnesium hydroxide is not expected to affect the breastfed infant’s serum magnesium. Magnesium hydroxide supplementation during pregnancy might delay the onset of lactation, but it can be taken during breastfeeding and no special precautions are required.

Ten women with pre-eclampsia were given 4 grams of magnesium sulfate intravenously followed by 1 gram per hour until 24 hours after delivery. While the average serum magnesium was 35.5 mg/L in treated women compared to 18.2 mg/L in 5 untreated controls, colostrum magnesium levels at the time of discontinuation of the infusion was 64 mg/L in treated women and 48 mg/L in the controls. By 48 hours after discontinuation, colostrum magnesium levels were only slightly above control values and by 72 hours they were virtually identical to controls ⁹.

Fifty mothers who were in the first day postpartum received 15 mL of either mineral oil or an emulsion of mineral oil and magnesium hydroxide equivalent to 900 mg of magnesium hydroxide, although the exact number who received each product was not stated. Additional doses were given on subsequent days if needed. None of the breastfed infants were noted to have any markedly abnormal stools, but all of the infants also received supplemental feedings ¹⁰.

One mother who received intravenous magnesium sulfate for 3 days for pregnancy-induced hypertension had lactogenesis II delayed until day 10 postpartum. No other specific cause was found for the delay, although a complete work-up was not done ¹¹. A subsequent controlled clinical trial found no evidence of delayed lactation in mothers who received intravenous magnesium sulfate therapy ¹². Some, but not all, studies have found a trend toward increased time to the first feeding or decreased sucking in infants of mothers treated with intravenous magnesium sulfate during labor because of placental transfer of magnesium to the fetus ¹³.

A study in 40 pairs of matched healthy women with vaginally delivered singleton pregnancies, outcome endpoints were compared in those receiving continuous oral magnesium aspartate HCl supplementation mean dose of 459 mg daily (range 365 to 729 mg of magnesium daily) for at least 4 weeks before delivery versus non-supplemented controls. In the magnesium group, significantly fewer women could breastfeed their infants exclusively at discharge (63% vs 80%) ¹⁴.

Magnesium hydroxide uses

Antacid: For the temporary relief of heartburn, upset stomach, sour stomach, or acid indigestion.

Laxative (occasional constipation): For relief of occasional constipation. This product generally produces bowel movement in 30 minutes to 6 hours.

Magnesium hydroxide come as a tablet and liquid to take by mouth. It usually is taken as needed for constipation. Follow the directions on the package or on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take magnesium hydroxide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Shake the liquid well before each use. All doses should be followed by 8 ounces of water.

Before taking magnesium hydroxide:

tell your doctor and pharmacist if you are allergic to magnesium hydroxide or any other drugs.
tell your doctor and pharmacist what prescription and nonprescription medications you are taking, including vitamins.
tell your doctor if you have or have ever had kidney disease.
tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking magnesium hydroxide, call your doctor.

Drug Interactions

Acalabrutinib: Antacids may decrease the serum concentration of Acalabrutinib. Management: Separate administration of acalabrutinib from the administration of any antacids by at least 2 hours in order to minimize the potential for a significant interaction. Consider therapy modification

Alfacalcidol: May increase the serum concentration of Magnesium Salts. Consider therapy modification

Allopurinol: Antacids may decrease the absorption of Allopurinol. Consider therapy modification

Alpha-Lipoic Acid: Magnesium Salts may decrease the absorption of Alpha-Lipoic Acid. Alpha-Lipoic Acid may decrease the absorption of Magnesium Salts. Consider therapy modification

Amphetamines: Antacids may decrease the excretion of Amphetamines. Monitor therapy

Antipsychotic Agents (Phenothiazines): Antacids may decrease the absorption of Antipsychotic Agents (Phenothiazines). Monitor therapy

Atazanavir: Antacids may decrease the absorption of Atazanavir. Consider therapy modification

Bictegravir: Antacids may decrease the serum concentration of Bictegravir. Management: Bictegravir, emtricitabine, and tenofovir alafenamide can be administered while fasting at least 2 hours before antacids. Giving with or 2 hours after antacids is not recommended. Consider therapy modification

Bisacodyl: Antacids may diminish the therapeutic effect of Bisacodyl. Antacids may cause the delayed-release bisacodyl tablets to release drug prior to reaching the large intestine. Gastric irritation and/or cramps may occur. Consider therapy modification

Bismuth Subcitrate: Antacids may diminish the therapeutic effect of Bismuth Subcitrate. Management: Avoid administration of antacids within 30 minutes of bismuth subcitrate (tripotassium bismuth dicitrate) administration. Consider therapy modification

Bisphosphonate Derivatives: Antacids may decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of antacids containing polyvalent cations within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Pamidronate; Zoledronic Acid. Consider therapy modification

Bisphosphonate Derivatives: Magnesium Salts may decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral magnesium salts within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Pamidronate; Zoledronic Acid. Consider therapy modification

Bosutinib: Antacids may decrease the serum concentration of Bosutinib. Management: Administer antacids more than 2 hours before or after bosutinib. Consider therapy modification

Bromperidol: Antacids may decrease the absorption of Bromperidol. Monitor therapy

Calcitriol (Systemic): May increase the serum concentration of Magnesium Salts. Management: Consider using a non-magnesium-containing antacid or phosphate-binding product in patients also receiving calcitriol. If magnesium-containing products must be used with calcitriol, serum magnesium concentrations should be monitored closely. Consider therapy modification

Calcium Channel Blockers: May enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers. Monitor therapy

Calcium Polystyrene Sulfonate: Laxatives (Magnesium Containing) may enhance the adverse/toxic effect of Calcium Polystyrene Sulfonate. More specifically, concomitant use of calcium polystyrene sulfonate with magnesium-containing laxatives may result in metabolic alkalosis or with sorbitol may result in intestinal necrosis. Management: Avoid concomitant use of calcium polystyrene sulfonate (rectal or oral) and magnesium-containing laxatives. Avoid combination

Captopril: Antacids may decrease the serum concentration of Captopril. Monitor therapy

Cefditoren: Antacids may decrease the serum concentration of Cefditoren. Management: Concomitant use of cefditoren with antacids is not recommended. Consider alternative methods to control acid reflux (eg, diet modification) or alternative antimicrobial therapy. If antacid therapy can not be avoided, separate dosing by several hours. Consider therapy modification

Cefpodoxime: Antacids may decrease the serum concentration of Cefpodoxime. Monitor therapy

Cefuroxime: Antacids may decrease the serum concentration of Cefuroxime. Management: Administer cefuroxime axetil at least 1 hour before or 2 hours after the administration of short-acting antacids. Consider therapy modification

Chloroquine: Antacids may decrease the serum concentration of Chloroquine. Management: Separate administration of antacids and chloroquine by at least 4 hours to minimize any potential negative impact of antacids on chloroquine bioavailability. Consider therapy modification

Corticosteroids (Oral): Antacids may decrease the bioavailability of Corticosteroids (Oral). Management: Consider separating doses by 2 or more hours. Budesonide enteric coated tablets could dissolve prematurely if given with drugs that lower gastric acid, with unknown impact on budesonide therapeutic effects. Consider therapy modification

Cysteamine (Systemic): Antacids may diminish the therapeutic effect of Cysteamine (Systemic). Monitor therapy

Dabigatran Etexilate: Antacids may decrease the serum concentration of Dabigatran Etexilate. Management: Dabigatran etexilate Canadian product labeling recommends avoiding concomitant use with antacids for 24 hours after surgery. In other situations, administer dabigatran etexilate 2 hours prior to antacids. Monitor clinical response to dabigatran therapy. Consider therapy modification

Dasatinib: Antacids may decrease the absorption of Dasatinib. Consider therapy modification

Deferiprone: Antacids may decrease the serum concentration of Deferiprone. Management: Separate administration of deferiprone and oral medications or supplements that contain polyvalent cations by at least 4 hours. Consider therapy modification

Deferiprone: Magnesium Salts may decrease the serum concentration of Deferiprone. Management: Separate administration of deferiprone and oral medications or supplements that contain polyvalent cations by at least 4 hours. Consider therapy modification

Delavirdine: Antacids may decrease the serum concentration of Delavirdine. Management: Separate doses of delavirdine and antacids by at least 1 hour. Monitor for decreased delavirdine therapeutic effects with this combination. Consider therapy modification

Dexmethylphenidate: Antacids may increase the absorption of Dexmethylphenidate. Specifically, antacids may interfere with the normal release of drug from the extended-release capsules (Focalin XR brand), which could result in both increased absorption (early) and decreased delayed absorption. Monitor therapy

Diacerein: Antacids may decrease the absorption of Diacerein. Monitor therapy

Dolutegravir: Magnesium Salts may decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral magnesium salts. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral magnesium salts. Consider therapy modification

Doxercalciferol: May enhance the hypermagnesemic effect of Magnesium Salts. Management: Consider using a non-magnesium-containing antacid or phosphate-binding product in patients also receiving doxercalciferol. If magnesium-containing products must be used with doxercalciferol, serum magnesium concentrations should be monitored closely. Consider therapy modification

Eltrombopag: Magnesium Salts may decrease the serum concentration of Eltrombopag. Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any magnesium-containing product. Consider therapy modification

Elvitegravir: Antacids may decrease the serum concentration of Elvitegravir. Management: Separate administration of antacids and elvitegravir-containing products by at least 2 hours in order to minimize the risk for an interaction. Consider therapy modification

Erlotinib: Antacids may decrease the serum concentration of Erlotinib. Management: Separate the administration of erlotinib and any antacid by several hours in order to minimize the risk of a significant interaction. Consider therapy modification

Fexofenadine: Antacids may decrease the serum concentration of Fexofenadine. Management: No specific recommendations concerning the time required between their administration are provided. Separate administration of each agent by as much time as possible to decrease the risk of an interaction. Consider therapy modification

Fosinopril: Antacids may decrease the serum concentration of Fosinopril. Management: The US and Canadian fosinopril manufacturer labels recommend separating the doses of antacids and fosinopril by 2 hours. Consider therapy modification

Gabapentin: Antacids may decrease the serum concentration of Gabapentin. Management: Administer gabapentin at least 2 hours after antacid administration. Monitor patients closely for evidence of reduced response to gabapentin therapy when both of these drugs are being used. Consider therapy modification

Gabapentin: Magnesium Salts may enhance the CNS depressant effect of Gabapentin. Specifically, high dose intravenous/epidural magnesium sulfate may enhance the CNS depressant effects of gabapentin. Magnesium Salts may decrease the serum concentration of Gabapentin. Management: Administer gabapentin at least 2 hours after oral magnesium salts administration. Monitor patients closely for evidence of reduced response to gabapentin therapy. Monitor for CNS depression if high dose IV/epidural magnesium sulfate is used. Consider therapy modification

Gefitinib: Antacids may decrease the serum concentration of Gefitinib. Management: Administer gefitinib at least 6 hours before or after administration of an antacid, and closely monitor clinical response to gefitinib. Consider therapy modification

Hyoscyamine: Antacids may decrease the serum concentration of Hyoscyamine. Management: Administer immediate release hyoscyamine before meals and antacids after meals when these agents are given in combination. Consider therapy modification

Iron Salts: Antacids may decrease the absorption of Iron Salts. Exceptions: Ferric Carboxymaltose; Ferric Citrate; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Isomaltoside; Iron Sucrose. Consider therapy modification

Itraconazole: Antacids may decrease the serum concentration of Itraconazole. Management: Administer itraconazole at least 1 hour after and 2 hours before administration of any antacids. Itraconazole oral suspension may be less sensitive to the effects of decreased gastric acidity. Consider therapy modification

Ketoconazole (Systemic): Antacids may decrease the serum concentration of Ketoconazole (Systemic). Management: Administer oral ketoconazole at least 2 hours prior to use of any antacid product. Monitor patients closely for signs of inadequate clinical response to ketoconazole. Consider therapy modification

Lanthanum: Antacids may diminish the therapeutic effect of Lanthanum. Consider therapy modification

Ledipasvir: Antacids may decrease the serum concentration of Ledipasvir. Management: Separate the administration of ledipasvir and antacids by 4 hours. Consider therapy modification

Levothyroxine: Magnesium Salts may decrease the serum concentration of Levothyroxine. Management: Separate administration of oral levothyroxine and oral magnesium salts by at least 4 hours. Consider therapy modification

Mesalamine: Antacids may diminish the therapeutic effect of Mesalamine. Antacid-mediated increases in gastrointestinal pH may cause the premature release of mesalamine from specific sustained-release mesalamine products. Management: Avoid concurrent administration of antacids with sustained-release mesalamine products. Separating antacid and mesalamine administration, and/or using lower antacid doses may be adequate means of avoiding this interaction. Consider therapy modification

Methenamine: Antacids may diminish the therapeutic effect of Methenamine. Consider therapy modification

Methylphenidate: Antacids may increase the absorption of Methylphenidate. Specifically, antacids may interfere with the normal release of drug from the extended-release capsules (Ritalin LA brand), which could result in both increased absorption (early) and decreased delayed absorption. Monitor therapy

MiSOPROStol: Antacids may enhance the adverse/toxic effect of MiSOPROStol. More specifically, concomitant use with magnesium-containing antacids may increase the risk of diarrhea. Management: Avoid concomitant use of misoprostol and magnesium-containing antacids. In patients requiring antacid therapy, employ magnesium-free preparations. Monitor for increased adverse effects (e.g., diarrhea, dehydration). Avoid combination

Multivitamins/Fluoride (with ADE): Magnesium Salts may decrease the serum concentration of Multivitamins/Fluoride (with ADE). Specifically, magnesium salts may decrease fluoride absorption. Management: To avoid this potential interaction separate the administration of magnesium salts from administration of a fluoride-containing product by at least 1 hour. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): Antacids may decrease the serum concentration of Multivitamins/Minerals (with ADEK, Folate, Iron). Specifically, antacids may decrease the absorption of orally administered iron. Management: Separate dosing of oral iron-containing multivitamin preparations and antacids by as much time as possible in order to minimize impact on therapeutic efficacy of the iron preparation. Consider therapy modification

Mycophenolate: Antacids may decrease the absorption of Mycophenolate. Management: Separate doses of mycophenolate and antacids by at least 2 hours. Monitor for reduced effects of mycophenolate if taken concomitant with antacids. Consider therapy modification

Mycophenolate: Magnesium Salts may decrease the serum concentration of Mycophenolate. Management: Separate doses of mycophenolate and oral magnesium salts. Monitor for reduced effects of mycophenolate if taken concomitant with oral magnesium salts. Consider therapy modification

Neratinib: Antacids may decrease the serum concentration of Neratinib. Specifically, antacids may reduce neratinib absorption. Management: Separate the administration of neratinib and antacids by giving neratinib at least 3 hours after the antacid. Consider therapy modification

Neuromuscular-Blocking Agents: Magnesium Salts may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Nilotinib: Antacids may decrease the serum concentration of Nilotinib. Management: Separate the administration of nilotinib and any antacid by at least 2 hours whenever possible in order to minimize the risk of a significant interaction. Consider therapy modification

PAZOPanib: Antacids may decrease the serum concentration of PAZOPanib. Management: Avoid the use of antacids in combination with pazopanib whenever possible. Separate doses by several hours if antacid treatment is considered necessary. The impact of dose separation has not been investigated. Consider therapy modification

PenicillAMINE: Antacids may decrease the serum concentration of PenicillAMINE. Management: Separate the administration of penicillamine and antacids by at least 1 hour. Consider therapy modification

PenicillAMINE: Magnesium Salts may increase the serum concentration of PenicillAMINE. Management: Separate the administration of penicillamine and oral magnesium salts by at least 1 hour. Consider therapy modification

Phosphate Supplements: Antacids may decrease the absorption of Phosphate Supplements. Management: This applies only to oral phosphate administration. Separating administer of oral phosphate supplements from antacid administration by as long as possible may minimize the interaction. Exceptions: Sodium Glycerophosphate Pentahydrate. Consider therapy modification

Phosphate Supplements: Magnesium Salts may decrease the serum concentration of Phosphate Supplements. Management: Administer oral phosphate supplements as far apart from the administration of an oral magnesium salt as possible to minimize the significance of this interaction. Exceptions: Sodium Glycerophosphate Pentahydrate. Consider therapy modification

Potassium Phosphate: Antacids may decrease the serum concentration of Potassium Phosphate. Management: Consider separating administration of antacids and oral potassium phosphate by at least 2 hours to decrease risk of a significant interaction. Consider therapy modification

QuiNIDine: Antacids may decrease the excretion of QuiNIDine. Monitor therapy

QuiNINE: Antacids may decrease the serum concentration of QuiNINE. Avoid combination

Quinolones: Antacids may decrease the absorption of Quinolones. Of concern only with oral administration of quinolones. Management: Avoid concurrent administration of quinolones and antacids to minimize the impact of this interaction. Recommendations for optimal dose separation vary by specific quinolone. Exceptions: LevoFLOXacin (Oral Inhalation). Consider therapy modification

Quinolones: Magnesium Salts may decrease the serum concentration of Quinolones. Management: Administer oral quinolones several hours before (4 h for moxi/pe/spar-, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for lome/pe-, 3 h for gemi-, and 2 h for levo-, nor-, or ofloxacin or nalidixic acid) oral magnesium salts. Exceptions: LevoFLOXacin (Oral Inhalation). Consider therapy modification

Raltegravir: Magnesium Salts may decrease the serum concentration of Raltegravir. Management: Avoid the use of oral / enteral magnesium salts with raltegravir. No dose separation schedule has been established that adequately reduces the magnitude of interaction. Avoid combination

Rilpivirine: Antacids may decrease the serum concentration of Rilpivirine. Management: Administer antacids at least 2 hours before or 4 hours after rilpivirine. Administer antacids at least 6 hours before or 4 hours after the rilpivirine/dolutegravir combination product. Consider therapy modification

Riociguat: Antacids may decrease the serum concentration of Riociguat. Management: Separate the administration of antacids and riociguat by at least 1 hour in order to minimize any potential interaction. Consider therapy modification

Rosuvastatin: Antacids may decrease the serum concentration of Rosuvastatin. Monitor therapy

Sodium Polystyrene Sulfonate: Laxatives (Magnesium Containing) may enhance the adverse/toxic effect of Sodium Polystyrene Sulfonate. More specifically, concomitant use of sodium polystyrene sulfonate with magnesium-containing laxatives may result in metabolic alkalosis or with sorbitol may result in intestinal necrosis. Management: Avoid concomitant use of sodium polystyrene sulfonate (rectal or oral) and magnesium-containing laxatives. Avoid combination

Sotalol: Antacids may decrease the serum concentration of Sotalol. Management: Avoid simultaneous administration of sotalol and antacids. Administer antacids 2 hours after sotalol. Consider therapy modification

Strontium Ranelate: Magnesium Hydroxide may decrease the serum concentration of Strontium Ranelate. Management: Separate administration of strontium ranelate and magnesium hydroxide by at least 2 hours whenever possible in order to minimize this interaction. Consider therapy modification

Sulpiride: Antacids may decrease the serum concentration of Sulpiride. Management: Separate administration of antacids and sulpiride by at least 2 hours in order to minimize the impact of antacids on sulpiride absorption. Consider therapy modification

Tetracyclines: Antacids may decrease the absorption of Tetracyclines. Management: Separate administration of antacids and oral tetracycline derivatives by several hours when possible to minimize the extent of this potential interaction. Consider therapy modification

Tetracyclines: Magnesium Salts may decrease the absorption of Tetracyclines. Only applicable to oral preparations of each agent. Consider therapy modification

Trientine: Antacids may decrease the absorption of Trientine. Management: Separate trientine dosing from other oral drugs (eg, antacids) by at least 1 hour. Monitor for decreased therapeutic effects of trientine if an antacid is initiated/dose increased, or increased effects if an antacid is discontinued/dose decreased. Consider therapy modification

Trientine: May decrease the serum concentration of Magnesium Salts. Magnesium Salts may decrease the serum concentration of Trientine. Consider therapy modification

Velpatasvir: Antacids may decrease the serum concentration of Velpatasvir. Management: Separate administration of velpatasvir and antacids by at least 4 hours. Consider therapy modification

Warnings and Precautions

Disease-related concerns:

Neuromuscular disease: Use with extreme caution in patients with myasthenia gravis or other neuromuscular disease.
Renal impairment: Use with caution in patients with renal impairment; accumulation of magnesium may lead to magnesium intoxication.

Other warnings and precautions

For occasional use only; serious side effects may occur with prolonged use. For use only under the supervision of a health care provider in patients with kidney dysfunction, a magnesium-restricted diet, stomach pain/nausea/vomiting, or with a sudden change in bowel habits which persist for >2 weeks. Patients should stop use as a laxative and notify health care provider of any rectal bleeding, if bowel movement does not occur after using product, or if use is needed for >1 week. Stop use as an antacid and notify health care provider if you have taken the maximum dose for >2 weeks. Not for over-the-counter use in children <2 years of age.

Magnesium hydroxide dosage

Adult Antacid (OTC Oral) Dose

Liquid: Magnesium hydroxide 400 mg/5 mL: 5 to 15 mL as needed up to 4 times/day; do not exceed 60 mL in 24 hours
Tablet, chewable: Magnesium hydroxide 311 mg/tablet: 2 to 4 tablets every 4 hours up to 4 times/day; do not exceed 4 doses in 24 hours

Adult Laxative (occasional constipation) Oral Dose

Liquid:

Magnesium hydroxide 400 mg/5 mL: 30 to 60 mL/day once daily at bedtime or in divided doses
Magnesium hydroxide 800 mg/5 mL: 15 to 30 mL/day once daily at bedtime or in divided doses
Magnesium hydroxide 1,200 mg/5 mL: 10 to 20 mL/day once daily at bedtime or in divided doses

Tablet, chewable:

Magnesium hydroxide 311 mg/tablet: 8 tablets/day once daily at bedtime or in divided doses

Pediatric Antacid (OTC Oral) Dose

Liquid: Magnesium hydroxide 400 mg/5 mL: Children ≥12 years: Refer to adult dosing.
Tablet, chewable: Magnesium hydroxide 311 mg/tablet:

Children <12 years: Use NOT recommended.

Children ≥12 years: Refer to adult dosing.

Pediatric Laxative (occasional constipation) Oral Dose

Liquid:

Children <2 years: Use NOT recommended.
Children 2 to 5 years: Magnesium hydroxide 400 mg/5 mL: 5 to 15 mL/day once daily at bedtime or in divided doses
Children 6 to 11 years:
- Magnesium hydroxide 400 mg/5 mL: 15 to 30 mL/day once daily at bedtime or in divided doses
- Magnesium hydroxide 1,200 mg/5 mL: 5 to 10 mL/day once daily at bedtime or in divided doses
Children ≥12 years: Refer to adult dosing.

Tablet, chewable Magnesium hydroxide 311 mg/tablet:

Children <3 years: Use NOT recommended.
Children 3 to 5 years: 2 tablets/day once daily at bedtime or in divided doses
Children 6 to 11 years: 4 tablets/day once daily at bedtime or in divided doses
Children ≥12 years: Refer to adult dosing.

Tablet, chewable Magnesium hydroxide 400 mg/tablet:

Children <2 years: Use NOT recommended.
Children 2 to 5 years: 1 to 3 tablets/day once daily or in divided doses (maximum daily dose: 3 tablets)
Children 6 to 11 years: 3 to 6 tablets/day once daily or in divided doses (maximum daily dose: 6 tablets)

What should I do if I forget a dose?

This medication usually is taken as needed. If your doctor has told you to take magnesium hydroxide regularly, take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Magnesium hydroxide side effects

Magnesium hydroxide may cause side effects. If you experience any of the following symptoms, call your doctor immediately:

stomach cramps
upset stomach
vomiting
diarrhea

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration’s (FDA) MedWatch Adverse Event Reporting program online (https://www.fda.gov/Safety/MedWatch/default.htm).

Gastrointestinal side effects

Diarrhea may occur and is occasionally severe enough to cause dehydration and electrolyte abnormalities.

Gastrointestinal side effects have included diarrhea and minor gastrointestinal discomfort.

General side effects

General side effects have included signs and symptoms of hypermagnesemia. These have included hypotension, nausea, vomiting, EKG changes, respiratory depression, mental depression and coma.

Magnesium may be systemically absorbed following administration of magnesium hydroxide. In patients with normal renal function, increased magnesium elimination in the urine occurs and no significant changes in serum magnesium levels would be expected. However, magnesium may accumulate in patients with renal insufficiency.

Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
Very upset stomach or throwing up.
Very loose stools (diarrhea).
Not hungry.
Muscle weakness.

A 28 yr old ingested magnesium hydroxide-aluminum hydroxide simethicone (average daily consumption of 21 g each of magnesium hydroxide and aluminum hydroxide) and developed phosphate depletion, nephrolithiasis, and bilateral ureteric obstruction ¹⁵. Myalgia, weakness, and bone pain were absent. Biochemical features included hypophosphatemia, hypercalcemia, hypophosphatasia, elevated plasma 1,2-dihydroxyvitamin D level, and low plasma intact parathyroid hormone level. These abnormalities were corrected when antacid ingestion was reduced and phosphate intake supplemented.

Magnesium hydroxide laxatives administered to infants and neonates may induce symptoms of severe magnesium intoxication with elevated serum magnesium levels. Renal immaturity may be a factor ¹⁶.

Most available toxicity data on magnesium hydroxide describe effects of acute exposure to magnesium hydroxide or of prolonged exposure to antacid or laxative products containing Mg(OH)₂. Magnesium intoxication has been reported in infants (2–42 days old) that received Mg²⁺-containing oral laxatives at Mg²⁺ doses of 224–917 mg/kg per day for 2–11 days ¹⁷. Whereas normal serum magnesium ranges from 1.4 to 2.4 mEq/L, these infants had concentrations of 3.5–11.7 mEq/L. In one case, Mg²⁺ body burden was high enough to cause perforation of the bowel ¹⁷.

In adults, serious toxic effects associated with excess magnesium intake occur at very high intake levels equating to serum concentrations of 4 mEq/L ¹⁸. Toxicity has been limited to persons with intestinal or renal disease ¹⁹. The Hazardous Substance Data Bank entry for magnesium hydroxide states that the probable oral lethal dose of magnesium hydroxide in humans is 5–15 g/kg in a 70-kg person ²⁰. Cardiac arrest has been reported at serum Mg²⁺ concentrations of 15–16 mEq/L ²¹. Respiratory depression, depression of the central nervous system, and coma occur in adult patients with plasma Mg²⁺ concentrations of 10–14 mEq/L ²². Hypotension, nausea, and vomiting occur at plasma concentrations of 3–8 mEq/L.

Reported fatal magnesium hydroxide dose

Probable oral lethal dose is 5 to 15 gram/kg body weight, between 1 pint (473 ml) and 1 quart (946 ml) for a 70 kg (150 lb) person ²⁰.

Cancer

The National Academy of Sciences subcommittee found no oral chronic toxicity studies or epidemiological studies that investigated the carcinogenicity of magnesium hydroxide in rodents or humans. The subcommittee concludes that magnesium hydroxide Mg(OH)₂ is not likely to be carcinogenic to humans by the oral route. No adequate data are available to assess the carcinogenicity of Mg(OH)₂ by the dermal or inhalation or routes of exposure.

Mice fed 0.5% or 2% of aqueous MgCl2 in their diet for 96 weeks (68, or 336 mg/kg per day for males; 87 or 470 mg/kg per day for females) showed no significant change in the incidence of malignant lymphoma and leukemia ²³. Dose-related increases in incidence of malignant lymphoma and leukemia occurred in male mice (controls, five of 50; low dose, seven of 50; high dose, eleven of 50), but not in females (controls, nine of 49; low dose, 17 of 50; high dose, 11 of 50). The incidence of hepatocellular carcinomas in male mice was decreased in a dose-related manner (controls, 13 of 50; low dose, six of 50; high dose, four of 50) and the incidence in high-dose males was significantly different from that in controls. Toxicity in female mice (i.e., decreased body weight) suggests that the study was conducted at or near the maximum tolerated dose for females.

There are insufficient data to assess the carcinogenicity of Mg(OH)₂. EPA, the National Toxicology Program (NTP), and the International Agency for Research on Cancer (IARC) have not evaluated the carcinogenicity of Mg(OH)₂.

A chronic study in mice exposed to Mg(OH)₂ filaments did not find evidence of carcinogenicity. Studies in rats suggest that Mg(OH)₂ incorporated into the diet can protect against some chemically induced cancers ²⁴. The subcommittee is not aware of any mutagenicity data on magnesium hydroxide. However, genotoxicity studies conducted with several magnesium salts have all been negative.

On the basis of the data available, the National Academy of Sciences subcommittee concludes that there are insufficient data on oral carcinogenicity of magnesium hydroxide to determine its carcinogenicity.

References

National Research Council (US) Subcommittee on Flame-Retardant Chemicals. Toxicological Risks of Selected Flame-Retardant Chemicals. Washington (DC): National Academies Press (US); 2000. 7, Magnesium Hydroxide. Available from: https://www.ncbi.nlm.nih.gov/books/NBK225636
FDA (U.S. Food and Drug Administration). 1999. Direct Food Substances Affirmed as Generally Recognized as Safe; Magnesium Hydroxide. Fed. Regist. 50(Apr. 5, 1985):13557, 21 CFR Part 184. 1428, as amended at Fed. Regist. 64 (Jan. 5, 1999):404–405.
Fire Retardant Chemicals Association. 1998. Textile Flame Retardant Applications by Product Classes for 1997 Within and Outside of the United States: Magnesium Hydroxide. Fire Retardants Chemicals Association, Lancaster, PA.
IPCS (International Programme on Chemical Safety). 1997. Flame Retardants: A General Introduction. Environmental Health Criteria 192. International Programme on Chemical Safety. Geneva: World Health Organization.
HSDB (Hazardous Substances Data Bank). 1998. Magnesium hydroxide.
Benech, H., A.Pruvost, A.Batel, M.Bourguignon, J.L.Thomas, and J.M.Grognet. 1998. Use of the stable isotopes technique to evaluate the bioavailability of a pharmaceutical form of magnesium in man. Pharm. Res. 15(2):347–351
Usami, M., K.Sakemi, M.Tsuda, and Y.Ohno. 1996. Teratogenicity study of magnesium chloride hexahydrate in rats. Eisei Shikenjo Hokoku 114:16–20. https://www.ncbi.nlm.nih.gov/pubmed/9037859
Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty’s Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 225
Cruikshank DP, Varner MW, Pitkin RM. Breast milk magnesium and calcium concentrations following magnesium sulfate treatment. Am J Obstet Gynecol. 1982;143:685-8. https://www.ncbi.nlm.nih.gov/pubmed/7091241
Baldwin WF. Clinical study of senna administration to nursing mothers. Can Med Assoc J. 1963;89:566-7.
Haldeman W. Can magnesium sulfate therapy impact lactogenesis? J Hum Lact. 1993;9:249-52. https://doi.org/10.1177/089033449300900426
Riaz M, Porat R, Brodsky NL et al. The effects of maternal magnesium sulfate treatment on newborns: a prospective controlled study. J Perinatol. 1998;18:449-54. https://www.ncbi.nlm.nih.gov/pubmed/9848759
Rasch DK, Huber PA, Richardson CJ et al. Neurobehavioral effects of neonatal hypermagnesemia. J Pediatr. 1982;100:272-6. https://www.jpeds.com/article/S0022-3476(82)80654-9/pdf
Meier B, Huch R, Zimmermann R et al. Does continuing oral magnesium supplementation until delivery affect labor and puerperium outcome? Eur J Obstet Gynecol Reprod Biol. 2005;123:157-61. https://www.ejog.org/article/S0301-2115(05)00152-1/fulltext
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn’s Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 759
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn’s Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 1585
Mofenson, H.C., and T.R.Caraccio. 1991. Magnesium intoxication in a neonate from oral magnesium hydroxide laxative. J. Toxicol. Clin. Toxicol. 29(2):215–222.
Rude, R.K., and F.R.Singer. 1981. Magnesium deficiency and excess. Ann. Rev. Med. 32:245–259.
Poisindex®. 1998. Toxicologic management of magnesium. 8/31/98. Micromedex, Inc.
HSDB (Hazardous Substances Data Bank). 1998. Magnesium hydroxide. https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@[email protected]+659
Dreisbach, R.H. 1977. Handbook of Poisoning: Diagnosis and Treatment, Ninth Edition. Los Altos, CA: Lange Medical Publications.
Ferdinandus, J., J.A.Pederson, and R.Whang. 1981. Hypermagnesemia as a cause of refractory hypotension, respiratory depression, and coma. Arch. Intern. Med. 141(5):669–670.
Kurata, Y., S.Tamano, M.A.Shibata, A.Hagiwara, S.Fukushima, and N.Ito. 1989. Lack of carcinogenicity of magnesium chloride in a long-term feeding study in B6C3F1 mice. Food Chem. Toxicol. 27(9):559–563.
Wang, A., N.Yoshimi, T.Tanaka, and H.Mori. 1994. The inhibitory effect of magnesium hydroxide on the bile acid-induced cell proliferation of colon epithelium in rats with comparison to the action of calcium lactate. Carcinogenesis 15(11):2661–2663.

Drugs Drugs & Supplements

Benzoyl peroxide

by Health Jade Team on August 6, 2018

What is benzoyl peroxide

Benzoyl peroxide is a commonly used topical (for the skin) treatment for mild acne. It is safe for adults and children, and can be used in pregnancy. Benzoyl peroxide may also be used for other skin conditions as determined by your doctor. Benzoyl peroxide is an oxidizing agent that possesses antibacterial properties and is classified as a keratolytic. Benzoyl peroxide is meant to help remove the layer of dead cells on the outer surface of your skin. This makes it easier for oil (sebum) to leave the skin pore, preventing the sebaceous glands from clogging. Benzoyl peroxide also has antibacterial properties and, unlike with antibiotics, there is no risk that bacteria will become resistant if you use it a lot.

Benzoyl peroxide has the following properties:

Antiseptic i.e. it reduces the number of skin surface bacteria (but it does not cause bacterial resistance and in fact can reduce bacterial resistance if this has arisen from antibiotic therapy). It also reduces the number of yeasts on the skin surface.
Oxidizing agent – this makes it keratolytic and comedolytic i.e. it reduces the number of comedones.
Anti-inflammatory action.

In mild to moderate acne, benzoyl peroxide can lead to an improvement within a few weeks. Results has been noted in as soon as 5 days ¹. But it can also irritate your skin, causing problems like redness and itching. If benzoyl peroxide comes into contact with clothes and hair it may bleach them, so it is advisable to be cautious when applying it. The effectiveness of benzoyl peroxide does not depend on which form it is used in. Benzoyl peroxide is available in the form of gels, lotions and creams. Benzoyl peroxide comes in various concentrations: 2.5%, 5% and 10%. Products with higher concentrations do not work better than those with lower concentrations, but side effects are more common when 10% benzoyl peroxide is used.

Benzoyl peroxide (C14H10O4) is represented by the structure in Figure 1. Benzoyl peroxide is available without prescription over the counter and benzoyl peroxide is also available on prescription in combination with other active agents.

A meta-analysis (a statistical procedure for combining data from multiple studies in an effort to increase power over individual studies to improve estimates of the size of the effect) comparing the effectiveness of multiple treatments containing 5% benzoyl peroxide, 1% to 1.2% clindamycin, 5% benzoyl peroxide with salicylic acid preparation and combination benzoyl peroxide plus clindamycin in acne lesion reduction ². Benzoyl peroxide and clindamycin combination is used to treat acne. It works by killing the bacteria that cause acne and by keeping the skin pores clean (tiny openings on the skin). The study authors found at 2 to 4 weeks, 5% benzoyl peroxide + salicylic acid had statistically greater percent acne lesion reductions over other groups (weighted mean inflammatory lesion reduction: benzoyl peroxide = 33.4%, clindamycin = 21.5%, benzoyl peroxide + salicylic acid = 55.2%, benzoyl peroxide + clindamycin = 40.7%, placebo = 7.3%; weighted mean noninflammatory lesion reduction: benzoyl peroxide = 19.1%, clindamycin = 10.0%, benzoyl peroxide + salicylic acid = 42.7%, benzoyl peroxide/clindamycin = 26.2%, placebo = 6.7%). At 10- to 12-week end points, 5% benzoyl peroxide + salicylic acid and benzoyl peroxide/clindamycin were similar, with overlapping confidence intervals (weighted mean inflammatory lesion reduction: benzoyl peroxide = 43.7%, clindamycin = 45.9%, benzoyl peroxide + salicylic acid = 51.8%, benzoyl peroxide/clindamycin = 55.6%, placebo = 26.8%; weighted mean noninflammatory lesion reduction: benzoyl peroxide = 30.9%, clindamycin = 32.6%, benzoyl peroxide + salicylic acid = 47.8%, benzoyl peroxide + clindamycin = 40.3%, placebo = 17.0%). In another word, the authors concluded that at two to four weeks, combination 5 percent benzoyl peroxide plus salicylic acid had the best profile for treating acne vulgaris; at 10 to 12 weeks, this combination treatment was similar to 5 percent benzoyl peroxide + clindamycin treatment. 5 percent benzoyl peroxide + clindamycin was only incrementally better than 5 percent benzoyl peroxide alone but was superior to 1% to 1.2% clindamycin alone. Potential limitations with the review process and the uncertain quality of included trials suggest that the authors’ conclusions should be treated with caution.

Topical antibiotics for acne accumulate in the hair follicle and have been postulated to work through antiinflammatory mechanisms and via antibacterial effects ³. These agents are best used in combination with benzoyl peroxide (wash-off or leave-on), which increases efficacy and decreases the development of resistant bacterial strains. Monotherapy with topical antibiotics in the management of acne is not recommended because of the development of antibiotic resistance. Clindamycin 1% solution or gel is currently the preferred topical antibiotic for acne therapy ⁴. Topical erythromycin in 2% concentration is available as a cream, gel, lotion, or pledget, but has reduced efficacy in comparison with clindamycin because of resistance of cutaneous Staphylococci and Propionibacterium acnes ³. Stable, fixed-combination agents are available with erythromycin 3%/benzoyl peroxide 5%, clindamycin 1%/benzoyl peroxide 5%, and clindamycin 1%/benzoyl peroxide 3.75% ⁵. Combination agents may enhance compliance with treatment regimens. Rare reports of diarrhea or Clostridium difficile–related colitis with clindamycin topically have appeared in the literature, but the risk appears low ⁶. Tolerance of these agents is excellent; clindamycin alone is pregnancy category B (Pregnancy category B means animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women).

How to use benzoyl peroxide products:

Make sure your skin is clean and dry before applying
Apply a thin smear to areas of skin affected by acne, initially every second night, then build up to once or twice daily as tolerated
It can be used on the face as well as the trunk
Be patient: acne responds very slowly to treatment. Results has been noted in as soon as 5 days ¹, but it may take several months to notice improvement

Problems with benzoyl peroxide products:

Dryness of the treated area can be expected and is usually mild. If the skin is visibly scaly, apply a light non-oily moisturizer.
Skin irritation is rarely severe. Occasionally, irritation means that product must be discontinued. Consider applying it less frequently.
Contact dermatitis (red, dry, itchy skin) can be due to irritation or allergy. It can be treated with a topical steroid such as hydrocortisone cream.
Rarely, serious allergic reactions to benzoyl peroxide, including anaphylaxis, have been reported.
Bleaching of clothing. Make sure the benzoyl peroxide has completely dried before the treated skin touches clothes or bedding. It is more likely to stain cotton and linen fabrics than polyester and fleece fabrics ⁷.

Figure 1. Benzoyl peroxide

Other treatment options for acne

There are many treatment options for acne, including topical and oral medication, and over-the-counter or prescription-only products. But what is the right product for you?

The treatment options for acne will depend on a number of different things. For instance:

How severe is your acne?
What is your skin type (dry, oily or combination)?
How upsetting do you find your acne?
Are you susceptible to acne scarring?
Do you have other health problems?
Are you male or female?
Which treatments have you already tried out and how well did they work?
What kinds of side effects do the different products have, and how unpleasant do you think those side effects are?

Nearly all acne treatments require a lot of patience. Many of them only start working after several weeks or months. But it can be worth the wait, and is better than constantly switching treatments, which can sometimes make you feel like nothing will help.

People with acne sometimes also use complementary or alternative medicines to try to improve their skin. These include things like herbal and homeopathic products, tea tree oil and purified bee venom. Acupuncture, cupping and special massages are offered for the treatment of acne too. But none of these products or approaches have been clearly proven to work yet.

Oral Hormones

One of the main causes of acne is higher levels of, or an increased sensitivity to, the hormone androgen. Certain hormone products can reduce the production and effect of androgen, leading to better skin.

Some hormone products can be prescribed especially for the treatment of acne. These medicines also have a contraceptive effect. Three combinations have been approved for the treatment of acne in girls and women:

Ethinyl estradiol / cyproterone acetate
Ethinyl estradiol / chlormadinone acetate
Ethinyl estradiol / dienoges

In women with moderate to severe acne, these hormone products are often used together with a topical treatment in order to improve the overall effect.

Hormone products such as birth control pills, on the other hand, are intended for contraceptive use and are usually not approved for the treatment of acne. But if girls and women who have acne use the contraceptive pill as a form of contraception, it may also have a positive effect on their acne. This is only true, though, if they take a pill that has the hormones estrogen and progestin in it.

Hormone products can also cause side effects, such as headaches and nausea. They increase the risk of deep vein thrombosis too – some more so than others.

Oral Retinoids

Retinoid tablets are the most effective medications for the treatment of acne, but they also have the most side effects. Because of this, they are generally only used if other medications have not worked. Retinoid tablets can lead to noticeable improvement, or might even make acne clear up completely. Acne sometimes comes back again after a while, though.

Because retinoids lower the production of oil in the skin, people who take them might have dry lips, skin and eyes. Other side effects include headaches, achy joints and backache. The higher the dose of retinoids you take, the more likely you are to experience side effects. Pregnant and breastfeeding women should not take retinoids.

Retinoids will only be considered as a treatment option for sexually active women if they use at least one contraceptive method, or preferably two at the same time. For example, if they take the pill and use condoms as well, to be on the safe side. Women must keep using contraception for at least four weeks after they stop taking retinoids. This is because retinoids can be harmful to unborn babies.

A few years ago there were a number of reports that taking isotretinoin led to a higher risk of suicide. This has not been confirmed by scientific studies. Still, it is important to look out for any unusual changes in mood if you are taking retinoids, and inform your doctor if you have any. In any case, it always makes sense to seek medical and/or psychological help if acne is a major problem for someone or if it causes mental health problems.

Light-based therapy

Besides topical and oral medications, different types of light-based therapy can be used to treat acne. Generally speaking, there has not been enough good-quality research on these approaches.

Laser treatment and intense pulsed light therapy

There is some evidence that laser treatment and intense pulsed light therapy can lead to a short-term improvement in inflammatory acne. But there is a lack of good research on the long-term benefits of these treatment approaches. So it is not clear whether they represent an alternative to other therapies that have been proven to be effective.

Phototherapy

Somewhat more research has been done on phototherapy. This treatment approach involves shining UV light on the affected areas of skin under medical supervision. This is meant to help kill bacteria in the acne. Research suggests that this treatment can improve acne, at least in the short term. Phototherapy is not the same as using a tanning bed.

Is benzoyl peroxide safe?

Yes, benzoyl peroxide is safe for skin (topical) use for acne. However, like any medicine benzoyl peroxide is not right for everyone. Do not use benzoyl peroxide if you had an allergic reaction to benzoyl peroxide.

Topical benzoyl peroxide has not been studied during breastfeeding. Because only about 5% is absorbed following topical application, it is considered a low risk to the nursing infant ¹⁷. Ensure that your baby’s skin does not come into direct contact with the areas of skin that have been treated. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking ¹⁸.

There is inadequate evidence in humans for the carcinogenicity of benzoyl peroxide. There is limited evidence in experimental animals for the carcinogenicity of benzoyl peroxide. Overall evaluation: Benzoyl peroxide is NOT classifiable as a human carcinogen ¹⁹. The International Agency for Research on Cancer ²⁰.

What does benzoyl peroxide do

Benzoyl peroxide is an oxidizing agent that possesses antibacterial properties and is classified as a keratolytic. Benzoyl peroxide is meant to help remove the layer of dead cells on the outer surface of your skin (comedolytic) ²¹. This makes it easier for oil (sebum) to leave the skin pore, preventing the sebaceous glands from clogging. Benzoyl peroxide also has antibacterial properties that kills Propionibacterium acnes bacteria and, unlike with antibiotics, there is no risk that bacteria will become resistant if you use it a lot. Propionibacterium acnes is a gram-positive human skin commensal that prefers anaerobic growth conditions and is involved in the development of acne ²². Benzoyl peroxide is an antibacterial agent that kills Propionibacterium acnes through the release of free oxygen radicals. The addition of benzoyl peroxide to regimens of antibiotic therapy enhances results and may reduce antibiotic resistance development. Benzoyl peroxide is available as topical washes, foams, creams, or gels, and can used as leave-on or wash-off agents. Strengths available for acne therapy range from 2.5% to 10%. Benzoyl peroxide therapy is limited by concentration-dependent irritation, staining and bleaching of fabric, and uncommon contact allergy. Total skin contact time and formulation can also affect efficacy. Lower concentrations (e.g, 2.5-5%), water-based, and wash-off benzoyl peroxide agents may be better tolerated in patients with more sensitive skin ²³. Results can be noted in as soon as 5 days ¹.

Benzoyl peroxide products

Acne-Clear, Benzac AC, BenzePrO, Benziq, BPO, Brevoxyl Acne Wash Kit, Clearplex, Clearskin, Desquam-X Wash, Fostex Wash 10%, NeoBenz Micro, Neutrogena Acne Mask, Oscion, Oxy Balance, Oxy Daily Wash, Oxy-10, Pacnex, PanOxyl, Persa-Gel, Riax, SoluCLENZ Rx, Triaz, Benzac, Desquam-X 10, Benzashave 5, Benzashave 10, Panoxyl AQ 2.5, Desquam-E, Benzac W, Brevoxyl, Panoxyl AQ 5, Panoxyl 5, Desquam-X 5, Persa-Gel W, Benzagel-5, Panoxyl 10, Panoxyl AQ 10, Benzagel-10, Peroxin A 10, Triaz Cleanser, Benoxyl 5, Acne Treatment, Ben-Aqua, Del-Aqua, Peroxin A, Zeroxin, Acne-10, Benoxyl 10, Fostex Bar 10%, Fostex Gel 10%, Clear By Design, Loroxide, Vanoxide, Oxy Vanishing Gel, Neutrogena On Spot Acne Treatment, Seba-Gel, Brevoxyl Creamy Wash, Clinac BPO, Benzagel Wash, Ethexderm, Oxy 10 Balance, Zaclir, Benziq LS, Benziq Wash, ZoDerm Redi-Pads (obsolete), Panoxyl Aqua Gel, Oscion Cleanser, Inova, NeoBenz Micro SD, Lavoclen-4 Creamy Wash, Lavoclen-8 Creamy Wash, Oxy Daily Wash Chill Factor, Oxy Spot Treatment, PanOxyl Maximum Strength Foaming Acne Wash, Lavoclen-4, Lavoclen-8, Breze, Brevoxyl-4 Creamy Wash Complete Pack, Brevoxyl-8 Creamy Wash Complete Pack, NeoBenz Micro Wash, NeoBenz Micro Wash Plus Pack, Triaz Foaming Cloths, Triaz Pads, BenzEFoam, Pacnex MX Wash, NeoBenz Micro Cream Plus Pack, Benzac AC Wash, BPO Foaming Cloths, Pacnex HP, Pacnex LP, BenzEFoam Ultra, BP Cleansing Lotion, BP Wash, OC8, Delos, PR Benzoyl Peroxide Wash and Differin Daily Deep Cleanser

Benzoyl peroxide uses

Benzoyl peroxide topical (for the skin) is used to treat acne.

The therapy of acne in children <12 years of age with products approved by the FDA has expanded. Fixed combination benzoyl peroxide 2.5%/adapalene 1% gel is approved for patients ≥9 years of age, and tretinoin 0.05% micronized tretinoin gel for patients ≥10 years of age. All other retinoids are approved by the FDA for patients ≥12 years of age. Current data show that retinoids in younger patients are effective and are not associated with increased irritation or risk.

How to use benzoyl peroxide

Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products.

Benzoyl peroxide is not right for everyone. Do not use benzoyl peroxide if you had an allergic reaction to benzoyl peroxide.

Bar, Cream, Foam, Gel/Jelly, Liquid, Lotion, Pad, Soap

When you first begin to use benzoyl peroxide, apply it to 1 or 2 small affected areas of the skin for 3 days. If no discomfort occurs, follow the directions on the product label or use benzoyl peroxide as directed by your doctor.

Use benzoyl peroxide only on your skin. Rinse it off right away if benzoyl peroxide gets on a cut or scrape. Do not get benzoyl peroxide in your eyes, nose, or mouth.

Missed dose: Apply a dose as soon as you can. If it is almost time for your next dose, wait until then and apply a regular dose. Do not apply benzoyl peroxide to make up for a missed dose.

Store benzoyl peroxide in a closed container at room temperature, away from heat, moisture, and direct light. Do not freeze.

Warnings

Tell your doctor if you are pregnant or breastfeeding, or if you ever had an allergic reaction to an acne product.

Benzoyl peroxide may bleach your hair or clothes.

Benzoyl peroxide may make your skin more sensitive to sunlight. Wear sunscreen. Do not use sunlamps or tanning beds.

Call your doctor if your symptoms do not improve or if they get worse.

Keep all medicine out of the reach of children. Never share your medicine with anyone.

Benzoyl peroxide side effects

Benzoyl peroxide topical can cause a rare but serious allergic reaction or severe skin irritation. These reactions may occur just a few minutes after you apply the medicine, or within a day or longer afterward.

Stop using benzoyl peroxide topical and get emergency medical help if you have signs of an allergic reaction: hives, itching; difficult breathing, feeling light-headed; swelling of your face, lips, tongue, or throat.

Some side effects of benzoyl peroxide topical may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

dryness or peeling of the skin (may occur after a few days)
feeling of warmth, mild stinging, and redness of the skin

Common side effects may include:

mild stinging or burning;
itching or tingly feeling;
skin dryness, peeling, or flaking; or
redness or other irritation.

Stinging or burning sensation for a brief time after benzoyl peroxide topical application, with continuous use these effects mostly disappear. After 1 or 2 weeks of benzoyl peroxide topical use there may be a sudden excess of dryness of your skin and peeling ²⁴.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

Call your doctor right away if you notice any of these side effects:

Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat, chest tightness, trouble breathing
Burning, blistering, swollen, or peeling skin
Fainting
Swelling of the eyes, face, lips, or tongue

Stop using benzoyl peroxide and call your doctor at once if you have any of these side effects on the treated skin:

severe itching or burning;
severe stinging or redness;
swelling; or
peeling.

Less common or rare side effects of benzoyl peroxide:

painful irritation of skin, including burning, blistering, crusting, itching, severe redness, or swelling
skin rash

Incidence not known

difficult breathing
fainting
hives
itching
swelling of the eyes, face, lips, or tongue
tightness in the throat

Get emergency help immediately if any of the following symptoms of overdose occur while taking benzoyl peroxide topical:

Symptoms of Overdose

Burning, itching, scaling, redness, or swelling of skin (severe).

References

Schutte H, Cunliffe WJ, Forster RA. The short-term effects of benzoyl peroxide lotion on the resolution of inflamed acne lesions. Br J Dermatol. 1982;106:91-94.
Meta-analysis comparing efficacy of benzoyl peroxide, clindamycin, benzoyl peroxide with salicylic acid, and combination benzoyl peroxide/clindamycin in acne. JAAD July 2010, Volume 63, Issue 1, Pages 52–62 https://www.jaad.org/article/S0190-9622(09)00987-6/fulltext
Mills O Jr, Thornsberry C, Cardin CW, Smiles KA, Leyden JJ. Bacterial resistance and therapeutic outcome following three months of topical acne therapy with 2% erythromycin gel versus its vehicle. Acta Derm Venereol. 2002;82:260-265.
Padilla RS, McCabe JM, Becker LE. Topical tetracycline hydrochloride vs. topical clindamycin phosphate in the treatment of acne: a comparative study. Int J Dermatol. 1981;20:445-448.
Pariser DM, Rich P, Cook-Bolden FE, Korotzer A. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 3.75% for the once-daily treatment of moderate to severe acne vulgaris. J Drugs Dermatol. 2014;13:1083-1089.
Mills OH, Jr., Kligman AM, Pochi P , Comite H. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. International journal of dermatology 1986;25:664-7.
Edwards T, Cardwell L, Patel N, Feldman SR, Title: Benzoyl Peroxide Gel Stains Synthetic Fabrics less than Cotton, Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2018.05.008.
Topical therapies: Recommendations. https://www.aad.org/practicecenter/quality/clinical-guidelines/acne/topical-therapies
Kircik LH. Efficacy and safety of azelaic acid (AzA) gel 15% in the treatment of post-inflammatory hyperpigmentation and acne: a 16-week, baseline-controlled study. J Drugs Dermatol. 2011;10:586-590.
Zouboulis CC, Derumeaux L, Decroix J, Maciejewska-Udziela B, Cambazard F , Stuhlert A. A multicentre, single-blind, randomized comparison of a fixed clindamycin phosphate/tretinoin gel formulation (Velac) applied once daily and a clindamycin lotion formulation (Dalacin T) applied twice daily in the topical treatment of acne vulgaris. Br J Dermatol 2000;143:498-505.
Cunliffe WJ, Caputo R, Dreno B, Forstrom L, Heenen M, Orfanos CE et al. Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials. Journal of the American Academy of Dermatology 1997;36:S126-34.
Del Rosso JQ, Kircik L, Gallagher CJ. Comparative efficacy and tolerability of dapsone 5% gel in adult versus adolescent females with acne vulgaris. J Clin Aesthet Dermatol. 2015;8:31-37.
Lucky AW, Cullen SI, Funicella T, et al. Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris. J Am Acad Dermatol. 1998;38:S24-S30.
Dreno B, Bettoli V, Ochsendorf F, et al. Efficacy and safety of clindamycin phosphate 1.2%/tretinoin 0.025% formulation for the treatment of acne vulgaris: pooled analysis of data from three randomised, double-blind, parallel-group, phase III studies. Eur J Dermatol. 2014;24:201-209.
Pedace FJ, Stoughton R. Topical retinoic acid in acne vulgaris. Br J Dermatol. 1971;84:465-469.
Lucky AW, Cullen SI, Funicella T, Jarratt MT, Jones T , Reddick ME. Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris. Journal of the American Academy of Dermatology 1998;38:S24-30.
Leachman SA, Reed BR. The use of dermatologic drugs in pregnancy and lactation. Dermatol Clin. 2006;24:167-97. https://www.ncbi.nlm.nih.gov/pubmed/16677965
Noti A, Grob K, Biedermann M et al. Exposure of babies to C(15)-C(45) mineral paraffins from human milk and breast salves. Regul Toxicol Pharmacol. 2003;38:317-25. https://www.ncbi.nlm.nih.gov/pubmed/14623482
American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 14
BENZOYL PEROXIDE. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. https://monographs.iarc.fr/ENG/Monographs/vol71/mono71-13.pdf
Cunliffe WJ, Dodman B, Ead R. Benzoyl peroxide in acne. Practitioner. 1978;220:479-482.
Kirschbaum JO, Kligman AM. The pathogenic role of Corynebacterium acnes in acne vulgaris. Archives of Dermatology. 1963;88:832–833
Fyrand O, Jakobsen HB. Water-based versus alcohol-based benzoyl peroxide preparations in the treatment of acne vulgaris. Dermatologica. 1986;172:263-267.
Osol, A. (ed.). Remington’s Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980., p. 728

Drugs Drugs & Supplements

Mannitol

by Health Jade Team on August 5, 2018

What is mannitol

Mannitol is a naturally occurring alcohol found in fruits and vegetables and mannitol is used as an osmotic diuretic and a renal diagnostic aid. Mannitol therapy is widely used in the clinical setting for acute and subacute reduction in brain edema, to decrease muscle damage in compartment syndrome, and to improve renal perfusion ¹. Mannitol is freely filtered by the kidney’s glomerulus and mannitol is poorly reabsorbed from the renal tubule, thereby causing an increase in osmolarity of the glomerular filtrate. An increase in osmolarity limits tubular reabsorption of water and inhibits the renal tubular reabsorption of sodium, chloride, and other solutes, thereby promoting diuresis. In addition, mannitol elevates blood plasma osmolarity, resulting in enhanced flow of water from tissues into interstitial fluid and plasma.

Osmotic diuresis is increased urination due to the presence of mannitol in the fluid filtered by the kidneys. This fluid eventually becomes urine. Mannitol causes additional water to come into the urine, increasing its amount.

Mannitol has little significant energy value as it is largely eliminated from the body before any metabolism can take place. Mannitol can be used to treat oliguria associated with kidney failure or other manifestations of inadequate renal function and has been used for determination of glomerular filtration rate (GFR). Mannitol is also commonly used as a research tool in cell biological studies, usually to control osmolarity.

Mannitol is removed by hemodialysis and peritoneal dialysis. These may be employed in the treatment of mannitol overdose. Eight patients with severe mannitol intoxication were treated. These patients had CNS (central nervous system) involvement out of proportion to uremia, severe hyponatremia, a large osmolality gap (high measured minus calculated serum osmolality), and fluid overload. Six patients were treated with hemodialysis and one patient received peritoneal dialysis ². One patient died before any treatment could be started. Mannitol has a half-life of approximately 36 hours during the intervals without treatment. The ideal treatment is hemodialysis that rapidly removes mannitol (half-life, six hours) and replaces it with sodium; peritoneal dialysis removed mannitol slowly (half-life, 21 hours) ².

Mannitol side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Tell your doctor right away if you have:

swelling in your hands or feet;
anxiety, sweating, severe shortness of breath, cough with foamy mucus, chest pain;
painful or difficult urination;
a light-headed feeling, like you might pass out;
pain, burning, irritation, or skin changes where the injection was given;
dehydration symptoms–feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin;
signs of an electrolyte imbalance–dry mouth, increased thirst, confusion, fast heart rate, increased urination, muscle pain or weakness, feeling light-headed, fainting, or seizure (convulsions); or
signs of a kidney problem–little or no urinating; painful or difficult urination; swelling in your feet or ankles; feeling tired or short of breath.

Common side effects may include:

increased urination;
nausea, vomiting;
fever, chills, headache, runny nose;
swelling, rapid weight gain;
chest pain;
skin rash; or
dizziness, blurred vision.

Figure 1. Mannitol

Mannitol mechanism of action

The mechanism of action of mannitol is as an osmotic agent ³. The physiologic effect of mannitol is by means of increased diuresis.

Mannitol, when administered intravenously, exerts its osmotic effect as a solute of relatively small molecular size being largely confined to the extracellular space. Only relatively small amounts of the dose administered is metabolized. Mannitol is readily diffused through the glomerulus of the kidney over a wide range of normal and impaired kidney function. In this fashion, approximately 80% of a 100 gram dose of mannitol will appear in the urine in three hours with lesser amounts thereafter. Even at peak concentrations, mannitol will exhibit less than 10% of tubular reabsorption and is not secreted by tubular cells. Mannitol will hinder tubular reabsorption of water and enhance excretion of sodium and chloride by elevating the osmolarity of the glomerular filtrate.

This increase in extracellular osmolarity effected by the intravenous administration of mannitol will induce the movement of intracellular water to the extracellular and vascular spaces. This action underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and elevated intraocular pressure.

Mannitol also acts as a bronchoconstrictor and may cause severe bronchospasm. Mannitol inhalation is used in patients 6 years of age and older to help diagnose asthma. It is used in a procedure called bronchial challenge test to help your doctor measure the effect of this medicine on your lungs and check if you have difficulty with breathing.

Mannitol precautions

General precautions

Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during parenteral therapy with a mannitol solution.

Mannitol solution should be used with care in patients with hypervolemia, renal insufficiency, urinary tract obstruction, or impending or frank cardiac decompensation.

The cardiovascular status of the patient should be carefully evaluated before rapidly administering mannitol since sudden expansion of the extracellular fluid may lead to fulminating congestive heart failure.

Shifting of sodium-free intracellular fluid into the extracellular compartment following mannitol infusion may lower serum sodium concentration and aggravate preexisting hyponatremia.

Mannitol administration may obscure and intensify inadequate hydration or hypovolemia by sustaining diuresis.

Electrolyte-free Mannitol Injection should not be given conjointly with blood. If it is essential that blood be given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol solution to avoid pseudoagglutination. In no other instance should additions be made to 20% Mannitol Injection USP. The addition of sodium chloride to 20% mannitol solution may result in precipitation of mannitol. The final infusate should therefore be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration.

Solutions of mannitol may crystallize when exposed to low temperatures. Concentrations greater than 15% have a greater tendency to crystallization. Inspect for crystals prior to administration. If crystals are observed, the container should be warmed by appropriate means to not greater than 60°C, shaken, then cooled to body temperature before administering. If all crystals cannot be completely redissolved, the container must be rejected. Administer intravenously using sterile, filter-type administration set.

Do not use plastic containers in series connection.

If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. If administration is not controlled by a pumping device, refrain from applying excessive pressure (>300mmHg) causing distortion to the container such as wringing or twisting. Such handling could result in breakage of the container.

This solution is intended for intravenous administration using sterile equipment. It is recommended that intravenous administration apparatus be replaced at least once every 24 hours.

Use only if solution is clear and container and seals are intact.

Laboratory Tests

Although blood levels of mannitol can be measured, there is little if any clinical virtue in doing so. The appropriate monitoring of blood levels of sodium and potassium; degree of hemoconcentration or hemodilution, if any; indices of renal, cardiac and pulmonary function are paramount in avoiding excessive fluid and electrolyte shifts. The routine features of physical examination and clinical chemistries suffice in achieving an adequate degree of appropriate patient monitoring.

Carcinogenesis, mutagenesis and impairment of fertility

Long term studies in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility of 20% Mannitol Injection USP have not been conducted.

Pregnancy Teratogenic Effects

Pregnancy Category C. Animal reproduction studies have not been conducted with 20% Mannitol Injection USP. It is also not known whether 20% Mannitol Injection USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 20% Mannitol Injection USP should be given to a pregnant woman only if clearly needed.

Breastfeeding

It is not known whether mannitol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 20% Mannitol Injection USP is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children below the age of 12 years have not been established.

Usage in Children

Dosage requirements for patients 12 years of age and under have not been established.

Geriatric Use

Clinical studies of 20% Mannitol Injection USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Mannitol is known to be substantially excreted by the kidney, and the risk of toxic reactions to mannitol may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

What is mannitol used for?

Mannitol is used as a diuretic. Mannitol is used to force urine production in people with acute (sudden) kidney failure. As a diuretic it can be used to treat patients with intractable edema states, to increase urine flow and flush out debris from the renal tubules in patients with acute tubular necrosis, and to increase toxin excretion in patients with barbiturate, salicylate or bromide intoxication ⁴. Increased urine production helps to keep the kidneys from shutting down, and also speeds up elimination of certain toxic substances in the body.

Mannitol is also used to reduce swelling and pressure inside the eye or around the brain.

Mannitol may be useful clinically both as a diuretic and as an obligate extracellular solute. As an obligate extracellular solute it may be useful to ameliorate symptoms of the dialysis disequilibrium syndrome, to decrease cerebral edema following trauma or cerebrovascular accident, and to prevent cell swelling related to renal ischemia following cross-clamping of the aorta. Largely unexplored uses for mannitol include its use as an osmotic agent in place of dextrose in peritoneal dialysis solutions, its use to maintain urine output in patients newly begun on hemodialysis, and its use to limit infarct size following acute myocardial infarction.

Mannitol inhalation is used in patients 6 years of age and older to help diagnose asthma. Mannitol is used in a procedure called bronchial challenge test to help your doctor measure the effect of this medicine on your lungs and check if you have difficulty with breathing ⁵. Aridol is a test kit containing one single patient use inhaler and 3 blister packs containing 19 capsules of mannitol for inhalation in marked doses to perform one bronchial challenge test. It is given by a doctor or other trained health professional who will be with you during the test. After you have completed the test, your doctor will know the result right away (positive or negative for asthma). You should not receive this medicine if you have had an allergic reaction to mannitol or gelatin. You should not receive this medicine if you have other conditions that may cause bronchospasm (lung spasms with breathing problems) such as a heart or blood vessel problem, high blood pressure that is not controlled, or a recent heart attack or stroke.

As a sugar, mannitol is often used as a sweetener in diabetic food, as it is poorly absorbed from the intestines ⁶. Mannitol increases blood glucose to a lesser extent than sucrose (thus having a relatively low glycemic index) so is used as a sweetener for people with diabetes, and in chewing gums ⁷.

Mannitol Injection

20% Mannitol Injection USP (United States Pharmacopeia) treats early kidney failure by increasing urination. This helps your body get rid of extra fluids. 20% Mannitol Injection USP treats brain swelling and increased pressure in the eye. Also treats poisoning by increasing urination to remove toxins from the body.

Promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established.
Reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass.
Reduction of elevated intraocular pressure when the pressure cannot be lowered by other means.
Promotion of urinary excretion of toxins.

You should not receive Mannitol Injection if you have severe dehydration (fluid loss). You should not receive Mannitol Injection if you have kidney failure and you have completely stopped passing urine. You should not use Mannitol Injection if you have bleeding problems in your brain. You should stop Mannitol Injection if it has not made your kidney failure better. You should stop Mannitol Injection if it has caused you to have heart failure or fluid in the lungs.

In patients with severe impairment of renal function, a test dose should be utilized. A second test dose may be tried if there is an inadequate response, but no more than two test doses should be attempted.

The obligatory diuretic response following rapid infusion of 20% Mannitol Injection USP may further aggravate preexisting hemoconcentration. Excessive loss of water and electrolytes may lead to serious imbalances. Serum sodium and potassium should be carefully monitored during mannitol administration.

If urine output continues to decline during mannitol infusion, the patient’s clinical status should be closely reviewed and mannitol infusion suspended if necessary. Accumulation of mannitol may result in overexpansion of the extracellular fluid which may intensify existing or latent congestive heart failure.

Excessive loss of water and electrolytes may lead to serious imbalances. With rapid or prolonged administration of mannitol, loss of water in excess of electrolytes can cause hypernatremia. Electrolyte measurements including sodium and potassium are therefore of vital importance in monitoring the infusion of mannitol.

Osmotic nephrosis, a reversible vacuolization of the tubules of no known clinical significance, may proceed to severe irreversible nephrosis, requiring close monitoring during mannitol infusion.

Mannitol contraindications

Mannitol is considered contraindicated in patients with well established anuria (no urine output) due to acute renal failure, severe pulmonary congestion or frank pulmonary edema, active intracranial bleeding (except during craniotomy), and severe dehydration.

20% Mannitol Injection USP (United States Pharmacopeia) is contraindicated in patients with:

Well-established anuria due to severe renal disease.
Severe pulmonary congestion or frank pulmonary edema.
Active intracranial bleeding except during craniotomy.
Severe dehydration.
Progressive renal damage or dysfunction after institution of mannitol therapy, including increasing oliguria and azotemia.
Progressive heart failure or pulmonary congestion after institution of mannitol therapy.

Mannitol therapy should be discontinued if progression in renal damage or dysfunction, heart failure, or pulmonary congestion occurs.

A test dose should be administered in patients with severe renal impairment.

Diuresis caused by mannitol administration may exacerbate electrolyte imbalances. Electrolytes should be closely monitored, especially sodium and potassium, during mannitol administration.

Urine output should be monitored during mannitol infusion. If output declines, consideration should be given to possible discontinuation of mannitol therapy.

Neurosurgical patients receiving intravenous mannitol should be monitored for increased cerebral blood flow.

Mannitol should not be administered until renal function and urinary output are determined to be adequate.

Cardiovascular status should be established prior to rapid administration of mannitol.

Do not administer electrolyte-free mannitol solutions with blood.

Bronchial challenge testing with mannitol inhalation should not be performed in children less than 6 years of age due to their inability to provide reliable spirometric measurements.

Mannitol powder by inhlation

You should not receive this medicine if you have had an allergic reaction to mannitol or gelatin. You should not receive this medicine if you have other conditions that may cause bronchospasm (lung spasms with breathing problems) such as a heart or blood vessel problem, high blood pressure that is not controlled, or a recent heart attack or stroke.

Mannitol dose

Mannitol by injection

Mannitol is injected into a vein through an IV. A healthcare provider will give you this injection.

Mannitol must be given slowly through an IV infusion, and you may receive the medication around the clock.

To be sure mannitol is helping your condition and not causing harmful effects, your blood will need to be tested often. This will help your doctor determine how long to treat you with mannitol. Your heart function will also need to be tested.

Adult dose for oliguria

A nurse or other health provider will give you this medicine. Your doctor will prescribe your dose and schedule. This medicine is given through a needle placed in a vein.

Renal function test dose prior to initiation of treatment: 0.2 g/kg IV over 3 to 5 min resulting in a urine flow of at least 30 to 50 mL/hr. A second test dose may be administered if the urine flow does not increase. If no response is seen following the second test dose, the patient should be reevaluated.

Treatment: 300 to 400 mg/kg (21 to 28 g for a 70 kg patient) or up to 100 g of 15% to 20% solution IV once. Treatment should not be repeated in patients with persistent oliguria.

Prevention (for use during cardiovascular and other types of surgery): 50 to 100 g IV. usually a 5 , 10, or 20% solution is used depending on the fluid requirements of the patient.

Adult dose for cerebral edema

0.25 to 2 g/kg as a 15 to 20% solution IV over at least 30 min administered not more frequently than every 6 to 8 hrs.

To yield a satisfactory reduction in intracranial pressure, the osmotic gradient between the blood and cerebrospinal fluid (CSF) should remain approximately 20 mOsmol.

In small and/or debilitated patients 500 mg/kg may be sufficient.

Renal dose adjustments

Do not initiate treatment until renal function and urinary output have been established as adequate. Mannitol is considered contraindicated in patients with well established anuria due to acute renal failure.

A test dose should be administered in patients with severe renal impairment.

Urine output should be monitored during mannitol infusion. If output declines, consideration should be given to possible discontinuation of mannitol therapy.

Liver dose adjustments

Data not available

How to use mannitol inhalation capsule

Mannitol inhalation is used in patients 6 years of age and older to help diagnose asthma. It is used in a procedure called bronchial challenge test to help your doctor measure the effect of this medicine on your lungs and check if you have difficulty with breathing.

Mannitol inhalation is to be given only by or under the immediate supervision of your doctor.

Mannitol acts as a bronchoconstrictor and may cause severe bronchospasm. Mannitol bronchial challenge testing is for diagnostic purposes only and should be conducted only by trained professionals under a physician familiar with the test and management of acute bronchospasm (ie, testing area equipped with appropriate medications and equipment). Immediately administer a short-acting inhaled beta-agonist in the event of severe bronchospasm. Do not perform bronchial challenge testing with mannitol in a patient with asthma or very low baseline pulmonary function tests (e.g, FEV1 less than 1 to 1.5 L or less than 70% of the predicted values) .

This medicine is used with a special inhaler which will measure the effect of Aridol™ on your lungs. It is given by a doctor or other trained health professional who will be with you during the test. After you have completed the test, your doctor will know the result right away (positive or negative for asthma).

Aridol™ is a test kit containing one single patient use inhaler and 3 blister packs containing 19 capsules of mannitol for inhalation in marked doses to perform one bronchial challenge test.

Do NOT put the capsules in your mouth or swallow them.

To perform the test:

Before doing the bronchial challenge test, your doctor may ask you to perform a breathing or lung test (such as spirometry test).
A nose clip will then be put on your nose so you will only able to breathe in and out of your mouth.
Place 0 mg capsule into the inhaler. Press the side buttons of the inhaler once to puncture the capsule.
To inhale this medicine, breathe out fully, trying to get as much air out of the lungs as possible. Put the inhaler just in front of your mouth.
Open your mouth and breathe in slowly and deeply (like yawning).
Hold your breath for about 5 seconds, then breathe out slowly before removal of the nose clip.
You will be asked to repeat the above steps up to 8 times (total of 9 increasing doses of Aridol™). This is to measure the effect of Aridol™ in your lungs.
Once you have finished the test, you will be given a short-acting inhaler to help you breathe (for patients who have a positive result).
Throw away the inhaler after using.

Mannitol side effects

Applies to mannitol powder inhalation capsule

Along with its needed effects, mannitol may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking mannitol ⁸:

Less Common

chest discomfort
cough
difficult or labored breathing
dry heaves
runny nose
shortness of breath
sore throat
tightness in the chest
troubled breathing
vomiting
wheezing

Incidence not known

Gagging

Some side effects of mannitol may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More Common

Headache

Less Common

dizziness
nausea
sore throat

Applies to mannitol compounding powder, inhalation kit, intravenous solution and irrigation solution

Call your doctor right away if you notice any of these side effects:

Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat, chest tightness, trouble breathing
Chest pain, arm pain, or a heartbeat that is fast or uneven.
Confusion, muscle weakness, or muscle cramps.
Constipation (hard dry stools that are less often than usual) or belly pain.
Coughing or shortness of breath.
Fever or chills.
Loss of feeling or tingling anywhere in your body.
No increase in passing urine, trouble passing urine, or a decrease in how much or how often you pass urine.
Seizures.
Skin rash.
Swelling in your hands, ankles, or feet.
Swelling, redness, or pain where the needle was placed.

If you notice these less serious side effects, talk with your doctor:

Blurred vision or problems with your eyes.
Dizziness, headache, or fainting.
Dry mouth or increased thirst.
Nausea or vomiting.
Runny nose.

If you notice other side effects that you think are caused by this medicine, tell your doctor.

Call your doctor for medical advice about side effects.

Cardiovascular

Cardiovascular side effects have included hypotension and tachycardia. Venous thrombosis or phlebitis extending from the injection site and hypervolemia have occurred rarely and are generally associated with the solution or technique used in administration.

Respiratory

Respiratory side effects have included pulmonary congestion and rhinitis. Respiratory side effects associated with mannitol inhalation have included cough, gagging, wheeze, and decreased forced expiratory volume.

Metabolic

Metabolic side effects have included fluid and electrolyte imbalance, acidosis, and electrolyte loss.

Nervous system

Nervous system side effects have included headache, convulsions, and dizziness.

Hematologic

Hematologic side effects have included thrombophlebitis.

Other

Eight cases of mannitol IV overdose in patients with preexisting renal failure were reviewed ². Symptoms presented in the reviewed cases were CNS involvement out of proportion to uremia, severe hyponatremia, large osmolality gap, and fluid overload. Six patients were treated with hemodialysis, one patient with peritoneal dialysis, and one patient died before initiation of treatment. All patients received large doses over 1 to 3 days with a mean dose of 310 +/- 182.8 g. CNS involvement consisted of CNS depression, confusion, lethargy, stupor, and coma ². Two patients recovered cerebral function and continued on lifetime dialysis, 3 patients recovered renal and cerebral function, and 1 patient recovered renal function but had severe cerebral dysfunction ².

Other side effects have included dryness of mouth, thirst, edema, arm pain, chills, dehydration, fever, mannitol intoxication, and angina-like pain.

Kidney

Renal side effects have included acute renal failure ⁹.

Local adverse reactions

Local side effects have included extravasation. This effect is generally attributed to the solution or technique used in administration.

Skin

Dermatologic side effects have included urticaria and skin necrosis.

Eyes

Ocular side effects have included blurred vision.

Immunologic

Immunologic side effects have included infection at the injection site and febrile response. These effects are usually attributed to solution or technique used in administration.

Gastrointestinal

Gastrointestinal side effects have included nausea and vomiting.

Genitourinary

Genitourinary side effects have included marked diuresis and urinary retention.

Psychiatric

Psychiatric side effects have rarely included mania (1 case report).

A 75-year-old woman with severe major depression experienced a manic episode 30 minutes after initiation of a 20% mannitol intravenous infusion for the treatment of acute angle closure glaucoma ¹⁰. The patient had been started on nortriptyline 50 mg per day for the treatment of depression ten days earlier. She received oral acetazolamide, topical pilocarpine, topical timolol, and topical dexamethasone concomitantly for the treatment of glaucoma. The mania resolved within approximately 1 hour following discontinuation of the mannitol infusion, and the patient returned to a severe depressive state. An extensive lab evaluation, toxicology screening, and medical examination failed to show additional secondary causes for mania in this patient.

Interactions with medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this diagnostic test, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Receiving this diagnostic test with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Arsenic Trioxide
Droperidol
Levomethadyl
Sotalol
Tobramycin

Receiving this diagnostic test with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Licorice

Other Interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

References

Mannitol at clinical concentrations activates multiple signaling pathways and induces apoptosis in endothelial cells. Stroke. 1998 Dec;29(12):2631-40. https://www.ncbi.nlm.nih.gov/pubmed/9836777/
Borges HF, Hocks J, Kjellstrand CM. Mannitol Intoxication in Patients With Renal Failure. Arch Intern Med. 1982;142(1):63–66. doi:10.1001/archinte.1982.00340140065013
Le TN, Blakley BW. Mannitol and the blood-labyrinth barrier. Journal of Otolaryngology – Head & Neck Surgery. 2017;46:66. doi:10.1186/s40463-017-0245-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725891/
Nissenson AR, Weston RE, Kleeman CR. Mannitol. Western Journal of Medicine. 1979;131(4):277-284. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1271822/pdf/westjmed00242-0017.pdf
Mannitol (By breathing). https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011032
Sweeteners: Nutritional Aspects, Applications, and Production Technology. CRC Press. pp. 59–60. ISBN 9781439876732
Grenby, T.H (2011) Advances in Sweeteners. Springer. ISBN 1461285224. p. 66
Mannitol (Inhalation route). https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0045434/#DDIC603407.side_effects_section
Doi K, Ogawa N, Suzuki E, Noiri E, Fujita T “Mannitol-induced acute renal failure.” Am J Med 115 (2003): 593-4
Navarro V, Vieta E, Gasto C “Mannitol-induced acute manic state.” J Clin Psychiatry 62 (2001): 126

Drugs Drugs & Supplements

Yohimbine

by Health Jade Team on July 28, 2018

What is yohimbine

Yohimbine is an indole alkaloid derived from the bark of the Central African Pausinystalia yohimbe tree with alpha-2-adrenergic blocking activity that is widely used as therapy for erectile dysfunction and as a mydriatic (induces dilation of the pupil). The Pausinystalia yohimbe tree bark is used to make extracts, tablets, and capsules. Yohimbe supplement, though banned in many countries, are sold in hundreds of dietary supplements in the USA. In the USA, dietary supplements are regulated as food rather than drugs ¹. In parts of Africa, tea made from yohimbe bark has been used as an aphrodisiac (to increase sexual desire). However, there are no human clinical studies of Pausinystalia yohimbe extract for low libido or erectile dysfunction ². As a leading P. johimbe expert has succinctly summarized, ‘Any discussion of the use of the Pausinystalia yohimbe tree bark for sexual enhancement begins and ends with folklore ². In African folk medicine, yohimbe is used for multiple conditions including cough, fever, leprosy, heart disease, impotence, athletic performance, weight loss, chest pain, high blood pressure, diabetic neuropathy and as an anesthetic, hallucinogen and aphrodisiac.

Yohimbine is promoted for erectile dysfunction, athletic performance, weight loss, angina (chest pain caused by not enough blood flow to the heart), high blood pressure, diabetic neuropathy, and more. However, there is very little research in people on the effects of yohimbe as a dietary supplement and there are no human clinical studies of Pausinystalia yohimbe extract for low libido or erectile dysfunction ². As a leading Pausinystalia yohimbe expert has succinctly summarized, “Any discussion of the use of the Pausinystalia yohimbe bark for sexual enhancement begins and ends with folklore” ². But studies have documented the risks of taking yohimbe supplements. The amount of yohimbine in dietary supplements may vary; some yohimbe products contain very little yohimbine. Yohimbe sold as a dietary supplement may not work like the prescription medication that contains yohimbine. In an analysis 49 brands of Yohimbe supplements labelled as containing yohimbe or yohimbine available for sale from seven major retailers in the USA ³. The quantity of the most active alkaloid, yohimbine, per recommended serving ranged from none detected to 12.1 mg ³. Thirty‐nine percent of the supplements (19/49) did not contain rauwolscine and corynanthine suggesting that the yohimbine was either from highly processed plant extract or synthetic in origin ³. Only 11 supplement brands (22%, 11/49) listed a specific quantity of yohimbine on the label ³. Most of these were inaccurately labelled (actual content ranged from 23% to 147% of the content on the label) ³. Eighteen percent (9/49) of the supplements’ labels did not provide any information about yohimbine’s adverse effects. Of the 49 yohimbine supplement brands sold at seven major retail chains in the USA, only 4.1% (2/49) provided consumers with both accurate information about the quantity of yohimbine as well as information about yohimbine’s known adverse effects ³.

Yohimbine hydrochloride is a standardized form of yohimbine, is available in the United States as a prescription drug for erectile dysfunction. This is a different product than dietary supplements made from the bark of the yohimbe tree. The amount of yohimbine in dietary supplements may vary; some yohimbe products contain very little yohimbine. Yohimbe sold as a dietary supplement may not work like the prescription medication that contains yohimbine. It is illegal in the United States to market an over-the-counter product containing yohimbine as a treatment for erectile dysfunction without getting approval from the U.S. Food and Drug Administration to do so. There is not enough research to say whether yohimbe as a dietary supplement is helpful for any condition, including erectile dysfunction, athletic performance, or weight loss.

Yohimbe has been associated with heart attacks and seizures.
Yohimbe caused stomach problems, tachycardia (a rapid heartbeat), anxiety, and high blood pressure, according to a study comparing calls about yohimbe and other substances made to the California Poison Control System between 2000 and 2006 ⁴. People calling about yohimbe were generally more likely to need medical care than other callers.
Most yohimbe products don’t say how much yohimbine they contain. The amount may vary a lot among products, according to a recent analysis of 49 brands of supplements labeled as containing yohimbe or yohimbine for sale in the United States. Some of the yohimbine was either synthetic or from highly processed plant extract.

The German Commission E (the German equivalent of the Food and Drug Administration [FDA]) ⁵, ⁶ has assessed yohimbehe cortex (yohimbe bark consisting of dried bark from the trunk and stems of Pausinystalia yohimbe and preparations made from them) as a herbal medicine. Its therapeutic use to treat sexual dysfunction, as an aphrodisiac and for fatigue and exhaustion, has been rejected because of inadequate proof of its efficacy, and the inability to carry out a risk-benefit assessment ⁷. The risks in the therapeutic use of the main alkaloid yohimbine are excitation, tremor, insomnia, fear, hypertension, tachycardia, nausea and vomiting. There were also interactions with psychotropic pharmaceuticals ⁷.

What is yohimbe vs yohimbine?

Yohimbe is an evergreen tree native to Central Africa. The Central African Pausinystalia yohimbe tree bark has three alkaloids – yohimbine (10–15% of total content), rauwolscine (alpha-Yohimbine) and corynanthine ⁸. alpha-Yohimbine (α-Yohimbine) is also called rauwolscine. Other alkaloids, including corynanthine, ajmalicine, and other yohimbine isomers, are also found in Pausinystalia yohimbe tree bark ⁹. But the focus of most interest has been yohimbine, an indole alkaloid which has been shown to be an alpha 2 adrenergic receptor antagonist. In animal models, yohimbine increases sexual activity and is likely to act by engagement and inhibition of the alpha 2 adrenergic receptors in the corpus cavernosum (part of the penis), causing sustained engorgement of the corporeal tissue of the penis (penile erection). Yohimbine has been chemically synthesized and is the synthetic form is currently marketed in the United States. The herbal bark extract may have other active components and is purported to be more potent and have more side effects. In clinical trials, synthetic yohimbine has had a consistent, although limited effect on erective dysfunction. Yohimbine effect on sexual desire is less well defined. The usual recommended dose of purified yohimbine is 5 to 10 mg three times a day. Drug tolerance or tachyphylaxis may occur. Side effects are usually mild and transient and are typical of alpha 2 adrenergic inhibition, including insomnia, anxiety, palpitations, chest pain, sweating, blurred vision and hypertension. Overdose can cause hypotension, tachycardia, seizures, paralysis and coma; deaths from overdose have been described.

Figure 1. Yohimbe tree bark alkaloids – yohimbine, rauwolscine (alpha-yohimbine) and corynanthine

Footnote: Structures of yohimbine, rauwolscine and corynanthine.

[Source ¹⁰ ]

Yohimbine effects

Yohimbine is marketed as a pharmaceutical prescribed for the treatment of erectile impotence and has been used in multiple clinical trials as a probe to identify abnormal physiological and affective responses to increased noradrenergic signaling, especially in patients with panic disorders ¹⁰. While Pausinystalia yohimbe bark extract has not been studied in human clinical trials, the most active alkaloid has been developed as a pharmaceutical drug, yohimbine hydrochloride (HCl), and studied in multiple clinical trials for treating sexual dysfunction ². Yohimbine is a potent α‐2 antagonist (alpha-2 adrenoceptors blocker), a moderate α‐1 antagonist (alpha-1 adrenoceptors blocker) and low affinity to some of the serotonin and dopamine receptors which likely has both peripheral and central nervous system effects ². Alpha-2 adrenoceptors mediate erection-inhibiting impulses in the central nervous system. Yohimbine is generally believed to enhance central sexual impulse by blocking the alpha-2 adrenoceptors in the locus coeruleus in the brain ¹¹. In the periphery, yohimbine has been suggested to inhibit alpha-1 and alpha-2 adrenoceptors as well as enhancing the release of nitric oxide (NO) from cavernosal endothelial cells, producing a relaxation of smooth muscle cells and consequent erection, increasing sexual potency ¹². In conclusion, the mechanism of action of yohimbine in enhancing sexual function is currently unclear.

Yohimbine hydrochloride is rapidly absorbed and the maximum plasma concentration is generally achieved in less than one hour after oral administration ¹³. The mean bioavailability is low and is subject to very high variation from one individual to another ¹⁴. The plasma concentration of yohimbine does not appear to correlate with the dose of the compound administered ⁷.

In humans, yohimbine has limited efficacy for sexual dysfunction and significant adverse effects including headaches, hypertension, and panic attacks ¹⁵. More effective and safer treatments for erectile dysfunction, such as sildenafil (Viagra), have therefore completely replaced yohimbine in the modern physician’s armamentarium ¹⁶. Prescriptions of yohimbine, previously available at dosages from 5 to 10 mg, have become so rare that most US pharmaceutical manufacturers have discontinued production of prescription capsules and tablets, and yohimbine has not appeared in the Physician’s Desk Reference since 2005 ¹⁷.

While prescription capsules and tablets of yohimbine are no longer prescribed by mainstream US physicians, yohimbine remains an ingredient in hundreds of dietary supplements, many marketed for sexual and sports enhancement. These yohimbine supplements can confer significant risks to consumers: researchers analyzing data from Poison Control Centers found that in California alone, yohimbine supplements were linked to more than 130 hospitalizations between 2000 and 2006 ¹⁸. Because of these risks, many countries have banned extracts of Pausinystalia yohimbe from supplements and foods ¹⁵. Yohimbine supplements are banned in Canada, Australia, the Netherlands, and the United Kingdom ¹⁵. In contrast, more than 550 brands of yohimbine supplements are available for sale as dietary supplements in the USA ³.

It is not known if supplements containing yohimbine available for sale in the USA at major retailers’ stores are labelled such that consumers are informed of the quantity and adverse effects of yohimbine.

Yohimbine uses

A meta-analysis in 1998 of seven clinical trials with yohimbine has shown a superiority of the compound over placebo in treatment of erectile dysfunction ¹⁹. Yohimbine has also been reported to be effective in treatment of orgasmic disorders such as delayed ejaculation ²⁰. There have been no clinical studies testing Yohimbe bark. The Clinical Guidelines Panel on Erectile Dysfunction of the American Urological Association has concluded that the data available on Yohimbine do not allow it to be recommended as standard treatment in erectile dysfunction particularly not in organic cause ²¹. International Society for Sexual Medicine Standards Committee has recently stated “if yohimbine has any potential indications for use in ED management, it would be among nonorganic ED; apart from ED, yohimbine has shown a limited efficacy in the treatment of premature ejaculation” ²².

The idea to use α₂-adrenoceptor antagonists, such as yohimbine, in the treatment of obesity has been considered by many researchers ²³. However, their side effects were unacceptable and their effectiveness was insufficient. Yohimbine, a well-known α₂-adrenoceptor antagonist, has an undesirable effect on blood pressure and heart rate ²³, due to its effect on both central and peripheral adrenoceptors. Moreover, the higher doses of this drug, which were used for weight reduction, affected α₁-adrenoreceptors as well. Since yohimbine at such doses can block both postsynaptic α₁– and α₂-adrenoceptors present in arterial vessels, there is a risk of a very significant drop in blood pressure. Yohimbine at the dose acting anorexically (reduces appetite) at 5 mg/kg body weight showed a hypotensive effect. This correlates with the findings that the drug blocks α₂-adrenoreceptors, and in large doses also α₁-adrenoreceptors. Non-selective α₂-adrenoreceptor antagonists possess hypotensive properties, because they cause vasodilation by blocking α_2B-adrenoreceptors and prevent vasospasm by blocking α_2C-adrenoreceptors ²⁴. Recent studies using the reinstatement model showed that the α-2 adrenoceptor antagonist yohimbine reinstates cocaine seeking in monkeys ²⁵ as well as alcohol and methamphetamine seeking in rats ²⁶.

Yohimbine is also frequently used as a pharmacological agent to study acute stress effects, since the compound can be studied across species and provides the opportunity to titrate stress with varying doses ²⁷. In humans, it has been shown that the administration of yohimbine leads to panic and anxious feelings, increased heart rate, and increased cortisol measures and noradrenaline metabolite levels ²⁸. The remarkable similarity between yohimbine and psychostimulants can be explained by the fact that psychostimulants have been shown to target both dopaminergic and noradrenergic signaling ²⁹, which is suggested to contribute to their effects on impulsive behavior ³⁰. Similarly, yohimbine not only elevates noradrenaline signaling but also increases dopamine release ³¹. This is in line with the observation that stress leads to increased striatal dopaminergic signaling ³², resulting in sensitization of dopaminergic motivation systems, which are involved in impulsive behavior and other psychiatric disorders related to stress such as substance abuse. This in turn may contribute to cross sensitization of stress and psychostimulants or other drugs of abuse, which is hypothesized to underlie the relation between stress and increased risk of substance abuse and relapse ³³. This increase in sensitivity of noradrenergic systems was revealed by administering yohimbine, which mimics the stress response by antagonizing α2-adrenergic receptors, to people with cocaine ³⁴, opioid ³⁵, or alcohol use disorder ³⁶. Yohimbine increased 3-methoxy-4-hydroxyphenylglycol, the main metabolite of norepinephrine, and induced panic attacks in people with cocaine use disorder with 1–2 days of abstinence, but not in the same people when they had 2 weeks of abstinence ³⁴. This suggests increased sensitivity of noradrenergic systems could diminish in 2 weeks of abstinence. However, although this may diminish effects on emotional systems, norepinephrine seems to remain sensitized and affect other systems suggested by yohimbine-induced increased startle in people with opioid dependence on methadone maintenance compared to healthy controls ³⁷, and increased startle in people with alcohol use disorder who had 2–4 weeks of abstinence who had more quit attempts ³⁶.

Yohimbine side effects

The side effects of yohimbine include high blood pressure, increased heart rate, manic reactions, bronchospasm, palpitations, insomnia, anxiety, irritability, shivering, sweating, nausea, flushing, chest pain, atrial fibrillation and headaches which all can be attributed to its central adrenergic activity ⁷.

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

dizziness
headache
irritability
nervousness or restlessness

Rare

nausea and vomiting
skin flushing
sweating
tremor

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects.

Nervous system

Nervous system side effects have included excitation, increased motor activity, tremor, and dizziness.

Cardiovascular

Cardiovascular side effects have included elevation in blood pressure and increase in heart rate.

Gastrointestinal

Gastrointestinal side effects have included nausea and vomiting, commonly reported after parenteral administration of yohimbine.

Psychiatric

Psychiatric side effects have included irritability and generalized anxiety.

General

General side effects have included headache and increase in sweating.

Dermatologic

Dermatologic side effects have included skin flushing reported with oral administration.

Other

A severe case of Raynaud’s phenomenon has been reported in a 65-year-old man diagnosed with CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia). Painful episodes which affected all toes and fingers and his penis lasted 10 to 15 minutes and were relieved with heat. Symptoms resolved slowly over time upon discontinuation of yohimbine. Upon rechallenge with yohimbine, the patient developed more severe Raynaud’s phenomenon.

Case reports concerning safety of yohimbine

Adverse events mostly due to self-administration of yohimbine have been reported since 1980s. In 1993, Sandler and Aronson have described the development of progressive renal failure, cutaneous eruption, and a lupus-like syndrome in a 42-year-old Afro-American man following yohimbine use ³⁸. Myers has reported a case of refractory priapism in a 42-year-old HIV infected and depressed man who self-administered a product containing yohimbine to treat his erectile dysfunction and was subsequently admitted to emergency department with a 20-hour lasting erection which required insertion of a proximal corpus cavernosum to spongiosum shunt (Quackles shunt) ³⁹. According to California Poison Control System, 238 cases of adverse reactions after yohimbine consumption have been identified within a 7-year period (2000–2006): most commonly reported adverse events have been gastrointestinal distress, tachycardia, anxiety, agitation, and hypertension ⁴⁰. US National Institute of Health also warns consumers about taking yohimbine supplements if they suffer from schizophrenia, anxiety, depression, or posttraumatic stress disorder ⁴¹. Additional situation of emergency has been reported in Amman where the public corporation of the food and the medicine warned the citizens about the use of some unlicensed sexual stimulants, such as yohimbine, for its inclusion of poisonous substance strychnine that caused convulsions, hallucinations, and heart and kidney failure ⁴². More recently, Yohimbine was detected in a product labelled as OxyELITE Pro and sold online as slimming pills. This caused the hospitalisation of two female patients aged 34 and 21 in Hong Kong for acute hepatitis symptoms. As a result, the Department of Health opened an investigation and appealed to members of the public not to buy or consume the product ⁴³.

Psychological side effects

As mentioned above, anxiety and agitation are among the most common side effects of yohimbine or yohimbine-containing products ⁴⁴. US National Institute of Health warns consumers about taking yohimbine or Yohimbe supplements with some of the antidepressants and antipsychosis drugs: “People should not combine Yohimbe with monoamine oxidase (MAO) inhibitors as effects may be additive. Yohimbe should be used with caution when taken with medicines for high blood pressure, tricyclic antidepressants, or phenothiazines (a group of medicines used mostly for mental health conditions such as schizophrenia). People with kidney problems and people with psychiatric conditions should not use Yohimbe” ⁴¹. In 1985, Linden et al. ⁴⁵ have reported a case of a 16-year-old girl who experienced an acute dissociative reaction accompanied by weakness, paraesthesia, incoordination, anxiety, headache, and chest pain after the ingestion of an aphrodisiac called “yo-yo,” which has been later identified as yohimbine. Acute neurotoxic effects related to the ingestion of yohimbine-containing products have been reported by Giampreti et al. ⁴⁶, who has reported the case of a 37-year-old bodybuilder presented with malaise, vomiting, loss of consciousness, and repeated seizures after ingestion of 5 g of yohimbine during a competition.

Yohimbine overdose

In case of overdose, weakness, generalized paresthesia, loss of coordination and memory problems, as well as severe headaches combined with dizziness, tremor,
palpitations and fear occur after 20-30 mins ⁷. After 4 hour severe chest pain can occur, lasting for several hours. Other side effects include headache, increased blood pressure, tachycardia lasting several hours, nausea, vomiting, mydriasis, increased saliva and tear flow and perspiration. Greatly increased norepinephrine values have been shown. Side effects may persist for 1-2 days. Instances of intoxication have been described at doses above 200 mg yohimbine HCl ⁷.

In one 16-year-old girl, 250 mg yohimbine brought about an overdose with dissociative reactions, weakness, paranoia, headache, nausea, chest pains, shivering, increased respiration rate, high blood pressure and tachycardia. The serum epinephrine and norepinephrine concentrations were increased. These symptoms persisted for 36 hours ⁴⁵. A dose of 1.8 g is reputed to have resulted in several hours’ loss of consciousness ⁷. In a 37-year-old body builder, 5 g of yohimbine resulted in neurotoxic effects after 2 hours. These expressed themselves in nausea, vomiting and repeated episodes, hypertension (259/107 mmHg) and tachycardia. The plasma levels measured 3, 6, 14 and 22 hours after intake were 5240, 2250, 1530 and 865 ng/ml ⁴⁶.

Acute toxicity (oral LD50 or lethal dose 50% where 50% of the test subjects die) in mice arises at less than 50 mg/kg body weight. The LD50 for humans has been calculated as 5 mg/kg body weight (= 350 mg/70 kg body weight). The lethal dose is ten times higher (50 mg/kg). There are no data available for repeated or chronic use ⁷.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking yohimbine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using yohimbine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Clomipramine
Clonidine
Guanabenz
Guanadrel
Guanethidine
Guanfacine
Lithium
Morphine
Morphine Sulfate Liposome
Naloxone
Naltrexone
Reserpine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using yohimbine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use yohimbine, or give you special instructions about the use of food, alcohol, or tobacco.

Ethanol

Appetite suppressant

by Health Jade Team on July 23, 2018

Appetite suppressant

Traditional methods for weight loss include reducing calorie intake, increasing physical activity, and behavior therapy. Other weight-loss options include appetite suppressants approved for use in the United States as adjuncts in the treatment of obesity, the amphetamine congeners benzphetamine, desoxyephedrine (methamphetamine), phendimetrazine, diethylpropion, and phentermine, which were approved more than 50 years ago ¹. These agents demonstrate a modest weight loss benefit when combined with dietary modifications and exercise. Few patients were exposed to these drugs for more than 12 weeks in subsequent efficacy assessments, and concerns existed about the potential for abuse and addiction. Consequently, the indication for weight loss was limited to short-term use only, specified in the labels as “a few weeks,” which is often interpreted as up to 12 weeks. Sibutramine (a serotonin and norepinephrine reuptake inhibitor) is an appetite suppressant that was withdrawn from the U.S. market in October 2010 for safety reasons. Sibutramine is known to increase blood pressure and/or pulse rate in some patients and may present a risk for patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke. Sibutramine may also interact, in life-threatening ways with other medications a consumer may be taking. Following the deaths of 2 young women taking sibutramine in Italy in 2002, that country temporarily suspended the drug’s marketing license ². Moreover, numerous once-promising weight-loss drugs have been abandoned because of serious toxic effects ³: aminorex (which caused pulmonary hypertension), fenfluramine and dexfenfluramine (valvulopathy – association with valvular heart disorders), phenylpropanolamine (stroke), rimonabant (suicidal ideation and behavior), and most recently sibutramine (myocardial infarction and stroke).

Mild amphetamine analogs such as diethylpropion and phentermine are among the most commonly used appetite suppressants ⁴. Bupropion, an analog of diethylpropion, also produces weight loss ⁵. The mechanisms by which these pro-drugs produce their anorexic effect are complex, because they modulate the concentrations of serotonin, norepinephrine, and dopamine ⁶ and evoke responses in various cortical and subcortical areas involved in feeding ⁷.

In humans the above-named amphetamine congeners produce the sensation of fullness (serotonin) and increase agitation, insomnia, and energy expenditure (norepinephrine), as well as affecting motivation and reward pathways (dopamine) ⁸.

In this national study ⁹ estimating the prescription antiobesity drug use in the United States for the years 1991–2011 showed that prescription weight-loss drugs were predominantly used by women, users were mostly between 17 and 44 years old, and only a small proportion of users were not overweight or obese. Approximately 1 in 10 patients prescribed a weight-loss drug had a BMI of 26.9 kg/m² or less. The duration of prescription antiobesity drug use was generally short, and most patients had only one episode of use during our 10-year study period. In about half of the patients, the longest treatment episode was 30 days or shorter, and only a quarter of the patients used antiobesity drugs for longer than 90 days.

To help obese and overweight Americans who have been unsuccessful in getting their weight under control with diet and exercise, the Food and Drug Administration (FDA) has recently in July 2012 approved two new medications—the first drugs for long-term weight management that FDA has approved in 13 years. Marketed as Belviq and Qsymia, these prescription medications would be taken for the rest of a person’s life ¹⁰. Belviq (lorcaserin) is a selective agonist of the serotonin (5-hydroxytryptamine or 5-HT) 2C (5-HT2C) receptor ¹¹. Qsymia (phentermine plus extended-release topiramate, Vivus) is a fixed-dose combination of the sympathomimetic amine phentermine, which is an anorectic agent, and the antiepileptic drug topiramate ¹¹. Both medications reduce appetite and, in some people, induce a negative energy balance.

You may be a candidate for taking Belviq or Qsymia if you are at least 18 and:

your body mass index (BMI) is 30 or greater (obese); or
your BMI is 27 or greater (overweight) and you have at least one other weight-related condition.

Women who are pregnant or thinking of becoming pregnant should not take either of these medications, Egan says, because weight loss offers no potential benefit to a pregnant woman and can cause fetal harm. Qsymia carries a risk for birth defects (cleft lip with or without cleft palate) in infants exposed during the first trimester of pregnancy.

Research suggests that safe weight loss involves combining a reduced-calorie diet with physical activity to lose 1/2 to 2 pounds a week (after the first few weeks of weight loss). Make healthy food choices. Eat small portions. Build exercise into your daily life. Combined, these habits may be a healthy way to lose weight and keep it off. These habits may also lower your chances of developing heart disease, high blood pressure, and type 2 diabetes.

To lose weight, reduce the number of calories you take in and increase the amount of physical activity you do each day. Create and follow a healthy eating plan that replaces less healthy options with a mix of fruits, veggies, whole grains, protein foods, and low-fat dairy:

Eat a mix of fat-free or low-fat milk and milk products, fruits, veggies, and whole grains.
Limit added sugars, cholesterol, salt (sodium), and saturated fat.
Eat low-fat protein: beans, eggs, fish, lean meats, nuts, and poultry.

Health care providers use your Body Mass Index (BMI), to measure of your weight in relation to your height, to define overweight and obesity and is universally expressed in units of kg/m², resulting from mass in kilograms and height in meters. People who have a BMI between 25 and 30 kg/m² are considered overweight. Obesity is defined as having a BMI of 30 kg/m² or greater. BMI is considered an important measure for understanding population trends. For individuals, it is one of many factors that should be considered in evaluating healthy weight, along with waist size, body fat composition, waist circumference, blood pressure, cholesterol level and blood sugar.

To calculate your body mass index, you divide your body weight in kilograms by your height in meter squared (commonly expressed as kg/m²), see the body mass index formula below.

To find out about your body mass index (BMI), you can use a FREE online BMI calculators from the Centers for Disease Control and Prevention (CDC) :

Adults (BMI Calculator Adults. https://www.cdc.gov/healthyweight/assessing/bmi/adult_BMI/english_bmi_calculator/bmi_calculator.html)

For children and adolescents (younger than 20 years of age), overweight and obesity are based on the Centers for Disease Control and Prevention’s (CDC’s) BMI-for-age growth charts, which are available at Centers for Disease Control and Prevention (CDC Clinical Growth Charts https://www.cdc.gov/growthcharts/clinical_charts.htm).

The CDC has a BMI percentile calculator for children and teens at ¹².

Children (BMI Calculator Children. https://www.cdc.gov/healthyweight/bmi/calculator.html)

Body Mass Index for Men and Women Adults

The body mass index is an attempt to quantify the amount of tissue mass (muscle, fat, and bone) in an individual, and then categorize that person as underweight, normal weight, overweight, or obese based on that value. Commonly accepted body mass index ranges are:

A) Underweight: under 18.5 kg/m²,

B) Normal weight: 18.5 to 25 kg/m²,

C) Overweight: 25 to 30 kg/m²,

D) Obese: over 30 to 39.9 kg/m².

E) Severely Obese: over 40 kg/m².

FDA approved appetite suppressant

Weight-loss medicines, weight loss pills or prescription appetite suppressants approved by the Food and Drug Administration (FDA) might be an option for some people.

If you’re not successful at losing 1 pound a week after 6 months of using lifestyle changes, medicines may help. You should only use medicines as part of a program that includes diet, physical activity, and behavioral changes.

Prescription medications to treat overweight and obesity work in different ways. For example, some medications may help you feel less hungry or full sooner. Other medications may make it harder for your body to absorb fat from the foods you eat e.g. Orlistat – blocks your body from absorbing about a third of the fat you eat.

Weight-loss medicines might be suitable for adults who are obese (a BMI of 30 or greater). People who have BMIs of 27 or greater, and who are at risk for heart disease and other health conditions like type 2 diabetes or high blood pressure, also may benefit from weight-loss medicines. You’ll still need to focus on diet and exercise while taking these drugs, and they’re not for everyone.

FDA approved appetite suppressants:

Amphetamine congeners:
- Benzphetamine,
- Desoxyephedrine (Methamphetamine),
- Diethylpropion,
- Phendimetrazine, and
- Phentermine
Lorcaserin (Belviq)
Phentermine-topiramate combination (Qsymia)
Naltrexone-bupropion combination (Contrave)
Liraglutide (Saxenda)

Only orlistat, lorcaserin (Belviq) and phentermine/topiramate (Qsymia) are FDA-approved for long-term use; the others are approved only for short-term use (usually considered ≤12 weeks).

Table 1. Drugs with an FDA-approved indication for obesity

Generic Name	Trade Name(s)	Mechanism of action	Dosage	Whole-sale price per mo.^*	Mean weight change relative to placebo at 1y, kg^**	Interactions	Contraindications^&	Common Adverse Events^&	Cautions and Warnings^&
Phentermine^a	Adipex-P, Fastin, Oby-Cap, lonamin, Others	Noradrenergic causing appetite suppression	15– 37.5mg/d	$6– $45	Not Available	Guanethidine, CNS stimulants, alcohol, tricyclic antidepressants; requirements for insulin or oral hypoglycemic medications may be altered	Pregnancy or nursing, advanced cardiovascular disease, uncontrolled hypertension, hyperthyroidism, glaucoma, agitated states, history of drug abuse, MAOIs	Insomnia, elevation in heart rate, dry mouth, taste alterations, dizziness, tremors, headache, diarrhea, constipation, vomiting, gastro- intestinal distress, anxiety, and restlessness.	Do not increase beyond recommended dose if tolerance to the anorexiant effect develops. Caution prescribing to patients with even mild hypertension. Caution for patients using alcohol or other CNS active drugs or engaging in hazardous activity.
Diethylpropion^a	Tenuate, Tenuate Dospan, Tepanil	Noradrenergic causing appetite suppression	25mg 3 times/d or 75mg sustained- release/d	$47– $120	Not Available	Same as phentermine	Same as phentermine	Same as phentermine	Same as phentermine
Phendimetrazine^b	Bontril	Noradrenergic	17.5–70mg 2–3 times/d or 105mg sustained- release/d	$6– $20	Not Available	Same as phentermine	Same as phentermine	Same as phentermine	Same as phentermine
Benzphetamine^b	Didrex	Noradrenergic causing appetite suppression	25–50mg 1–3 times/d	$20– $50	Not Available	Same as phentermine	Same as phentermine	Same as phentermine	Same as phentermine
Orlistat^c	Xenical, Alli	Lipase inhibitor causing excretion of ~30% of ingested triglycerides in stool	60 or 120mg 3 times/d within 1 hr of a fat- containing meals, plus a daily multi- vitamin	For 60mg TID: $45 For 120mg TID: $207	For 60mg TID:−2.5 kg (−1.5 to −3.5) For 120mg TID: −3.4 kg (−3.2 to −3.6)	Decreased drug concentrations of cyclosporine and levothyroxine. Doses should be temporally separated from orlistat. Fat soluble vitamin absorption is decreased by orlistat	Pregnancy, chronic malabsorption syndromes, cholestasis	Oily Spotting, Flatus with Discharge, Fecal Urgency, Fatty/Oily Stool, Increased Defecation, Fecal Incontinence	Use with caution in those at risk for renal insufficiency, since treatment may increase urinary oxalate. Cholelithiasis and, rarely, severe liver injury including hepatocellular necrosis and acute hepatic failure leading to death, have been reported
Lorcaserin^a	Belviq	Highly selective serotonergic 5-HT2C receptor agonist causing appetite suppression	10mg two times/d	$240	−3.2 kg (−2.7 to −3.8)	Triptans, MAOIs including linezolid, SSRIs, SNRIs, dextro- methorphan, tricyclic antidepressants, bupropion, lithium, tramadol, tryptophan, and St. John’s Wort	Pregnancy	Headache, dizziness, fatigue, nausea, dry mouth, cough, and constipation, and back pain, cough and hypoglycemia in patients with type 2 diabetes.	Risk for Serotonin Syndrome or Neuroleptic Malignant Syndrome-like Reactions. Evaluate patients for signs or symptoms of valvular heart disease. Euphoria, hallucination, and dissociation have been seen with supra- therapeutic doses. Use with caution in men at risk for priapism
Phentermine / Topiramate-ER^a	Qsymia	Noradrenergic + GABA- receptor activator, kainite/AMPA glutamate receptor inhibitor causing appetite suppression	3.75/23mg /d for 2 weeks, then 7.5/46mg/ d, escalating to a maximum of 15/92mg/d	$140 – $195	For 7.5/46mgd: −6.7 kg (−5.9 to −7.5) For 15/92mg/d −8.9 kg (−8.3 to −9.4)	Oral contraceptives, alcohol and other CNS depressants, non-potassium- sparing diuretics	Pregnancy, Glaucoma, Hyperthyroidism, MAOIs

Abbreviations: MAOI = monoamine oxidase inhibitor, CNS = central nervous system, SSRI = selective serotonin-reuptake inhibitors, SNRI = selective serotonin-norepinephrine reuptake inhibitors.

*Reference prices found on March 8, 2013.
**Weight change relative to placebo (95 percentile confidence interval) using intent-to-treat analyses for each medication at 1 year. No studies for older noradrenergic agents (phentermine, diethylpropion, phendimetrazine, and benzphetamine) met inclusion criteria for length of treatment, sample size, and attrition.
^a Medications listed on Drug Enforcement Administration Schedule IV are associated with a lower risk of abuse than
^b Medications on Schedule III;
^c Orlistat is a non-Drug Enforcement Administration scheduled drug.
^& Common adverse events for noradrenergic agents include those listed as common in the NIDDK Weight-control Information Network Fact Sheet “Prescription Medications for the Treatment of Obesity”100 as adverse event frequency is not available in the drug package inserts for these agents. For orlistat, lorcaserin, and phentermine/topiramate ER, common adverse events are those listed in the drug package inserts that are reported to occur more frequently than placebo and with more than 5% prevalence.

[Source ¹³]

Belviq—the trade name for the drug lorcaserin— is a 10 mg tablet taken twice a day that works by activating a part of the brain that controls hunger.

Belviq was tested in three clinical trials that lasted from 52 to 104 weeks and included nearly 8,000 obese and overweight patients.

The average weight loss for patients taking Belviq ranged from 3 to 3.7 percent over those taking a placebo.
In studies of patients without type 2 diabetes, about 47 percent of patients lost at least 5 percent of their weight compared with 23 percent of patients treated with placebo.

Belviq should be discontinued if you fail to lose 5 percent of your weight after 12 weeks of treatment, as it is unlikely that continued treatment will be successful.

Qsymia is a combination of two FDA-approved drugs: phentermine, an appetite suppressant, and topiramate, used to treat epilepsy and migraines. Qsymia is taken once a day, with patients starting at the lowest dose (3.75 mg phentermine/23 mg topiramate extended-release), then increasing to the recommended dose (7.5 mg/46 mg). In some circumstances, patients may have their dose increased to the highest dose (15 mg/92 mg).

Qsymia, was tested in two clinical trials which included nearly 3,700 obese and overweight patients treated for up to one year.

The average weight loss of patients taking Qsymia ranged from 6.7 percent (lowest dose) to 8.9 percent (recommended dose) over those taking a placebo.
Sixty-two percent of patients on the lowest dose and 70 percent on the recommended dose lost at least 5 percent of their weight compared with 20 percent treated with placebo.

If after 12 weeks, you have not lost 3 percent of your weight on the recommended dose of Qsymia, FDA recommends that treatment be discontinued or increased to the highest dose. If after an additional 12 weeks on the highest dose, you do not lose at least 5 percent of weight, Qsymia should be discontinued gradually.

Who might benefit from weight-loss medications?

Weight-loss medications are meant to help people who may have health problems related to overweight or obesity. Before prescribing a weight-loss medication, your doctor also will consider:

the likely benefits of weight loss
the medication’s possible side effects
your current health issues and other medications
your family’s medical history
cost

Your doctor may prescribe a medication to treat your overweight or obesity if you are an adult with

a BMI of 30 or more or
a BMI of 27 or more and you have weight-related health problems, such as high blood pressure or type 2 diabetes.

Weight-loss medications aren’t for everyone with a high BMI. Some people who are overweight or obese may lose weight with a lifestyle program that helps them change their behaviors and improve their eating and physical activity habits. A lifestyle program may also address other factors that affect weight gain, such as eating triggers and not getting enough sleep.

Orlistat (Xenical)

How it works: Blocks your body from absorbing about a third of the fat you eat. Orlistat is a gastrointestinal lipase inhibitor which, when taken three times a day during or up to 1 hour after meals, leads to the excretion of approximately 30% of ingested fat.

Orlistat is available both in prescription (120mg) and over-the-counter (60mg) strength. Orlistat 120mg is FDA-approved for use in adults and adolescents age 12–16years.

When a doctor prescribes orlistat, it’s called Xenical (Orlistat 120mg). If you get it without a prescription, it’s called Alli, which has half of Xenical’s dose. Alli is the reduced-strength, 60-milligram version of orlistat (Xenical) a 120-milligram prescription drug.

The mean weight reduction attributable to orlistat 120mg three times daily at 12 months is modest: among adults participating in behavioral weight control programs and prescribed a lower fat diet (~30% of calories from fat), orlistat-treated patients lost on average 3.4 kg (~3.1% of initial weight) more than placebo-treated participants. The percentage of orlistat 120mg-treated participants who achieved clinically-meaningful (≥5%) weight loss at 1 year varied from 35–73% and the proportion losing ≥10% varied from 14–41%, with both ≥5% and ≥10% weight loss at 1 year significantly greater for orlistat-treated than for placebo-treated participants. At the end of a second year of treatment when a weight-maintenance diet was prescribed, orlistat 120mg-treated participants had lost approximately 3.3 kg (~3.3% of initial weight) more and orlistat 60mg-treated participants had lost approximately 2.5 kg (~2.5% of initial weight) more than those given placebo.

Because of its weight-loss related and weight-loss independent ¹⁴ actions, orlistat 120mg treatment is associated with significant improvements in cardiovascular risk factors including decreases in total- and LDL- cholesterol, fasting glucose, and systolic and diastolic blood pressures after 1 year of treatment ¹⁵.

Data from the XENDOS trial ¹⁶ of 3,305 patients treated for up to 4 years (attrition at 4 years: 48% for orlistat-treated and 66% for placebo-treated) found, in an intention-to-treat approach, that orlistat use decreased body weight over 4 years by 2.7 kg (approximately 2.4% of initial body weight) more than placebo and significantly decreased risk for developing type 2 diabetes from 9.0% with placebo to 6.2% with orlistat. Because orlistat leads to obligate increases in undigested stool triglycerides, it may cause considerable gastrointestinal adverse effects that may be decreased by co-administration of fiber-containing supplements ¹⁷.

Side effects include abdominal cramping, passing gas, leaking oily stool, having more bowel movements, and not being able to control bowel movements.

These side effects are generally mild and temporary. But they may get worse if you eat high-fat foods.

These adverse effects may cause patients who do not reduce their fat intake to discontinue therapy. Indeed, despite being FDA-approved in 1999 for indefinite treatment of obesity, among those prescribed orlistat 120mg clinically, fewer than 10% take it for at least 1y and <2% of patients use the medication for 2 years ⁴.

Rare cases of severe liver injury have been reported in people taking orlistat, but it’s not certain that the drug caused those problems.

What else you should know: You should be on a low-fat diet (less than 30% of your daily calories from fat) before taking orlistat.

Also, take a multivitamin at least 2 hours before or after taking orlistat, because the drug temporarily makes it harder for your body to absorb vitamins A, vitamin D, vitamin E, and vitamin K.

Orlistat is the only drug of its kind that’s approved in the U.S. All other prescription weight loss drugs curb your appetite, including the following.

Belviq (Lorcaserin Hydrochloride)

How it works: Curbs your appetite. Lorcaserin is a selective serotonin 2C (5HT_2c) receptor agonist that was anticipated to recapitulate the weight loss effects of fenfluramine without its adverse cardiac effects ¹⁸. Lorcaserin 10mg twice daily was FDA-approved in 2012 on the basis of two large randomized, placebo-controlled trials in nondiabetic patients (BLOOM n=3182, 50% attrition) ¹⁹; BLOSSOM n=4004, 45% attrition) ²⁰, along with a third, smaller trial in adults with type 2 diabetes (BLOOM-DM n=603, 34% attrition) ²¹. In these trials, participants received low-intensity nutritional and exercise counseling. Lorcaserin decreased body weight modestly, by about 3.2 kg (~3.2% of initial body weight) more than placebo ²². However, significantly more patients treated with lorcaserin 10mg twice daily than placebo lost ≥5% (BLOOM: 47 vs. 20%, BLOSSOM: 47 vs. 25%, BLOOM-DM: 37 vs. 16%) or ≥10% (BLOOM: 23 vs. 8%, BLOSSOM: 23 vs. 10%, BLOOM-DM: 16 vs. 4%) of their initial weight. Reduction in body weight below baseline in the one study ¹⁹ with data from participants who took lorcaserin for 2 years had average weight loss of 5.6 kg, versus 2.4 kg among placebo-treated participants. Blood pressure, total cholesterol, LDL”bad” cholesterol, and triglycerides also decreased significantly more in lorcaserin-treated participants ²³. Among patients with diabetes, lorcaserin treatment led to lower body weight and improved glycated hemoglobin concentrations.30 Adverse effects (Table 1) include headache, nausea, fatigue, and dizziness ²³. Although neither incidence of valvulopathy nor hypertension was statistically greater during lorcaserin than placebo treatment, both were numerically somewhat more prevalent and the FDA has requested that a post-approval trial to assess the long-term cardiovascular effects of lorcaserin be conducted ²⁴.

Side effects: The most common side effects in people who don’t have diabetes are headache, dizziness, nausea, fatigue, dry mouth, and constipation.

The most common side effects in those who have diabetes are low blood sugar (hypoglycemia), headache, back pain, cough, and fatigue.

People taking some depression medications with Belviq need to be monitored very closely for a rare but serious reaction that includes fever and confusion.

Women who are pregnant or planning to get pregnant shouldn’t take Belviq.

What else you should know: If you don’t lose 5% of your weight after 12 weeks of taking Belviq, you should stop taking it, because it’s unlikely to work for you, the FDA says.

Contrave (naltrexone and bupropion)

How it works: Contrave is a combination of two FDA-approved drugs, naltrexone and bupropion, in an extended-release formula. Naltrexone is approved to treat alcohol and opioid dependence. Bupropion is approved to treat depression, seasonal affective disorder, and help people stop smoking.

Side effects: The most common side effects include nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea. Contrave has a boxed warning about the increased risk of suicidal thoughts and behaviors associated with bupropion. The warning also notes that serious neuropsychiatric issues linked to bupropion have been reported. Contrave can cause seizures and must not be used in patients who have seizure disorders. The drug can also increase blood pressure and heart rate.

What else you should know: If you don’t lose 5% of your weight after 12 weeks of taking Contrave, you should stop taking it, because it’s unlikely to work for you, the FDA says.

Saxenda

How it works: Saxenda is a higher dose of the type 2 diabetes drug Victoza. It mimics an intestinal hormone that tells the brain your stomach is full.

Side effects: Nausea, vomiting, diarrhea, constipation, low blood pressure, and increased appetite. Serious side effects can include raised heart rate, pancreatitis, gallbladder disease, kidney problems, and suicidal thoughts.

What else you should know: If you don’t lose 4% of your weight after 16 weeks of taking Saxenda, you should stop taking it, because it’s unlikely to work for you, the FDA says.

Qsymia

How it works: Curbs your appetite. Qsymia combines phentermine with the seizure/migraine drug topiramate. Topiramate causes weight loss in several ways, including helping you feel full, making foods taste less appealing, and burning more calories.

Phentermine/topiramate-Extended Release (ER) is the first FDA-approved combination drug for obesity, combining low-dose phentermine with a non-standard dose of the antiepileptic medication topiramate-Extended Release (ER).

Phentermine/topiramate-ER, is administered as a once-daily capsule in 4 fixed-dose combinations: 3.75mg phentermine/23mg topiramate (starting dose); 7.5mg phentermine/46mg topiramate (recommended dose); 11.25mg phentermine/69mg topiramate (titration dose); and 15mg phentermine/92mg topiramate (top dose). Dosage is increased over 14 days to 7.5mg phentermine/46mg topiramate, with additional titration to the top dose if weight loss is inadequate ²⁵.

Phentermine/topiramate-ER was recommended for approval based largely on 2 one-year Phase 3 clinical trials (EQUIP, n=1267) ²⁶; CONQUER, n=2487) ²⁷. All groups received a low-intensity lifestyle program. All underwent dose titration over 4 weeks to assigned dose followed by 52 weeks on drug or placebo. EQUIP ²⁶; CONQUER, n=2487) ²⁸ randomized a higher-risk sample of adults with BMI 27–45 kg/m² and ≥2 obesity-associated comorbid conditions, to placebo or phentermine/topiramate-ER. 31% of participants withdrew. One year weight loss was 8.1 kg (7.8%) with the recommended dose and 10.2 kg (9.8%) with the top dose, vs. 1.4 kg (1.2%) with placebo. In addition, 62% (recommended dose) and 70% (top dose) lost ≥5% of initial weight vs. 21% for placebo, with 37%, 48%, and 7% respectively losing ≥10% of initial weight. Many cardiovascular disease risk factors improved with active drug treatment at recommended- or top-dose ²⁹. SEQUEL ³⁰ an extension to CONQUER, followed 78% of CONQUER participants at sites selected for high enrollment and retention and who had completed the initial 56-week trial for a total of 108 weeks. 84% completed their second year of treatment with sustained weight loss of 9.3% and 10.5% at the recommended and top doses, respectively, vs. 1.8% for placebo, and continued differences in many cardiovascular disease risk factors. In addition, there was a significantly lower incidence of progression to type 2 diabetes in the top-dose group (0.9%) vs. placebo (3.7%).

An area of considerable concern, given that most users of obesity medications are women of reproductive age, is the potential for oral clefts in the offspring of women who become pregnant while taking topiramate ³¹. A risk evaluation and mitigation strategy was developed to minimize the likelihood of pregnancy in women with reproductive potential that includes provider training, dispensing only via certified pharmacies, and supplying patient information regarding risks and the necessity of using effective contraception ³². Women with childbearing potential should have a negative pregnancy test prior to starting phentermine/topiramate-ER and monthly thereafter ³². A small increase in resting heart rate has been observed in the clinical trials of phentermine/topiramate-ER at higher doses, with more patients on top-dose (56.1%) than placebo (42.1%) having increases of more than 10 beats per minute, leading to some concerns regarding its potential long-term effect on cardiovascular disease events. Phentermine/topiramate-ER was approved with a requirement for a post-marketing trial of to assess long-term cardiovascular safety ²⁴. The labeling recommends against prescription in patients with recent or unstable cardiac or cerebrovascular disease, and suggests regular monitoring of resting heart rate ²⁵.

Side effects: The most common side effects are tingling hands and feet, dizziness, altered sense of taste, insomnia, constipation, and dry mouth.

Serious side effects include certain birth defects (cleft lip and cleft palate), faster heart rate, suicidal thoughts or actions, and eye problems that could lead to permanent vision loss if not treated.

Women who might become pregnant should get a pregnancy test before taking Qsymia, and should use birth control and get monthly pregnancy tests while on the drug.

You also shouldn’t take Qsymia if you have glaucoma, hyperthyroidism, heart disease, or stroke. Get regular checks of your heart when starting the drug or increasing the dose.

What else you should know: If you don’t lose 3% of your weight after 12 weeks on Qsymia, the FDA recommends that you stop taking it or that your doctor increase your dose for the next 12 weeks — and if that doesn’t work, you should gradually stop taking it.

Phentermine

Your doctor may prescribe this under the names Adipex or Suprenza.

Phentermine is by far the most widely prescribed obesity medication in the US, with 25.3 million prescriptions dispensed to an estimated 6.2 million users between 2008–2011 ⁴. Phentermine originally approved indication was obesity; and the drug was used on-label until 1977 when it, along with all other drugs approved for treating obesity, were approved a second time after an amendment to the Food Drug and Cosmetic Act required that the FDA approve new drugs based on efficacy as well as safety. There was protracted opposition to re-approval from those who maintained the sympathomimetic obesity drugs that had dangerous addiction potential. No evidence of addiction had appeared during 18 years of increasingly frequent use, but the FDA re-approved them all, having silenced the opposition by announcing the drugs would be approved for short-term use only ³³. The FDA has jurisdiction over pharmaceutical companies but cannot regulate medical practice, jurisdiction over which resides in the individual US states. US physicians treating obesity, well aware of these statuary boundaries, continued to use phentermine and the other sympathomimetic amine anorectic drugs off-label long-term. Surveys of prescribing practices among physicians treating obesity have confirmed that a majority of these physicians continue to prescribe the sympathomimetics off-label in this manner ³⁴.

A meta-analysis of 6 studies ranging from 2 to 24 weeks ³⁵ found that patients using 15–30mg/day phentermine had a mean additional weight loss relative to placebo of 3.6 kg, with mean total weight loss of 6.3 kg. The longest published placebo-controlled trial of phentermine ³⁶ lasted 36 weeks in 108 obese women treated with phentermine 30mg/day either continuously or intermittently (alternating months) and found similar weight loss in the continuous (12.2 kg) and intermittent (13.0 kg) arms vs. 4.8 kg with placebo. However, attrition was 41%, and data were presented only for completers, which is likely to overstate efficacy ³⁶. Among completers, transient symptoms of central nervous system stimulation such as insomnia, irritability, and anxiety did not differ between those receiving continuous (24%) vs. intermittent (27%) therapy, compared with 8% for those taking placebo. Several short-term placebo-controlled studies of phentermine have shown elevations in pulse or smaller decreases in pulse and/or blood pressure than would be expected given the degree of weight loss ³⁷.

Phentermine is also used off-label in several ways other than long-term. Phentermine is, and has long been, prescribed for patients whose excess adiposity is below the conventional BMI cutoffs. Maffetone et al. ³⁸ have suggested the use of BMI cutoffs has seriously underestimated the extent of an “overfat pandemic comprised of people who exhibit metabolic health impairments associated with excess fat mass relative to lean body mass.” They point out that there are a very large number of individuals who have excess fat mass but with BMIs below the cutoffs, that such individuals have increased health risks, and imply that some deserve treatment. Viewed from Maffetone et al’s perspective, private obesity medicine practitioners have been treating these overfat patients with obesity drugs off-label despite not labeling them with the proposed terminology.

Prescribed phentermine doses higher than the limit suggested are common. The label lists 37.5 mg per day as the “usual dose” (30 mg of phentermine resin is the same dose). A separate paragraph warns, “When tolerance to the anorectic effect develops, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued.” At the time the original phentermine label was written, tolerance was considered a prelude to addiction, but it is now well known that tolerance is not the same as dependence or addiction. The phenomenon referred to may be related both to intra-species variability of drug metabolism and dose–time induction of more rapid drug metabolism. Whatever the theoretical explanation, doses higher than 37.5 mg/day have been found effective and safe in a number of observational studies ³⁹, ⁴⁰.

Physicians treating attention-deficit/hyperactivity disorder (ADHD) use dose-to-effect titration with methamphetamine up to 1 mg/kg/day and methylphenidates up to 2 or 3 mg/kg/day ⁴¹. Attention-deficit/hyperactivity disorder (ADHD) medicines have considerably greater potentials for abuse than sympathomimetic anorectics. Current treatment recommendations for attention-deficit/hyperactivity disorder (ADHD) call for a starting dose of amphetamine of 0.3 mg/kg/day, then titrating up, if needed, to a maximum of 1.0 mg/kg/day. The variation in dose required for effective treatment is thought to be due to intra-individual variability in drug metabolism and plasma clearance. A study in baboons found that intravenous amphetamine and phentermine produced equivalent plasma levels of norepinephrine. This suggests that oral doses of these drugs would have equivalent effects in humans on plasma norepinephrine levels. Surveys indicate that the average phentermine dose employed in the USA is about 60 mg/day, and that some physicians have used up to 112 mg/day ⁴². These doses are comparable with the doses of amphetamine used to treat attention deficit with respect to norepinephrine plasma levels and are not excessive ⁴².

The prevalence of overweight and obesity in patients with attention-deficit/hyperactivity disorder (ADHD) is high, perhaps as high as 30% ⁴³ and patients with this combination frequently present at weight management clinics. Some of these patients are being treated for attention deficit, but many are not. It is common knowledge among obesity medicine practitioners that obese patients with attention deficit often experience clinical improvement when treated with phentermine, particularly if they are not currently being treated for their attention deficit. Effective dosages for weight loss or maintenance for these patients vary widely but most require or tolerate higher phentermine doses than patients without attention deficit.

The label suggests the drug not be used in pediatric patients aged <16 and be used with caution in older adults. Phentermine was used safely for treating overweight children by pediatricians until it became unpopular in the 1980s. There are no reports of harm from phentermine treatment in either very young or elderly patients ⁴². The surveys of obesity medicine physicians cited above indicate that a majority use phentermine in treating adolescents. The same surveys suggest that these physicians do not recognize an upper age limit for treatment. Populations selected for the long-term clinical trials for phentermine/topiramate did not include very young or very old subjects, so there are no modern clinical trial data on such populations. However, observational reports have included patients safely treated with phentermine as young as 3 years ⁴⁴ and as old as 88 years ⁴⁵.

How it works: Curbs your appetite.

Approved for long-term use ? No. It’s approved for short-term use (a few weeks) only.

Side effects can be serious, such as raising your blood pressure or causing heart palpitations, restlessness, dizziness, tremor, insomnia, shortness of breath, chest pain, and trouble doing activities you’ve been able to do.

Phentermine may make you drowsy, hampering your ability to drive or operate machinery. As with some other appetite suppressants, there’s a risk of becoming dependent upon the drug.

Less serious side effects include dry mouth, unpleasant taste, diarrhea, constipation, and vomiting.

Don’t take it late in the evening, as it may cause insomnia.

If you take insulin for diabetes, let your doctor know before you take phentermine, as you may need to adjust your insulin dose.

You should not take phentermine if you have a history of heart disease, stroke, congestive heart failure, or uncontrolled high blood pressure. You also shouldn’t take it if you have glaucoma, hyperthyroidism, or a history of drug abuse, or if you are pregnant or nursing.

What else you should know: Phentermine is an amphetamine. Because of the risk of addiction or abuse, such stimulant drugs are “controlled substances,” which means they need a special type of prescription.

Although there are no published data on the frequency of use, phentermine is occasionally prescribed for patients with label contraindications. Coronary artery disease, stroke, arrhythmias, congestive heart failure, and uncontrolled hypertension are listed specifically. In the absence of controlled data supporting these contraindications, there is no unambiguous evidence that suggests these conditions are absolute contraindications. However, US obesity medicine specialists, based on the known mechanism of action of phentermine, and the pathophysiology of the illness, would consider congestive heart failure, uncontrolled hypertension, untreated clinically significant arrhythmias, and severe advanced coronary artery disease to be absolute contraindications ⁴². However, in cases of less severe coronary artery disease, medically treated arrhythmias and patients who have past history of stroke, some US obesity medicine specialists would weigh the benefits of weight loss in obese, overweight and overfat subjects after a thorough assessment, that would likely include consultation with the patient’s cardiologist and/or medical specialist ⁴². This viewpoint is supported by reduced mortality observed in the Sibutramine Cardiovascular Outcomes (SCOUT) trial for patients with cardiovascular disease who had moderate weight loss ⁴⁶. The expectation is that the same will be discovered with cardiovascular outcome trials that the FDA has mandated for the newer obesity drugs since weight loss in overweight and obese patients induces improvement in cardiac dysfunction common in such patients ⁴⁷.

Other contraindications include hyperthyroidism, glaucoma and history of drug abuse ⁴². Most physicians would likely agree that phentermine not be used until hyperthyroidism has been treated but most would also agree a history of successful treatment of hyperthyroidism is not a contraindication. As with other medications that have anticholinergic side effects, phentermine is contraindicated in patients with narrow-angle glaucoma. However, it is not contraindicated in patients with open-angle glaucoma.

Phentermine use in clinical practice has not been associated with phentermine cravings, withdrawal, or excessive use leading to psychological or physical impairment. Although there is a widespread presumption that phentermine abuse is common, actual phentermine abuse is not common and appears limited to the use of the drug as a stimulant among people trying to stay awake and those trying to boost their energy level. Phentermine is longer acting than caffeine and does not have the adverse gastrointestinal effects of high doses of caffeine, so some students studying for exams and some long-haul truck drivers use it to stay awake and alert. Evidently, some patients with stimulant use disorder who use cocaine, methamphetamine or other strong stimulants add phentermine to a drug cocktail in an attempt to heighten the stimulant effects, but no data have been published on the frequency of this practice. A telephone survey of 50 addiction treatment centers in the USA found only 2 instances of patients using such cocktails among several thousand admissions, suggesting the addition of phentermine to such cocktails is uncommon ⁴⁸. Stimulant use disorder due to phentermine alone as the favored drug has not been described, and no such entity is included in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) ⁴⁹. Clinically significant psychiatric distress similar to that described in the DSM-5 in discussing stimulant use disorders has never been observed in overweight or obese patients treated with phentermine. A phentermine withdrawal syndrome has never been observed or described. Patients with either overt attention deficit or some of its symptoms typically “like” phentermine because they function better when taking it. Patients who have difficulty staying in control of eating also “like” phentermine because they have less cravings and enjoy better control of their eating behaviors. Patients with symptoms of attention deficit are quite common among the overweight and obese. For these reasons, “liking” phentermine should not be interpreted as an indication phentermine has high abuse potential. Phentermine treatment enhances control of impulsive behavior and control of other harmful eating behaviors; these are goals of behavioral treatment in obese patients.

It may be reasonable to prescribe phentermine for subjects who have a history of recovery from drug abuse. The author has found this safe in carefully selected patients provided their recovery is genuine, recovery has endured for at least several years and phentermine does not induce phentermine cravings or desire for their former drugs of abuse.

The label also lists contraindications that are absolute and seldom ignored, and these include recent monoamine oxidase inhibitor use, agitated states, pregnancy, nursing mothers and known hypersensitivity or idiosyncratic reactions to sympathetic amines.

Phentermine label warnings

Some consider prescribing phentermine despite specific label warnings to be an off-label use. It is recommended that the label warnings be included in an informed consent, and that any concern of the patient be thoroughly discussed and the discussion documented. The rationale for decisions to prescribe phentermine contrary to a warning would best be explicitly documented in the patient record.

Co-administration with other weight-loss drugs

US physicians view this warning as an anachronism since the FDA has approved the two combination drugs phentermine/topiramate and bupropion/naltrexone ⁴². The warning against combining weight-loss medicines appeared in the phentermine label in 2000 after 1997 reports of valvulopathy induced by the combination of phentermine and fenfluramine, and both dexfenfluramine and fenfluramine were taken off-market. Surveys of US physicians treating obesity have revealed these physicians frequently combined the various antiobesity drugs with other drugs approved for obesity and with a variety of other drugs that have an effect on weight loss. For example, these physicians combined phentermine and topiramate long before the FDA approved a fixed dose combination (Qsymia) in 2012 ⁴². Other combinations in use are discussed.

Primary pulmonary hypertension

Primary pulmonary hypertension has not been associated with phentermine monotherapy. As discussed in a previous communication, isolated reports of primary pulmonary hypertension occurring in patients who have taken phentermine have relied on theoretical but unproven adverse effects and ignored the underlying incidence of idiopathic pulmonary hypertension ⁵⁰.

Valvular heart disease

This warning first appeared in the label in 2000 after valvulopathy was discovered in patients taking phentermine and fenfluramine in 1997 and before publication of a report suggesting that fenfluramine, but not phentermine, activated cardiac 5HT2B serotonin receptors that then induced valvulopathy ⁵¹. Although the label states “… there have been rare cases of valvular heart disease in patients who reportedly have taken phentermine alone.”

Tolerance

Tolerance refers to a reduced response to a drug after repeated use. Tolerance is a normal physiologic process that occurs with substances of abuse but also with some medicines (e.g., diphenhydramine). Tachyphylaxis refers to very rapid development of tolerance.

Hazardous task ability

Labels for most drugs that work in the central nervous system include this warning. There is no specific evidence that phentermine degrades mental or physical performance. Generally, stimulants will enhance rather than degrade mental and physical performance until extremely high doses are used. The Federal Aviation Administration (FAA) has not accepted phentermine for pilots ⁵⁰. The only antiobesity drug acceptable to the FAA is orlistat ⁵⁰.

Risk of abuse and addiction

The Diagnostic and Statistical Manual of Mental Disorders: DSM-5 ⁴⁹ does not have criteria for “addiction” but instead sets forth criteria for diagnosing stimulant-related disorders and discusses “stimulant use disorder” and “stimulant withdrawal” with amphetamine and cocaine as prototypical stimulants. Phentermine is not specifically mentioned in the DSM-5. Stimulant use disorder is defined as a pattern of repeated use leading to clinically significant impairment or distress as manifested by two or more of a list of 11 symptoms, including intense cravings for the substance leading to self-destructive social and job or profession-related behaviors. In phentermine post-marketing studies, we found that long-term phentermine use, even at doses higher than 37.5 mg/day, did not induce phentermine cravings, and that abrupt cessation of long-term phentermine did not induce a stimulant withdrawal syndrome ⁵².

Assessment of drug “liking” is currently used as a measure of addiction potential ⁵³. Phentermine has been used in studies as an example of a liked drug ⁵⁴. However, patients taking phentermine often “like” the drug for a variety of valid reasons but do not have other signs or symptoms of addiction or physical dependence. Some like phentermine because they have lost weight taking it and enjoy a better quality of life. Many patients in medical weight management programs have adult attention deficit or at least some symptoms of attention deficit, and many are not taking specific attention medicines. These patients typically are less scattered, can focus better and are more productive when taking phentermine and, realizing this, “like” taking the drug. Discussions of drug liking of phentermine as a sign of addiction typically fail to consider the prevalence of attention deficit in the obese population as a reason for drug liking. Nor do such discussions differentiate between hedonic drug liking versus drug liking because of medical benefits.

Use with alcohol

There is an extensive literature on the effects of ethanol and a wide variety of stimulants in animals and humans. However, there are no specific reports on the effects of combining phentermine and ethanol in humans.

Hypertension

Phentermine-induced increases in blood pressure are often mentioned in both the medical and general literature, but few instances have been recorded ⁵⁵. US obesity medicine practitioners typically do not prescribe phentermine with poorly controlled hypertension until it is under control, but they do prescribe it in the presence of controlled hypertension, then monitor the patient’s blood pressure closely, discontinuing phentermine if blood pressure rises ⁵⁰.

Diethylpropion

Diethylpropion has a similar adverse-effect and weight loss profile to phentermine, but is much less frequently prescribed, with approximately 1 million prescriptions dispensed between 2008–2011 ⁴. A meta-analysis of 9 small studies ranging from 6–52 weeks ⁵⁶ found that patients using diethylpropion 75mg/day had a mean additional weight loss relative to placebo of 3.0 kg, with a mean total weight loss of 6.5 kg.

Phendimetrazine

Phendimetrazine, despite the paucity of randomized controlled trials ⁵⁶ is prescribed three times more frequently than diethylpropion for obesity treatment, with more than 3 million phendimetrazine prescriptions estimated to have been filled between 2008–2011 ⁴. In the completer’s analyses from two small 12-week trials ⁵⁷, phendimetrazine appears to have similar weight loss to other noradrenergic drugs.

Benzphetamine

Benzphetamine is less commonly prescribed for obesity treatment than the other noradrenergic drugs ⁵⁶ and there are few data from controlled trials evaluating its safety or efficacy ⁵⁶.

Common adverse effects of noradrenergic drugs are shown in Table 1. Because these medications were approved prior to the requirements for long-term trials with adequate power to ascertain clinical endpoints, an adverse effect of noradrenergic obesity drugs on cardiovascular disease events cannot be excluded, and is of concern given their known effect on heart rate and blood pressure.

Drugs used off-label for weight management

Off-label drug use generally means that a drug is being used for an unapproved indication, population or at an unapproved dosage. In addition to these unapproved uses, antiobesity may be also employed for longer than recommended durations, when contraindicated, or in other ways contrary to the US FDA-approved label. Countries other than the USA typically have their own drug approval processes, but their labels commonly include language similar to that of the FDA label. Discussion of off-label drug use here is limited to US obesity medicine physicians and the US FDA label, and is intended to review some of the data on how US physicians are actually using drugs off-label. The uses of drugs that are approved for other diseases that have weight loss as a side effect and that are used in treating overweight or obese patients with the indicated diseases are not discussed.

While, in general, off-label drug use is neither illegal nor unethical, some jurisdictions may limit the use of specific medications for specific situations. For example, in the USA, the state of Ohio forbids proscribing any controlled substance for weight loss in any manner contrary to the FDA label (Ohio Administrative Code 4731-11-04). Penalties may include forfeiture of medical license. In addition, the state prosecutors may charge an offending doctor who dispenses medications with felony, drug trafficking and money laundering. Physicians should not presume off-label use of controlled substance antiobesity medicines is freely permitted in their own location but should investigate local regulations and laws carefully before prescribing these drugs off-label.

Drugs commonly used off-label for weight management are discussed in the following section.

Amphetamine

Methamphetamine (desoxyephedrine) was first approved in 1943 by the FDA for treating narcolepsy, mild depression, postencephalitic Parkinson syndrome, chronic alcoholism, cerebral arteriosclerosis, and hay fever. Later, in 1947, methamphetamine was also approved as the first drug for treating obesity. Both approvals were made at a time when when US law required the FDA to only consider whether new drugs were safe without consideration of their effectiveness. Later, in 1962, the US congress amended the Food Drug and Cosmetic Act requiring the FDA to approve new drugs based on their safety but only if the new drug demonstrated proven effectiveness for the stipulated indication. Today, methamphetamine remains FDA-approved for treating attention deficit (ADHD) and obesity and is still available as Desoxyn®. Methamphetamine is a category II controlled substance and although today this drug is apparently rarely used for treating obesity, such usage is not off-label. Physicians used 5 mg methamphetamine tablets up to 3 times daily before meals in the 1940s and 1950s for treating obesity, but then turned toward using sympathomimetic amines as these became available beginning with phenmetrazine in 1956; phentermine, diethylpropion and phendimetrazine in 1959; and benzphetamine in 1960.

Diabetic medicines

It is appropriate to monitor blood sugars during treatment for obesity since dose lowering or elimination of diabetic medicines is often a benefit and is to be expected with weight loss. Phentermine is not contraindicated in patients with either treated or untreated diabetes ⁵⁰.

Metformin

Although the label for metformin specifies diabetes as the sole indication, the drug has been prescribed with increasing frequency for overweight and obese patients with impaired fasting glucose following a report that long-term metformin delayed or prevented diabetes and induced weight loss in such patients ⁵⁸. Metformin is known to induce modest weight loss in overweight patients even without glucose abnormalities and is prescribed off-label as an adjunct to weight loss ⁵⁹. Metformin, increasing used off-label in prediabetes and other insulin resistant states, produces small sustained weight losses of about 2% relative to placebo ⁶⁰. Metformin improves insulin sensitivity, has a good safety profile, and long-term clinical experience. As weight loss attributable to metformin is small, its usefulness as monotherapy for obesity treatment is limited, but its salutary effects on body weight make it a good choice when other indications warrant its prescription. Metformin has also been used to prevent or ameliorate weight gain with atypical antipsychotic agents and mood stabilizers. A meta-analysis examining the effect of medications for attenuation of antipsychotic weight gain found an approximate 3 kg additional weight loss relative to placebo attributable to metformin ⁶¹.

Bupropion

Bupropion, a norepinephrine and dopamine reuptake inhibitor, was tested as monotherapy for up to one year as a weight loss medication. A pooled analysis of 3 studies ranging from 6 to 12 months showed additional weight loss relative to placebo of 2.8 kg in patients receiving 400mg/d bupropion, with total weight loss of 4.4 kg ⁶².

Topiramate

Topiramate was FDA-approved for treatment of refractory epilepsy in 1996. Weight loss was immediately noted as a side effect ⁶³. Soon thereafter, reports began appearing that topiramate was effective in treating binge eating disorder ⁶⁴ and obesity ⁶⁵. A survey of US obesity medicine physicians performed in early 2008 and published in 2009 revealed that 50% were prescribing topiramate as monotherapy for obesity ⁶⁶. In 2012, in a survey conducted before the FDA approved the combination phentermine and topiramate for obesity, 63% of those surveyed were already using topiramate for treating obesity and 61% were combining it with phentermine in some patients ⁶⁷. Thus, topiramate has been used off-label, both as monotherapy and in combination.

Zonisamide

Zonisamide, an antiepileptic medication, also induces weight loss. A 12-month randomized controlled trial of 225 adults, with 97% follow-up found that a 400mg dose led to significantly greater weight loss than placebo (6.8% vs. 3.7%), as well as a greater proportion losing ≥5% and ≥10% of initial weight ⁶⁸. However, adverse effects were limiting. Overall, fatigue was the only adverse effect that occurred at a significantly higher frequency for zonisamide treatment than for placebo. Although not observed frequently in this study, the following adverse effects occurred frequently with zonisamide therapy in epilepsy trials: dizziness, cognitive impairment, and somnolence ⁶⁹. Because zonisamide is a sulfonamide, there is a potential for hypersensitivity reactions. Although rare, kidney stones and serious hematologic events have been reported with zonisamide therapy in patients with epilepsy. Consistent with data from epilepsy trials, an increase in serum creatinine concentration with zonisamide therapy, but not with placebo. Whereas the increase in the first 16 weeks (approximately 16%) was significant, there was no further increase in the extension phase; no value exceeded the upper limit of normal range, and there were no clinical events associated with the increase.

Pramlintide

Pramlintide is a synthetic analogue of human amylin, which is administered subcutaneously at meal times as an adjunct to insulin for patients with type 1 and type 2 diabetes. A meta-analysis ⁷⁰ of 8 studies in patients with type 2 diabetes and obese non-diabetic populations found additional weight loss relative to placebo of about 2.2 kg for both groups. One study ⁷¹ evaluating pramlintide in combination with phentermine vs. pramlintide alone found significantly greater weight loss with combination therapy, although diastolic blood pressure and heart rate increased despite greater weight loss with the combination.

Sympathomimetics other than phentermine

Other sympathomimetics include diethylpropion (1959), and phendimetrazine (1959), both of which have FDA-approved labels with indications, contraindications and warnings identical or similar to those in the phentermine label. Diethylpropion is a category IV controlled substance, and phendimetrazine is a category III. Both drugs are frequently used off-label in the US in manners similar to phentermine. In the 2012 survey, 63% of surveyed physicians used diethylpropion in an average of 18% of their patients and 60% used phendimetrazine in an average of 20% of their patients. Benzphetamine, a category III drug, is another older sympathomimetic drug that is still in use but apparently less often used than diethylpropion or phendimetrazine. The surveys did not include questions regarding benzphetamine, so we have no data but answers to queries to US pharmaceutical wholesalers reveal that their benzphetamine sales are much lower than the other sympathomimetics.

Drugs approved for uses other than obesity

Certain drugs approved for indications other than obesity but inducing weight loss when given on-label to overweight patients could potentially be used off-label to treat overweight and obese patients who do not have the indicated diagnosis. There is little or no data on whether any of these are actually being used off-label for obesity, but given the proclivity of obesity practitioners to adopt drugs that induce weight loss without regard to approved indications, one can expect some to use these off-label drugs for weight loss. Some of these drug candidates for off-label use are listed in the following section.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors

SGLT2 inhibitors, including canagliflozin, dapagliflozin, and empagliflozin, are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. In diabetics, these also induce modest weight loss. A recent report of a trial combining canagliflozen and phentermine for overweight patients without diabetes suggests this off-label combination can induce weight loss superior to diet and lifestyle modification without these medications ⁷².

Exenatide

Approved for treating diabetes, exenatide also induces weight loss in overweight diabetics ⁷³. This drug has been used off-label for weight loss, but apparently infrequently.

Metreleptin

Approved for congenital or acquired generalized lipodystrophy, metreleptin is a synthetic leptin analog. Obese patients typically have high circulating leptin levels, and clinical trials have shown that leptin administration does not induce weight loss. However, leptin levels fall during weight loss and remain low afterward ⁷⁴ and leptin administration after weight loss in obese patients reverses some of the neuroendrocrine adaptations involved in weight regain ⁷⁴. These data suggest that daily leptin injections could possibly be useful in preventing weight regain after a significant weight loss. Resolution of the issue whether or not leptin analogs will be a solution to the problem of weight regain will require further research.

OTC appetite suppressant

There are very few proven choices in over-the-counter (OTC) or nonprescription medications for effective weight loss. One agent that is available without a prescription is Orlistat (a lower-dose version of the prescription drug Xenical) which blocks your body from absorbing about a third of the fat you eat and is not an appetite suppressant.

Do not take Orlistat if you are pregnant. Weight loss is not recommended during pregnancy.

You should not use Orlistat if you have a digestive disorder (problems absorbing food). You should not use Xenical if you have gallbladder problems, or if you are pregnant. Do not use Orlistat if you have had an organ transplant, if you use cyclosporine, or if you are not overweight.

Orlistat is only part of a complete program of treatment that also includes diet, exercise, and weight control. Your daily intake of fat, protein, and carbohydrates should be evenly divided over all of your daily meals. Follow your diet, medication, and exercise routines very closely.

Avoid a diet that is high in fat. High-fat meals taken in combination with orlistat can increase your risk of unpleasant side effects on your stomach or intestines.

Many people who are trying to lose weight may attempt to use dietary supplements or herbal medications, but most of these products have not been adequately studied for effectiveness or safety and none are approved by the U.S. Food and Drug Administration (FDA) for weight loss. Check with a healthcare provider for advice before using herbal or dietary supplements for weight loss.

References

Anorectics on trial: a half century of federal regulation of prescription appetite suppressants. Colman E. Ann Intern Med. 2005 Sep 6; 143(5):380-5. http://annals.org/aim/fullarticle/718716/anorectics-trial-half-century-federal-regulation-prescription-appetite-suppressants
Willam P. Italian ban places question over anti-obesity drug. The Guardian. 8 March 2002.
The FDA’s Assessment of Two Drugs for Chronic Weight Management. N Engl J Med 2012; 367:1577-1579 DOI: 10.1056/NEJMp1211277
Use of prescription antiobesity drugs in the United States. Hampp C, Kang EM, Borders-Hemphill V. Pharmacotherapy. 2013 Dec; 33(12):1299-307. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740913/
Gadde KM, Xiong GL. Bupropion for weight reduction. Expert Rev Neurother 7: 17–24, 2007.
Baumann MH, Ayestas MA, Dersch CM, Brockington A, Rice KC, Rothman RB. Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications. Synapse 36: 102–113, 2000.
Safta L, Cuparencu B, Sirbu A, Secareanu A. Experimental observations on the effect of amphepramone on the behavior, locomotion, pentretrazol seizures and electroencephalogram. Psychopharmacology (Berl) 50: 165–169, 1976.
Moyers SB. Medications as adjunct therapy for weight loss: approved and off-label agents in use. J Am Diet Assoc 105: 948–959, 2005
Hampp C, Kang EM, Borders-Hemphill V. Use of Prescription Antiobesity Drugs in the United States. Pharmacotherapy. 2013;33(12):1299-1307. doi:10.1002/phar.1342. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740913/
Medications Target Long-Term Weight Control. https://www.fda.gov/forconsumers/consumerupdates/ucm312380.htm
[email protected]: FDA Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
Centers for Disease Control and Prevention. BMI Percentile Calculator for Child and Teen. https://www.cdc.gov/healthyweight/bmi/calculator.html
Yanovski SZ, Yanovski JA. Long-term Drug Treatment for Obesity: A Systematic and Clinical Review. JAMA : the journal of the American Medical Association. 2014;311(1):74-86. doi:10.1001/jama.2013.281361.
Cholesterol lowering effect of dietary weight loss and orlistat treatment–efficacy and limitations. Erdmann J, Lippl F, Klose G, Schusdziarra V. Aliment Pharmacol Ther. 2004 Jun 1; 19(11):1173-9. https://www.ncbi.nlm.nih.gov/pubmed/15153170/
Long-term changes in blood pressure following orlistat and sibutramine treatment: a meta-analysis. Johansson K, Sundström J, Neovius K, Rössner S, Neovius M. Obes Rev. 2010 Nov; 11(11):777-91. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0030322/
Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27(1):155–161 http://care.diabetesjournals.org/content/27/1/155.long
Cavaliere H, Floriano I, Medeiros-Neto G. Gastrointestinal side effects of orlistat may be prevented by concomitant prescription of natural fibers (psyllium mucilloid) Int J Obes Relat Metab Disord. 2001;25(7):1095–1099.
Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337(9):581–588.
Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363(3):245–256.
Fidler MC, Sanchez M, Raether B, et al. A One-Year Randomized Trial of Lorcaserin for Weight Loss in Obese and Overweight Adults: The BLOSSOM Trial. J Clin Endocrinol Metab. 2011
O’Neil PM, Smith SR, Weissman NJ, et al. Randomized Placebo-Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 Diabetes Mellitus: The BLOOM-DM Study. Obesity (Silver Spring) 2012;20(7):1426–1436.
Chan EW, He Y, Chui CS, Wong AY, Lau WC, Wong IC. Efficacy and safety of lorcaserin in obese adults: a meta-analysis of 1-year randomized controlled trials (RCTs) and narrative review on short-term RCTs. Obesity reviews : an official journal of the International Association for the Study of Obesity. 2013;14(5):383–392.
BELVIQ (lorcaserin hydrochloride) tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022529lbl.pdf
Colman E, Golden J, Roberts M, Egan A, Weaver J, Rosebraugh C. The FDA’s assessment of two drugs for chronic weight management. The New England journal of medicine. 2012;367(17):1577–1579.
Qsymia (phentermine and topiramate extended-release) capsules, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022580s004lbl.pdf
Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP) Obesity (Silver Spring) 2012;20(2):330–342. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270297/
Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341–1352. https://www.ncbi.nlm.nih.gov/pubmed/21481449
Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight a randomized adults without diabetes and with BMI ≥35 kg/m² to placebo, phentermine/topiramate-ER 3.75/23mg (starting dose), or 15/92mg (top dose). 40% of participants withdrew. At the top dose, mean 1 year weight loss was 10.9% vs. 1.6% of initial weight for placebo. 67% of patients given the top dose lost ≥5% of initial weight and 47% lost ≥10% of initial weight, compared with 17% and 7%, respectively for placebo. CONQUER ((Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341–1352. https://www.ncbi.nlm.nih.gov/pubmed/21481449
Davidson MH, Tonstad S, Oparil S, Schwiers M, Day WW, Bowden CH. Changes in cardiovascular risk associated with phentermine and topiramate extended-release in participants with comorbidities and a body mass index >/=27 kg/m(2) The American journal of cardiology. 2013;111(8):1131–1138.
Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95(2):297–308. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260065/
Margulis AV, Mitchell AA, Gilboa SM, et al. Use of topiramate in pregnancy and risk of oral clefts. American journal of obstetrics and gynecology. 2012;207(5):405, e401–407. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484193/
QSYMIA (phentermine and topiramate extended-release) Capsules. Risk evaluation and mitigation strategy (REMS). https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm361075.pdf
Colman E. Anorectics on trial: a half century of federal regulation of prescription appetite suppressants. Ann Intern Med. 2005;143(5):380–385
Schmidt SL, Bryman D, Greenway FL, Hendricks EJ. How physician obesity medicine specialists treated obesity before 2012 new drug approvals. Obes Surg. 2015;25(1):186–190. https://www.ncbi.nlm.nih.gov/pubmed/25344465
Haddock CK, Poston WS, Dill PL, Foreyt JP, Ericsson M. Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obes Relat Metab Disord. 2002;26(2):262–273
Munro JF, MacCuish AC, Wilson EM, Duncan LJ. Comparison of continuous and intermittent anorectic therapy in obesity. Br Med J. 1968;1(5588):352–354. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1984840/pdf/brmedj02070-0040.pdf
Ryan DH, Bray GA. Pharmacologic treatment options for obesity: what is old is new again. Curr Hypertens Rep. 2013;15(3):182–189.
Maffetone PB, Rivera-Dominguez I, Laursen PB. Overfat and underfat: new terms and definitions long overdue. Front Public Health. 2016;4:279. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206235/
Hendricks EJ, Greenway FL, Westman EC, Gupta AK. Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity. Obesity (Silver Spring) 2011;19(12):2351–2360 https://www.ncbi.nlm.nih.gov/pubmed/21527891
Hendricks EJ, Rothman RB, Greenway FL. How physician obesity specialists use drugs to treat obesity. Obesity (Silver Spring) 2009;17(9):1730–1735 https://www.ncbi.nlm.nih.gov/pubmed/19300434
Stevens JR, Wilens TE, Stern TA. Using stimulants for attention-deficit/hyperactivity disorder: clinical approaches and challenges. Prim Care Companion CNS Disord. 2013;15(2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733520/
Hendricks EJ. Off-label drugs for weight management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2017;10:223-234. doi:10.2147/DMSO.S95299. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473499/
Pagoto SL, Curtin C, Lemon SC, et al. Association between adult attention deficit/hyperactivity disorder and obesity in the US population. Obesity (Silver Spring) 2009;17(3):539–544. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221303/
Lorber J. Obesity in childhood. A controlled trial of anorectic drugs. Arch Dis Child. 1966;41(217):309–312. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2019558/pdf/archdisch01570-0083.pdf
Hendricks EJ, Srisurapanont M, Schmidt SL, et al. Addiction potential of phentermine prescribed during long-term treatment of obesity. Int J Obes (Lond) 2014;38(2):292–298 https://www.ncbi.nlm.nih.gov/pubmed/23736363
Caterson ID, Finer N, Coutinho W, et al. Maintained intentional weight loss reduces cardiovascular outcomes: results from the Sibutramine Cardiovascular OUTcomes (SCOUT) trial. Diabetes Obes Metab. 2012;14(6):523–530.
de las Fuentes L, Waggoner AD, Mohammed BS, et al. Effect of moderate diet-induced weight loss and weight regain on cardiovascular structure and function. J Am Coll Cardiol. 2009;54(25):2376–2381.
Bryman D, Hendricks EJ, Schmidt SL. Incidence of addiction and abuse due to phentermine, diethylpropion, and phendimetrazine in the United States. Telephone Survey of Emergency Rooms and Addiction Treatment Centers ed. Unpublished manuscript. 2013
American Psychiatric Association, DSM-5 Task Force . Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed. American Psychiatric Association: Arlington, VA; 2013.
Hendricks EJ, Rothman RB. RE: pulmonary hypertension associated with use of phentermine? Yonsei Med J. 2011;52(5):869–870 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159930/
Rothman RB, Baumann MH, Savage JE, et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102(23):2836–2841.
Hendricks EJ, Greenway FL. A study of abrupt phentermine cessation in patients in a weight management program. Am J Ther. 2011;18(4):292–299.
Berridge KC, Robinson TE. Liking, wanting, and the incentive-sensitization theory of addiction. Am Psychol. 2016;71(8):670–679.
Schoedel KA, Addy C, Chakraborty B, et al. Human abuse potential and cognitive effects of taranabant, a cannabinoid 1 receptor inverse agonist: a randomized, double-blind, placebo- and active-controlled, crossover study in recreational polydrug users. J Clin Psychopharmacol. 2012;32(4):492–502.
Hendricks EJ, Rothman RB. Phentermine therapy for obesity does not elevate blood pressure. Diabetes Obes Metab. 2011;13(10):963–964. https://www.ncbi.nlm.nih.gov/pubmed/21896124
Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Haddock CK, Poston WS, Dill PL, Foreyt JP, Ericsson M. Int J Obes Relat Metab Disord. 2002 Feb; 26(2):262-73. https://www.ncbi.nlm.nih.gov/pubmed/11850760/
Sustained-action phendimetrazine in obesity. Hadler AJ. J Clin Pharmacol J New Drugs. 1968 Mar-Apr; 8(2):113-7. https://www.ncbi.nlm.nih.gov/pubmed/4871210/
Diabetes Prevention Program Research Group Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care. 2012;35(4):731–737.
Igel LI, Sinha A, Saunders KH, Apovian CM, Vojta D, Aronne LJ. Metformin: an old therapy that deserves a new indication for the treatment of obesity. Curr Atheroscler Rep. 2016;18(4):16.
LeBlanc E, O’Connor E, Whitlock EP, Patnode C, Kapka T. U.S. Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews. Agency for Healthcare Research and Quality; Rockville (MD): 2011. Screening for and Management of Obesity and Overweight in Adults. Report No.: 11-05159-EF-1.
Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis. Maayan L, Vakhrusheva J, Correll CU. Neuropsychopharmacology. 2010 Jun; 35(7):1520-30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055458/
Meta-analysis: pharmacologic treatment of obesity. Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC. Ann Intern Med. 2005 Apr 5; 142(7):532-46. https://www.ncbi.nlm.nih.gov/pubmed/15809465/
Shorvon SD. Safety of topiramate: adverse events and relationships to dosing. Epilepsia. 1996;37(Suppl 2):S18–S22. https://www.ncbi.nlm.nih.gov/pubmed/8641242
Shapira NA, Goldsmith TD, McElroy SL. Treatment of binge-eating disorder with topiramate: a clinical case series. J Clin Psychiatry. 2000;61(5):368–372. https://www.ncbi.nlm.nih.gov/pubmed/10847312
Bray GA, Hollander P, Klein S, et al. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res. 2003;11(6):722–733 https://www.ncbi.nlm.nih.gov/pubmed/12805393
Hendricks EJ, Rothman RB, Greenway FL. How physician obesity specialists use drugs to treat obesity. Obesity (Silver Spring) 2009;17(9):1730–1735
Schmidt SL, Bryman D, Greenway FL, Hendricks EJ. How physician obesity medicine specialists treated obesity before 2012 new drug approvals. Obes Surg. 2015;25(1):186–190.
Gadde KM, Franciscy DM, Wagner HR, 2nd, Krishnan KR. Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA. 2003;289(14):1820–1825. https://jamanetwork.com/journals/jama/fullarticle/196347
Oommen KJ, Mathews S. Zonisamide: a new antiepileptic drug. Clin Neuropharmacol.1999;22:192-200.
Singh-Franco D, Perez A, Harrington C. The effect of pramlintide acetate on glycemic control and weight in patients with type 2 diabetes mellitus and in obese patients without diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2011;13(2):169–180. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0031948/
Aronne LJ, Halseth AE, Burns CM, Miller S, Shen LZ. Enhanced weight loss following coadministration of pramlintide with sibutramine or phentermine in a multicenter trial. Obesity (Silver Spring) 2010;18(9):1739–1746.
Hollander P, Bays HE, Rosenstock J, et al. Coadministration of canagliflozin and phentermine for weight management in overweight and obese individuals without diabetes: a randomized clinical trial. Diabetes Care. 2017;40(5):632–639.
McAdam-Marx C, Nguyen H, Schauerhamer MB, et al. Glycemic control and weight outcomes for exenatide once weekly versus liraglutide in patients with type 2 diabetes: a 1-year retrospective cohort analysis. Clin Ther. 2016;38(12):2642–2651
Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597–1604.