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

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.

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

Footnotes:

a Where available.

b Composition or particle size not given.

c LDH = lactate dehydrogenase.

d MMAD = mass median aerodynamic diameter.

Table 3. Toxicity of kaolin and illite clay in vitro

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.

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

Footnotes:

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

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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.

1. 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[↩]
2. 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.[↩]
3. 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.[↩]
4. 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.[↩][↩]
5. HSDB (Hazardous Substances Data Bank). 1998. Magnesium hydroxide.[↩]
6. 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[↩][↩][↩]
7. 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[↩][↩]
8. 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[↩][↩][↩]
9. 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[↩]
10. Baldwin WF. Clinical study of senna administration to nursing mothers. Can Med Assoc J. 1963;89:566-7.[↩]
11. Haldeman W. Can magnesium sulfate therapy impact lactogenesis? J Hum Lact. 1993;9:249-52. https://doi.org/10.1177/089033449300900426[↩]
12. 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[↩]
13. 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[↩]
14. 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[↩]
15. 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[↩]
16. 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[↩]
17. 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.[↩][↩]
18. Rude, R.K., and F.R.Singer. 1981. Magnesium deficiency and excess. Ann. Rev. Med. 32:245–259.[↩]
19. Poisindex®. 1998. Toxicologic management of magnesium. 8/31/98. Micromedex, Inc.[↩]
20. HSDB (Hazardous Substances Data Bank). 1998. Magnesium hydroxide. https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+659[↩][↩]
21. Dreisbach, R.H. 1977. Handbook of Poisoning: Diagnosis and Treatment, Ninth Edition. Los Altos, CA: Lange Medical Publications.[↩]
22. 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.[↩]
23. 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.[↩]
24. 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.[↩]

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.

Other Topical medications

There are a variety of creams, lotions and gels that can be applied directly to the skin (topically) with different drugs in them. All of these treatments need to be used for several weeks or months before they start working. To prevent new pimples from forming, they have to be applied to the skin surrounding existing pimples too.

Some medications can irritate the skin, causing things like redness and itching. You can reduce this risk by starting with a low dose and then gradually increasing it. If your skin becomes irritated, lowering the dose can help. If your skin stays irritated or if the medication has not worked after some time, you could try a different medication.

• Summary of acne and acne vulgaris topical treatment options for adolescents to adults ⁸:Benzoyl peroxide and/ or combinations with erythromycin or clindamycin are effective acne treatments and are recommended as monotherapy for mild acne, or in conjunction with a topical retinoid, or systemic antibiotic therapy for moderate to severe acne.
• Benzoyl peroxide is effective in the prevention of bacterial resistance and is recommended for patients on topical or systemic antibiotic therapy.
• Topical antibiotics (e.g., erythromycin and clindamycin) are effective acne treatments but are not recommended as monotherapy due risk of bacterial resistance.
• Topical retinoids are important in addressing the development and maintenance of acne and are recommended as monotherapy in primarily comedonal acne, or in combination with topical or oral antimicrobials in patients with mixed or primarily inflammatory acne lesions.
• Employing multiple topical agents that affect different aspects of acne pathogenesis can be useful. Combination therapy should be used in the majority of patients with acne.
• Topical adapalene, tretinoin and benzoyl peroxide can be safely used in the management of preadolescent acne in children.
• Azelaic acid is a useful adjunctive acne treatment and is recommended in the treatment of postinflammatory dyspigmentation.
• Topical dapsone 5% gel is recommended for inflammatory acne, particularly in adult females with acne.
• There is limited evidence to support recommendations for sulfur, nicotinamide, resorcinol, sodium sulfacetamide, aluminum chloride, and zinc in the treatment of acne.

Other products for topical use

Azelaic acid helps prevent oil glands in the skin from becoming clogged and can improve acne. It has an antibacterial and anti-inflammatory effect. The possible side effects include skin irritations such as itching and burning. Azelaic acid 20% is mildly effective as a comedolytic, antibacterial, and antiinflammatory agent. Azelaic acid has use in patients with sensitive skin or of Fitzpatrick skin types IV or greater because of the lightening effect of the product on dyspigmentation ⁹. Azelaic acid is category B in pregnancy.

Pregnancy Category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Many acne products, such as cleansing toners and creams, contain salicylic acid. This ingredient is believed to work by removing dead skin cells from blocked pores (comedolytic agent). It is not clear whether products containing salicylic acid help reduce acne. Salicylic acid can also have side effects such as redness, dryness and peeling. Salicylic acid is a comedolytic agent that is available over the counter in 0.5% to 2% strengths for the therapy of acne vulgaris. Both wash-off and leave-on preparations are well tolerated. Clinical trials demonstrating the efficacy of salicylic acid in acne are limited ¹⁰.

The sulfone agent, dapsone 5% gel, is available as a twice-daily agent for the therapy of acne vulgaris. In clinical trials, topical dapsone showed modest to moderate efficacy, primarily in the reduction of inflammatory lesions ¹¹. Combination with topical retinoids may be indicated if comedonal components are present. The mechanism of action is poorly understood, and its ability to kill Propionibacterium acnes (is a gram-positive human skin commensal bacteria and is involved in the pathogenesis of acne) has been poorly studied. It is generally thought to work as an antiinflammatory agent. The benefit in women seems to exceed the benefit in male and adolescent patients ¹². Topical dapsone may be oxidized by the coapplication of benzoyl peroxide, causing orange-brown coloration of the skin which can be brushed or washed off. Topical dapsone 5% gel is pregnancy category C and has efficacy and safety data down to patients 12 years of age. Glucose-6-phosphate dehydrogenase testing is not required before starting topical dapsone.

Pregnancy Category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Topical Antibiotics

In inflammatory forms of acne, the skin is infected with bacteria. Antibiotics that are applied to the skin have an anti-inflammatory effect and can reduce inflammatory forms of acne. They are not effective in the treatment of non-inflammatory acne.

Topical antibiotics need to be used for quite some time before they can have an effect. In US and other countries, they are only available on prescription. The treatment takes at least three weeks, and many people only see an improvement after three to six months. One problem with antibiotics is that there is always a risk of bacteria becoming resistant. In other words, the bacteria may get used to the drug if it is used too often. As a result, the antibiotics do not work as well the next time you use them, or they may not work at all. So antibiotics are not suitable for repeated long-term use.

Topical Retinoids

Topical retinoids are vitamin A derivatives that are prescription agents with randomized, double-blind, placebo-controlled trials supporting their use for acne treatment ¹³. The retinoids used in the topical treatment of acne include adapalene, isotretinoin and tretinoin. Three active agents are available: tretinoin (0.025-0.1% in cream, gel, or microsphere gel vehicles), adapalene (0.1%, 0.3% cream, or 0.1% lotion73,74), and tazarotene (0.05%, 0.1% cream, gel or foam). Each retinoid binds to a different set of retinoic acid receptors: tretinoin to alpha, beta, and gamma, and tazarotene and adapalene, selectively, to beta and gamma—thereby conferring slight differences in activity, tolerability, and efficacy. Retinoids are the core of topical therapy for acne because they are comedolytic, resolve the precursor microcomedone lesion, and are antiinflammatory. In US and other countries, topical retinoids are prescription-only and are available as creams, gels or solutions. They can help in both inflammatory and non-inflammatory acne. Treatment with retinoids can lead to a visible improvement within a few weeks.

Side effects such as redness, burning and itching may occur. Retinoids have NOT been approved for use in women who are pregnant or breastfeeding.

Topical retinoids enhance any topical acne regimen and allow for maintenance of clearance after discontinuation of oral therapy. Retinoids are ideal for comedonal acne and, when used in combination with other agents, for all acne variants. Three topical agents are available that contain retinoids in combination with other products: adapalene 0.1%/benzoyl peroxide 2.5%, approved for use in patients ≥9 years of age, and 2 agents with fixed combination clindamycin phosphate 1.2%/tretinoin 0.025% gel, approved for patients ≥12 years of age ¹⁴.

Retinoid use may be limited by side effects, including dryness, peeling, erythema, and irritation, which can be mitigated by reduced frequency of application ¹⁵. Given any single agent, higher concentrations may be more efficacious, but with greater side effects ¹⁵. Some formulations of tretinoin (primarily generic products) are not photostable and should be applied in the evening. Tretinoin also may be oxidized and inactivated by the coadministration of benzoyl peroxide. It is recommended that the 2 agents be applied at different times. Tretinoin microsphere formulation, adapalene, and tazarotene do not have similar restrictions. Topical retinoids have been associated with an increased risk of photosensitivity; concurrent daily sunscreen can be used to reduce the risk of sunburn.

There are several head-to-head studies with retinoid products. Some support greater efficacy of tazarotene over adapalene and tretinoin, and adapalene over tretinoin, but the concentrations and formulations used were varied ¹⁶. Data suggest that adapalene is better tolerated than multiple concentrations of tretinoin, but this is based on older formulations ¹⁶. Overall, the limitations of the existing studies prohibit direct efficacy comparisons of topical retinoids.

Tretinoin and adapalene are pregnancy category C, while tazarotene is category X; therefore, patients should be counseled on these pregnancy risks when starting a retinoid or if a woman patient desires pregnancy.

Pregnancy Category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Pregnancy Category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Oral medications

Oral medications are usually considered in people with moderate to severe acne, or if topical treatment has not led to a big enough improvement.

Oral Antibiotics

Antibiotic tablets can help improve inflammatory acne when taken for several weeks or months.

Oral antibiotics can have side effects, including dizziness, digestive problems and allergic reactions such as rashes. The antibiotics called tetracycline and minocycline are not suitable for anyone who is pregnant or breastfeeding. People who take minocycline for longer than three weeks should have a blood test before starting the treatment, as well as regular blood tests during the treatment. This is done in order to detect any problems with the liver, kidney or the formation of blood as soon as possible.

As with topical antibiotics, there is a risk that the bacteria may become resistant and that oral antibiotics will then stop working if they are used too often.

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).

1. 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.[↩][↩][↩]
2. 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[↩]
3. 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.[↩][↩]
4. 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.[↩]
5. 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.[↩]
6. 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.[↩]
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.[↩]
8. Topical therapies: Recommendations. https://www.aad.org/practicecenter/quality/clinical-guidelines/acne/topical-therapies[↩]
9. 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.[↩]
10. 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.[↩]
11. 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.[↩]
12. 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.[↩]
13. 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.[↩]
14. 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.[↩]
15. Pedace FJ, Stoughton R. Topical retinoic acid in acne vulgaris. Br J Dermatol. 1971;84:465-469.[↩][↩]
16. 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.[↩][↩]
17. 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[↩]
18. 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[↩]
19. 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[↩]
20. 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[↩]
21. Cunliffe WJ, Dodman B, Ead R. Benzoyl peroxide in acne. Practitioner. 1978;220:479-482.[↩]
22. Kirschbaum JO, Kligman AM. The pathogenic role of Corynebacterium acnes in acne vulgaris. Archives of Dermatology. 1963;88:832–833[↩]
23. Fyrand O, Jakobsen HB. Water-based versus alcohol-based benzoyl peroxide preparations in the treatment of acne vulgaris. Dermatologica. 1986;172:263-267.[↩]
24. Osol, A. (ed.). Remington’s Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980., p. 728[↩]

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.

1. 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/[↩]
2. 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[↩][↩][↩][↩][↩]
3. 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/[↩]
4. 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[↩]
5. Mannitol (By breathing). https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011032[↩]
6. Sweeteners: Nutritional Aspects, Applications, and Production Technology. CRC Press. pp. 59–60. ISBN 9781439876732[↩]
7. Grenby, T.H (2011) Advances in Sweeteners. Springer. ISBN 1461285224. p. 66[↩]
8. Mannitol (Inhalation route). https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0045434/#DDIC603407.side_effects_section[↩]
9. Doi K, Ogawa N, Suzuki E, Noiri E, Fujita T “Mannitol-induced acute renal failure.” Am J Med 115 (2003): 593-4[↩]
10. Navarro V, Vieta E, Gasto C “Mannitol-induced acute manic state.” J Clin Psychiatry 62 (2001): 126[↩]

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.

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

Other Medical Problems

The presence of other medical problems may affect the use of yohimbine. Make sure you tell your doctor if you have any other medical problems, especially:

• Angina pectoris or
• Depression or
• Other psychiatric illness or
• Heart disease or
• High blood pressure or
• Kidney disease—Yohimbine may make these conditions worse

Liver disease—Effects of yohimbine may be increased because of slower removal from the body.

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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

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.

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.

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What is carbidopa and levodopa

The combination of levodopa and carbidopa is used to treat the symptoms of Parkinson’s disease and Parkinson’s-like symptoms (parkinsonism) that may develop after encephalitis (swelling of the brain) or injury to the nervous system caused by carbon monoxide poisoning or manganese poisoning. Current evidence indicates that symptoms of Parkinson’s disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson’s disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine (an aromatic amino acid precursor of dopamine), does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson’s disease. Levodopa is a prodrug that is converted to dopamine by DOPA decarboxylase and can cross the blood-brain barrier. Levodopa is the most commonly used treatment for Parkinson’s disease and levodopa is converted to dopamine in the brain. Carbidopa is a peripheral decarboxylase inhibitor that helps prevent the breakdown of levodopa before it can reach the brain and take effect. Carbidopa has little or no pharmacological activity when given alone in usual doses. Carbidopa inhibits the peripheral decarboxylation of levodopa to dopamine; and as carbidopa does not cross the blood-brain barrier, unlike levodopa, effective brain concentrations of dopamine are produced with lower doses of levodopa. At the same time, reduced peripheral formation of dopamine reduces peripheral side-effects, notably nausea and vomiting, and cardiac arrhythmias, although the dyskinesias and adverse mental effects associated with levodopa therapy tend to develop earlier. Carbidopa is a also used with levodopa to treat muscle symptoms similar to Parkinson’s disease that are caused by certain drugs such as chlorpromazine (Thorazine), fluphenazine (Prolixin), perphenazine (Trilafon), and others.

Note: Carbidopa has no antiparkinsonian effect when given alone. Carbidopa is indicated for use with carbidopa-levodopa or levodopa. Carbidopa does not decrease adverse reactions due to central effects of levodopa. When carbidopa is to be given to carbidopa-naive patients who are being treated with levodopa alone, the two drugs should be given at the same time. At least twelve hours should elapse between the last dose of levodopa and initiation of therapy with carbidopa and levodopa in combination. Start with no more than one-fifth (20%) to one-fourth (25%) of the previous daily dosage of levodopa when given without carbidopa. The addition of carbidopa with levodopa or carbidopa-levodopa reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa. Because carbidopa permits more levodopa to reach the brain and more dopamine to be formed, certain adverse central nervous system (CNS) effects, e.g., dyskinesias (involuntary movements), may occur at lower dosages and sooner with levodopa in combination with carbidopa than with levodopa alone.

Parkinson’s disease is a progressive disorder of the nervous system marked by resting muscle tremors, muscle rigidity, decreased mobility, stooped posture, slow voluntary movements, and a mask-like facial expression. Parkinson’s disease affects over six million people worldwide, making it the most common neurodegenerative disease after Alzheimer’s disease ¹. Parkinson’s disease can be very hard to live with because it severely restricts mobility and as a result makes daily activities increasingly difficult. Parkinson’s symptoms, including tremors (shaking), stiffness, and slowness of movement, are caused by a lack of dopamine, a natural substance usually found in the brain. There is no cure for Parkinson’s disease and its exact cause is not known, but there are effective treatments that can relieve the symptoms. Levodopa is in a class of medications called central nervous system agents. Although the optimal timing of the initiation of levodopa therapy is controversial, some investigators have suggested that early treatment of parkinsonism with levodopa delays disease progression and decreases mortality. Some patients require the combination of medicine, while others benefit from levodopa alone. By improving muscle control, levodopa allows more normal movements of the body. Levodopa works by being converted to dopamine in the brain. Carbidopa is in a class of medications called decarboxylase inhibitors. It works by preventing levodopa from being broken down before it reaches the brain. This allows for a lower dose of levodopa, which causes less nausea and vomiting.

Three main types of medication are commonly used for Parkinson’s disease:

1. Levodopa
2. Dopamine agonists. Dopamine agonists act as a substitute for dopamine in the brain and have a similar but milder effect compared with levodopa. They can often be given less frequently than levodopa. Sometimes dopamine agonists are taken at the same time as levodopa, as this allows lower doses of levodopa to be used.
3. Monoamine oxidase-B inhibitors (e.g., selegiline and rasagiline). They block the effects of an enzyme or brain substance that breaks down dopamine (monoamine oxidase-B), increasing dopamine levels.

Your specialist can explain your medication options, including the risks associated with each medication, and discuss which may be best for you. Regular reviews will be required as the condition progresses and your needs change.

Catechol-O-methyltransferase (COMT) inhibitors are prescribed for people in later stages of Parkinson’s disease. They prevent levodopa from being broken down by the enzyme COMT.

Side effects of catechol-O-methyltransferase inhibitors include:

• nausea or vomiting
• diarrhoea
• abdominal pain

Carbidopa levodopa pharmacodynamics

When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. For this reason, large doses of levodopa are required for adequate therapeutic effect and these may often be accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed in extracerebral tissues.

The route of entry of levodopa is oral. Levodopa is rapidly absorbed from the small intestine by an active transport system for aromatic amino acids. Concentrations of drug in plasma usually peak between 0.5 and 2 hours after an oral dose. The rate of absorption of levodopa is greatly dependent upon the rate of gastric emptying, the pH of gastric juice and the length of time the drug is exposed to the degradative enzymes of the gastric mucosa and intestinal flora. Hyperacidity of gastric juice, and competition for absorption sites in the small intestine by amino acids each may interfere with the bioavailability of vodopa.

Distribution by route of exposure: Levodopa is widely distributed to most body tissues, but less to the central nervous system (CNS). Little unchanged drug reaches the cerebral circulation and probably less than 1% penetrates into the CNS.

Biological half-life by route of exposure: Levodopa has relatively short plasma half-life of 1 to 3 hours.

Levodopa metabolism: More than 95% of levodopa is decarboxylated by the widely distributed extracerebral aromatic l-amino acid decarboxylase. The drug is extensively decarboxylated in its first passage through the liver, which is rich in decarboxylase. A small amount is methylated to 3-0-methyldopa, which accumulates in the CNS due to its long half-life. Most is converted to dopamine, small amounts of which in turn are metabolized to norepinephrine and epinephrine (adrenaline). Biotransformation of dopamine proceeds rapidly to yield the principal excretion products, 3-4-dihydroxy-phenylacetic acid (DOPAC) and 3-methoxy-4-hydroxy-phenylacetic acid (homovanillic acid, HVA). At least 30 metabolites of levodopa have been identified. The evidence indicates that the metabolism of levodopa may be accelerated during prolonged therapy possibly due to enzyme induction.

Levodopa excretion: Metabolites of dopamine are rapidly excreted in the urine; 80% of a radioactively labelled dose is recovered within 24 hours. The principal metabolites 3-4-dihydroxy-phenylacetic acid and homovanillic acid account for up to 50% of the administered dose. Negligible amounts are found in the feces.

The incidence of levodopa-induced nausea and vomiting is less when levodopa is used with carbidopa than when levodopa is used without carbidopa. In many patients this reduction in nausea and vomiting will permit more rapid dosage titration.

Carbidopa inhibits decarboxylation of peripheral levodopa. Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the recommended doses. Carbidopa does not appear to cross the blood-brain barrier readily and does not affect the metabolism of levodopa within the central nervous system at doses of carbidopa that are recommended for maximum effective inhibition of peripheral decarboxylation of levodopa.

Carbidopa is combined with levodopa in carbidopa-levodopa or carbidopa-levodopa extended release tablets.

Since carbidopa’s decarboxylase-inhibiting activity is limited primarily to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain. However, since levodopa and carbidopa compete with certain amino acids for transport across the gut wall, the absorption of levodopa and carbidopa may be impaired in some patients on a high protein diet.

Carbidopa levodopa pharmacokinetics

Levodopa is the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the basal ganglia. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson’s disease, because it replaces depleted brain dopamine in these patients.

Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid.

In clinical pharmacologic studies, simultaneous administration of separate tablets of carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the excretion of dopamine when compared to the two drugs administered at separate times.

Supplemental pyridoxine (vitamin B6) can be given to patients when they are receiving carbidopa and levodopa concomitantly or the fixed combination carbidopa-levodopa or carbidopa-levodopa extended release. Previous reports in the medical literature cautioned that high doses of vitamin B6 should not be taken by patients on levodopa therapy alone because exogenously administered pyridoxine would enhance the metabolism of levodopa to dopamine. The introduction of carbidopa to levodopa therapy, which inhibits the peripheral decarboxylation of levodopa to dopamine, counteracts the metabolic-enhancing effect of vitamin B6 (pyridoxine).

Before using levodopa precautions

In deciding to use levodopa, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make.

Levodopa may cause some people to become dizzy, confused, or have blurred or double vision. Make sure you know how you react to levodopa before you drive, use machines, or do anything else that could be dangerous if you are not alert or not able to see well.

Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position. Getting up slowly may help. If the problem continues or gets worse, check with your doctor.

For levodopa, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to levodopa or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Studies on levodopa have been done only in adult patients, and there is no specific information comparing use of levodopa or carbidopa in children with use in other age groups.

Geriatric

Elderly people are especially sensitive to the effects of levodopa. This may increase the chance of side effects during treatment.

Pregnancy

• Pregnancy Category C (all Trimesters): Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

• Studies suggest that levodopa may alter milk production or composition. If an alternative to this medication is not prescribed, you should monitor the infant for side effects and adequate milk intake.

Patients with diabetes

Levodopa may cause test results for urine sugar or ketones to be wrong. Check with your doctor before depending on home tests using the paper-strip or tablet method.

Levodopa interactions with other medicines

When you are taking levodopa, 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.

Levodopa is always combined with carbidopa (a dopa decarboxylase inhibitor) to reduce peripheral side effects and enhance absorption.

Administration of levodopa with nonspecific inhibitors of monoamine oxidase inhibitor (MAO), such as phenelzine and tranylcypromine, markedly accentuates the actions of levodopa & may precipitate life-threatening hypertensive crisis & hyperpyrexia; nonspecific monoamine oxidase inhibitors always should be discontinued at least 14 days before levodopa is admin (note that this prohibition does not include the monoamine oxidase-B subtype-specific inhibitor selegiline, which, as discussed below, often is admin safely in combination with levodopa). Abrupt withdrawal of levodopa or other dopaminergic medications may precipitate the neuroleptic malignant syndrome more commonly observed after treatment with dopamine antagonists.

Antipsychotic drugs, such as phenothiazines, butyrophenones and reserpine can produce a parkinsonism-like syndrome, and since these drugs interfere with the therapeutic effects of levodopa, they are contraindicated. Therefore the phenothiazines should not be used to combat the emetic effect of levodopa. Nonspecific monoamine oxidase inhibitors interfere with inactivation of dopamine, norepinephrine and other catecholamines. Hence, they unpredictably exaggerate the central effects of levodopa and its catecholamine metabolites. Hypertensive crisis and hyperpyrexia are very real and dangerous sequelae of concurrent administration of two such drugs.

Using levodopa with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amisulpride
• Bromopride
• Clorgyline
• Furazolidone
• Iproniazid
• Isocarboxazid
• Linezolid
• Methylene Blue
• Moclobemide
• Nialamide
• Pargyline
• Phenelzine
• Procarbazine
• Sulpiride
• Toloxatone
• Tranylcypromine

Using levodopa 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.

• Bupropion
• Isoniazid
• Macimorelin
• Metoclopramide

Using levodopa 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.

• Fosphenytoin
• Indinavir
• Iron
• Kava
• Phenylalanine
• Phenytoin
• Spiramycin
• Tyrosine

For patients taking levodopa by itself:

• Pyridoxine (vitamin B6) has been found to reduce the effects of levodopa when levodopa is taken by itself. This does not happen with the combination of carbidopa and levodopa. If you are taking levodopa by itself, do not take vitamin products containing vitamin B6 during treatment, unless prescribed by your doctor.
• Large amounts of pyridoxine are also contained in some foods such as bananas, egg yolks, lima beans, meats, peanuts, and whole grain cereals. Check with your doctor about how much of these foods you may have in your diet while you are taking levodopa. Also, ask your health care professional for help when selecting vitamin products.

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. Since protein may interfere with the body’s response to levodopa, high protein diets should be avoided. Intake of normal amounts of protein should be spaced equally throughout the day, or taken as directed by your doctor. 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 levodopa 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 levodopa, or give you special instructions about the use of food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of levodopa. Make sure you tell your doctor if you have any other medical problems, especially:

• Diabetes mellitus (sugar diabetes)—The amount of insulin or antidiabetic medicine that you need to take may change
• Emphysema, asthma, bronchitis, or other chronic lung disease or
• Glaucoma or
• Heart or blood vessel disease or
• Hormone problems or
• Melanoma (a type of skin cancer) (or history of) or
• Mental illness—Levodopa may make the condition worse
• Kidney disease or
• Liver disease—Higher blood levels of levodopa may occur, increasing the chance of side effects
• Seizure disorders, such as epilepsy (history of)—The risk of seizures may be increased
• Stomach ulcer (history of)—The ulcer may occur again

Carbidopa-levodopa patient advice

It is important that carbidopa with levodopa be taken at regular intervals according to the schedule outlined by the health care provider. Caution patients not to change the prescribed dosage regimen and not to add any additional antiparkinson medications, including other carbidopa-levodopa preparations without first consulting a physician.

• Occasionally dark color may appear in saliva, urine, or sweat after ingestion of carbidopa.
• A change in diet to high-protein foods may delay the absorption of levodopa.
• Carbidopa-levodopa therapy may lead to sudden onset of sleep during daily activities or somnolence. Avoid driving or operating machinery if you experience these symptoms.
• As with levodopa alone, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are recommended during extended concomitant therapy with carbidopa and levodopa, or with carbidopa and carbidopa-levodopa, or any combination of these drugs.

Patients should be aware of a ‘wearing-off’ effect that may occur at the end of the dosing interval. Patients should to notify the prescriber if such response poses a problem to lifestyle.

Patients should be advised that occasionally dark color (red, brown, or black) may appear in saliva, urine, or sweat after ingestion of carbidopa and levodopa. Although the color appears to be clinically insignificant, garments may become discolored.

The patient should be advised that a change in diet to foods that are high in protein may delay the absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also delays stomach emptying thus delaying the absorption of levodopa. Iron salts (such as in multivitamin tablets) may also reduce the amount of levodopa available in the body. The above factors may reduce the clinical effectiveness of the carbidopa and levodopa therapy.

Alert patients to the possibility of sudden onset of sleep during daily activities, in some cases without awareness or warning signs, when they are taking dopaminergic agents, including levodopa. Advise patients to exercise caution while driving or operating machinery and that if they have experience somnolence and/or sudden sleep onset, they must refrain from these activities.

There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease, including carbidopa and levodopa. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges, or other intense urges while taking carbidopa and levodopa. Physicians should consider dose reduction or stopping carbidopa and levodopa if a patient develops such urges while taking carbidopa with carbidopa/levodopa.

Patients taking carbidopa-levodopa products alone or with other dopaminergic drugs have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation of motor vehicles). Some of these episodes resulted in automobile accidents. Although many of these patients reported somnolence while on dopaminergic medications, some did perceive that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some patients reported these events one year after the initiation of treatment.

Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre-existing somnolence, although some patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with carbidopa when taking it with other carbidopa-levodopa products.

Before initiating treatment with carbidopa, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with carbidopa such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing carbidopa in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with carbidopa continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Impulse Control/Compulsive Behaviors

Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications that are used for the treatment of Parkinson’s disease and that increase central dopaminergic tone, including carbidopa taken with levodopa and carbidopa. In some cases, although not all, these urges were reported to have stopped when the dose of anti-Parkinson medications was reduced or discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with carbidopa. Physicians should consider dose reduction or stopping carbidopa or levodopa if a patient develops such urges while taking carbidopa with carbidopa/levodopa.

Hallucinations/Psychotic-Like Behavior

Hallucinations and psychotic like behavior have been reported with dopaminergic medications. In general, hallucinations present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming. Carbidopa when taken with carbidopa-levodopa may have similar effects on thinking and behavior. This abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.

Ordinarily, patients with a major psychotic disorder should not be treated with carbidopa and carbidopa-levodopa, because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of carbidopa.

Dyskinesia

Carbidopa may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia.

Depression

Patients treated with carbidopa and carbidopa-levodopa should be observed carefully for the development of depression with concomitant suicidal tendencies.

Melanoma

Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using carbidopa tablets for Parkinson’s disease.

Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Laboratory Tests

Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood urea nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during concomitant administration of Carbidopa and levodopa than with levodopa alone.

Levodopa and carbidopa-levodopa combination products may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria.

Hyperpyrexia and Confusion

Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as levodopa, carbidopa-levodopa, or carbidopa-levodopa extended-release. Therefore, patients should be observed carefully when the dosage of levodopa or carbidopa-levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.

Neuroleptic malignant syndrome (NMS) is an uncommon but life-threatening syndrome characterized by fever or hyperthermia. Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating, hyper-or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin, have been reported.

The early diagnosis of this condition is important for the appropriate management of these patients. Considering neuroleptic malignant syndrome (NMS) as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of neuroleptic malignant syndrome (NMS) should include: 1) intensive symptomatic treatment and medical monitoring and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used in the treatment of neuroleptic malignant syndrome (NMS); however, their effectiveness has not been demonstrated in controlled studies.

Carbidopa levodopa drug interactions

Symptomatic postural hypotension has occurred when carbidopa, given with levodopa or carbidopa-levodopa combination products, was added to the treatment of a patient receiving antihypertensive drugs. Therefore, when therapy with carbidopa, given with or without levodopa or carbidopa-levodopa combination products, is started, dosage adjustment of the antihypertensive drug may be required.

For patients receiving monoamine oxidase inhibitors (Type A or B). Concomitant therapy with selegiline or rasigiline and carbidopa and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone.

There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa preparations.

Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in Parkinson’s disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with carbidopa and levodopa or carbidopa-levodopa combination products should be carefully observed for loss of therapeutic response.

Carbidopa and iron salts or multi vitamins containing iron salts should be co administered with caution. Iron salts can form chelates with levodopa and carbidopa and consequently reduce the bioavailability of carbidopa and levodopa.

Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties.

Droxidopa: Carbidopa may diminish the therapeutic effect of Droxidopa. Carbidopa may decrease serum concentrations of the active metabolite(s) of Droxidopa. Carbidopa may increase the serum concentration of Droxidopa. Monitor therapy

Spiramycin: May decrease the serum concentration of Carbidopa. And thus may decrease the effectiveness of levodopa. Monitor therapy

Test Interactions

False-positive reaction for urinary glucose with Clinitest®; false-negative reaction using Clinistix®; false-positive urine ketones with Acetest®, Ketostix®, Labstix®.

Carbidopa levodopa contraindications

Carbidopa is contraindicated in patients with known hypersensitivity to any component of this drug.

Levodopa is contraindicated for melanoma and glaucoma in patients with known hypersensitivity to the drug. Levodopa should be administered cautiously to patients with severe cardiovascular or pulmonary disease, asthma, renal, hepatic or endocrine disease. Care should be exercised in administering levodopa to patients with history of myocardial infarction who have residual atrial nodal or ventricular arrhythmias. If levodopa is necessary in this type of patient, it should be used in a facility with a coronary care unit or an intensive care unit.

Levodopa is contraindicated in patients with severe psychotic disorders, it should be used with caution in patients with psychiatric disturbance. This drug should not be used in pregnancy and should not be used in nursing mothers. The safety under the age of 12 has not been established.

Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with levodopa or carbidopa-levodopa combination products with or without carbidopa. These inhibitors must be discontinued at least two weeks prior to initiating therapy with levodopa. Carbidopa-levodopa, or levodopa may be administered concomitantly with the manufacturer’s recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline HCl).

Levodopa or carbidopa-levodopa products, with or without carbidopa, are contraindicated in patients with narrow-angle glaucoma.

Carbidopa levodopa uses

Most people with Parkinson’s disease eventually need a medication called levodopa.

Levodopa is absorbed by the nerve cells in your brain and turned into the chemical dopamine, which is used to transmit messages between the parts of the brain and nerves that control movement.

Increasing the levels of dopamine using levodopa usually improves movement problems.

It is usually taken as a tablet or liquid, and is often combined with other medication, such as benserazide or carbidopa.

These medications stop the levodopa being broken down in the bloodstream before it has a chance to get to the brain.

They also reduce the side effects of levodopa, which include:

• feeling sick (nausea) or vomiting
• tiredness
• dizziness

If you’re prescribed levodopa, the initial dose is usually very small and will be gradually increased until it takes effect.

At first, levodopa can cause a dramatic improvement in the symptoms.

However, its effects can be less long-lasting over the following years – as more nerve cells in the brain are lost, there are fewer of them to absorb the medicine. This means the dose may need to be increased from time to time.

Long-term use of levodopa is also linked to problems such as uncontrollable, jerky muscle movements (dyskinesias) and “on-off” effects, where the person rapidly switches between being able to move (on) and being immobile (off).

Carbidopa levodopa is used in the treatment of idiopathic Parkinson disease (paralysis agitans), postencephalitic parkinsonism and symptomatic parkinsonism, which may follow injury to the nervous system by carbon monoxide and/or manganese intoxication.

Note: Administration of carbidopa allows use of a lower dosage of levodopa, more rapid titration, and a decrease in nausea and vomiting associated with levodopa; use with carbidopa/levodopa in patients requiring additional carbidopa; has no effect without levodopa.

Although the administration of carbidopa permits control of parkinsonism and Parkinson’s disease with much lower doses of levodopa, there is no conclusive evidence at present that this is beneficial other than in reducing nausea and vomiting, permitting more rapid titration, and providing a somewhat smoother response to levodopa.

Certain patients who responded poorly to levodopa alone have improved when carbidopa and levodopa were given concurrently. This was most likely due to decreased peripheral decarboxylation of levodopa rather than to a primary effect of carbidopa on the peripheral nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa.

In deciding whether to give carbidopa with carbidopa-levodopa or with levodopa to patients who have nausea and/or vomiting, the physician should be aware that, while many patients may be expected to improve, some may not. Since one cannot predict which patients are likely to improve, this can only be determined by a trial of therapy. It should be further noted that in controlled trials comparing carbidopa and levodopa with levodopa alone, about half the patients with nausea and/or vomiting on levodopa alone improved spontaneously despite being retained on the same dose of levodopa during the controlled portion of the trial.

Carbidopa is for use with carbidopa-levodopa in patients for whom the dosage of carbidopa-levodopa provides less than adequate daily dosage (usually 70 mg daily) of carbidopa.

Carbidopa is for use with levodopa in the occasional patient whose dosage requirement of carbidopa and levodopa necessitates separate titration of each medication.

Carbidopa is used with carbidopa-levodopa or with levodopa to permit the administration of lower doses of levodopa with reduced nausea and vomiting, more rapid dosage titration, and with a somewhat smoother response. However, patients with markedly irregular (“on-off”) responses to levodopa have not been shown to benefit from the addition of carbidopa.

Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine (vitamin B6), supplemental pyridoxine (vitamin B6), can be given to patients when they are receiving carbidopa and levodopa concomitantly or as carbidopa-levodopa.

Carbidopa levodopa dosage

Take levodopa only as directed. Do not take more or less of it, and do not take it more often than your doctor ordered.

For patients taking carbidopa and levodopa extended-release tablets:

• Swallow the tablet whole without crushing or chewing, unless your doctor tells you not to. If your doctor tells you to, you may break the tablet in half.

Some people must take levodopa for several weeks or months before full benefit is received. Do not stop taking it even if you do not think it is working. Instead, check with your doctor.

Monitoring:

• Periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function.
• Psychiatric: Development of new or increased gambling urges, sexual urges, or other intense urges.

Levodopa dose

The dose of levodopa will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of levodopa as a guide. If your levodopa dose is different, do NOT change it unless your doctor tells you to do so.

The amount of levodopa that you take depends on the strength of the levodopa. Also, the number of levodopa doses you take each day, the time allowed between doses, and the length of time you take the levodopa depend on the medical problem for which you are using the medicine.

For Parkinson’s disease

For oral levodopa dosage form (tablets):

• Adults and teenagers—At first, 250 milligrams (mg) two to four times a day. Your doctor may increase your dose if needed. However, the dose is usually not more than 8000 mg (8 grams) a day.
• Children up to 12 years of age—Use and dose must be determined by your doctor.

Missed dose

If you miss a dose of levodopa, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Levodopa and carbidopa combination

When carbidopa tablet is to be given to carbidopa-naive patients who are being treated with levodopa, the two drugs should be given at the same time, starting with no more than 20 to 25% of the previous daily dosage of levodopa when given without carbidopa tablets. At least twelve hours should elapse between the last dose of levodopa and initiation of therapy with carbidopa and levodopa.

Most patients respond to a 1:10 proportion of carbidopa and levodopa, provided the daily dosage of carbidopa is 70 mg or more a day. The maximum daily dosage of carbidopa should not exceed 200 mg, since clinical experience with larger dosages is limited. If the patient is taking carbidopa-levodopa, the amount of carbidopa in carbidopa-levodopa should be considered when calculating the total amount of carbidopa to be administered each day.

Patients receiving carbidopa-levodopa who require additional carbidopa

Some patients taking carbidopa-levodopa may not have adequate reduction in nausea and vomiting when the dosage of carbidopa is less than 70 mg a day, and the dosage of levodopa is less than 700 mg a day. When these patients are taking carbidopa-levodopa, 25 mg of carbidopa may be given with the first dose of carbidopa-levodopa each day. Additional doses of 12.5 mg or 25 mg may be given during the day with each dose of carbidopa-levodopa. Carbidopa may be given with any dose of carbidopa-levodopa as required for optimum therapeutic response. The maximum daily dosage of carbidopa, given as carbidopa tablets and as carbidopa-levodopa, should not exceed 200 mg.

Patients requiring individual titration of carbidopa and levodopa dosage

Although carbidopa-levodopa is the most frequently used of carbidopa and levodopa administration, there may be an occasional patient who requires individually titrated doses of these two drugs. In these patients, carbidopa should be initiated at a dosage of 25 mg three or four times a day. The two drugs should be given at the same time, starting with no more than one-fifth (20%) to one-fourth (25%) of the previous or recommended daily dosage of levodopa when given without carbidopa. In patients already receiving levodopa therapy, at least twelve hours should elapse between the last dose of levodopa and initiation of therapy with carbidopa and levodopa. A convenient way to initiate therapy in these patients is in the morning following a night when the patient has not taken levodopa for at least twelve hours. Health care providers who prescribe separate doses of carbidopa and levodopa should be thoroughly familiar with the directions for use of each drug.

Dosage adjustment

Dosage of carbidopa may be adjusted by adding or omitting one-half or one tablet a day. Because both therapeutic and adverse responses occur more rapidly with combined therapy than when only levodopa is given, patients should be monitored closely during the dose adjustment period. Specifically, involuntary movements will occur more rapidly when carbidopa and levodopa are given concomitantly than when levodopa is given without carbidopa. The occurrence of involuntary movements may require dosage reduction. Blepharospasm may be a useful early sign of excess dosage in some patients.

Current evidence indicates other standard antiparkinsonian drugs may be continued while carbidopa and levodopa are being administered. However, the dosage of such other standard antiparkinsonian drugs may require adjustment.

Interruption of therapy

Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and withdrawal of carbidopa-levodopa or carbidopa-levodopa Extended Release. Patients should be observed carefully if abrupt reduction or discontinuation of carbidopa-levodopa or carbidopa-levodopa Extended-Release is required, especially if the patient is receiving neuroleptics.

If general anesthesia is required, therapy may be continued as long as the patient is permitted to take fluids and medication by mouth. When therapy is interrupted temporarily, the patient should be observed for symptoms resembling neuroleptic malignant syndrome (NMS), and the usual daily dosage may be resumed as soon as the patient is able to take medication orally.

For oral levodopa and carbidopa tablet dosage form:

• Adults—At first, 1 tablet three or four times a day. Your doctor may need to change your dose, depending on how you respond to this combination medicine.
• Children and teenagers—Use and dose must be determined by your doctor.

For oral extended-release levodopa and carbidopa tablet dosage form:

• Adults—At first, 1 tablet two times a day. However, you may need to take more than this. Your doctor will decide the right dose for you, depending on your condition and the other medicines you may be taking for Parkinson’s disease.
• Children and teenagers—Use and dose must be determined by your doctor.

Usual Adult Dose for Parkinsonian Tremor

Patients on carbidopa-levodopa therapy requiring additional carbidopa:

• Initial dose: 25 mg orally with the first dose of carbidopa-levodopa each day
• Maintenance dose: Additional doses of 12.5 mg or 25 mg may be given with each dose of carbidopa-levodopa
• Maximum dose: 200 mg orally per day

Patients requiring individual titration of carbidopa and levodopa:

• Initial dose: 25 mg orally three to four times a day, given at the same time as levodopa
• Maximum dose: 200 mg orally per day

Comments:

• In patients already on levodopa, allow 12 hours between the last dose of levodopa and the initiation of therapy with carbidopa and levodopa.
• If the patient is taking carbidopa-levodopa, the amount of carbidopa in carbidopa-levodopa should be considered when calculating the total daily dose.
• Blepharospasm may be used as an early sign of excess dosage in some patients.
• Therapeutic and adverse responses occur more rapidly with concomitant carbidopa and levodopa compared with levodopa given alone.
• Patients should be carefully monitored for signs and symptoms of neuroleptic malignant syndrome if treatment is abruptly reduced or discontinued.

Dose adjustments

Dose reduction may be required if there is occurrence of involuntary movements.

Concomitant levodopa:

• Most patients respond to a 1:10 proportion of carbidopa and levodopa, provided the daily dosage of carbidopa is 70 mg or more per day.
• If levodopa and carbidopa are titrated individually, levodopa should be initiated at 20% to 25% of the previous or recommended daily dosage of levodopa when taken alone.

Renal dose adjustments

• Data not available

Liver dose adjustments

• Data not available

Dialysis

• Data not available.

Carbidopa levodopa side effects

Levodopa side effects

Along with its needed effects, a medicine 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 as soon as possible if any of the following side effects occur:

More common

• abnormal thinking: holding false beliefs that cannot be changed by fact
• agitation
• anxiety
• clenching or grinding of teeth
• clumsiness or unsteadiness
• confusion
• difficulty swallowing
• dizziness
• excessive watering of mouth
• false sense of well being
• feeling faint
• general feeling of discomfort or illness
• hallucinations (seeing, hearing, or feeling things that are not there)
• hand tremor, increased
• nausea or vomiting
• numbness
• unusual and uncontrolled movements of the body, including the face, tongue, arms, hands, head, and upper body
• unusual tiredness or weakness

Less common

• blurred vision
• difficult urination
• difficulty opening mouth
• dilated (large) pupils
• dizziness or lightheadedness when getting up from a lying or sitting position
• double vision
• fast, irregular, or pounding heartbeat
• hot flashes
• increased blinking or spasm of eyelids
• loss of bladder control
• mental depression
• other mood or mental changes
• skin rash
• unusual weight gain or loss

Rare

• back or leg pain
• bloody or black tarry stools
• chills
• convulsions (seizures)
• fever
• high blood pressure
• inability to move eyes
• loss of appetite
• pain, tenderness, or swelling of foot or leg
• pale skin
• prolonged, painful, inappropriate penile erection
• sore throat
• stomach pain
• swelling of face
• swelling of feet or lower legs
• vomiting of blood or material that looks like coffee grounds

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:

More common

• abdominal pain
• dryness of mouth
• loss of appetite
• nightmares
• passing gas

Less common

• constipation
• diarrhea
• flushing of skin
• headache
• hiccups
• increased sweating
• muscle twitching
• trouble in sleeping

Levodopa may sometimes cause the urine, saliva, and sweat to be darker in color than usual. The urine may at first be reddish, then turn to nearly black after being exposed to air. Some bathroom cleaning products will produce a similar effect when in contact with urine containing levodopa. This is to be expected during treatment with levodopa. Also, levodopa may cause a bitter taste, or a burning sensation of the tongue.

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 side effects

Nervous system side effects most frequently reported have included involuntary movements and mental status changes (in as many as 50% of treated patients on long-term therapy). The types of involuntary movements due to levodopa have been characterized as choreiform, dystonic and dyskinetic. Fluctuations in motor function occur frequently and often increase as the duration of therapy increases.

Choreiform movements due to levodopa therapy may occur in as many as 80% of patients treated for one year and frequently involve facial grimacing, exaggerated chewing, and twisting and protrusion of the tongue.

Several types of motor fluctuations may occur and result in “bradykinetic episodes”. Some motor fluctuations are related to the timing of levodopa dosage administration. For example, patients may experience “peak of the dose dyskinesia” and a wearing-off effect called “end of the dose akinesia”. The “wearing-off effect may result in early morning dystonia. Such motor fluctuations may be managed by increasing the frequency of dosage administration and decreasing the dose administered to achieve a smoother therapeutic effect.

Other motor fluctuations are not related to the timing of dose administration. Such fluctuations are characterized by sudden loss of levodopa effect which may last for minutes to hours and result in akinesia followed by a sudden return of levodopa effect. These “on-off” fluctuations may occur many times per day. “On-off” fluctuations may respond to more frequent dose administration.

Finally, akinesia paridoxica is a sudden episode of akinesia which occurs as patients begin to walk. Akinesia paridoxica frequently results in falls and often responds to levodopa dose reductions.

Other adverse nervous system effects due to levodopa include myoclonus, sleep disturbances (including insomnia, daytime somnolence, altered dreams and episodic nocturnal myoclonus), Meige’s syndrome (blepharospasm-oromandibular dystonia) and ocular dyskinesia. In addition, the orofacial movements induced by levodopa have occasionally been reported to cause severe dental erosion.

Some investigators have suggested that levodopa may cause brain dysfunction and may have negative effects on cognitive performance. Levodopa “drug holidays” have been proposed by some investigators as potentially beneficial (perhaps by causing dopamine receptor resensitization). However, the therapeutic value of these drug holidays is controversial.

Gastrointestinal side effects

Exacerbation of preexisting stomach ulcer disease with severe upper gastrointestinal bleeding has been reported.

Gastrointestinal side effects most commonly reported have included nausea and vomiting. Anorexia and gastrointestinal hemorrhage have been reported rarely.

Psychiatric side effects

Some authors have suggested that clozapine may be useful in the management of levodopa-induced psychotic symptoms.

Other investigators have suggested that levodopa may induce alterations in the noradrenergic systems of the CNS which may lead to panic attacks.

Psychiatric side effects have included hallucinations (particularly visual hallucinations), psychosis, confusion, anxiety, mania, hypomania, depression, rapid mood cycling, nightmares, and hypersexuality.

Neuroleptic malignant syndrome

Fever, altered consciousness, autonomic dysfunction and muscle rigidity are the hallmarks of the neuroleptic malignant syndrome. The neuroleptic malignant syndrome (NMS) is associated with a case fatality rate of about 20%. If withdrawal of dopaminergic therapy is suspected as the cause of NMS (neuroleptic malignant syndrome), dopaminergic therapy should be restarted. If a neuroleptic agent is suspected as the cause, the neuroleptic agent should be immediately discontinued. For patients with NMS (neuroleptic malignant syndrome) suspected to be due to neuroleptic therapy, consideration should be given to dantrolene (or bromocriptine) administration. Intensive monitoring and supportive care are indicated for all patients with NMS (neuroleptic malignant syndrome).

Sudden discontinuation or rapid tapering of levodopa therapy may result in acute worsening of parkinsonism or less frequently, in a syndrome resembling the neuroleptic malignant syndrome. Cases of psychologic levodopa addiction have also been reported rarely.

Cardiovascular side effects

Some authors have reported marked hemodynamic and clinical improvements in patients with congestive heart failure treated with oral levodopa. However, at least one author has reported marked hemodynamic deterioration following such treatment.

Cardiovascular side effects have included hypotension and syncope. Arrhythmias have also been reported rarely.

Dermatologic side effects

Dermatologic side effects have included a number of cases of malignant melanoma in patients taking levodopa for Parkinson’s Disease. Additionally, several cases of maculopapular skin rashes have been reported in patients taking levodopa-containing drugs.

Despite reports of melanoma occurring in levodopa-treated patients, some authors have suggested that a causal association is tenuous and other authors have suggested that levodopa may have an antitumor effect on melanoma. Nevertheless, the manufacturers of levodopa-containing drugs report that either the history of melanoma or the presence of suspicious skin lesions is a contraindication for the use of levodopa-containing drugs.

Immunologic side effects

Immunologic side effects have included rare reports of a lupus-like syndrome.

Hematologic side effects

Hematologic side effects reported rarely have included severe hemolytic and nonhemolytic anemias.

Respiratory side effects

Respiratory side effects have included dyskinesias (occasionally of life-threatening severity).

Liver side effects

Hepatic side effects have included rare cases of asterixis (without abnormalities of liver function tests). The manufacturer of levodopa-containing products reports that abnormal liver function tests may occur.

Endocrine side effects

Endocrine side effects have included elevated urinary vanillylmandelic acid levels which have occasionally led to confusion concerning the diagnosis of pheochromocytoma.

Kidney side effects

Renal side effects have included hypokalemia and hyponatremia. Chronic administration of levodopa may also slightly but significantly increase BUN without changes in the glomerular filtration rate.

Carbidopa side effects

Adverse reactions are associated with concomitant administration with levodopa.

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

The following side effects may occur when carbidopa is taken with levodopa.

Cardiovascular: Cardiac arrhythmia, chest pain, edema, flushing, hypertension, hypotension, myocardial infarction, orthostatic hypotension, palpitation, phlebitis, syncope

Central nervous system: Abnormal dreams, abnormal gait, agitation, anxiety, ataxia, confusion, decreased mental acuity, delusions, dementia, depression (with or without suicidal tendencies), disorientation, dizziness, drowsiness, euphoria, extrapyramidal reaction, falling, fatigue, glossopyrosis, hallucination, headache, Horner’s syndrome, impulse control disorder, insomnia, malaise, memory impairment, nervousness, neuroleptic malignant syndrome, nightmares, numbness, on-off phenomenon, paranoia, paresthesia, pathological gambling, peripheral neuropathy, psychosis, seizure (causal relationship not established), trismus

Dermatologic: Alopecia, bulla, diaphoresis, discoloration of sweat, skin rash

Endocrine and metabolic: Abnormal lactate dehydrogenase, glycosuria, hot flash, hyperglycemia, hypokalemia, increased libido (including hypersexuality), increased uric acid, weight changes

Gastrointestinal: Abdominal distress, abdominal pain, anorexia, bruxism, constipation, diarrhea, discoloration of saliva, duodenal ulcer, dysgeusia, dyspepsia, dysphagia, flatulence, gastrointestinal hemorrhage, heartburn, hiccups, nausea, sialorrhea, sore throat, vomiting, xerostomia

Genitourinary: Priapism, proteinuria, urinary frequency, urinary incontinence, urinary retention, urinary tract infection, urine discoloration

Hematologic and oncologic: Abnormal Coombs’ test, agranulocytosis, anemia, decreased hematocrit, decreased hemoglobin, hemolytic anemia, leukopenia, malignant melanoma, thrombocytopenia

Hepatic: Abnormal alanine aminotransferase, abnormal alkaline phosphatase, abnormal aspartate transaminase, abnormal bilirubin levels, abnormal lactate dehydrogenase

Hypersensitivity: Angioedema, hypersensitivity reaction (bulla, IgA vasculitis, pruritus, urticaria)

Neuromuscular and skeletal: Back pain, dyskinesia (including choreiform, dystonic, and other involuntary movements), leg pain, muscle cramps, muscle twitching, shoulder pain, tremor, weakness

Ophthalmic: Blepharospasm, blurred vision, diplopia, mydriasis, oculogyric crisis (may be associated with acute dystonic reactions)

Renal: Increased blood urea nitrogen, increased serum creatinine

Respiratory: Cough, dyspnea, hoarseness, upper respiratory tract infection

Call your doctor at once if you have:

• uncontrolled muscle movements in your face (chewing, lip smacking, frowning, tongue movement, blinking or eye movement);
• worsening of tremors (uncontrolled shaking);
• severe nausea, vomiting, or diarrhea;
• confusion, hallucinations, unusual changes in mood or behavior;
• depression or suicidal thoughts;
• seizure (convulsions); or
• severe nervous system reaction–very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out.

Some people taking carbidopa with levodopa have fallen asleep during normal daytime activities such as working, talking, eating, or driving. Tell your doctor if you have any problems with daytime sleepiness or drowsiness.

You may have increased sexual urges, unusual urges to gamble, or other intense urges while taking this medicine. Talk with your doctor if this occurs.

You may notice that your sweat, urine, or saliva appears dark in color, such as red, brown, or black. This is not a harmful side effect, but it may cause staining of your clothes or bed sheets.

Common side effects may include:

• nausea, upset stomach;
• headache, dizziness;
• sleep problems (insomnia), dreaming more than usual;
• dry mouth, burning feeling in your tongue;
• weight changes; or
• abnormal liver function tests.

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

Nervous system side effects

Symptoms related to neuroleptic malignant syndrome are characterized by fever or hyperthermia. Other findings include neurological symptoms such as muscle rigidity, involuntary movements, altered consciousness, mental status changes, other disturbances such as autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension, and laboratory findings such as elevated creatine phosphokinase, leukocytosis, myoglobinuria, and increased serum myoglobin.

A causal relationship with concomitant carbidopa and levodopa and the reported side effect of convulsions has not been established.

Frequency not reported: Bradykinetic episodes (“on-off” phenomenon), convulsions, dizziness, dyskinesias such as choreiform, dystonic and other involuntary movements, headache, neuroleptic malignant syndrome, oculogyric crises, paresthesia, peripheral neuropathy, somnolence, syncope, taste alterations

Psychiatric side effects

Frequency not reported: Agitation, bruxism, confusion, dementia, depression with or without development of suicidal tendencies, dream abnormalities (including nightmares), impulse control symptoms, increased libido (including hypersexuality), insomnia, pathological gambling, psychotic episodes (including delusions, hallucinations and paranoid ideation)

Psychiatric side effects were reported with concomitant administration of levodopa or carbidopa-levodopa.

Cardiovascular side effects

Frequency not reported: Cardiac irregularities, chest pain, hot flashes, hypertension, hypotension (including orthostatic hypotension), myocardial infarction, palpitation, phlebitis

Gastrointestinal side effects

Frequency not reported: Abdominal pain and distress, burning sensation of the tongue, constipation, dark saliva, development of duodenal ulcer, diarrhea, dry mouth, dyspepsia, dysphagia, flatulence, gastrointestinal bleeding, gastrointestinal pain, heartburn, hiccups, nausea, sialorrhea, vomiting

Hematologic side effects

Frequency not reported: Abnormal Coombs test, agranulocytosis, decreased hemoglobin and hematocrit, decreased white blood cell count, hemolytic and nonhemolytic anemia, leukopenia, thrombocytopenia

Metabolic side effects

Frequency not reported: Abnormal lactic dehydrogenase, anorexia, edema, elevated serum glucose, elevated serum potassium, weight gain, weight loss

Musculoskeletal side effects

Frequency not reported: Back pain, leg pain, muscle cramps, shoulder pain

Respiratory side effects

Frequency not reported: Bizarre breathing patterns, cough, dyspnea, pharyngeal pain, upper respiratory infection

Dermatologic side effects

Frequency not reported: Alopecia, angioedema, bullous lesions (including pemphigus-like reactions), dark sweat, flushing, Henoch-Schonlein purpura, increased sweating, malignant melanoma, pruritus, rash, urticaria

Ocular side effects

Frequency not reported: Blurred vision, dilated pupils, diplopia

Genitourinary side effects

Frequency not reported: Dark urine, priapism, urinary frequency, urinary incontinence, urinary retention, urinary tract infection

Other side effects

Frequency not reported: Asthenia, faintness, fatigue, hoarseness, malaise, sense of stimulation

Hepatic side effects

Frequency not reported: Abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), and bilirubin.

Renal side effects

Frequency not reported: Abnormal blood urea nitrogen (BUN), increased serum creatinine and uric acid, protein and glucose in the urine, white blood cells, bacteria and blood in the urine,

Carbidopa levodopa side effects long term

One of the complications of long‐term treatment of Parkinson’s disease with levodopa is the development of motor complications e.g. dyskinesia; a jerky, dance‐like movement of the body. Generally clinicians add on drugs (to the levodopa regimen) from one of the other three classes of anti‐Parkinsonian treatments available (e.g. dopamine agonists, catechol‐O‐methyl transferase inhibitors or monoamine oxidase type B inhibitors). However, despite clinical trials having shown that these drugs are beneficial compared to placebo, it remains unclear as to the best way to treat patients experiencing motor complications and in particular, whether one class of drug may be more effective than another.

Carbidopa levodopa overdose

Spasm or closing of eyelids are possible early sign of overdose. Nausea, vomiting, cardiac arrhythmias, involuntary movements of the body, including the face, tongue, arms, hand, head, and upper body; choreiform and other involuntary movements occur in 50% to 80% of patients. This effect is dose related.

Acute levodopa overdose was reported in a 61-yr old man following ingestion of 100 g of levodopa. He experienced hypertension initially, followed by hypotension for a few hrs, mild nausea, & severe anorexia that gradually resolved over 1 week. He had insomnia for about 1 week, confusion for 2 days and agitation for 3-4 days ².

In the event of overdosage, general supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered judiciously, and an adequate airway maintained. Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as carbidopa should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known. Pyridoxine is not effective in reversing the actions of carbidopa.

Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are expected to die (levodopa LD50 mouse oral 2363 mg/kg). A significant proportion of infant rats of both sexes are expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a significant proportion of mice are expected to die to 3360 mg/kg.

1. Schapira AHV. Parkinson’s disease. BMJ : British Medical Journal. 1999;318(7179):311-314. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1114782/[↩]
2. 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. 879[↩]

What is clenbuterol

Clenbuterol is a substituted phenylaminoethanol and a long-acting beta-2 adrenergic agonist with sympathomimetic activity used to prevent asthma in humans, by inhibiting smooth muscle contraction and increasing epithelial mucus clearance, in some countries and its use in the United States is strictly restricted to farm animals (veterinary use only). Clenbuterol is NOT approved by the FDA for human use. Clenbuterol selectively binds to and activates beta-2 adrenergic receptors in bronchiolar smooth muscle, thereby causing stimulation of adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cAMP). Increased intracellular cAMP levels cause relaxation of smooth muscle. In addition, clenbuterol also stimulates central nervous system (CNS), and causes an increase in blood pressure and heart rate due to both beta-2 and beta-1 adrenergic activities. This agent may also exert an anabolic or anti-catabolic effect due to as of yet unidentified mechanisms.

Clenbuterol, one of the selective β2-adrenergic agonists, is known to induce a specific protein anabolic effect in skeletal muscle ¹. Because of this effect, clenbuterol has been extensively studied in animals, especially for its therapeutic potential in various diseases affecting muscle mass or weakness. Effects of β2-adrenergic agonist treatment on muscle mass have been demonstrated in the contexts of muscular dystrophy, disuse ², ageing, denervation and amyotrophic lateral sclerosis in both animals and humans ¹. In addition to the effect on muscle mass, chronic clenbuterol treatment induces a fiber-type transition from slow to fast twitch fibers in animal models ³. The phenotypic and metabolic changes induced by clenbuterol have raised questions about the impact of this treatment on muscle contractile function and ATPase activity. Previous studies have shown greater force-producing capacity in clenbuterol-treated muscle in both fast and slow twitch muscles ⁴. Nevertheless, when maximal tetanic contraction was corrected for muscle cross-sectional area, muscle force was unchanged and even altered in soleus muscle ⁵. These results suggest a potentially deleterious effect of chronic clenbuterol treatment on the skeletal muscle contractile machinery. Chronic clenbuterol treatment leads to hypertrophy but reduced specific force in slow twitch muscle ⁶. The beneficial anabolic effects of high-dose β₂-agonists for treatment of sarcopenia, muscle weakness and muscular dystrophy seem counterbalanced, at least in part, by deleterious effects on muscle contractility, relaxation kinetics and Ca²⁺ handling ⁶. A preliminary study suggested that chronic clenbuterol treatment induces significant changes in the calcium (Ca2+) signals associated with excitation–contraction coupling in fast twitch skeletal muscles ⁷. However, the mechanisms responsible for the changes in clenbuterol-induced contractility are not well understood.

The World Anti-Doping Agency (WADA) Ruling on Clenbuterol ⁸

1. Clenbuterol is a prohibited substance and there is no threshold under which this substance is not prohibited.
2. At present there is no plan to introduce a threshold level for clenbuterol.
3. It is possible that under certain circumstances the presence of a low level of clenbuterol in an athlete sample can be the result of food contamination. However, each case is different and all elements need to be taken into account.
4. Under the World Anti-Doping Code, result management of cases foresees the opportunity for an athlete to explain how a prohibited substance entered his/her body.

Although traditionally used for treating bronchospasm, it became apparent that some β-agonists could increase skeletal muscle mass and decrease body fat. Clenbuterol has been shown to increase lean mass and lean/fat ratio as well as a significant increase in maximal strength. These so-called “repartitioning effects” proved desirable for the livestock industry trying to improve feed efficiency and meat quality ⁹.

Studying
β-agonist effects on skeletal muscle has identified potential therapeutic applications for muscle wasting conditions such as sarcopenia, cancer cachexia, denervation, and neuromuscular diseases, aiming to attenuate (or potentially reverse) the muscle wasting and associated muscle weakness, and to enhance muscle growth and repair after injury. Sarcopenia is considered to be a primarily age‐dependent syndrome and was initially defined as the age‐related loss of skeletal muscle of the limbs 2 SD below the mean of a healthy young reference group, and has been associated with a range of adverse outcomes ¹⁰. In contrast to cachexia, sarcopenia and muscle wasting cannot be diagnosed by simply weighing the patients longitudinally to detect unintentional weight loss ¹¹. Sarcopenia affects 5–13% of elderly persons aged 60–70 years and up to 50% of all octogenarians ¹². Not surprisingly, β-agonists were soon being used by those engaged in competitive bodybuilding and by other athletes, especially those in strength- and power-related sports.

So far, there are only limited treatment options for sarcopenic patients, which include (resistance) exercise ¹³, nutritional strategies to increase intake of proteins and micronutrients ¹⁴ and finally, drug treatment, including compounds like testosterone ¹⁵, growth hormone and IGF‐1 ¹⁶.

Resistance exercise is often used in combination with nutrition support, which increases muscle mass and muscle strength more than exercise alone ¹⁷. Supplementation of a low dose creatine in combination with resistance training improved lean mass in elderly over a period of 12 weeks ¹⁸. In a patient‐centered exercise approach in frail elderly and older adults with mobility limitations, physical activity was considered to improve effective quality of life and reduce frailty, while also being cost‐effective ¹⁹. An accelerometer‐determined physical activity showed an independent, dose‐response relationship with lean mass percentage and lower limb strength ²⁰.

As a consequence of their muscle anabolic actions, the effects of β-agonist administration on skeletal muscle have been examined in a number of animal models (and in humans) in the hope of discovering therapeutic applications, particularly for muscle wasting conditions such as sarcopenia (age-related muscle wasting and associated weakness), cancer cachexia, sepsis, and other forms of metabolic stress, denervation, disuse, inactivity, unloading or microgravity, burns, human immunodeficiency virus (HIV)-acquired immunodeficiency syndrome, chronic kidney or heart failure, chronic obstructive pulmonary disease, muscular dystrophies, and other neuromuscular disorders. For many of these conditions, the anabolic properties of β-agonists may attenuate (or potentially reverse) the muscle wasting, muscle fiber atrophy, and associated muscle weakness. β-Agonists also have clinical significance for enhancing muscle repair and restoring muscle function after injury or following reconstructive surgery.

Despite their muscle anabolic properties, β-agonists have also been associated with some undesirable side effects, including increased heart rate (tachycardia) and muscle tremor, which have so far limited their therapeutic potential. The endurance and exercise duration decreased after clenbuterol ²¹. In fact, many athletes are not aware of the deleterious cardiovascular effects of chronic high-dose β-agonist administration and in many cases rely on anecdotal information about these compounds from nonscientific sources ⁹. Some undesirable cardiovascular side effects of
-agonists have so far limited their therapeutic potential.

Other options to increase muscle mass include β2‐adrenergic agonists like salbutamol and formoterol. These compounds have beneficial effects on muscle mass, most likely via an induction of protein synthesis in myocytes and increased blood flow ²². Patients with chronic heart failure were prone to develop detrimental ventricular arrhythmias when treated with salbutamol ²³. In contrast, in experimental cancer cachexia, formoterol has been shown to improve muscle mass, reduce progression of cachexia and improve survival, while also being cardio‐protective ²⁴. Espindolol, the s‐enantiomer of pindolol, may be the more interesting compound to use. It is a beta‐1 receptor antagonist, a partial beta‐2 receptor agonist and also has 5‐HT1a receptor activities. In old rats, it has been shown to significantly increase muscle mass, while reducing fat mass without negative affecting cardiac function, making it an interesting compound to use in sarcopenic obesity ²⁵. Also, it has shown very promising results in Phase IIa cancer cachexia study leading to an increase in muscle mass and hand grip strength ²⁶.

A greater understanding of β-adrenergic signaling in skeletal muscle is important for identifying its role in muscle growth, development, and muscle regeneration and for identifying new therapeutic targets. Research is needed to understand how the β-adrenergic signaling pathway can be manipulated for the purposes of 1) attenuating the muscle wasting associated with many diseases and conditions and 2) enhancing muscle fiber growth and improving the functional repair of damaged and regenerating skeletal muscle after injury.

Use of Clenbuterol by Athletes for Performance Enhancement

β-Agonist (clenbuterol) usage is highest among bodybuilders for its muscle anabolic properties, but primarily for its lipolytic effects. The exact dosage of clenbuterol that results in the greatest improvements in muscle mass and reductions in body fat has not yet been identified. These criteria are especially important for bodybuilders before competitions where the maintenance of muscle mass is critical during periods of strict dieting. The dosages used by bodybuilders exceed that recommended for asthmatics for therapeutic purposes. Typically, the dose of clenbuterol used ranges from 50–100 or 80–140 μg/day taken over the course of the day, depending on the individual’s tolerance ²⁷. The fact that clenbuterol is not approved by the United States Food and Drug Administration for use on humans means that little information is available in the scientific literature concerning its use and abuse by athletes ²⁸.

To prevent receptor downregulation, clenbuterol is often used in two or three week “on and off” cycles. Comparing the doses that are effective in rats and translating these for use in humans is obviously difficult due to the differences in size, growth, and metabolism between the species. However, some authors have made interspecies comparisons based on metabolic measurements. For example, Maltin et al. ²⁹ suggested that a dose of 10 μg/kg for the rat was equivalent to 1.0 μg/kg for humans, a dose considered to be safe ³⁰. Even if a theoretical safe dosage of clenbuterol was prescribed for promoting muscle mass in humans, it is unlikely that this level would be adhered to by bodybuilders given that some of these athletes are notorious for taking anabolic steroids in excess of 26 times the therapeutic dose ³¹. Another confounding issue is the fact that many bodybuilders take more than one drug at any one time, and the supposed increases in muscle mass following clenbuterol administration are hard to gauge when, for example, it is taken in conjunction with either one or more anabolic steroids.

Traditionally, the use of anabolic steroids and growth hormone (GH) has dominated the world of performance-enhancing drugs. However, the use of β-agonists, particularly clenbuterol, for athletic and cosmetic purposes has been increasing steadily ³². The notoriety of clenbuterol emerged during the 1992 Summer Olympic Games in Barcelona, Spain, when two athletes tested positive for its use. Clenbuterol has a long half-life of ∼35 h ³³, and subsequently, the drug will accumulate with repeated doses ³⁴. It can be detected via hair and urine analysis; however, veterinary studies have shown that 97% of the drug will be removed from the body within ∼10–11 days ³⁵.

Clenbuterol was banned by the International Olympic Committee on April 21, 1992. Regardless, many athletes still abuse this substance, with most not aware of its potentially lethal side effects when taken in excessive dosages. Sadly, the combination of clenbuterol use with diuretics, for example, has been thought to be responsible for the deaths of several prominent professional bodybuilders ³⁶. There have been case reports describing myocardial infarction in young male body builders either only taking clenbuterol or a combination of clenbuterol and anabolic steroids ³⁷, ³⁸.

It is clear that athletes taking clenbuterol in excessive doses and for extended periods are at greater risk for cardiovascular events. Although many of the side effects (i.e., sweating, tachycardia, and tremor) will cease once the treatment is stopped, the question of whether the deleterious effects on the heart are reversible is more difficult to answer. Urhausen et al. ³⁹ reported that even several years after discontinuation of anabolic steroid abuse, strength athletes still showed a slight concentric left ventricular hypertrophy compared with drug-free strength athletes. Evidence from animals treated chronically with a high dose of clenbuterol indicates that the deposition of noncontractile fibrotic material in the ventricular walls is likely to affect cardiac mechanics and impair exercise performance. Based on its deleterious and potentially lethal side effects, athletes would be advised not to experiment with these compounds for nonmedical use ⁴⁰.

Adrenoceptors and the Sympathetic Nervous System

The sympathetic nervous system is comprised of two major chemical signaling molecules, the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine). Adrenaline is produced and released from the adrenal glands, and noradrenaline is produced and released from nerve axons following stimulation with acetylcholine. Binding of one of these chemicals to an adrenergic receptor will elicit a response, depending on the receptor subtype bound.

To date, there are at least nine subtypes of adrenoceptors that have been cloned, including six α- and three β-subtypes, which are located in different proportions in numerous tissues throughout the body, with the β-adrenoceptor family predominating in skeletal muscle. Over the past 20 years there have been a multitude of studies demonstrating the growth-promoting actions of β-adrenoceptor stimulation in skeletal muscle ⁴¹. However, very little work has focused on the role of this pathway in normal muscle growth and development, muscle fiber regeneration after injury, or its involvement in pathological conditions where muscle wasting and weakness are indicated.

All adrenoceptors belong to the guanine nucleotide-binding G protein-coupled receptor (GPCR) family, the largest group of cell-surface receptors in mammals and which comprise >1% of the human genome ⁴². The most well-characterized family of guanine nucleotide-binding G protein-coupled receptors is the rhodopsin receptors, which include the dopaminergic, adenosine, histamine, α-, and β-adrenergic receptors ⁴². One of the defining features of the guanine nucleotide-binding G protein-coupled receptor superfamily is that all of the receptors couple to heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins). These molecules received their name from the typical three subunit composition (designated “αβγ”).

β-Adrenoceptors

β-Adrenoceptors play a regulatory role in cardiovascular, respiratory, metabolic, and reproductive function. Therefore, it is not surprising that the β-adrenoceptor family is the most widely studied of all the adrenergic receptors. Three subtypes of β-adrenoceptors have been identified and cloned: β1-, β2-, and β3-adrenoceptors ⁴³, each with a 65–70% homology in their amino acid composition ⁴⁴. The β-adrenoceptor family was originally believed to signal predominantly via coupling with Gαs; however, more recent studies suggest that both β2- and β3-adrenoceptors are also capable of coupling to Gαi ⁴⁵. The crystal structure of the β2-adrenoceptor has been described in two studies ⁴⁶.

The most well-documented β-adrenoceptor signaling pathway involves the cAMP-protein kinase A (PKA) signaling pathway, which has been characterized in numerous cell types and tissue systems ⁴⁷. In skeletal muscle, activation of this pathway is believed to be, at least in part, responsible for the anabolic response of skeletal muscle to β-adrenoceptor stimulation.

β-Adrenoceptor signaling in skeletal muscle

Much of our current knowledge of β-adrenoceptor signaling in skeletal muscle is based on work conducted in cardiac muscle ⁴⁸. It is only recently that scientists have begun to appreciate the importance of this system in skeletal muscle growth, development, and repair after injury ⁴⁹.

Skeletal Muscle β-Adrenoceptor Subtypes

Skeletal muscle contains a significant proportion of β-adrenoceptors, which are mostly of the β2-subtype, but there are ∼7–10% β1-adrenoceptors present ⁵⁰ as well as a smaller population of α-adrenoceptors, usually found in higher proportions in slow-twitch muscles ⁵¹. Slow-twitch muscles, such as the soleus muscle, have a greater density of β-adrenoceptors than fast-twitch muscles, such as the extensor digitorum longus ⁵². Although the functional significance of this difference in β-adrenoceptor density is not yet fully understood, the response to β-agonist administration appears to be greater in fast- than in slow-twitch skeletal muscles ⁵³.

Recently, a fourth β-adrenoceptor subtype (designated as a “putative” β4-adrenoceptor) was proposed to exist in the mouse ⁵⁴ but was later reclassified as a novel β3-adrenoceptor isoform (designated as β3a- and β3b-adrenoceptors) ⁵⁵. Both β3-adrenoceptors are believed to have stimulatory effects that are mediated through a Gαs pathway ⁵⁶. The β3b-adrenoceptor is also believed to be coupled to a second pathway involving the inhibitory G protein, Gαi ⁵⁷.

One of the most important characteristics of adrenoceptors is that a catecholamine can elicit very different responses depending on the adrenoceptor that it activates. This enables the adrenoceptors to be targeted specifically and to be manipulated by synthetically tailored agents. Many synthetic adrenoceptor agonists and antagonists have been developed for the treatment of (primarily) cardiovascular diseases. β-Adrenoceptors have been the main focus of most investigations regarding adrenergic receptors ⁵⁸, and information gathered from this receptor has helped develop a family of β2-adrenoceptor agonists (β2-agonists) for clinical purposes ⁵⁹.

G Protein Coupling in Skeletal Muscle

While β2-adrenoceptor-mediated signaling has been traditionally believed to involve selective coupling to Gαs to initiate downstream signaling via AC pathways, recent studies suggest that the β2-adrenoceptor may exhibit dual coupling to both Gαs and Gαi ⁶⁰. This dual coupling mechanism has been described in numerous studies involving cardiac muscle ⁶¹, and more recently in skeletal muscle ⁶². In addition to the well-documented inhibition of AC activity, β2-adrenoceptor coupling to Gαi appears to activate Gαs independent pathways ⁶³.

To further complicate skeletal muscle β2-adrenoceptor signaling, the Gβγ dimer has been found to initiate intracellular signaling pathways independent of the Gα subunit ⁶⁴. Specifically, Gβγ activates the phosphoinositol 3-kinase (PI3K)-AKT signaling pathway ⁶⁴. PI3K is thought to phosphorylate the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2), generating phosphatidylinositol-3,4,5-trisphosphate (PIP3), and creating two lipid-binding sites on the cell membrane for the serine/threonine kinase AKT (also referred to as protein kinase B) and 3′-phosphoinositide-dependent protein kinase 1 (PDK). AKT is phosphorylated at the membrane by PDK, and once activated, AKT phosphorylates numerous proteins involved in protein synthesis, gene transcription, cell proliferation, and survival ⁶⁵.

Clenbuterol side effects

Despite the clinical potential of manipulating the β-adrenergic signaling pathway, current approaches stimulating the pathway with β-agonists are not without side effects, and many of these less well-reported deleterious effects have important implications for the health of athletes taking these drugs for performance enhancement. Since the early 1990s, the use of β-agonists for the purpose of enhancing sporting performance has become increasingly prevalent. Despite the so-called desirable effects of increasing muscle bulk and decreasing body fat, many athletes are not aware of the deleterious effects of chronic high-dose β-agonist administration.

The side effects associated with long-term therapeutic use of β-agonists have been detailed ⁶⁶, ⁶⁷, ⁶⁸. Excluding athletes, there are two groups of individuals exposed to β-agonists: patients being treated with the drugs and individuals who eat the meat of animals that have been treated with the drugs ⁶⁹.

The most frequently reported side effects associated with the use of β-agonists include:

• nausea,
• headaches, and
• insomnia.

Excessive use of β-agonists can lead to symptoms such as muscle tremor, palpitations, muscle cramps, headache, and peripheral vasodilatation ³⁶.

Clenbuterol administration has been linked to alterations in animal behavior including increased aggression in mice ⁷⁰ and suppression of feeding following acute treatment in rats ⁷¹. Interestingly, data from Benelli et al. ⁷² indicated that clenbuterol negatively affects the copulatory behavior of sexually vigorous male rats, but improved that of sexually sluggish ones, providing evidence that central β-adrenoceptor activation can alter behaviors. Clenbuterol has been shown to produce effects on behavior similar to those seen after administration of clinically active antidepressant drugs, indicating that clenbuterol and related β2-agonists may have antidepressant activity ³⁴.

Studies on the effects of chronic high-dose β-agonist administration on exercise performance have been conducted on animals. Ingalls et al. ⁷³ subjected mice to a combination of 8 wk of treadmill running (3 sets of 3 min, 36–40 m/min, 10–17% grade, 30-s recovery, 4 days/wk) and clenbuterol treatment (1.6 mg/kg, 4 days/wk) and found that clenbuterol treatment decreased total work performance. Although clenbuterol increased muscle mass, it had antagonistic effects on running performance ⁷³. Clenbuterol administration to rats altered the normal adaptations of skeletal muscle to endurance exercise training ⁷⁴. Clenbuterol treatment (0.8 mg/kg for 8 wk) decreased glucose transporter (GLUT-4) content within the muscle and decreased citrate synthase activity ⁷⁵. Other studies have shown that similar high-dose clenbuterol treatments can reduce citrate synthase activity in skeletal muscles ⁷⁶ as well as decrease capillary density in the left ventricle and skeletal muscles of rats, thereby increasing the diffusion distances for oxygen in the heart and skeletal muscles ⁷⁷.

Effects of β-Agonists on Cardiac Muscle Structure and Function

In addition to these potentially deleterious effects on skeletal muscle, chronic β-agonist administration has been found to have toxic effects on the heart ⁷⁸. There are three β-adrenoceptors in the heart ⁷⁹, so it is not surprising that adrenergic stimulation following systemic β-agonist administration can also have major effects on cardiac as well as skeletal muscle ⁸⁰. Tachycardia (rapid heart beat) is one of the first indications that β-agonists such as clenbuterol are having an effect. Sudden death due to cardiac failure associated with clenbuterol administration has been reported in both humans ³⁸ and rats during high-intensity swimming exercise ⁸¹. Chronic administration of β-agonists such as clenbuterol or salbutamol in rats almost invariably produces significant cardiac hypertrophy ⁸². Clenbuterol treatment in rats has also been shown to increase cortisol and corticosterone secretions and increase the size of the adrenal glands due to hyperplasia of adrenocortical cells ⁸³.

Cardiac hypertrophy is commonly observed in rats and mice when treated chronically with high doses of β-agonists such as clenbuterol and fenoterol ⁸⁴. In adult and aged rats treated daily with an intraperitoneal injection of fenoterol (1.4 mg/kg) for 4 weeks, cardiac hypertrophy was evident in both groups, and a decrease in cardiac function was observed in the adult rats ⁸⁵. The cardiac hypertrophy in fenoterol-treated aged rats was associated with an increase in midventricular collagen deposition, whereas adult rats exhibited no change in collagen with treatment. Although previous studies found that β-agonist treatment could increase collagen content in the heart ⁸¹, the study by Gregorevic et al. ⁸⁵ that employed a working heart preparation to evaluate cardiac function suggested that other mechanisms could be responsible for the detrimental effects of high-dose fenoterol treatment in adult rats. Furthermore, areas of apoptotic activity were observed in rat hearts after chronic high dose (5 mg/kg) clenbuterol administration ⁸⁶ and it is possible that similar damage can contribute to a deterioration of cardiac muscle integrity, collagen infiltration, and impaired cardiac function.

Interestingly, acute periods of clenbuterol administration did not appear to affect cardiac function despite left ventricular hypertrophy ⁸⁷. Similar findings of little or no change in cardiac function have been reported in rats treated with low doses (0.2–0.4 mg/kg body mass) of isoproterenol ⁸⁸, although it has been suggested that in rats, the changes to the heart during isoproterenol-induced cardiac hypertrophy are not homogeneous and that myocardial mass, myocardial relaxation, left ventricular stiffness, and systolic function can differ between subgroups of animals ⁸⁹.

On the contrary, rats administered high doses of clenbuterol (2 mg/kg) daily for several months showed significant cardiac hypertrophy, infiltration of collagen in the left ventricular walls ⁸¹, and impaired cardiac mechanics, including reductions in left ventricular pressure ⁹⁰. Histological examination of the myocardium of dogs following chronic treatment with isoprenaline (in mg/kg doses) revealed severe necrosis ⁶⁷, while congestion, interstitial edema, hypertrophy of muscle fibers, and myocardial necrosis were evident in rats given very large doses (between 17 and 150 mg/kg daily) of another β-agonist, salbutamol, for 1 mo ⁹¹. Severe myocardial lesions have been observed in the hearts of sheep given intravenous doses of either salbutamol, fenoterol, or isoprenaline (128 μg/kg at 15-min intervals), for 4 days ⁹², and isoproterenol treatment produced necrosis and an increase in collagen content in the hearts of rats ⁹³ even when given in low doses ⁹⁴.

It should also be noted that the β-agonist-induced increases in skeletal and cardiac mass have been utilized favorably in combination with left ventricular devices for treating end-stage cardiac failure to reverse or prevent the adverse effects of unloading-induced cardiac atrophy ⁹⁵. The rationale is that increasing the frequency and durability of myocardial recovery could reduce or postpone the need for subsequent heart transplantation ⁹⁶. It is proposed that the cardiac hypertrophy associated with β-agonist administration confers physiological benefits by attenuating myocyte atrophy associated with left ventricular assist devices. Left ventricular device support can restore β-adrenergic receptor signaling in patients with chronic heart failure ⁹⁷. Birks et al. ⁹⁸ treated 15 human patients who had undergone implantation of left ventricular assist devices with clenbuterol at an initial dose of 40 μg twice daily, then at a dose of 40 μg three times daily, and finally at a dose of 700 μg three times daily. The dose of clenbuterol was adjusted to maintain the patient’s resting heart rate at a level below 100 beats/min. After clenbuterol administration, no serious side effects were observed, but most patients developed a mild tremor, four developed muscle cramps, one developed diaphoresis, and although no new arrhythmias were evident, heart rate increased as expected following β-agonist administration ⁹⁸. The authors acknowledged that the potential benefits of clenbuterol administration in cases of heart failure should be interpreted with caution, since adverse effects on the heart and the skeletal muscle have been reported in animal models ⁸⁶.

Summary

The action of β-agonists on β-adrenoceptors in smooth muscle facilitates their life-saving role in the prevention and treatment of bronchospasm in asthma. On the other hand, most evidence obtained from rigorously controlled animal studies has found that chronic stimulation of the β-adrenoceptors in skeletal muscle can elicit anabolic effects. This knowledge has served as the basis for many of the potential therapeutic applications of β-agonists for skeletal muscle wasting disorders, including many neuromuscular diseases, aging, and several metabolic conditions that cause muscle catabolism. Although there is great promise that β-agonists can be used for treating these conditions, their clinical application has been limited by cardiovascular side effects, especially when β-agonists are administered chronically and at high doses. Newer generation β-agonists (such as formoterol) have been shown to elicit an anabolic response in skeletal muscle even at very low doses, and this has renewed enthusiasm for their clinical application, especially because they exhibit reduced effects on the heart and cardiovascular system compared with older generation β-agonists (such as fenoterol and clenbuterol). However, the potentially deleterious cardiovascular side effects of β-agonists have not been obviated completely, so it is important to refine their development. In so doing, it is hoped that beneficial effects of β-agonists can find application to these severe muscle-wasting conditions that impact not only on the ability to perform the tasks of daily living, or quality of life, but ultimately on life itself, since the maintenance of functional muscle mass is critical for survival. It is likely that a greater understanding of the β-adrenergic signaling pathway in skeletal muscle will reveal novel targets that will facilitate the development of new therapeutic strategies, ones that manipulate pathways that benefit skeletal muscle by increasing protein synthesis or reducing protein degradation, without simultaneously activating pathways that affect the cardiovascular system deleteriously.

Despite warnings to athletes about the potential side effects of using β-agonists for athletic performance or enhancing physical appearance, there is no doubt that these drugs will continue to be used either alone or in conjunction with other compounds. It is hoped that the wealth of evidence presented in this review regarding the effects of β-agonists on skeletal muscle (and on other tissues) might help to encourage athletes not using these drugs safely for the purpose they were originally intended (i.e., bronchospasm), to reconsider their actions. Although very promising, the therapeutic potential of β-agonists for muscle-wasting conditions will not be realized until all aspects relating to their safety can be established, especially for their chronic, long-term administration necessary for attenuating the loss of muscle size and strength in these severe muscle-wasting conditions.

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What is modafinil

Modafinil is a medication that promotes wakefulness (a class of medications called wakefulness promoting agent). Modafinil works by changing the amounts of certain natural substances in the area of the brain that controls sleep and wakefulness. But the exact way modafinil promotes “wakefulness” is not fully understood. Modafinil is used to treat excessive sleepiness caused by narcolepsy (a condition that causes excessive daytime sleepiness), or shift work sleep disorder to stay awake during the day (sleepiness during scheduled waking hours and difficulty falling asleep or staying asleep during scheduled sleeping hours in people who work at night or on rotating shifts). Modafinil is also used along with breathing devices or other treatments to prevent excessive sleepiness caused by obstructive sleep apnea/hypopnea syndrome (OSAHS; a sleep disorder in which the patient briefly stops breathing or breathes shallowly many times during sleep and therefore doesn’t get enough restful sleep). Modafinil does not cure these conditions and will only work as long as you continue to take it. Modafinil may also be used for purposes not listed in this medication guide; ask your doctor or pharmacist for more information.

Modafinil is available only with your doctor’s prescription.

You must NOT take Modafinil if you:

• are allergic to modafinil or any of the other ingredients listed at the end of this leaflet. Signs of allergic reaction may include a skin rash, itching, shortness of breath or swelling of the face, lips or tongue
• are pregnant, or likely to become pregnant.

Do not take Modafinil if the packaging is torn or shows signs of tampering or the tablets do not look quite right.

Do not take Modafinil if the expiry date on the pack has passed.

If you are not sure about whether you should start taking Modafinil, you should contact your doctor.

Your doctor should check your progress at regular visits to make sure that this medicine is working properly. Your blood pressure may need to be checked more often while taking this medicine.

It is important to tell your doctor if you become pregnant. Your doctor may want you to join a pregnancy registry for patients taking this medicine.

Serious skin reactions can occur with this medicine. Stop using this medicine and check with your doctor right away if you have blistering, peeling, or loosening of the skin; red skin lesions; severe acne or skin rash; sores or ulcers on the skin; or fever or chills while you are using this medicine.

This medicine may cause you to have a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Stop taking this medicine and call your doctor right away if you have a skin rash; itching; hives; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth while you are using this medicine.

This medicine may cause serious allergic reactions affecting multiple body organs (e.g., heart, liver, or blood cells). Stop using this medicine and check with your doctor right away if you have the following symptoms: chest pain or discomfort, fever and chills, dark urine, headache, rash, stomach pain, unusual tiredness, unusual bleeding or bruising, or yellow eyes or skin.

If you think modafinil is not working properly after you have taken it for a few weeks, do not increase the dose. Instead, check with your doctor.

If you are using a medicine for birth control (such as birth control pills, implants, shots, patches, vaginal rings, or an IUD), it may not work properly while you are taking modafinil. To keep from getting pregnant, use another form of birth control while you are using this medicine and for one month after your last dose. Other forms of birth control include condoms, diaphragms, or contraceptive foams or jellies.

Modafinil may cause some people to feel dizzy, drowsy, have trouble thinking or controlling movements, or trouble seeing clearly. Make sure you know how you react to this medicine before you drive, use machines, or do other jobs that require you to be alert, well-coordinated, or able to think or see well.

Stop using this medicine and check with your doctor right away if you have the following symptoms while taking the medicine: aggressive behavior, anxiety, depression, hallucinations, mania, thoughts of suicide, or other mental problems.

If you have been taking this medicine for a long time or in large doses and you think you may have become mentally or physically dependent on it, check with your doctor. Some signs of dependence on modafinil are ¹:

• a strong desire or need to continue taking the medicine.
• a need to increase the dose to receive the effects of the medicine.
• withdrawal side effects when you stop taking the medicine.

While you are taking this medicine, be careful to limit the amount of alcohol that you drink.

If you have been taking this medicine in large doses or for a long time, do not stop taking it without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping it completely.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

How should modafinil be used?

Modafinil comes as a tablet to take by mouth. It is usually taken once a day with or without food. If you are taking modafinil to treat narcolepsy or obstructive sleep apnea/hypopnea syndrome, you will probably take it in the morning. If you are taking modafinil to treat shift work sleep disorder, you will probably take it 1 hour before the beginning of your work shift. Take modafinil at the same time every day. Do not change the time of day that you take modafinil without talking to your doctor. Talk to your doctor if your work shift does not begin at the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take modafinil exactly as directed.

Modafinil may be habit-forming. Do not take a larger dose, take it more often, or take it for a longer period of time than prescribed by your doctor.

Modafinil may decrease your sleepiness, but it will not cure your sleep disorder. Continue to take modafinil even if you feel well-rested. Do not stop taking modafinil without talking to your doctor.

Modafinil should not be used in place of getting enough sleep. Follow your doctor’s advice about good sleep habits. Continue to use any breathing devices or other treatments that your doctor has prescribed to treat your condition, especially if you have obstructive sleep apnea/hypopnea syndrome.

Before taking modafinil – precautions

• tell your doctor and pharmacist if you are allergic to modafinil, armodafinil (Nuvigil), or any other medications.
• tell your doctor you have heart problems, including, for example, angina (chest pain), previous heart attack, enlarged heart
• tell your doctor you have an abnormal/irregular heart rhythm
• tell your doctor you have high blood pressure or your high blood pressure is controlled by medication
• tell your doctor you have kidney or liver problems
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking. Be sure to mention any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin); certain antidepressants such as amitriptyline, amoxapine, clomipramine (Anafranil), desipramine (Norpramin), doxepin (Sinequan), imipramine (Tofranil), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil); certain antifungals such as itraconazole (Sporanox) and ketoconazole (Nizoral); cyclosporine (Neoral, Sandimmune); diazepam (Valium); certain medications for seizures such as carbamazepine (Tegretol), phenobarbital, and phenytoin (Dilantin); monoamine oxidase (MAO) inhibitors, including isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate); propranolol (Inderal); selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft); rifampin (Rifadin, Rimactane); and triazolam (Halcion). Many other medications may also interact with modafinil, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you drink or have ever drunk large amounts of alcohol, use or have ever used street drugs, or have overused prescription medications, especially stimulants. Also tell your doctor if you have ever had chest pain, an irregular heartbeat, or other heart problems after taking a stimulant, and if you have or have ever had high blood pressure; a heart attack; chest pain; a mental illness such as depression, mania (frenzied, abnormally excited mood), or psychosis (difficulty thinking clearly, communicating, understanding reality, and behaving appropriately); or heart, liver, or kidney disease.
• you should know that modafinil may decrease the effectiveness of hormonal contraceptives (birth control pills, patches, rings, implants, injections, and intrauterine devices). Use another form of birth control while taking modafinil and for 1 month after you stop taking it. Talk to your doctor about types of birth control that will work for you during and after your treatment with modafinil.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking modafinil, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking modafinil.
• you should know that modafinil may affect your judgment or thinking and may not completely relieve the sleepiness caused by your disorder. Do not drive a car or operate machinery until you know how this medication affects you. If you avoided driving and other dangerous activities because of your sleep disorder, do not start performing these activities again without talking to your doctor even if you feel more alert.
• be aware that you should avoid drinking alcohol while taking modafinil.

Talk to your doctor about eating grapefruit or drinking grapefruit juice while you are taking this medication.

Things you must do

• If you become pregnant while you are taking Modafinil, stop taking it and tell your doctor immediately.
• If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking Modafinil.
• Tell your doctor if you believe that Modafinil is not helping your condition. Your doctor may need to change the dose.

Things you must NOT do

• Do not give Modafinil to anyone else, even if they have the same symptoms as you.

Things to be careful of

Modafinil may reduce the effectiveness of oral contraceptives. If you are using these forms of contraceptives while taking Modafinil (and for 1 month after you stop treatment with Modafinil) you should either use: an alternative birth control method or another effective birth control method together with your current contraceptive.

Do not drive or operate machinery until you know how Modafinil affects you.

Serious Rash, including Stevens Johnson syndrome

Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of Modafinil.

In clinical trials of Modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age < 17-years); these rashes included 1 case of possible Stevens Johnson syndrome and 1 case of apparent multi-organ hypersensitivity reaction. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13-days. No such cases were observed among 380 pediatric patients who received placebo. Modafinil is not approved for use in pediatric patients for any indication.

Rare cases of serious or life-threatening rash, including Stevens Johnson syndrome, Toxic Epidermal Necrolysis and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide postmarketing experience. The reporting rate of Toxic Epidermal Necrolysis and Stevens Johnson syndrome associated with Modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years.

There are no factors that are known to predict the risk of occurrence or the severity of rash associated with Modafinil. Nearly all cases of serious rash associated with Modafinil occurred within 1-week to 5-weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3-months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash.

Although benign rashes also occur with Modafinil, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, Modafinil should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.

Angioedema and Anaphylaxis Reactions

Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed in patients treated with armodafinil, the R enantiomer of Modafinil (which is the racemic mixture). No such cases were observed in Modafinil clinical trials. However, angioedema has been reported in postmarketing experience with Modafinil. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness).

Multi-organ Hypersensitivity Reactions

Multi-organ hypersensitivity reactions, including at least one fatality in postmarketing experience, have occurred in close temporal association (median time to detection 13-days: range 4 to 33) to the initiation of Modafinil.

Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur.

If a multi-organ hypersensitivity reaction is suspected, Modafinil should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.

Persistent Sleepiness

Patients with abnormal levels of sleepiness who take Modafinil should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking Modafinil, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities.

Psychiatric Symptoms

Psychiatric adverse reactions have been reported in patients treated with Modafinil.

In the adult Modafinil controlled trials, psychiatric symptoms resulting in treatment discontinuation (at a frequency ≥ 0.3%) and reported more often in patients treated with Modafinil compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (< 1%), confusion (< 1%), agitation (< 1%), and depression (< 1%).

Postmarketing adverse reactions associated with the use of Modafinil have included mania, delusions, hallucinations, suicidal ideation, and aggression, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of Modafinil (three times the recommended dose) and sleep deprivation. There was no evidence of psychosis 36-hours after drug discontinuation.

Caution should be exercised when Modafinil is given to patients with a history of psychosis, depression, or mania. Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in patients treated with Modafinil. If psychiatric symptoms develop in association with Modafinil administration, consider discontinuing Modafinil.

Effects on Ability to Drive and Use Machinery

Although Modafinil has not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating automobile or other hazardous machinery until it is reasonably certain that Modafinil therapy will not adversely affect their ability to engage in such activities.

Cardiovascular Events

In Modafinil clinical studies, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on ECG occurred in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. In a Canadian clinical trial, a 35-year old obese narcoleptic male with a prior history of syncopal episodes experienced a 9-second episode of asystole after 27-days of Modafinil treatment (300 mg/day in divided doses). Modafinil is not recommended in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation. Consider increased monitoring in patients with a recent history of myocardial infarction or unstable angina.

Blood pressure monitoring in short term (≤ 3-months) controlled trials showed no clinically significant changes in mean systolic and diastolic blood pressure in patients receiving Modafinil as compared to placebo. However, a retrospective analysis of the use of antihypertensive medication in these studies showed that a greater proportion of patients on Modafinil required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential use was slightly larger when only studies in OSA were included, with 3.4% of patients on Modafinil and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication. Increased monitoring of heart rate and blood pressure may be appropriate in patients on Modafinil. Caution should be exercised when prescribing Modafinil to patients with known cardiovascular disease.

Pregnancy

Pregnancy Category C (all trimesters): Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breastfeeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of modafinil in children younger than 17 years of age. Safety and efficacy have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of modafinil have not been performed in the geriatric population, geriatric-specific problems are not expected to limit the usefulness of modafinil in the elderly. However, elderly patients may have a slower removal of this medicine from the body, which may require an adjustment in the dose for patients receiving modafinil.

‘Smart drug’ modafinil may not make you smarter

It is claimed one in five students have taken the ‘smart’ drug Modafinil to boost their ability to study and improve their chances of exam success. But a new randomized controlled trial ² into the effects of Modafinil has shown that healthy students could find their performance impaired by the drug. Researchers gave 64 healthy volunteers either modafinil 200mg or a placebo and asked them to complete a spoken language test. Contrary to the media headline, the people who took modafinil had slowed responses, and were no more accurate than the placebo. The randomized controlled trial that aimed to determine the effects of modafinil (a licensed treatment for narcolepsy) on the performance of healthy people in the Hayling Sentence Completion Test. The Hayling test involves listening to sentences with a missing word and providing either the missing word or a word unrelated to the sentence. The Hayling test consisted of 30 sentences, each missing the last word, which were constructed to strongly constrain what the missing word should be. In the first section, people were asked to listen to sentences, and were asked to provide, as quickly as possible, a word that correctly and sensibly completed the sentence. Participants were then asked to complete sentences, as quickly as possible, with words unrelated to the meaning of the sentences in every way. Both responses and reaction times were recorded, and the performance of people who were randomized to modafinil compared to those randomized to placebo. The researchers performed this experiment because it has been suggested that modafinil might improve task performance, while slowing it – a phenomenon that has been referred to as “delay-dependent cognitive enhancement”. Modafinil is reportedly used off-label (outside of its licensed indication) by some healthy people, notably students, as a “smart drug” to try to enhance cognitive performance. One student website’s survey estimates that 20% of students may have taken modafinil, with almost half buying it online and many taking it daily.

The results of that research ² showed people who took modafinil took significantly longer to provide a word. There was no difference in the number of errors made on the test between people who received modafinil and people received placebo, showing that modafinil did not improve accuracy. This study has cast doubt upon these supposed effects. In this randomized controlled trial ², modafinil slowed responses while having no effect on the accuracy of performance on the Hayling Sentence Completion Test. This study has only assessed the one-off use of this drug in a relatively small sample of people. The study has not looked at safety outcomes, and scientists don’t know what adverse effects there might be for healthy individuals regularly taking this drug solely for the purpose of trying to enhance cognitive performance.

Modafinil Drug Interactions

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 modafinil, 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 modafinil 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.

• Axitinib
• Bosutinib
• Citalopram
• Clarithromycin
• Clozapine
• Cobimetinib
• Daclatasvir
• Darunavir
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Elbasvir
• Enzalutamide
• Fentanyl
• Grazoprevir
• Hydrocodone
• Ifosfamide
• Nifedipine
• Olaparib
• Piperaquine
• Simeprevir
• Sofosbuvir
• Sonidegib
• Tacrolimus
• Tolvaptan
• Velpatasvir
• Venetoclax

Using modafinil 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
• Cyclosporine
• Desogestrel
• Dienogest
• Drospirenone
• Estradiol Cypionate
• Estradiol Valerate
• Ethinyl Estradiol
• Ethynodiol Diacetate
• Etonogestrel
• Levonorgestrel
• Mestranol
• Norelgestromin
• Norethindrone
• Norgestimate
• Norgestrel
• Ospemifene
• Triazolam

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.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, history of or
• Drug abuse or dependence, history of—Dependence may be more likely to develop.
• Angina (severe chest pain), unstable or
• Heart attack, recent or
• Heart disease—Use with caution. It is not known how modafinil will affect these conditions.
• Depression, history of or
• Hypertension (high blood pressure) or
• Mania, history of or
• Psychosis (mental illness), history of—Use with caution. May make these conditions worse.
• Left ventricular hypertrophy (heart disease), history of or
• Mitral valve prolapse (heart disease) after receiving CNS stimulants—Use is not recommended in patients with these conditions.
• Liver disease, severe—Use with caution. You may require a dose adjustment. Talk with your doctor if you have concerns about this.

What is modafinil used for

Modafinil is used to improve wakefulness in people with excessive daytime sleepiness associated with the medical condition known as narcolepsy or with obstructive sleep apnea/hypopnea syndrome (OSAHS), or shift work sleep disorder (SWSD).

In narcolepsy, there is a sudden and irresistible tendency to fall asleep during normal waking hours. This happens at unpredictable times, even when it is inappropriate or may be unsafe to do so. Modafinil decreases this unwanted excessive daytime sleepiness.

With obstructive sleep apnea/hypopnea syndrome, daytime sleepiness may occur due to an interrupted night time sleep. Modafinil only treats the symptom of sleepiness and does not treat the cause of obstructive sleep apnea/hypopnea syndrome. Whilst taking Modafinil you should continue with treatments intended to help manage your underlying medical condition, such as Continuous Positive Airway Pressure, unless your doctor tells you otherwise.

If you have been diagnosed with moderate to severe chronic Shift Work Sleep Disorder (SWSD) and non-drug therapies have been unsuitable or unsuccessful, Modafinil may be prescribed to keep you awake during your work shift.

Precisely how Modafinil works is not known, but it is known that it acts on the central nervous system (the brain). It differs from other stimulant medicines that promote wakefulness. Modafinil increases wakefulness.

Your doctor may have prescribed Modafinil for another reason. Ask your doctor if you have any questions about why Modafinil has been prescribed for you.

Modafinil dosage

The dose of modafinil will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of modafinil. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of modafinil that you take depends on the strength of the modafinil. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take modafinil depend on the medical problem for which you are using the modafinil.

Usual Adult Dose for Narcolepsy

200 mg orally once a day in the morning

Comments:

• In obstructive sleep apnea (OSA), this drug is not a treatment for the underlying obstruction.
• If continuous positive airway pressure (CPAP) is the treatment of choice for excessive sleepiness, a maximal effort to treat with CPAP for an adequate period of time should be made prior to and during treatment with this drug.

Use:

Treatment to improve wakefulness in patients with excessive sleepiness associated with narcolepsy and OSA.

Usual Adult Dose for Obstructive Sleep Apnea/Hypopnea Syndrome

200 mg orally once a day in the morning

Comments:

• In obstructive sleep apnea (OSA), this drug is not a treatment for the underlying obstruction.
• If continuous positive airway pressure (CPAP) is the treatment of choice for excessive sleepiness, a maximal effort to treat with CPAP for an adequate period of time should be made prior to and during treatment with this drug.

Use:

Treatment to improve wakefulness in patients with excessive sleepiness associated with narcolepsy and OSA.

Usual Adult Dose for Shift Work Sleep Disorder

200 mg orally once a day, approximately 1 hour prior to the start of the work shift

Use:

Treatment to improve wakefulness in patients with excessive sleepiness associated with shift work disorder.

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

• Mild to moderate hepatic impairment: There are no dosage adjustments provided in the manufacturer product information.
• Severe hepatic impairment: Dose should be reduced by half.

Dialysis

Data not available

When and how should you take modafinil

Take modafinil only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. If too much is taken, it may become habit-forming.

Modafinil comes with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

Modafinil does not take the place of getting enough sleep. It should not be used for occasional sleepiness that has not been diagnosed as narcolepsy, sleep apnea, or shift work sleep problems. Ask your doctor for advice about good sleep habits.

If you have sleep apnea and use a continuous positive airway pressure (CPAP) machine at night, continue using this machine with modafinil.

Take modafinil at the same time each day. Do not change the time of day you take modafinil without talking first with your doctor.

You may take modafinil with or without food.

For oral dosage form (tablets):

• For narcolepsy or obstructive sleep apnea/hypopnea syndrome:
  • Adults and teenagers 17 years of age and older—200 milligrams (mg) once a day, in the morning or split the dose in half taking one (100 mg) in the morning and one (100 mg) at midday. For narcolepsy or obstructive sleep apnea/hypopnea syndrome, do not take your Modafinil tablets later than midday, or you may have trouble sleeping at night. Your doctor may increase your dose as needed.
  • Teenagers and children younger than 17 years of age—Use and dose must be determined by your doctor.
• For shift work sleep disorder:
  • Adults and teenagers 17 years of age and older—200 milligrams (mg) one hour before you begin working. For shift work sleep disorder, you should take your Modafinil tablets as a single dose 1 hour prior to commencing your shift work.
  • Teenagers and children younger than 17 years of age—Use and dose must be determined by your doctor.

Swallow the tablets whole with a little water.

NOTE: Your doctor may start your treatment with less than two tablets a day.

If you need more than two tablets per day, your doctor should increase the dose stepwise, one additional tablet at a time, depending on how you respond to the treatment. The highest dose is four tablets per day.

If you are currently on another treatment for narcolepsy, your doctor will advise you how best to withdraw from that treatment and begin taking Modafinil. Other stimulants used for narcolepsy may cause a “high” feeling. Be aware therefore that you may feel different as you withdraw from other stimulants.

Modafinil only treats the symptom of sleepiness. Other treatments intended to help manage your underlying medical condition should still be used regularly, unless your doctor tells you otherwise. You should commence or continue disease-modifying interventions (for example, Continuous Positive Airway Pressure).

What should I do if I forget a dose?

You should skip the missed dose. Wait until the next time you are supposed to take modafinil, and then take your normal dose. If you take modafinil too late in your waking day, you may find it harder to go to sleep. Do not take a double dose to make up for a missed one.

If you miss a dose of modafinil and you remember it before 12:00 noon the same day, take the missed dose as soon as possible.

How long does modafinil last?

Modafinil is a 1:1 racemic compound, whose enantiomers have different pharmacokinetics (e.g., the half-life of R-Modafinil is approximately three times that of S-Modafinil in adult humans). The enantiomers do not interconvert. At steady state, total exposure to R-Modafinil is approximately three times that for S-Modafinil. The trough concentration (Cmin,ss) of circulating Modafinil after once daily dosing consists of 90% of R-Modafinil and 10% of S-Modafinil. The effective elimination half-life of Modafinil after multiple doses is about 15-hours. The enantiomers of Modafinil exhibit linear kinetics upon multiple dosing of 200 mg/day to 600 mg/day once daily in healthy volunteers. Apparent steady states of total Modafinil and R-Modafinil are reached after 2-days to 4-days of dosing.

Absorption

Modafinil is readily absorbed after oral administration, with peak plasma concentrations occurring at 2-hours to 4-hours. The bioavailability of Modafinil tablets is approximately equal to that of an aqueous suspension. The absolute oral bioavailability was not determined due to the aqueous insolubility (< 1 mg/mL) of Modafinil, which precluded intravenous administration. Food has no effect on overall Modafinil bioavailability; however, time to reach peak concentration (tmax) may be delayed by approximately one hour if taken with food.

Distribution

Modafinil has an apparent volume of distribution of approximately 0.9 L/kg. In human plasma, in vitro, Modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of Modafinil with highly protein-bound drugs is considered to be minimal.

Metabolism and Elimination

The major route of elimination is metabolism (approximately 90%), primarily by the liver, with subsequent renal elimination of the metabolites. Urine alkalinization has no effect on the elimination of Modafinil.

Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent compound. In a clinical study using radiolabeled Modafinil, a total of 81% of the administered radioactivity was recovered in 11-days post-dose, predominantly in the urine (80% vs. 1% in the feces). The largest fraction of the drug in urine was Modafinil acid, but at least six other metabolites were present in lower concentrations. Only two metabolites reach appreciable concentrations in plasma, i.e., Modafinil acid and Modafinil sulfone. In preclinical models, Modafinil acid, Modafinil sulfone, 2-[(diphenylmethyl)sulfonyl]acetic acid and 4-hydroxy Modafinil, were inactive or did not appear to mediate the arousal effects of Modafinil.

In adults, decreases in trough levels of Modafinil have sometimes been observed after multiple weeks of dosing, suggesting auto-induction, but the magnitude of the decreases and the inconsistency of their occurrence suggest that their clinical significance is minimal. Significant accumulation of Modafinil sulfone has been observed after multiple doses due to its long elimination half-life of 40-hours. Auto-induction of metabolizing enzymes, most importantly cytochrome P-450 CYP3A4, has also been observed in vitro after incubation of primary cultures of human hepatocytes with Modafinil and in vivo after extended administration of Modafinil at 400 mg/day.

Specific Populations

Age

A slight decrease (approximately 20%) in the oral clearance (CL/F) of Modafinil was observed in a single dose study at 200 mg in 12 subjects with a mean age of 63-years (range 53-years to 72-years), but the change was considered not likely to be clinically significant. In a multiple dose study (300 mg/day) in 12 patients with a mean age of 82-years (range 67-years to 87-years), the mean levels of Modafinil in plasma were approximately two times those historically obtained in matched younger subjects. Due to potential effects from the multiple concomitant medications with which most of the patients were being treated, the apparent difference in Modafinil pharmacokinetics may not be attributable solely to the effects of aging. However, the results suggest that the clearance of Modafinil may be reduced in the elderly.

Modafinil side effects

Modafinil may cause you to have a serious rash.

Stop Modafinil and call your doctor right away or get emergency treatment if you have a skin rash, hives, sores in your mouth, or your skin blisters and peels, or if you have any sudden wheeziness, difficulty in breathing, swelling, rash or itching (especially affecting the whole body).

Modafinil may cause the following side effects in some people. In clinical studies, these side effects also occurred in people who received non-active (sugar) tablets.

Modafinil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• headache
• dizziness
• difficulty falling asleep or staying asleep
• drowsiness
• nausea
• diarrhea
• constipation
• gas
• heartburn
• loss of appetite
• unusual tastes
• dry mouth
• excessive thirst
• nosebleed
• flushing
• sweating
• tight muscles or difficulty moving
• back pain
• confusion
• uncontrollable shaking of a part of your body
• burning, tingling, or numbness of the skin
• difficulty seeing or eye pain

Some side effects can be serious. If you experience any of these symptoms, stop taking modafinil and call your doctor immediately:

• rash
• blisters
• peeling skin
• mouth sores
• hives
• itching
• hoarseness
• difficulty breathing or swallowing
• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• chest pain
• fast, pounding, or irregular heartbeat
• frenzied, abnormally excited mood
• hallucinating (seeing things or hearing voices that do not exist)
• anxiety
• depression
• thinking about killing or harming yourself

Modafinil may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that makes you feel unwell. Do not be alarmed by this list of possible side effects. You may not experience any of them.

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)

Modafinil overdose

In case of modafinil overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can’t be awakened, immediately call your local emergency services number.

Symptoms of modafinil overdose may include:

• difficulty falling asleep or staying asleep
• agitation
• restlessness
• confusion
• hallucinations (seeing things or hearing voices that do not exist)
• nervousness
• uncontrollable shaking of a part of the body
• fast, slow, or pounding heartbeat
• chest pain
• nausea
• diarrhea

1. Dependence on supratherapeutic doses of modafinil: a case report. The Primary Care Companion for CNS Disorders. 2012;14(5):PCC.11l01333. doi:10.4088/PCC.11l01333 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583757/[↩]
2. Modafinil Increases the Latency of Response in the Hayling Sentence Completion Test in Healthy Volunteers: A Randomised Controlled Trial. PLOS One Published: November 12, 2014 https://doi.org/10.1371/journal.pone.0110639[↩][↩][↩]

What is dobutamine

Dobutamine is a synthetic catecholamine with sympathomimetic activity that is often used to stimulate your heart muscle and improves blood flow by helping your heart pump better. Dobutamine is a direct-acting inotropic agent and an adrenergic agonist that stimulates primarily the beta-1 adrenoceptor, with lesser effect on beta-2 or alpha receptors. Via beta-1 adrenoceptor of the heart, Dobutamine induces positive inotropic effect with minimal changes in chronotropic activities or systemic vascular resistance. Dobutamine also causes vasodilation by stimulating beta-2 adrenergic receptors in blood vessels, augmented by reflex vasoconstriction resulting in increased cardiac output.

Dobutamine is used short-term to treat cardiac decompensation due to weakened heart muscle.

Dobutamine is usually given after other heart medicines have been tried without success.

Dobutamine may also be used for purposes not listed in this medication guide.

Dobutamine Contraindications

Dobutamine hydrochloride is contraindicated in patients with idiopathic hypertrophic subaortic stenosis and in patients who have shown previous manifestations of hypersensitivity to dobutamine injection. Dobutamine is contraindicated in patients with idiopathic hypertrophic subaortic stenosis because Dobutamine’s strong inotropic effect is potentially harmful in the presence of such severe mechanical obstruction.

Dobutamine Warnings

Dobutamine administration may produce symptomatic benefits in patients with acute decompensated heart failure, however, routine use of intermittent inotropic infusions has been shown to increase mortality in patients with chronic heart failure. The American Heart Association guidelines for management of chronic heart failure recommend that intermittent intravenous positive inotropic therapy has no proven value in patients with Stage C chronic heart failure; however, the guidelines suggest that continuous intravenous inotrope infusions may be considered for palliation of symptoms in patients with end-stage heart failure (e.g., Stage D).

Increase in Heart Rate or Blood Pressure

Dobutamine hydrochloride may cause a marked increase in heart rate or blood pressure, especially systolic pressure. Approximately 10% of patients in clinical studies have had rate increases of 30 beats/minute or more, and about 7.5% have had a 50 mm Hg or greater increase in systolic pressure. Usually, reduction of dosage promptly reverses these effects. Because Dobutamine hydrochloride facilitates atrioventricular conduction, patients with atrial fibrillation are at risk of developing rapid ventricular response. Patients with pre-existing hypertension appear to face an increased risk of developing an exaggerated pressor response.

Ectopic Activity

Dobutamine hydrochloride may precipitate or exacerbate ventricular ectopic activity, but it rarely has caused ventricular tachycardia.

Hypersensitivity

Reactions suggestive of hypersensitivity associated with administration of Dobutamine injection, including skin rash, fever, eosinophilia, and bronchospasm, have been reported occasionally.

Dobutamine injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Corn hypersensitivity and sulfite hypersensitivity

Dobutamine is contraindicated in patients with a hypersensitivity to dobutamine or any of its components. Formulations containing dextrose (e.g., premixed bags) may be contraindicated in patients with a known corn hypersensitivity. Some preparations of dobutamine contain sulfites; use these preparations with caution in individuals with sulfite hypersensitivity because these antioxidant compounds can cause allergic reactions, including anaphylaxis. This reaction appears to be more common in patients with asthma than non-asthmatic patients.

Dobutamine Injection Precautions

General

1. During the administration of Dobutamine injection, as with any adrenergic agent, ECG and blood pressure should be continuously monitored. In addition, pulmonary wedge pressure and cardiac output should be monitored whenever possible to aid in the safe and effective infusion of Dobutamine hydrochloride.
2. Hypovolemia should be corrected with suitable volume expanders before treatment with Dobutamine hydrochloride is instituted.
3. No improvement may be observed in the presence of marked mechanical obstruction, such as severe valvular aortic stenosis.

Usage Following Acute Myocardial Infarction

Clinical experience with Dobutamine hydrochloride following myocardial infarction has been insufficient to establish the safety of the drug for this use. There is concern that any agent that increases contractile force and heart rate may increase the size of an infarction by intensifying ischemia, but it is not known whether Dobutamine hydrochloride does so.

Hypovolemia

Do not administer dobutamine to patients with uncorrected hypovolemia; correct hypovolemia with volume expanders before initiating dobutamine.

Geriatric hypotension

Geriatric patients may have a variable dose-response to dobutamine. In general, the initial dose for an elderly patient should start at the low end of the dosing range. Reported clinical experience with dobutamine suggests that the incidence of significant hypotension is a function of both dose and age, with elderly patients having a greater incidence of hypotension.

Atrial fibrillation, cardiac arrhythmias, ventricular arrhythmias

Use dobutamine with caution in patients with cardiac arrhythmias such as atrial fibrillation and ventricular arrhythmias. Dobutamine increases atrioventricular conduction; patients with atrial fibrillation should be adequately digitalized before administration of dobutamine. Dobutamine may precipitate or exacerbate ventricular ectopic activity. Dobutamine may be associated with sinus tachycardia or premature ventricular contractions (PVCs) due to its stimulatory effect on cardiac conduction. Dobutamine rarely induces ventricular tachycardia; however it can cause a marked increase in heart rate in susceptible patients.

Acute myocardial infarction, angina, coronary artery disease, hypertension

Use dobutamine with caution in patients with certain types of cardiac disease including acute myocardial infarction, unstable angina, or severe coronary artery disease because dobutamine can intensify or extend myocardial ischemia. Use dobutamine with caution in patients with hypertension as these patients are at risk for developing an exaggerated pressor response.

Laboratory Tests

Dobutamine, like other β2-agonists, can produce a mild reduction in serum potassium concentration, rarely to hypokalemic levels. Accordingly, consideration should be given to monitoring serum potassium.

Drug Interactions

Animal studies indicate that Dobutamine may be ineffective if the patient has recently received a β-blocking drug. In such a case, the peripheral vascular resistance may increase.

Preliminary studies indicate that the concomitant use of Dobutamine and nitroprusside results in a higher cardiac output and, usually, a lower pulmonary wedge pressure than when either drug is used alone.

There was no evidence of drug interactions in clinical studies in which Dobutamine was administered concurrently with other drugs, including digitalis preparations, furosemide, spironolactone, lidocaine, nitroglycerin, isosorbide dinitrate, morphine, atropine, heparin, protamine, potassium chloride, folic acid, and acetaminophen.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies to evaluate the carcinogenic or mutagenic potential of Dobutamine hydrochloride, or its potential to affect fertility, have not been conducted.

Pregnancy – Teratogenic Effects

Dobutamine is classified as FDA pregnancy risk category B. Animal studies have revealed no toxicities; however, no adequate or well-controlled pregnancy studies have been done in humans. Use of dopamine during pregnancy should be avoided unless the potential benefits outweigh the unknown potential risks to the fetus.

Reproduction studies performed in rats at doses up to the normal human dose (10 mcg/kg/min for 24 h, total daily dose of 14.4 mg/kg), and in rabbits at doses up to twice the normal human dose, have revealed no evidence of harm to the fetus due to Dobutamine hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

The effect of Dobutamine hydrochloride on labor and delivery is unknown.

Breastfeeding Mothers

According to the manufacturer, it is not known whether dobutamine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when administering dobutamine to a breast-feeding woman. If a mother requires dobutamine therapy, the manufacturer recommends that breast-feeding be discontinued for the duration of drug administration. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Pediatric Use

The safety and effectiveness of Dobutamine injection for use in pediatric patients have not been studied.

Premature neonates

Dobutamine has been shown to increase cardiac output and systemic pressure in pediatric patients of every age group. In premature neonates, however, dobutamine is less effective than dopamine in raising systemic blood pressure without causing undue tachycardia, and dobutamine has not been shown to provide any added benefit when given to such infants already receiving optimal infusions of dopamine. In addition, because of variation in development, there is significant interpatient variability in response to dobutamine in neonates. Very preterm neonates are likely to have an attenuated reduction in systemic vascular resistance (SVR) compared to term neonates and therefore, experience a more pronounced increase in blood pressure. Titrate dosage carefully with close monitoring.

Renal failure

Monitor patients with renal failure carefully during dobutamine administration. Reports indicate that the continuous infusion of dobutamine in patients with end stage renal disease may produce myoclonia (e.g., muscle spasms). Although etiology of this reaction remains unclear, proposed mechanisms include an increase in dobutamine uptake by the central nervous system secondary to renal failure and an increase in the permeability of the blood-brain barrier caused by P-glycoprotein inhibition of concomitant medications.

Dobutamine mechanism of action

Dobutamine hydrochloride is a direct-acting inotropic agent whose primary activity results from stimulation of the β receptors of the heart while producing comparatively mild chronotropic, hypertensive, arrhythmogenic, and vasodilative effects. Dobutamine directly stimulates beta-1 receptors of the heart to increase myocardial contractility and stroke volume, resulting in increased cardiac output. Dobutamine does not cause the release of endogenous norepinephrine, as does dopamine. In animal studies, Dobutamine hydrochloride produces less increase in heart rate and less decrease in peripheral vascular resistance for a given inotropic effect than does isoproterenol.

In patients with depressed cardiac function, both Dobutamine hydrochloride and isoproterenol increase the cardiac output to a similar degree. In the case of Dobutamine hydrochloride, this increase is usually not accompanied by marked increases in heart rate (although tachycardia is occasionally observed), and the cardiac stroke volume is usually increased. In contrast, isoproterenol increases the cardiac index primarily by increasing the heart rate while stroke volume changes little or declines.

Facilitation of atrioventricular conduction has been observed in human electrophysiologic studies and in patients with atrial fibrillation.

Systemic vascular resistance is usually decreased with administration of Dobutamine hydrochloride. Occasionally, minimum vasoconstriction has been observed.

Most clinical experience with Dobutamine hydrochloride is short-term − not more than several hours in duration. In the limited number of patients who were studied for 24, 48, and 72 hours, a persistent increase in cardiac output occurred in some, whereas output returned toward baseline values in others.

The onset of action of Dobutamine is within 1 to 2 minutes; however, as much as 10 minutes may be required to obtain the peak effect of a particular infusion rate.

The plasma half-life of Dobutamine hydrochloride in humans is 2 minutes. The principal routes of metabolism are methylation of the catechol and conjugation. In human urine, the major excretion products are the conjugates of Dobutamine and 3-O-methyl Dobutamine. The 3-O-methyl derivative of Dobutamine is inactive.

Alteration of synaptic concentrations of catecholamines with either reserpine or tricyclic antidepressants does not alter the actions of Dobutamine in animals, which indicates that the actions of Dobutamine hydrochloride are not dependent on presynaptic mechanisms.

Dobutamine uses

Dobutamine injection is indicated when parenteral therapy is necessary for inotropic support in the short-term treatment of adults with cardiac decompensation due to depressed contractility resulting either from organic heart disease, congestive heart failure, cardiogenic shock, septic shock (off-label use) or from cardiac surgical procedures.

In patients who have atrial fibrillation with rapid ventricular response, a digitalis preparation should be used prior to institution of therapy with Dobutamine hydrochloride.

Dobutamine stress echo

Dobutamine stress echocardiography is a non-invasive method with established accuracy for diagnosing coronary artery disease ¹. Dobutamine infusion in combination with radionuclide myocardial perfusion imaging is an alternative pharmacological stress test for detection of myocardial ischemia in patient who is not able to tolerate dipyridamole or adenosine infusion. It is commonly used in patients with chronic obstructive pulmonary disease (COPD) ².

As a catecholamine with predominant β1 receptor against, dobutamine increases heart rate, systolic blood pressure and myocardial contractility. Consequently, myocardial oxygen demand increases. Although its hemodynamic effect is similar to physical exercise, dobutamine stress test is not a substitute for exercise stress test. Serious side effects may occur during dobutamine stress test including myocardial infarction (heart attack), ventricular arrhythmia, hypotension and prolonged ischemia ³. However ST-segment elevation with chest pain is a rare event in dobutamine stress test with myocardial perfusion imaging.

Numerous studies have demonstrated that dobutamine stress test in association with radionuclide or echocardiographic imaging is sensitive and specific diagnostic test for coronary artery disease. In order to maintain sensitivity of dobutamine stress test, it is important to reach target heart rate during the test. Atropine is usually combined with dobutamine infusion to increase heart rate. It has been demonstrated that β-agonists treatment shortly prior to dobutamine stress test reduced amounts and duration of dobutamine infusion as well as requirement of atropine ⁴.

The mechanism of dobutamine induced vasospasm with or without β-agonists is complex. Dobutamine primarily stimulates cardiomyocyte sarcolemma β1-adrenergic receptors, but also has effect on β2- and α1-receptors. Increase in myocardial oxygen demand and coronary flow causes α-adrenergic mediated vasoconstriction that has been observed during exercise. In fact exercise-induced coronary spasm is a result of α1 receptor stimulation. Higher doses of dobutamine, as in dobutamine stress test, generate more α1-adrenergic effect that may induce coronary spasm, particularly in the presence of endothelial dysfunction ⁵. Moreover, dobutamine-induced coronary vasoconstriction is mediated through postjunctional α2-adrenergic receptors ⁶.

β-agonists cause cardiovascular side effects including angina, tachyarrhythmias, hypertension and myocardial injury by increasing myocardial oxygen consumption. Albuterol activates β2-adrenergic receptors particularly in coronary resistant vessels that are partially mediated by the endothelium at the microcirculatory level. Endothelial function plays important role in β2-agonist effect on vascular tone. Intracoronary infusion of salbutamol induces vasoconstriction in stenotic coronary arteries without increase in heart rate and blood pressure ⁷.

Albuterol pre-treatment with dobutamine stress test may induce coronary spasm in association with chest pain and ST-segment elevation. This clinical condition may lead to invasive procedures like cardiac catheterization and possible complications. Although the true incidence of coronary vasospasm with ST-segment elevation during dobutamine stress test with albuterol pre-treatment is not known, nuclear cardiologist must be aware of this potentially life threatening complication of this non-invasive diagnostic test. Coronary spasm should be considered in all patients with ST-segment elevation and chest pain during dobutamine stress test, particularly following β-agonist treatment. The safety of this combination must be re-examined. Thus, the patients should not be subjected to the dobutamine stress test if they are treated with β-agonist before the test ².

Dobutamine dose

Applies to the following dobutamine strengths: 12.5 mg/mL; 1 mg/mL-dextrose5%; 2 mg/mL-dextrose5%; 4 mg/mL-dextrose5%; 500 mcg/mL-dextrose5%

Administration advice:

• Administer through a suitable IV catheter or needle.
• A calibrated electronic infusion device is recommended for controlling the rate of flow.

Storage requirements: Do not freeze.

Reconstitution/preparation techniques: The manufacturer product information should be consulted.

IV compatibility:

• Do not administer solutions containing dextrose through the same administration set as blood.
• Do not add supplementary medications to this drug; do not administer this drug simultaneously with strong alkaline solutions, solutions containing sodium bicarbonate, or other agents or diluents containing both sodium bisulfite and ethanol.

General: Dobutamine Injection USP is a clear, practically colorless, sterile, nonpyrogenic solution of Dobutamine hydrochloride for intravenous use only. Each milliliter contains 12.5 mg (41.5 µmol) Dobutamine, as the hydrochloride and sodium metabisulfite, 0.2 mg added as antioxidant. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. pH is 3.3 (2.5 to 5.5).

Dobutamine Hydrochloride USP is chemically designated (±)-4-[2-[[3-(ρ-hydroxyphenyl)-1-methylpropyl] amino]ethyl]-pyrocatechol hydrochloride.

Dobutamine may exhibit a pink color that, if present, will increase with time. This color change indicates slight oxidation but no significant loss of potency.

Monitoring:

• Cardiovascular: ECG and blood pressure should be monitored continuously; pulmonary wedge pressure and cardiac output should be monitored whenever possible.
• Metabolic: Consider monitoring serum potassium.

Usual Adult Dose for Congestive Heart Failure

• Initial dose: 0.5 to 1 mcg/kg/min IV infusion
• Maintenance dose: 2 to 20 mcg/kg/min IV infusion
• Maximum dose: 40 mcg/kg/min IV infusion

Initially 0.5 to 1 mcg/kg/minute as a continuous IV infusion, then titrated every few minutes. The usual dosage range is 2 to 20 mcg/kg/minute IV. Another manufacturer recommends a usual dosage range of 2.5 to 15 mcg/kg/minute IV. Titrate dosage based on hemodynamic response, including systemic blood pressure, urine flow, frequency of ectopic activity, heart rate, and (whenever possible) measurements of cardiac output, central venous pressure, and/or pulmonary capillary wedge pressure. Infusion rates higher than 20 mcg/kg/minute may produce tachycardia or ventricular ectopy. On rare occasions, infusion rates up to 40 mcg/kg/minute IV have been required to obtain the desired clinical response. Septic shock clinical practice guidelines recommend dobutamine in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressors. Titrate to an endpoint reflecting perfusion; reduce rate or discontinue if worsening hypotension or arrhythmias occur.

Comments:

• Rate of administration and duration of therapy should be based on blood pressure, heart rate, frequency of ectopic activity, and urine flow; cardiac output, central venous pressure, and pulmonary capillary wedge pressure should also be considered whenever possible.
• Concentrations up to 5000 mcg/mL have been administered to humans. Determine final volume based on fluid requirements of the patient.
• No controlled-trial experience exists beyond 48 hours of repeated boluses and/or continuous infusions.

Use:

• Inotropic support when parenteral therapy is needed in the short-term treatment of patients with cardiac decompensation due to depressed contractility resulting from organic heart disease or cardiac surgical procedures.

Usual Infants, Children, and Adolescents Dose for Congestive Heart Failure

• Initial dose: 0.5 to 1 mcg/kg/min IV infusion
• Maintenance dose: 2 to 20 mcg/kg/min IV infusion
• Maximum dose: 40 mcg/kg/min IV infusion

0.5 to 1 mcg/kg/minute as a continuous IV infusion, then titrated every few minutes to clinical response. The usual dosage range is 2 to 20 mcg/kg/minute IV. Infusion rates higher than 20 mcg/kg/minute may produce tachycardia or ventricular ectopy. On rare occasions, infusion rates up to 40 mcg/kg/minute IV have been required to obtain the desired clinical response. If IV access is not available during hypotensive states post-cardiopulmonary resuscitation, the same dobutamine dosage listed for IV use may be administered using the intraosseous route.

Neonates

0.5 to 1 mcg/kg/minute as a continuous IV infusion initially, then titrated every few minutes to clinical response. The usual dosage range is 2 to 20 mcg/kg/minute IV. Infusion rates higher than 20 mcg/kg/minute may produce tachycardia or ventricular ectopy. Because of variation in development, there is significant interpatient variability in response to dobutamine in neonates. Very preterm neonates are likely to have an attenuated reduction in systemic vascular resistance (SVR) compared to term neonates and, therefore, experience a more pronounced increase in blood pressure.

Comments:

• Certain container systems of this drug may be inappropriate for the dosage requirements of pediatric patients less than 30 kg.
• Rate of administration and duration of therapy should be based on systemic blood pressure, heart rate, frequency of ectopic activity urine flow; cardiac output, central venous pressure, and pulmonary capillary wedge pressure should also be considered whenever possible.
• Concentrations up to 5000 mcg/mL have been administered to humans. Determine final volume based on fluid requirements of the patient.
• No controlled-trial experience exists beyond 48 hours of repeated boluses and/or continuous infusions.

Use:

• Inotropic support when parenteral therapy is needed in the short-term treatment of patients with cardiac decompensation due to depressed contractility resulting from organic heart disease or cardiac surgical procedures.

Renal Dose Adjustments

Specific guidelines for dosage adjustments are not available; it appears that no dosage adjustments are needed. Titrate the dobutamine infusion rate to attain clinical goals.

Liver Dose Adjustments

Specific guidelines for dosage adjustments are not available; it appears that no dosage adjustments are needed. Titrate the dobutamine infusion rate to attain clinical goals.

Dialysis

It is unknown whether dobutamine is dialyzable. Titrate the dobutamine infusion rate to attain clinical goals.

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Premixed bags of dobutamine in 5% Dextrose Injection solutions may exhibit a pink color that, if present, will increase with time. This color change is due to slight oxidation of the drug, but there is no significant loss of potency.

Intravenous Administration

Dilution

Concentrate for injection must be diluted with a compatible IV solution (e.g., 5% Dextrose Injection, 10% Dextrose Injection, 0.9% Sodium Chloride Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, Lactated Ringer’s Injection) prior to administration.
Institute for Safe Medication Practices (ISMP)/Vermont Oxford Network (VON) Recommended Standard Concentration for Neonatal Infusions: 2,000 mcg/mL
Maximum concentration should not exceed 5,000 mcg/mL.

Intravenous Infusion Administration

Administer diluted solution by IV infusion using a controlled infusion device.
Infuse into a large vein whenever possible.
Use caution to avoid inadvertent bolus administration or inadvertent interruption of the infusion, particularly during line changes, when flushing the line, or during syringe/bag changes.
Do not administer dobutamine simultaneously with solutions containing sodium bicarbonate or strong alkaline solutions (incompatible). Solutions containing dextrose should not be administered through the same administration set as blood, as this may cause pseudoagglutination or hemolysis.
Initiate infusion at a low rate and titrate every few minutes to reach the optimal dosage based on patient response. Dosage titration is guided by the patient’s response, including systemic blood pressure, urine flow, frequency of ectopic activity, heart rate, and (whenever possible) measurements of cardiac output, central venous pressure, and/or pulmonary capillary wedge pressure.

Other Injectable Administration

Intraosseous infusion

NOTE: Dobutamine is not approved by the FDA for intraosseous administration.
During cardiopulmonary resuscitation, the same dosage may be given via the intraosseous route when IV access is not available.

Dobutamine 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.

Common side effects include:

• ectopic heartbeats,
• increased heart rate,
• elevations in BP (hypertension),
• hypotension (low blood pressure),
• phlebitis,
• local inflammatory changes,
• leg cramps,
• headache,
• fever,
• tingly feeling,
• nausea and vomiting.

The most common adverse reaction was heart rate increased by 30 beats per minute or more.

Tell your caregiver right away if you have:

• shortness of breath (even with mild exertion), swelling, rapid weight gain;
• chest pain, fast or pounding heartbeats;
• a light-headed feeling, like you might pass out;
• wheezing, chest tightness;
• dangerously high blood pressure-severe headache, blurred vision, buzzing in your ears, anxiety, confusion, uneven heartbeats, seizure; or
• signs of infection in your catheter–pain, swelling, warmth, redness, oozing, or skin changes where the medicine is injected.

Increased Heart Rate, Blood Pressure, and Ventricular Ectopic Activity − A 10 to 20 mm increase in systolic blood pressure and an increase in heart rate of 5 to 15 beats/minute have been noted in most patients. Approximately 5% of patients have had increased premature ventricular beats during infusions. These effects are dose related.

Hypotension − Precipitous decreases in blood pressure have occasionally been described in association with Dobutamine therapy. Decreasing the dose or discontinuing the infusion typically results in rapid return of blood pressure to baseline values. In rare cases, however, intervention may be required and reversibility may not be immediate.

Reactions at Sites of Intravenous Infusion − Phlebitis has occasionally been reported. Local inflammatory changes have been described following inadvertent infiltration. Isolated cases of cutaneous necrosis (destruction of skin tissue) have been reported.

Miscellaneous Uncommon Effects − The following adverse effects have been reported in 1% to 3% of patients: nausea, headache, anginal pain, nonspecific chest pain, palpitations, and shortness of breath. Isolated cases of thrombocytopenia have been reported.

Administration of Dobutamine hydrochloride, like other catecholamines, can produce a mild reduction in serum potassium concentration, rarely to hypokalemic levels.

Longer-Term Safety − Infusions of up to 72 hours have revealed no adverse effects other than those seen with shorter infusions.

Severe side effects

• ventricular tachycardia / Early / Incidence not known
• arrhythmia exacerbation / Early / Incidence not known
• pulmonary edema / Early / Incidence not known
• skin necrosis / Early / Incidence not known
• bronchospasm / Rapid / Incidence not known
• anaphylactoid reactions / Rapid / Incidence not known

Moderate side effects

• hypertension / Early / 7.5-7.5
• angina / Early / 1.0-3.0
• palpitations / Early / 1.0-3.0
• dyspnea / Early / 1.0-3.0
• thrombocytopenia / Delayed / 0-1.0
• sinus tachycardia / Rapid / Incidence not known
• premature ventricular contractions (PVCs) / Early / Incidence not known
• chest pain (unspecified) / Early / Incidence not known
• hypotension / Rapid / Incidence not known
• hypokalemia / Delayed / Incidence not known
• myoclonia / Delayed / Incidence not known
• phlebitis / Rapid / Incidence not known
• eosinophilia / Delayed / Incidence not known

Mild side effects

• headache / Early / 1.0-3.0
• nausea / Early / Incidence not known
• injection site reaction / Rapid / Incidence not known
• fever / Early / Incidence not known
• rash / Early / Incidence not known

Cardiovascular

• Very common (10% or more): Heart rate increased by 30 beats per minute (bpm) or more (10%)
• Common (1% to 10%): Systolic blood pressure increased by 50 mmHg or more, premature ventricular beats increased, anginal pain, palpitations, blood pressure decreased, ventricular dysrhythmia, dose-dependent ventricular extrasystoles, ventricular frequency increased in patients with atrial fibrillation, vasoconstriction in patients previously treated with beta blockers, supraventricular extrasystoles, ventricular tachycardia
• Uncommon (0.1% to 1%): Ventricular fibrillation
• Very rare (less than 0.01%): Bradycardia, myocardial ischemia, myocardial infarction, cardiac arrest, second degree atrioventricular block, coronary vasospasms, hypertensive/hypotensive blood pressure decompensation, intracavitary pressure gradients
• Frequency not reported: Systolic blood pressure increased by 10 to 20 mmHg, heart rate increased by 5 to 15 bpm, blood pressure decreased precipitously, pulmonary capillary pressure decreased, pectoral anginal discomfort, stress cardiomyopathy, eosinophilic myocarditis, fatal cardiac rupture

Dermatologic

• Common (1% to 10%): Exanthema, skin rash
• Very rare (less than 0.01%): Petechial bleeding
• Frequency not reported: Pruritus of the scalp

Local reactions

• Common (1% to 10%): Phlebitis, inflammation
• Very rare (less than 0.01%): Cutaneous necrosis

Hematologic

• Common (1% to 10%): Eosinophilia, thrombocyte aggregation inhibited when continuing infusion over a number of days
• Frequency not reported: Thrombocytopenia

Other

Common (1% to 10%): Nonspecific chest pain, fever

Frequency not reported: Feeling of heat and anxiety

Respiratory

Common (1% to 10%): Shortness of breath, bronchospasm

Nervous system

Common (1% to 10%): Headache

Frequency not reported: Paresthesia, tremor

Genitourinary

Common (1% to 10%): Urgency increased at high doses of infusion

Frequency not reported: Urinary urgency

Gastrointestinal

Common (1% to 10%): Nausea

Metabolic

Very rare (less than 0.01%): Hypokalemia

Frequency not reported: Serum potassium decreased

Immunologic

Frequency not reported: Hypersensitivity

Musculoskeletal

Frequency not reported: Myoclonic spasm

Psychiatric

Frequency not reported: Restlessness, anxiety

Dobutamine Overdose

Overdoses of dobutamine have been reported rarely. The following is provided to serve as a guide if such an overdose is encountered.

Signs and Symptoms– Toxicity from dobutamine hydrochloride is usually due to excessive cardiac β receptor stimulation. The duration of action of dobutamine hydrochloride is generally short (T1/2 = 2 minutes) because it is repidly metabolized by catechol-0-methyltransferase. The symptoms of toxicity may include anorexia, nausea, vomiting, tremor, anxiety, palpitations, headache, shortness of breath, and anginal and nonspecific chest pain. The positive inotropic and chronotropic effects of dobutamine on the myocardium may cause hypertension, tachyarrhythmias, myocardial ischemia, and ventricular fibrillation.

Hypotension may result from vasodilation.

Treatment

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

The initial actions to be taken in a dobutamine hydrochloride overdose are discontinuing administration, establishing and airway, and ensuring oxygenation and ventilation. Resuscitative measures should be initiated promptly. Severe ventricular tachyarrhythmias may be successfully treated with propranolol or lidocaine. Hypertension usually responds to a reduction in dose or discontinuation of therapy.

Protect the patient’s airway and support ventilation and perfusion. If needed, meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. If the product is infested, unpredictable absorption may occur from the mouth and the gastrointestinal tract. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis of labage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten eliminiation of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastirc emptying or charcoal.

Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of dobutamine hydrochloride.

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