Tizanidine

Tizanidine is a short-acting muscle relaxant that is used to treat muscle spasms caused by multiple sclerosis (MS), stroke and brain or spinal injury ¹, ². Tizanidine has also been shown to be clinically effective in managing patients suffering from chronic neck and lumbosacral neuralgia with a myofascial component to their pain and regional musculoskeletal pain syndromes. It is also prescribed off-label for migraine headaches, insomnia, and as an anticonvulsant. Tizanidine can also be applied as part of a detoxification therapy regimen in patients exhibiting analgesic rebound headaches to assist with analgesic withdrawal. Tizanidine works by slowing action in your brain and nervous system to allow your muscles to relax. Tizanidine was approved for use in the United States in 1996 and currently several million prescriptions are filled yearly.

Tizanidine comes as a tablet and a capsule of 2, 4 or 6 mg to be takeb by mouth. Tizanidine is usually taken consistently either always with or always without food two or three times a day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tizanidine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Tizanidine capsules may be opened and sprinkled on soft foods such as applesauce. Talk to your doctor before opening the capsules because the effects of tizanidine when used in this manner may be different than when swallowing the capsule whole.

Tizanidine in the capsule is absorbed differently by the body than tizanidine in the tablet, so one product cannot be substituted for the other. Each time you have your prescription filled, look at the tablets or capsules in the bottle and make sure that you have received the right product. If you think you received the wrong medication, talk to your doctor or pharmacist right away.

Your doctor will probably start you on a low dose of tizanidine and gradually increase your dose, depending on your response to this medication. The recommended starting dose of tizanidine is 2 mg every 6 to 8 hours, up to a maximum of 3 doses in 24 hours. Do not take more than 36 mg of tizanidine in a 24-hour period ³. Too much of tizanidine can damage your liver and a few of which have been fatal ⁴. Cold or allergy medicine, narcotic pain medicine, sleeping pills, other muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by tizanidine.

Do not stop taking tizanidine without talking to your doctor. If you suddenly stop taking tizanidine, your heart may beat faster and you may have increased blood pressure or tightness in your muscles. Your doctor will probably decrease your dose gradually.

Tizanidine common side effects include tiredness, drowsiness, dizziness, muscular weakness, dry mouth and occasionally low blood pressure (hypotension).

How long does it take for tizanidine to work?

Tizanidine normally starts working 1 to 2 hours after taking it ⁵, ⁶. It wears off about 3 hours to 6 hours after taking it. Tizanidine can be taken up to 3 times a day to help relieve muscle spasms.

How long does tizanidine stay in my body?

Tizanidine is metabolized extensively in the liver by cytochrome P450-1A2 to inactive metabolites ¹. Tizanidine has an elimination half-life of 2.5 hours, follows linear pharmacokinetics, and is excreted 60% through urine and 20% through feces ⁷. The maximum effect of tizanidine occurs about 1 hour to 2 hours after taking a dose. It wears off in about 3 to 6 hours after taking it. Tizanidine is typically given no more than 3 times a day. Tizanidine is usually taken up to 3 times in one day, starting at 2mg per dose. Allow 6 to 8 hours to pass between doses. Do not take more than 36 mg in a 24-hour period ³. Too much of tizanidine can damage your liver ⁴.

Does tizanidine lower my blood pressure?

Tizanidine is known to cause low blood pressure (hypotension). In some cases, it may cause low blood pressure that is so low that you could faint or pass out. The chances of fainting can be lowered if your doctor raises the dose of tizanidine very slowly. You may also have to be careful when you move from a sitting position to a standing position. In clinical trials, the most common side effects of tizanidine were dry mouth, sleepiness, dizziness and asthenia (defined as weakness, fatigue and/or tiredness).

Can I take tizanidine to help me sleep?

Tizanidine can cause sleepiness, but it has not been approved by the U.S. Food and Drug Administration (FDA) to treat sleep disorders. Tizanidine is a skeletal muscle relaxant. It is approved by the FDA to help relieve muscle spasms.

Sleep medicines called hypnotics can be prescribed by your doctor to help reduce the time it takes you to fall asleep. The most commonly used hypnotics are:

• Zolpidem (Ambien)
• Zaleplon (Sonata)
• Eszopiclone (Lunesta)
• Ramelteon (Rozerem)

How does tizanidine work?

Tizanidine is an imidazoline derivative and a centrally acting alpha-2 receptor agonist ¹. Tizanidine inhibits the release of excitatory amino acids like glutamate and aspartate from spinal interneurons ¹. Consequently, tizanidine enhances the presynaptic inhibition of motor neurons. Tizanidine has significant action on spinal polysynaptic pathways ⁸.

The overall effect of these actions is to reduce the facilitation of spinal motor neurons. Similarly, alpha-2 receptor-mediated inhibition of inter-neuronal activity appears to underlie tizanidine’s additional anti-nociceptive (pain reliever) and anti-convulsant activities. Spasm frequency and clonus are also reduced by tizanidine ⁹.

Tizanidine also has an affinity for the alpha-1 receptors but to a lesser degree, which may explain its mild and transitory effect on the cardiovascular system compared to clonidine despite their structural and biochemical similarity ¹⁰.

Tizanidine monitoring

• Creatinine and liver function tests require measurement at baseline, then one month after the maintenance dose is achieved. Periodically monitor liver function tests in patients managed with tizanidine chronically and in higher doses ⁴
• Monitor blood pressure and heart rate before increasing the dosage because of the risk of severe hypotension associated with the higher dose ¹¹
• Monitor the level of spasticity by Ashworth and modified Ashworth Scales ¹²
• In patients with multiple sclerosis, monitor spasticity using Multiple Sclerosis Spasticity Scale (MSSS-88) ¹³

Tizanidine precautions

Tizanidine is a short-acting muscle relaxant that should be taken only for daily activities that require relief from muscle spasms. You should not take tizanidine if you are also taking fluvoxamine (Luvox) or ciprofloxacin (Cipro).

Do not use tizanidine at a time when you need muscle tone for safe balance and movement during certain activities. In some situations, tizanidine may endanger your physical safety to be in a state of reduced muscle tone.

Switching between tablets and capsules, or changing the way you take tizanidine with regard to eating can cause an increase in side effects or a decrease in therapeutic effect. Follow your doctor’s instructions carefully. After making any changes in how you take tizanidine, contact your doctor if you notice any change in how well the medicine works or if it causes increased side effects.

Avoid drinking alcohol. It can increase some of the side effects of tizanidine.

Before taking tizanidine:

• tell your doctor and pharmacist if you are allergic to tizanidine or any other medications.
• tell your doctor if you are taking ciprofloxacin (Cipro) or fluvoxamine. Your doctor will probably tell you not to take tizanidine if you are taking either of these medications.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: acyclovir (Zovirax); amiodarone (Cordarone, Pacerone); baclofen; cimetidine (Tagamet); clonidine (Catapres, Catapres-TTS); dantrolene (Dantrium); diazepam (Valium); famotidine (Pepcid, Pepcid AC); medications for anxiety, seizures, or high blood pressure; mexiletine (Mexitil); oral contraceptives (birth control pills); propafenone (Rythmol); fluoroquinolones such as gemifloxacin (Factive), levofloxacin (Levaquin), moxifloxacin (Avelox), norfloxacin (Noroxin), and ofloxacin (Floxin); ticlopidine (Ticlid); sedatives; sleeping pills; tranquilizers; verapamil (Calan, Covera, Isoptin, Verelan); and zileuton (Zyflo). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Other medications may also interact with tizanidine, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor if you have or have ever had kidney or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking tizanidine, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking tizanidine.
• you should know that this medication may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
• remember that alcohol can add to the drowsiness caused by this medication.
• you should know that tizanidine may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. This is more common when you first start taking tizanidine. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.tizanidine can decrease muscle tone, so be careful when walking or doing other activities where you rely on your muscle tone to help with your posture or balance.

Patients with Liver Impairment

The consequence of Hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. However, tizanidine is extensively metabolized by the liver; therefore, hepatic impairment would significantly influence the pharmacokinetics of tizanidine. Therefore, tizanidine should be avoided or used with extreme caution in patients with hepatic impairment.

Patients with Kidney Impairment

Tizanidine should be used cautiously in patients with renal impairment (creatinine clearance < 25 mL/min), as clearance is decreased by more than 50%. Start with a low dose, evaluate the response to therapy, and if a higher dose is needed, the dose can be increased rather than increasing the frequency of administration. The clinician should monitor the patient closely for adverse drug reactions such as dry mouth, drowsiness, asthenia, and dizziness as indicators of toxicity.

Pregnancy

The use of tizanidine in managing spinal cord injury during pregnancy has been described in case reports.[22] However, it is important to note that tizanidine is a former FDA pregnancy category-C and should be used only if indicated after careful risk-benefit evaluation.

Breastfeeding

Tizanidine is a lipid-soluble drug; hypothetically, it may be present in breast milk; its use during lactation is not advised.

Tizanidine drug interactions

Taking tizanidine with other drugs that make you sleepy or slow your breathing can cause dangerous side effects or death. Ask your doctor before using opioid medication, a sleeping pill, a muscle relaxer, or medicine for anxiety or seizures.

Tell your doctor about all your other medicines, especially:

• acyclovir
• ticlopidine
• zileuton
• birth control pills
• antibiotic – ciprofloxacin, levofloxacin, moxifloxacin, or ofloxacin
• blood pressure medicine – clonidine, guanfacine, methyldopa
• heart rhythm medicine – amiodarone, mexiletine, propafenone, verapamil
• stomach acid medicine – cimetidine, famotidine

This list is not complete. Other drugs may interact with tizanidine, including prescription and over-the-counter medicines, vitamins, and herbal products.

Tizanidine contraindications

• Hypersensitivity to tizanidine or its ingredients is a contraindication to the use of tizanidine.
• Tizanidine use requires caution in patients with hepatic impairment. Review articles on tizanidine report cases of severe hepatotoxicity, acute liver failure, and death ⁴
• According to product labeling, tizanidine use requires caution in patients with renal impairment (creatinine clearance < 25 mL/min). In such patients, decrease the dose. If high doses are necessary, increase the individual dosage rather than the dosage frequency.

Tizanidine uses

Tizanidine is an U.S. Food and Drug Administration (FDA) approved muscle relaxant caused by multiple sclerosis (MS), spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), and traumatic brain injury ¹. Tizanidine has also been shown to be clinically effective in managing patients suffering from chronic neck and lumbosacral neuralgia with a myofascial component to their pain and regional musculoskeletal pain syndromes. It is also prescribed off-label for migraine headaches, insomnia, and as an anticonvulsant. Tizanidine can also be applied as part of a detoxification therapy regimen in patients exhibiting analgesic rebound headaches to assist with analgesic withdrawal.

Tizanidine FDA-approved uses:

• Tizanidine is indicated for spasticity management due to multiple sclerosis, spinal cord injury, stroke, amyotrophic lateral sclerosis, and traumatic brain injury ¹⁴, ¹⁵, ¹⁶.

Tizanidine Off-label Use:

• Chronic neck and lower back pain ¹⁷
• Rebound headaches due to analgesic withdrawal ¹⁸
• Chronic migraine headaches ¹⁹
• Refractory insomnia in spastic quadriplegic patients ²⁰
• Regional musculoskeletal pain syndromes ¹⁷

Placebo-controlled studies confirm the significant efficacy of tizanidine in reducing muscle spasm in patients with spinal cord-induced spasticity. Medical literature suggests that patients with severe spasticity are more likely to benefit from tizanidine. Drug comparison studies have shown no differences in the efficacy of tizanidine compared with baclofen or diazepam. The tizanidine treatment group did not report increased weakness compared to the controls. Furthermore, patients given tizanidine experienced fewer side effects than those using controlled substances ²¹.

Studies exhibit that tizanidine, baclofen, and diazepam effectively decreased excessive muscle tone in patients with multiple sclerosis (MS) or cerebrovascular lesions. Muscle strength improved in all three treatment groups, but the improvement was most significant with tizanidine. Shakespeare et al. ²² also reported similar findings showing no differences in efficacy between tizanidine, baclofen, and dantrolene compared to diazepam. However, diazepam was associated with more sedation. Another study by Lataste et al. ²³ showed no significant differences between tizanidine and baclofen or diazepam for muscle tone, muscle spasms, clonus, muscle strength, or overall anti-spastic effect. However, tizanidine tolerance is slightly better than diazepam and baclofen.

Groves et al. ²⁴ report no significant differences between tizanidine, baclofen, or diazepam for spasticity by Ashworth score. However, applying global tolerability to treatment favored tizanidine compared to baclofen and diazepam.

A recent study indicates that tizanidine and other alpha-2 agonists can be used for medically supervised opioid withdrawal ²⁵.

Animal studies have shown that tizanidine provides benefits in the perioperative period and the management of neuropathic pain, such as trigeminal neuralgia, similar to the effects of clonidine under similar circumstances.

The American Academy of Neurology guidelines reports that tizanidine should be used for generalized spasticity in cerebral palsy, for segmental/localized spasticity treatment with botulinum toxin-A is more effective ²⁶.

Tizanidine dosage

Tizanidine is taken orally as 2 mg, 4 mg, and 6 mg capsules or as 2 mg and 4 mg tablets. Dosage starts with 2 mg orally and may repeat every 6 to 8 hours as needed. The dosage may gradually increase by 2 to 4 mg per dose for 1 to 4 days in between until there is a noticeably significant reduction of spasticity. Maximum dosing is three doses every 24 hours, up to 36 mg daily ³.

If tizanidine is used for more than nine weeks or given in high doses ranging from 20 mg to 36 mg daily, taper the dose gradually. The recommendation is to taper the dose to 2 to 4 mg daily to reduce the risk of tachycardia, rebound hypertension, and increased spasticity ²⁷.

The patient may open the capsule and sprinkle the contents into food. Patients can take tizanidine with food or on an empty stomach. It is important to note that the extent of absorption is greater when taken with food. The tablet and capsule dosage forms are not bioequivalent when administered with food. Therefore, the clinician should counsel the patient to take tizanidine with or without food but be consistent to avoid fluctuations in concentration ²⁸. It is also important to recognize that smoking decreases tizanidine’s plasma concentration and exposure ²⁹.

What should I do if I forget a dose?

If your doctor has told you to take tizanidine regularly, take the missed dose as soon as you remember it. However, if it is almost time for your 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.

Tizanidine side effects

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

• dizziness ³⁰
• drowsiness
• blurred vision
• weakness
• nervousness
• depression
• hallucination
• vomiting
• tingling sensation in the arms, legs, hands, and feet
• dry mouth (xerostomia) ⁹
• rhinitis (runny nose)
• constipation
• diarrhea
• stomach pain
• heartburn
• increased muscle spasms
• back pain
• rash
• sweating

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

• nausea
• extreme tiredness
• unusual bleeding or bruising
• lack of energy
• loss of appetite
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• unexplained flu-like symptoms
• seeing things or hearing voices that do not exist
• slow heartbeat
• changes in vision

Tizanidine may cause other side effects. Call your doctor if you have any unusual problems while taking tizanidine.

Tizanidine withdrawal symptoms:

• rapid heart rate (tachycardia)
• rebound hypertension
• increased spasticity
• withdrawal symptoms are more likely to occur when discontinuing tizanidine abruptly ²⁷

Symptoms of tizanidine overdose may include:

• drowsiness
• extreme tiredness
• confusion
• slow heartbeat (bradycardia)
• fainting
• dizziness
• slow or shallow breathing
• loss of consciousness
• coma

Management of tizanidine overdose

• There is no antidote for tizanidine toxicity.
• Tizanidine overdose management is by close monitoring of airways, administration of intravenous fluid, and vasopressors as necessary ¹¹
• The pediatric case report described an overdose of tizanidine in spastic quadriplegia and toxicity presented with multiple organ dysfunction in the absence of sepsis ³
• A recent case report described the altered mental status and hemodynamic instability due to tizanidine overdose, and naloxone 10 mg IV administration improved Richmond Agitation-Sedation Scale (RASS) ³¹. The study concluded that naloxone could be used in tizanidine overdose in emergency settings; however, naloxone does not reverse the hemodynamic parameters ³².

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Pregabalin

Pregabalin also called Lyrica is an anti-epileptic drug or an anticonvulsant. Pregabalin is available only with your doctor’s prescription. Pregabalin works by slowing down impulses in the brain that cause seizures or epilepsy. Pregabalin also affects chemicals in the brain that send pain signals across the nervous system or damaged nerves in the body. Pregabalin is used to treat pain caused by fibromyalgia (a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep) or nerve pain (neuropathic pain from damaged nerves) in people with diabetes called diabetic neuropathy that can occur in your arms, hands, fingers, legs, feet, or toes and herpes zoster post-herpetic neuralgia (the burning, stabbing pain or aches that may last for months or years after an attack of shingles), or spinal cord injury. Pregabalin is also used with other medications (adjunctive therapy) to treat partial-onset seizures in adults and children aged at least 1 month of age and older. Pregabalin will not cure epilepsy and will only work to control seizures for as long as you continue to take it.

Pregabalin is available in capsules in varying concentrations from 25 to 300 mg under the brand name of Lyrica, an oral solution (liquid) and as an extended-release (long-acting) tablet to take by mouth. Pregabalin capsules and oral solution are usually taken with or without food two or three times a day. Pregabalin extended-release tablets are usually taken once daily after an evening meal. Take pregabalin at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand.

Swallow the extended-release tablets whole; do not cut, chew, or crush them.

Your doctor will probably start you on a low dose of pregabalin and may gradually increase your dose during the first week of treatment.

Take pregabalin exactly as directed. Pregabalin 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.

Pregabalin may help control your symptoms but will not cure your condition. It may take several weeks or longer before you feel the full benefit of pregabalin. Continue to take pregabalin even if you feel well. Do not stop taking pregabalin without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood. If you suddenly stop taking pregabalin, you may experience withdrawal symptoms, including trouble falling asleep or staying asleep, nausea, diarrhea, headaches, or seizures. Your doctor will probably decrease your dose gradually over at least 1 week.

Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with pregabalin and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the manufacturer’s website to obtain the Medication Guide.

Most reported adverse effects caused by pregabalin were mild to moderate intensity, dose-dependent, and occurred within the first two weeks of initiating treatment. The most common side effects of pregabalin are dose related and include peripheral swelling (edema), weight gain, dizziness, somnolence, confusion, headache, blurred vision, tremor and ataxia ¹. The most common adverse reactions reported across all patient populations in premarketing controlled trials, which occurred in greater than or equal to 5% of patients taking pregabalin and twice the rate reported by patients receiving placebo, were: somnolence, dizziness, blurred vision, difficulty with concentration/attention, dry mouth, edema, and weight gain ², ³. Rare but potentially severe adverse events include depression, suicidal ideation and behaviors, angioedema, and hypersensitivity reactions ⁴, ⁵.

Weight gain associated with pregabalin is dose-dependent and occurred in up to 14% of patients receiving 600 mg per day.

Following rapid or abrupt discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, anxiety, nervousness, irritability, hyperhidrosis, and diarrhea ¹.

Chronic use of pregabalin can result in physical dependence, and there is a risk of abuse associated with its use, especially in patients on opioid medicines or who have a history of substance abuse ⁶.

Pregabalin special precautions

Before taking pregabalin:

• tell your doctor and pharmacist if you are allergic to pregabalin, any other medications, or any of the ingredients in pregabalin preparations. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: angiotensin converting enzyme (ACE) inhibitors such as benazepril (Lotensin, in Lotrel), captopril (Capoten, in Capozide), enalapril (Vasotec, in Vaseretic, Lexxel), fosinopril (Monopril), lisinopril (Prinivil, Zestril, in Prinzide, Zestoretic), moexipril (Univasc, in Uniretic), perindopril (Aceon), quinapril (Accupril, in Accuretic, Quinaretic), ramipril (Altace), and trandolapril (Mavik, in Tarka); antidepressants; antihistamines; medications for anxiety including lorazepam (Ativan); medications for mental illness or seizures; certain medications for diabetes such as pioglitazone (Actos, in Duetact) and rosiglitazone (Avandia, in Avandaryl, Avandamet); opioid (narcotic) pain medications including hydrocodone (in Hydrocet, in Vicodin, others), morphine (Avinza, Kadian, MSIR, others), or oxycodone (OxyContin, in Percocet, others); sedatives; sleeping pills; and tranquilizers. 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. Also tell your doctor if you have or have ever had swelling of the eyes, face, lips, tongue, or throat; vision problems; heart failure; bleeding problems or a low number of platelets (type of blood cell needed for blood clotting) in your blood, or lung, heart, or kidney disease.
• tell your doctor if you are pregnant or if you or your partner plans to become pregnant. Also tell your doctor if you are breastfeeding. If you or your partner becomes pregnant while you are taking pregabalin, call your doctor. Pregabalin has caused decreased fertility in male animals and birth defects in the offspring of male and female animals who were treated with the medication. There is not enough information to tell if pregabalin causes these problems in humans.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking pregabalin.
• you should know that pregabalin may make you dizzy or drowsy. Do not drive a car operate machinery, or do other dangerous activities until you know how this medication affects you. Ask your doctor when you may do these activities.
• do not drink alcohol while taking pregabalin. Alcohol can add to the drowsiness caused by this medication.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking pregabalin for the treatment of epilepsy, mental illness, or other conditions. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as pregabalin to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as 1 week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as pregabalin, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); talking or thinking about wanting to hurt yourself or end your life; withdrawing from friends and family; preoccupation with death and dying; giving away prized possessions; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to pregabalin 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.

Kidney impaired patients

Pregabalin is eliminated primarily by kidney excretion. Adjust the dose in patients with impaired kidney function. According to drug manufacturers the following are recommendations on dose reductions for patients with reduced creatinine clearance (CrCl) and those undergoing hemodialysis.

• Creatinine clearance (CrCl) greater than or equal to 60 mL/min- no dose modification recommended
• Creatinine clearance (CrCl) 30 – 60 mL/min – 50% dose of recommended daily dose
• Creatinine clearance (CrCl) 15- 30 mL/min – 25% dose of recommended daily dose
• Creatinine clearance (CrCl) less than or equal to 15 mL/min – 16% to 8% dose of recommended daily dose
• Supplementary dosage of approximately an additional 25 mg of recommended daily dose following hemodialysis is recommended

Children

Appropriate studies have not been performed on the relationship of age to the effects of pregabalin in children younger than 1 month of age for partial onset seizures. Safety and efficacy have not been established for other conditions.

Breastfeeding women

Pregabalin has been detected in the milk of lactating women; thus, breastfeeding is not advisable, and an alternative agent is preferred ⁷. 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 Pregabalin while breastfeeding.

Pregnancy

Pregabalin may cause fetal harm. Advise patients there is a potential risk to the fetus ⁸. To monitor pregnancy outcomes in women exposed to pregabalin during pregnancy and provide information on the effects of in utero exposure to pregabalin, clinicians should help enroll pregnant patients in the North American Antiepileptic Drug Pregnancy Registry (https://www.aedpregnancyregistry.org).

Liver Impairment

Although not explicitly studied, because pregabalin is not protein-bound, it is unlikely that patients with hepatic impairment require dosing modifications.

Elderly patients

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of pregabalin in the elderly. However, elderly patients are more likely to have unwanted effects (eg, dizziness, blurred vision, confusion, or clumsiness) and age-related kidney problems, which may require an adjustment in the dose for patients receiving pregabalin.

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 pregabalin, 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 pregabalin 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.

• Acepromazine
• Alfentanil
• Alprazolam
• Amobarbital
• Anileridine
• Aripiprazole
• Asenapine
• Baclofen
• Benperidol
• Benzhydrocodone
• Bromazepam
• Buprenorphine
• Buspirone
• Butabarbital
• Butorphanol
• Calcifediol
• Calcium Oxybate
• Cannabidiol
• Carbinoxamine
• Carisoprodol
• Carphenazine
• Chloral Hydrate
• Chlordiazepoxide
• Chlorpromazine
• Chlorzoxazone
• Clobazam
• Clonazepam
• Clorazepate
• Clozapine
• Codeine
• Cyclobenzaprine
• Dexmedetomidine
• Diacetylmorphine
• Diazepam
• Dichloralphenazone
• Difenoxin
• Dihydrocodeine
• Diphenhydramine
• Diphenoxylate
• Doxylamine
• Droperidol
• Enflurane
• Esketamine
• Estazolam
• Eszopiclone
• Ethchlorvynol
• Ethopropazine
• Ethylmorphine
• Fentanyl
• Flibanserin
• Fluphenazine
• Flurazepam
• Fluspirilene
• Fospropofol
• Gabapentin
• Gabapentin Enacarbil
• Halazepam
• Haloperidol
• Halothane
• Hexobarbital
• Hydrocodone
• Hydromorphone
• Hydroxyzine
• Isoflurane
• Ketamine
• Ketazolam
• Ketobemidone
• Levorphanol
• Lorazepam
• Loxapine
• Magnesium Oxybate
• Meclizine
• Melperone
• Meperidine
• Mephobarbital
• Meprobamate
• Meptazinol
• Mesoridazine
• Metaxalone
• Methadone
• Methdilazine
• Methocarbamol
• Methohexital
• Methotrimeprazine
• Methylene Blue
• Midazolam
• Molindone
• Moricizine
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Nicomorphine
• Nitrazepam
• Nitrous Oxide
• Olanzapine
• Opium
• Opium Alkaloids
• Orlistat
• Orphenadrine
• Oxazepam
• Oxycodone
• Oxymorphone
• Papaveretum
• Paregoric
• Pentazocine
• Pentobarbital
• Perampanel
• Perazine
• Periciazine
• Perphenazine
• Phenobarbital
• Pimozide
• Piperacetazine
• Pipotiazine
• Piritramide
• Potassium Oxybate
• Prazepam
• Primidone
• Prochlorperazine
• Promazine
• Promethazine
• Propofol
• Quazepam
• Quetiapine
• Ramelteon
• Remifentanil
• Remimazolam
• Remoxipride
• Secobarbital
• Sertindole
• Sodium Oxybate
• Sufentanil
• Sulpiride
• Suvorexant
• Tapentadol
• Temazepam
• Thiethylperazine
• Thiopental
• Thiopropazate
• Thioridazine
• Tilidine
• Tizanidine
• Tolonium Chloride
• Topiramate
• Tramadol
• Triazolam
• Trifluoperazine
• Trifluperidol
• Triflupromazine
• Trimeprazine
• Zaleplon
• Zolpidem
• Zopiclone
• Zotepine

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 pregabalin. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol or drug abuse, history of or
• Angioedema (severe swelling), history of or
• Congestive heart failure or
• Diabetes: May cause side effects to become worse.
• Behavior changes, history of or
• Bleeding disorder or
• Depression, history of or
• Edema (body swelling or fluid retention) or
• Heart rhythm problem (eg, prolonged PR interval) or
• Lung or breathing problems (eg, respiratory depression) or
• Thrombocytopenia (low platelets in the blood): Use with caution. May make these conditions worse.
• Kidney disease: Use with caution. The effects may be increased because of slower removal of the medicine from the body.

How does pregabalin work?

Pregabalin is an alkylated analogue of gamma-aminobutyric acid (GABA) and is structurally related to gabapentin. However, pregabalin does not directly bind to GABA-A or GABA-B receptors ⁹. Additionally, Pregabalin is not metabolized to a GABA receptor agonist. In animal models, pregabalin binds to presynaptic voltage-gated calcium channels at the alpha-2-delta subunit in central nervous system tissues. The binding of the alpha-2-delta subunit decreases the depolarization-induced influx of calcium into neurons and reduces the release of excitatory neurotransmitters by hyperexcited neurons ¹⁰, ¹¹, ¹². This action may account for the anticonvulsant and analgesic effects of pregabalin. Pregabalin has no known activity at sodium channels, dopamine receptors, serotonin receptors, opiate receptors and does not modify cyclooxygenase activity ¹³.

Pregabalin has antiepileptic, analgesic, and anxiolytic effects. Pregabalin has been shown to be effective in reducing neuropathic pain from diabetic and postherpetic neuropathy and is an effective anticonvulsant ¹².

Pregabalin works in different ways:

• In epilepsy Pregabalin stops seizures by reducing the abnormal electrical activity in your brain
• With nerve pain Pregabalin blocks pain by affecting the pain messages traveling through your brain and down your spinal cord
• In anxiety Pregabalin stops your brain from releasing the chemicals that make you feel anxious.

Pregabalin uses

Pregabalin was approved for use in the United States in 2004 to treat epilepsy and anxiety. Pregabalin is an anticonvulsant and neuropathic pain agent. Pregabalin works in the central nervous system (CNS) to control seizures and pain. Pregabalin is used with other medicines to help control partial-onset seizures (convulsions) in the treatment of epilepsy in patients 1 month of age and older. Pregabalin will not cure epilepsy and will only work to control seizures for as long as you continue to take it.

Pregabalin United States Food and Drug Administration (FDA)-approved indications ¹⁴, ¹, ¹⁵, ¹⁶:

• Treatment of nerve pain or neuropathic pain associated with diabetic peripheral neuropathy (diabetic neuropathy or pain caused by nerve damage from diabetes)
• Treatment of nerve pain or neuropathic pain associated with spinal cord injury
• Neuropathic pain originating from postherpetic neuralgia (nerve pain that occurs after shingles)
• Treatment of fibromyalgia (muscle pain and stiffness).
• Adjunctive therapy for partial-onset seizures in adults with epilepsy

Pregabalin Off-label Uses ¹⁷, ¹⁸, ¹⁹:

• Generalized anxiety disorder
• Social anxiety disorder
• Bipolar disorder
• Insomnia
• Chronic pain conditions
• Chronic Pruritus (chronic itch)
• Chronic cough
• Migraine
• Restless leg syndrome

There is significant disagreement regarding the effectiveness of pregabalin for the psychiatric disorders listed above. Therefore, prescribers should be careful and monitor patients for therapeutic success when treating patients with pregabalin ⁹.

Pregabalin dosage

Pregabalin is only available on prescription. It comes as capsules, tablets (extended release) or a liquid that you swallow. Take Ppregabalin exactly as prescribed by your doctor and read all medication guides or instruction sheets about pregabalin. Your doctor may occasionally change your dose. Pregabalin recommended initial dose for neuropathic pain is 50 to 75 mg two to three times daily, the maximum dose being 300 mg daily. Higher doses are used in treating seizures. The dose should be increased and tapered gradually.

Take pregabalin exactly 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. To do so may increase the chance of side effects.

Pregabalin capsule or oral liquid may be taken with or without food.

Take the extended-release tablet after an evening meal. Swallow it whole. Do not crush, break, or chew it.

Measure the oral liquid using a marked measuring spoon, oral syringe, or medicine cup. The average household teaspoon may not hold the right amount of liquid.

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

Do not stop using pregabalin suddenly, even if you feel fine. Stopping suddenly may cause increased seizures or unpleasant withdrawal symptoms. Follow your doctor’s instructions about tapering your dose for at least 1 week before stopping completely.

In case of emergency, wear or carry medical identification to let others know you take seizure medication.

Store at room temperature away from moisture, heat, and light.

The dose of pregabalin 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 pregabalin. If your dose is different, do not change it unless your doctor tells you to do so.

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

Diabetic nerve pain

For oral dosage forms (capsules and solution):

• Adults: At first, 50 milligrams (mg) 3 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 300 mg per day (maximum therapeutic dose is 300 mg/day). The dose can increase up to 300 mg/day within one week of starting treatment ¹⁴.
• Children: Use and dose must be determined by your doctor.

For oral dosage forms (extended-release tablets):

• Adults: At first, 165 milligrams (mg) once a day for 1 week. Your doctor may increase your dose as needed and tolerated. However, the dose is usually not more than 330 mg per day.
• Children: Use and dose must be determined by your doctor.

Partial-onset seizures

For oral dosage forms (capsules and solution):

• Adults and children 17 years of age and older: At first, 150 milligrams (mg) per day given in 2 or 3 divided doses. Your doctor may adjust your dose as needed. However, the dose is usually not more than 600 mg per day. The effective dose is 150 mg to 600 mg per day, divided 2 or 3 times per dosing. The suggested starting dose is no greater than 150 mg per day. The total dose can increase to a maximum of 600 mg per day.
• Children 1 month of age and older weighing 30 kilograms (kg) or more: Use is based on body weight and must be determined by your doctor. The usual dose is 2.5 milligram per kilogram (mg/kg) per day given in 2 or 3 divided doses. Your doctor may adjust your dose as needed. However, the dose is usually not more than 10 mg/kg (600 mg) per day.
• Children 1 month of age and older weighing less than 30 kilograms (kg): Use is based on body weight and must be determined by your doctor. The usual dose is 3.5 milligram per kilogram (mg/kg) per day given in 3 divided doses. Your doctor may adjust your dose as needed. However, the dose is usually not more than 14 mg/kg per day.
• Children younger than 1 month of age: Use and dose must be determined by your doctor.

Fibromyalgia

For oral dosage forms (capsules and solution):

• Adults: At first, 75 milligrams (mg) 2 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 450 mg per day. The recommended therapeutic dose is 300 mg to 450 mg per day. The recommended starting dose is 150 mg/day divided into twice per day dosing. The dose can increase to 300 mg per day within one week of starting treatment. Patients with suboptimal pain relief on 300 mg per day may further increase to 450 mg per day, divided into twice per day dosing.
• Children: Use and dose must be determined by your doctor.

Post-herpetic neuralgia

For oral dosage forms (capsules and solution):

• Adults: At first, 75 to 150 milligrams (mg) 2 times a day, or 50 to 100 mg 3 times a day. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 600 mg per day. The recommended therapeutic dose is 150 mg to 300 mg per day, divided into dosing 2 or 3 times per day. The recommended starting dose is 75 mg two times per day or 50 mg three times per day. The dose can increase up to 300 mg per day within one week of starting treatment. After 2 to 4 weeks of treatment with 300 mg per day, patients with suboptimal pain relief can be increased to 600 mg per day, divided into twice per day or three times per dosing.
• Children: Use and dose must be determined by your doctor.

For oral dosage forms (extended-release tablets):

• Adults: At first, 165 milligrams (mg) once a day for 1 week. Your doctor may increase your dose to 330 mg as needed and tolerated. However, the dose is usually not more than 660 mg per day.
• Children: Use and dose must be determined by your doctor.

Spinal cord injury nerve pain

For oral dosage forms (capsules and solution):

• Adults: At first, 75 milligrams (mg) 2 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 600 mg per day. The dose may be increased to 150 mg twice per day within one week of initiating treatment. Patients with suboptimal pain relief following 2 to 3 weeks of treatment with 150 mg twice a day may be increased up to 300 mg twice per day. In spinal cord injury, pain improvement can be seen as early as one week after initiating treatment. However, to evaluate the efficacy of pregabalin, it is recommended to try the medication for 4 to 6 weeks if tolerated by the patient ²⁰.
• Children: Use and dose must be determined by your doctor.

Refractory Chronic Cough

Pregabalin is off-label used in refractory chronic cough conditions. The initial starting dose is 75 mg per day, which may increase by 75 mg per day during the first week of treatment. The maximum dose can be up to 300 mg per day, divided into three times per dosing ²¹.

Generalized Anxiety Disorder (GAD)

Pregabalin is also off-label used in generalized anxiety disorder. The initial starting dose is 75 mg per day, which may increase by 75 mg per day during the first week of treatment. The maximum dose can be up to 300 mg per day, divided into three times per dosing ²².

Social Anxiety Disorder (SAD)

Pregabalin is off-label used as mono or adjuvant therapy in social anxiety disorder, cough, and chronic refractory conditions. The initial starting dose is 100 mg three times a day, which may increase by 150 mg per day over one week. This dose may go up to 600 mg daily based on response and tolerability ²³.

Chronic Pruritus (Chronic Itch)

Pregabalin is also off-label used as a preferred treatment in patients with brachioradial pruritus, a rare type of chronic pruritus that usually localized at the dorsolateral part of the forearms. Itching, burning, or pain are common symptoms at the involved areas. The causal factors are still unknown but sun exposure and/or cervical spine lesions seem to be trigerring or precipiting factors ²⁴. Neuropathogenic mechanism plays role in etiopathogenesis of brachioradial pruritus, therefore, antiepileptic drugs such as gabapentin, oxcarbazepine. and pregabalin are suggested medications for BRP. Herein, we report three cases with brachioradial pruritus successfully treated with pregabaline. The initial starting dose is 75 mg twice daily, which may increase by 150 mg to 300 mg in two to three divided doses daily. This dose may go up to 600 mg daily in oncology patient populations ²⁴.

Restless Legs Syndrome

Another off-label use of pregabalin is in restless legs syndrome. The initial starting dose is 50 mg to 75 mg daily before bedtime, which may increase by 75 mg to 150 mg every week. The usual therapeutic dose is up to 150 mg to 450 mg daily based on the effectiveness and tolerability of therapy ²⁵.

What should I do if I forget a dose?

If you are taking pregabalin capsules or the oral solution and forget to take a dose and remember a few hours later, 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.

If you are taking pregabalin extended-release tablets and forget to take a dose after your evening meal, take the missed dose before bedtime after a snack. If you miss taking the dose prior to bedtime, take your dose the following day after breakfast. If you miss taking the dose after breakfast, take your dose at the usual time after an evening meal and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Pregabalin side effects

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

• tiredness
• dizziness
• headache
• dry mouth
• nausea
• vomiting
• constipation
• gas
• bloating
• ”high” or elevated mood
• speech problems
• difficulty concentrating or paying attention
• difficulty remembering or forgetfulness
• anxiety
• lack of coordination
• loss of balance or unsteadiness
• uncontrollable shaking or jerking of a part of the body
• muscle twitching
• weakness
• increased appetite
• weight gain
• back pain

Some side effects can be serious. If you experience any of these symptoms, see your doctor immediately:

• blurred vision, double vision, or other changes in eyesight
• hives
• rash
• itching
• blisters
• swelling of the eyes, face, throat, mouth, lips, gums, tongue, head or neck
• swelling of the arms, hands, feet, ankles, or lower legs
• shortness of breath
• wheezing
• muscle pain, tenderness, soreness, or weakness, especially if it comes along with fever
• chest pain
• difficulty breathing; bluish-tinged skin, lips, or fingernails; confusion; or extreme sleepiness

If you have diabetes, you should know that pregabalin has caused skin sores in animals. Pay extra attention to your skin while taking pregabalin, and tell your doctor if you have any sores, redness, or skin problems.

Pregabalin may cause other side effects. Call your doctor if you have any unusual problems while taking pregabalin.

Pregabalin overdose

There is limited information regarding overdose with pregabalin. The highest known accidental overdose of pregabalin during clinical development was 8000 mg; this event was without significant clinical consequences. There is no specific antidote for overdose with pregabalin.

The most commonly reported adverse events with overdose were reduced consciousness, confusional state, agitation, depression/anxiety, and restlessness in the postmarketing studies. In addition, heart block, seizures, and death have also been reported in some patients taking combination with other central nervous system depressants ²⁶.

Pregabalin overdose treatment

• If required, elimination of unabsorbed drugs can be performed by gastric lavage or emesis. General supportive care should be provided to the patient. Maintain airway and monitor vital signs and clinical status of the patient. Contact a Certified Poison Control Center (https://poisonhelp.hrsa.gov/poison-centers/find-poison-center) for up-to-date information on the management of overdose with pregabalin. The national, toll-free Poison Help line, 1-800-222-1222, connects you to your local poison center and is your resource for help in a poisoning emergency. You can call from anywhere in the United States and many territories.
• Pregabalin can be removed by standard hemodialysis procedures, resulting in approximately 50% clearance of pregabalin in 4 hours.

Pregabalin Contraindications

Pregabalin is contraindicated in patients who have a known hypersensitivity to pregabalin. Hypersensitivity reactions have occurred in patients receiving pregabalin, including angioedema ⁵. There are no adequate studies with pregabalin in pregnant women. Pregabalin may cause fetal harm. Advise patients there is a potential risk to the fetus ⁸. Pregabalin has been detected in the milk of lactating women; thus, breastfeeding is not advisable, and an alternative agent is preferred ⁷. 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 Pregabalin while breastfeeding.

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15. Bidari A, Moazen-Zadeh E, Ghavidel-Parsa B, Rahmani S, Hosseini S, Hassankhani A. Comparing duloxetine and pregabalin for treatment of pain and depression in women with fibromyalgia: an open-label randomized clinical trial. Daru. 2019 Jun;27(1):149-158. doi: 10.1007/s40199-019-00257-4[↩]
16. Abou-Khalil BW. Update on Antiepileptic Drugs 2019. Continuum (Minneap Minn). 2019 Apr;25(2):508-536. doi: 10.1212/CON.0000000000000715[↩]
17. Goodman CW, Brett AS. A Clinical Overview of Off-label Use of Gabapentinoid Drugs. JAMA Intern Med. 2019 May 1;179(5):695-701. doi: 10.1001/jamainternmed.2019.0086[↩]
18. Parikh SK, Silberstein SD. Current Status of Antiepileptic Drugs as Preventive Migraine Therapy. Curr Treat Options Neurol. 2019 Mar 18;21(4):16. doi: 10.1007/s11940-019-0558-1[↩]
19. Bendtsen L, Zakrzewska JM, Abbott J, Braschinsky M, Di Stefano G, Donnet A, Eide PK, Leal PRL, Maarbjerg S, May A, Nurmikko T, Obermann M, Jensen TS, Cruccu G. European Academy of Neurology guideline on trigeminal neuralgia. Eur J Neurol. 2019 Jun;26(6):831-849. doi: 10.1111/ene.13950[↩]
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21. Vertigan AE, Kapela SL, Ryan NM, Birring SS, McElduff P, Gibson PG. Pregabalin and Speech Pathology Combination Therapy for Refractory Chronic Cough: A Randomized Controlled Trial. Chest. 2016 Mar;149(3):639-48. doi: 10.1378/chest.15-1271[↩]
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Minoxidil

Minoxidil liquid to be applied to your scalp is used to stimulate hair growth and to slow hair loss and Minoxidil tablet to be taken by mouth is used with other medications to treat high blood pressure not responding to maximum doses of 3 different antihypertensive medications also called resistant hypertension. In some countries, Minoxidil is available in other formulations such as foam or gel. Minoxidil liquid to be applied to your scalp is most effective for people under 40 years of age whose hair loss is recent. Minoxidil liquid to be applied to your scalp has no effect on receding hairlines. Minoxidil liquid to be applied to your scalp does not cure baldness; most new hair is lost within a few months after Minoxidil is stopped. In United States, Minoxidil Foam or Minoxidil Solution is available without a prescription. Furthermore, Minoxidil is marketed in an oral tablet formulation and as a topical agent in foam and solution formulations for both male and female patients.

Minoxidil is in a class of medications called vasodilators (medicines that open blood vessels). Minoxidil works by relaxing the blood vessels so that blood can flow more easily through your body. Minoxidil was originally marketed in a tablet form for the treatment of high blood pressure (hypertension). When Minoxidil tablet was used to treat high blood pressure (hypertension) one of the side effects of Minoxidil was unwanted hair growth. This side effect promoted researchers to produce Minoxidil topical solution for treating hair loss.

Topical Minoxidil is used in the treatment of male pattern hair loss in men (MPHL), and female pattern hair loss in women (FPHL) commonly known as androgenetic alopecia (androgenic alopecia). Topical Minoxidil is occasionally useful for other forms of hair loss (alopecia), including alopecia areata, and after hair replacement surgery or chemotherapy. Minoxidil effectiveness may be enhanced by concurrent use of a topical retinoid (medications derived from vitamin A formulated as a cream, lotion, foam, emulsion, or gel).

Minoxidil is marketed as Rogaine Topical Solution (5%) and Headway Topical Solution (2% and 5%). Minoxidil 5% solution is probably more effective but it may result in greater irritation than Minoxidil 2% solution. Minoxidil Topical Solution is applied to the affected area of the scalp once or twice daily for a minimum of 6 months. If it is found to be effective, it may be continued long term.

Follow the directions on your package or prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Use minoxidil exactly as directed. Do not use more or less of it or use it more often than directed by your doctor.

Exceeding the recommended dosage does not produce greater or faster hair growth and may cause increased side effects. You must use Minoxidil Topical Solution for at least 4 months, and possibly for up to 1 year, before you see any effect.

Three special applicators are provided: a metered-spray applicator for large scalp areas, an extender spray applicator (used with the metered-spray applicator) for small areas or under the hair, and a rub-on applicator.

Remove the outer and inner caps from the bottle, choose an applicator, and screw it tightly onto the bottle.

To use the extender spray applicator, first assemble the metered-spray applicator and then follow the instructions provided to attach the extender spray applicator. Pump the metered-spray or extender spray applicator six times for each dose. Try not to inhale the mist. Place the large cap on the metered-spray bottle or the small cap on the extender spray nozzle when not in use.

To use the rub-on applicator, hold the bottle upright and squeeze it until the upper chamber of the applicator is filled to the black line. Then turn the bottle upside down and rub on the medication. Place the large cap on the bottle when not in use. If you use your fingertips to apply the medication, wash them thoroughly afterwards.

Apply Minoxidil Topical Solution to dry hair and scalp only. Do not apply it to other body areas, and keep it away from your eyes and sensitive skin. If it accidentally comes in contact with these areas, wash them with lots of cool water; call your doctor if they become irritated.

Do not apply minoxidil to a sunburned or irritated scalp.

Minoxidil side effects include local irritation most often resulting in itching or stinging. Contact allergy to minoxidil or propylene glycol (the main component of Minoxidil solution) occurs rarely, and results in dermatitis.

Unwanted hair growth might occur (hypertrichosis), for example if Minoxidil solution is dripped onto the forehead.

Internal effects are not likely as there is minimal absorption into your body. However, hair growth in distant sites such as your arms, chest and lower back has occasionally been reported when Minoxidil 5% solution has been used.

Hypotension (low blood pressure) is a rare occurrence in patients using topical minoxidil. Nonetheless, some clinicians advise consistent monitoring of blood pressure, heart rate, and electrocardiographic changes for patients undergoing topical minoxidil therapy. Clinicians should conduct thorough assessments to eliminate secondary causes of hypertension, such as renal artery stenosis, primary aldosteronism, pheochromocytoma, and Cushing syndrome, warranting minoxidil treatment. Regular monitoring of fundoscopic examination, renal function, echocardiogram, and ankle-brachial index is recommended to assess potential target organ damage for patients taking minoxidil ¹.

Minoxidil is best avoided during pregnancy and breastfeeding (Pregnancy Category C, i.e., Drugs that, owing to their pharmacological effects, have caused or maybe suspected of causing harmful effects on the human fetus or neonate without causing malformations) ².

What causes hair loss in men and women?

Male pattern hair loss also called androgenetic alopecia (androgenic alopecia) is an inherited condition caused by a genetically determined excessive sensitivity to the effects of dihydrotestosterone (DHT) in some areas of the scalp that affects up to 50% of males and females ⁷, ⁸, ⁹. Male pattern hair loss (androgenetic alopecia) is characterized by progressive loss of terminal hair of the scalp any time after puberty, in a characteristic distribution in both males and females. In males, hair loss is most prominent in the crown (the vertex, the highest point on your scalp) and frontotemporal regions, while in women the frontal hairline is typically spared with diffuse hair loss at the crown and top of head, with loss often marked by a wider center part ¹⁰, ¹¹, ¹².

Dihydrotestosterone (DHT) is believed to shorten the growth or anagen, phase of the hair cycle, from a usual duration of 3 to 6 years to just weeks or months ¹³, ¹⁴. This occurs together with miniaturization of the hair follicles and progressively produces fewer and finer hairs. The production of dihydrotestosterone (DHT) is regulated by an enzyme called 5-alpha reductase (5α-reductase). 5-alpha reductase (5α-reductase) enzyme is involved in processing androgens, which are sex hormones that direct male sexual development that help start puberty and play a role in reproductive health and body development. Specifically, the steroid 5-alpha reductase 2 enzyme is responsible for a chemical reaction that converts the hormone Testosterone to Dihydrotestosterone (DHT). DHT has a critical role in male sexual development, and a shortage of this hormone disrupts the formation of the external sex organs before birth.

Several genes are involved, accounting for differing age of onset, progression, pattern and severity of hair loss in family members. The hair loss genes are inherited from both mother and father. At this time, genetic testing for prediction of balding is unreliable.

A few women present with male pattern hair loss because they have excessive levels of androgens as well as genetic predisposition. These women also tend to suffer from acne, irregular menses and excessive facial and body hair. These symptoms are characteristic of polycystic ovarian syndrome (PCOS) although the majority of women with PCOS (polycystic ovarian syndrome) do not experience hair loss. Less often, congenital adrenal hyperplasia (CAH or 21-hydroxylase deficiency) may be responsible. Females that are losing their hair with age are more likely to present with female pattern hair loss, in which hormone tests are normal.

Figure 1. Hair loss in women (androgenic alopecia in women)

Footnote: Female pattern hair loss (androgenic alopecia in women) showing hair thinning mostly confined to the crown (top of scalp) with retention of frontal hairline.

Figure 2. Androgenetic alopecia female (female pattern baldness)

Footnote: Androgenetic alopecia in women with ‘Christmas Tree Pattern’

Figure 3. Male pattern hair loss

What is hair growth cycle?

The human scalp contains about 100,000 hair follicles. These anchor the hair to the skin and contain the cells that produce new hairs. A hair in the scalp grows for two to five years, at a rate of around 0.33 mm/day (about 1/64 inch). Variations in hair growth rate and the duration of the hair growth cycle account for individual differences in uncut hair length. Hair grows in 3 developmental stages:

1. Anagen. The anagen phase or actively hair growing phase starts the growing of new hair. The anagen phase is genetically determined and can vary from 2 to 6 years (the average is just under 3 years). Most hair follicles on the scalp are in the anagen phase.
2. Catagen. The catagen phase is a transition stage (in-between phase) between the growing and resting phases and lasts 2-3 weeks. The catagen phase is when hair growth stops and the hair follicle shrinks. About 1–3% of hairs are in the catagen phase (in-between phase).
3. Telogen. The telogen phase or resting phase is a mature hair with a root, which is held very loosely in the follicle. The telogen phase (resting phase) generally lasts about 4-5 months. Up to 10% of hairs in a normal scalp are in the telogen phase (resting phase). About 100 telogen hairs are lost from the human scalp each day.

Everyone is born with a fixed number of hair follicles on the scalp that produce hairs throughout life. Hair grows from the base of the follicle at a rate of about one centimetre a month for about three years. This growth phase is called anagen. After anagen, the hair dies (catagen hair) and no longer grows. It sits dormant in the follicle for a three-month phase called telogen. After telogen, the hair follicle undergoes another anagen phase to produce new hair that grows out of the same follicle. As it grows, the old telogen hair is dislodged or pushed out. The hair cycle continues throughout life.

At any given time, about 90% of the scalp follicles are in the Anagen stage. In this stage, stem cells from the bulge in the hair follicle multiply and travel downward, pushing the dermal papilla deeper into the skin and forming the epithelial root sheath. Root sheath cells directly above the papilla form the hair matrix. Here, sheath cells transform into hair cells, which synthesize keratin and then die as they are pushed upward away from the papilla. The new hair grows up the follicle, often alongside an old club hair left from the previous cycle.

Hair length depends on the duration of anagen stage. Short hairs (eyelashes, eyebrows, hair on arms and legs) have a short anagen phase of around one month. Anagen lasts up to 6 years or longer in scalp hair.

In the Catagen stage, mitosis in the hair matrix ceases and sheath cells below the bulge die. The follicle shrinks and the dermal papilla draws up toward the bulge. The base of the hair keratinizes into a hard club and the hair, now known as a club hair, loses its anchorage. Club hairs are easily pulled out by brushing the hair, and the hard club can be felt at the hair’s end. When the papilla reaches the bulge, the hair goes into a resting period called the Telogen stage. Eventually, anagen begins anew and the cycle repeats itself. A club hair may fall out during catagen or telogen, or as it is pushed out by the new hair in the next anagen phase.

You lose about 50 to 100 scalp hairs daily. In a young adult, scalp follicles typically spend 6 to 8 years in anagen, 2 to 3 weeks in catagen, and 1 to 3 months in telogen. Scalp hairs grow at a rate of about 1 mm per 3 days (10–18 cm/yr) in the anagen phase.

Hair grows fastest from adolescence until the 40s. After that, an increasing percentage of follicles are in the catagen and telogen phases rather than the growing anagen phase. Hair follicles also shrink and begin producing wispy vellus hairs instead of thicker terminal hairs. Thinning of the hair or baldness, is called alopecia. It occurs to some degree in both sexes and may be worsened by disease, poor nutrition, fever, emotional stress, radiation, or chemotherapy. In the great majority of cases, however, it is simply a matter of aging.

Pattern baldness is the condition in which hair is lost unevenly across the scalp rather than thinning uniformly. It results from a combination of genetic and hormonal influences. The relevant gene has two alleles: one for uniform hair growth and a baldness allele for patchy hair growth. The baldness allele is dominant in males and is expressed only in the presence of the high level of testosterone characteristic of men. In men who are either heterozygous or homozygous for the baldness allele, testosterone causes terminal hair to be replaced by vellus hair, beginning on top of the head and later the sides. In women, the baldness allele is recessive. Homozygous dominant and heterozygous women show normal hair distribution; only homozygous recessive women are at risk of pattern baldness. Even then, they exhibit the trait only if their testosterone levels are abnormally high for a woman (for example, because of a tumor of the adrenal gland, a woman’s principal source of testosterone). Such characteristics in which an allele is dominant in one sex and recessive in the other are called sex-influenced traits.

Excessive or undesirable hairiness in areas that are not usually hairy, especially in women and children, is called hirsutism. It tends to run in families and usually results from either masculinizing ovarian tumors or hypersecretion of testosterone by the adrenal cortex. It is often associated with menopause.

Contrary to popular misconceptions, hair and nails do not continue to grow after a person dies, cutting hair does not make it grow faster or thicker, and emotional stress cannot make the hair turn white overnight.

Different causes of hair loss affect the hair follicles in different phases of growth.

Figure 4. Hair growth cycle

How does minoxidil work?

Topical minoxidil functions as a stimulant for hair growth. The precise mechanism of action for minoxidil remains inadequately understood. The sulfotransferase enzyme in the human scalp converts minoxidil into minoxidil sulfate, which is the active form of minoxidil ¹⁷. Differences in sulfotransferase activity among individuals can affect minoxidil’s effectiveness, leading to inconsistencies in minoxidil therapy ¹⁸.

Minoxidil shortens the telogen phase to prompt the dormant hair follicles for premature transition into the anagen phase. The shortening of the telogen phase might lead to telogen effluvium following minoxidil therapy. Furthermore, minoxidil extends the anagen phase, resulting in increased hair length and thickness, thereby representing the observable outcomes of minoxidil therapy ¹⁹.

The initial outcomes of minoxidil become apparent after approximately 8 weeks of initiating the treatment, with the maximum effects manifesting around 4 months. Minoxidil affects the potassium channels present in vascular smooth muscles and hair follicles ¹⁹. This potassium channel activity may induce the following effects:

• Stimulation of the microcirculation around the hair follicles induces arteriolar vasodilation, thereby encouraging conditions conducive to hair growth.
• Induction of the vascular endothelial growth factor expression leads to heightened vascularization around the hair follicles, thereby promoting hair growth.
• Activation of the prostaglandin-endoperoxide synthase-1 enzyme leads to the enhancement of hair growth.
• Inhibition of androgen-related effects on androgen-sensitive hair follicles.
• Direct stimulation of the hair follicles as the drug acts as an epidermal growth factor on the matrix cells, slowing their aging process and extending their anagen phase. This process is achieved through the activation of the beta-catenin pathway.
• Display of antifibrotic characteristics due to its impact on collagen synthesis.

Hypertension

Minoxidil exerts its antihypertensive effect by opening adenosine triphosphate (ATP) sensitive potassium channels. As a result, when the smooth muscle vasculature is relaxed, it reduces peripheral resistance, which ultimately helps to lower blood pressure levels. Consequently, this process increases plasma renin activity, which, in turn, triggers salt and water retention in a patient’s body. Additionally, minoxidil triggers the activation of the sympathetic nervous system, resulting in tachycardia and heightened cardiac output. Therefore, clinicians prescribe beta-blockers and diuretics alongside minoxidil to mitigate potential adverse effects ²⁰.

What happens if minoxidil treatment is stopped?

If Minoxidil treatment is stopped, the pretreatment appearance will normally return within 3 or 4 months. If Minoxidil is stopped after several years of use, the hair that was genetically programmed to be lost during that time will fall out.

Minoxidil special precautions

Before using minoxidil:

• tell your doctor and pharmacist if you are allergic to minoxidil or any other drugs.
• tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially guanethidine (Ismelin), other medications for high blood pressure, and vitamins.
• tell your doctor if you have or have ever had heart, kidney, liver, or scalp disease.
• you should not use minoxidil if you have pheochromocytoma (adrenal gland tumor).
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while using minoxidil, call your doctor.
• plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Minoxidil may make your skin sensitive to sunlight.

It is important that your doctor check your progress at regular visits to make sure that minoxidil is working properly and to check for unwanted effects.

Your hair loss may continue for 2 weeks after you start using minoxidil. Tell your doctor if your hair loss continues after 2 weeks. Also, tell your doctor if your hair growth does not increase after using minoxidil for 4 months.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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.

Children

Appropriate studies have not been performed on the relationship of age to the effects of topical minoxidil in children. Safety and efficacy have not been established. The recommended initial dosage of oral minoxidil in patients younger than 12 is 0.2 mg/kg daily. Typically, the maintenance dosage of minoxidil ranges from 0.25 to 1 mg/kg per day, and the maximum recommended dosage is 50 mg per day ²¹. Clinicians may suggest topical minoxidil in children; however, it is considered an off-label drug indication ²².

Elderly patients

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of topical minoxidil in the elderly. However, studies have shown that minoxidil works best in younger patients who have a short history of hair loss. Minoxidil has not been studied in patients older than 65 years of age.

Oral minoxidil should be initiated at a lower dose in older patients as clinicians recommend, considering comorbidities, polypharmacy, and increased risk of falls in this population.

Pregnant women

As animal reproductive studies have indicated specific adverse effects of minoxidil in pregnant women, it is not advisable to use this drug. Minoxidil holds an U.S. Food and Drug Administration (FDA) pregnancy category C classification ².

Breastfeeding women

Studies in women suggest that minoxidil poses minimal risk to the infant when used during breastfeeding. As minoxidil is excreted in breast milk, its use is not recommended in breastfeeding women ¹⁹.

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. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

• Systemic cyclosporine can exacerbate adverse effects such as hypertrichosis when combined with topical minoxidil. Notably, hypertrichosis symptoms significantly improved after discontinuing topical minoxidil for 2 months ²³.
• Coadministration of low-dose aspirin and minoxidil may diminish the effectiveness of topical minoxidil. This decrease in effectiveness is attributed to the inhibitory effect of low-dose aspirin on sulfotransferase enzymes in human hair ²⁴.
• Concurrent use of guanethidine with minoxidil can cause severe hypotension ⁴

Medical Problems

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

• Any other skin problems, an irritation, or a sunburn on the scalp: These conditions may cause too much topical minoxidil to be absorbed into the body and may increase the chance of side effects.
• Heart disease or
• Hypertension (high blood pressure): Topical minoxidil has not been studied in patients who have these conditions, but more serious problems may develop for these patients if they use more medicine than is recommended over a large area and too much minoxidil is absorbed into the body.

Minoxidil uses

Minoxidil was initially developed as a potent peripheral vasodilator agent for treating severe difficult to control high blood pressure (Resistant hypertension). However, owing to the significant side effects of oral minoxidil use, Minoxidil tablet is currently used only for patients with resistant hypertension who do not adequately respond to the maximum doses of 3 different antihypertensive medications ²⁵.

Androgenic alopecia and female pattern hair loss is the only indication approved by the U.S. Food and Drug Administration (FDA) for topical minoxidil ¹⁹.

Off-label uses of topical minoxidil are as follows ²⁵:

• Alopecia areata: Minoxidil has demonstrated the ability to elicit a favorable clinical response when used as a standalone treatment for alopecia areata or in conjunction with other medications, such as corticosteroids.
• Chemotherapy-induced alopecia: In this case, minoxidil has exhibited the capacity to reduce hair loss and expedite the process of hair regrowth.
• Hair transplant: Hair loss, also known as telogen effluvium, is a common observation after a hair transplant. Minoxidil can be used before and after hair transplantation to reduce hair loss in patients. However, the treatment should be temporarily suspended for 3 days before the hair transplant to prevent excessive bleeding.
• Scarring alopecia: Minoxidil has displayed evidence of having an antifibrotic effect on this condition. Consequently, topical minoxidil treatment could be a viable therapeutic option during the initial stages of dermatoses, leading to scarring alopecia, such as those stemming from scalp burns.
• Monilethrix: Minoxidil induces the synchronization of hair follicles entering the anagen phase in patients experiencing this condition.
• Loose anagen hair syndrome: Loose anagen hair syndrome is due to defective keratinization of the inner root sheath, rather than the hair shaft itself. The loose hair shaft can be easily pulled out of the follicle, leaving localized or diffuse bald areas of the scalp. Loose anagen hair syndrome results in short, brittle hair. Although both sexes may be affected, it most often presents in young girls over the age of 2 years. They usually have blond or red colored hair. It may be diagnosed by the painless extraction of at least 10 hairs on a hair pull test of which over 80% of the hairs are in the anagen phase.
• Telogen effluvium: Telogen effluvium is the name for a common cause of temporary hair loss due to the excessive shedding of resting or telogen hair after some shock to your system. New hair continues to grow. Telogen hair is also known as a club hair due to the shape of the root. Regrowth usually occurs after removal of the trigger causing telogen effluvium. However, repeated episodes of acute telogen effluvium can sometimes evolve into female pattern hair loss.
• Hereditary alopecia or hypotrichosis: Minoxidil has demonstrated its beneficial effects by promoting hair shaft thickening in hypotrichosis.

Topical Minoxidil

Minoxidil applied to the scalp is used to stimulate hair growth in adult men and women with androgenic alopecia. If hair growth is going to occur with the use of Minoxidil, it usually occurs after the medicine has been used for 4 to 6 months and lasts only as long as the medicine continues to be used. Hair loss will begin again within a few months after minoxidil treatment is stopped.

It is very important that you use minoxidil only as directed. Do not use more of it and do not use it more often than your doctor ordered. To do so may increase the chance of it being absorbed through your skin. For the same reason, do not apply minoxidil to other parts of your body. Absorption into the body may affect your heart and blood vessels and cause unwanted side effects.

Do not use any other skin products on the same skin area on which you use minoxidil. Hair coloring, hair permanents, and hair relaxers may be used during minoxidil therapy as long as the scalp is washed just before applying the hair coloring, permanent, or relaxer. Minoxidil should not be used 24 hours before and after the hair treatment procedure. Be sure to not double your doses of minoxidil to make up for any missed doses.

To apply minoxidil topical solution:

• Make sure your hair and scalp are completely dry before applying minoxidil.
• Apply the amount prescribed to the area of the scalp being treated, beginning in the center of the area. Follow your doctor’s instructions on how to apply the solution, using the applicator provided.
• Do not shampoo your hair for 4 hours after applying minoxidil.
• Immediately after using minoxidil, wash your hands to remove any medicine that may be on them.
• Do not use a hairdryer to dry the scalp after you apply minoxidil solution. Blowing with a hairdryer on the scalp may make the treatment less effective.
• Allow the minoxidil to completely dry for 2 to 4 hours after applying it, including before going to bed. Minoxidil can stain clothing, hats, or bed linen if your hair or scalp is not fully dry after using the medicine.
• Avoid transferring the medicine while wet to other parts of the body. This can occur if the medicine gets on your pillowcase or bed linens or if your hands are not washed after applying minoxidil.

To apply minoxidil topical foam:

• Open the container by matching the arrow on can ring with the arrow on cap. Pull off the cap.
• Part the hair into one or more rows to expose the hair thinning area on the scalp.
• Hold the can upside down and press the nozzle to put foam on your fingers.
• Use your fingers to spread the foam over the hair loss area and gently massage into your scalp.
• Immediately after using minoxidil, wash your hands to remove any medicine that may be on them .

If your scalp becomes abraded, irritated, or sunburned, check with your doctor before applying minoxidil.

Minoxidil topical foam or solution is for use on the scalp only. Keep minoxidil away from the eyes, nose, and mouth. If you should accidentally get some in your eyes, nose, or mouth, flush the area thoroughly with cool tap water. If you are using the pump spray, be careful not to breathe in the spray .

Do not use the foam near heat or open flame, or while smoking. Do not puncture, break, or burn the aerosol can.

Oral Minoxidil

According to the American College of Cardiology and the American Heart Association, resistant hypertension is characterized by elevated blood pressure levels exceeding the target range, despite the simultaneous utilization of 3 different classes of antihypertensive medications ²⁶, ²⁷, ²⁸. The classes of antihypertensive medications typically include a combination of a calcium channel blocker, a renin-angiotensin-aldosterone system blocker (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. These drugs are administered at the highest daily doses a patient can tolerate. The FDA approves minoxidil for maintaining blood pressure levels in patients with resistant hypertension ²⁰.

Many forms of alopecia (hair loss) are off-label indications for oral or sublingual minoxidil. Recently, multiple studies have explored the use of low-dose oral minoxidil (less than 5mg daily) for treating many forms of alopecia, including male-patterned and female-patterned hair loss, with the goal to treat hair loss without adverse reactions ²⁹. The low adverse-effect profile of low-dose oral minoxidil aids in long-term adherence to treatment and positive clinical response ³⁰, ³¹. More studies are needed to test the effectiveness of oral and sublingual minoxidil when treating various types of alopecia (hair loss) to improve patient outcomes and to provide an alternative for those having difficulty with topical formulations ²⁹.

Minoxidil dosage

The dose of minoxidil 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 minoxidil. If your dose is different, do not change it unless your doctor tells you to do so.

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

Hair loss

Minoxidil topical solution dosage:

• Adults: Apply 1 milliliter (mL) to the scalp two times a day.
  • Women should apply 1 mL of the 2% topical minoxidil solution to their scalp twice daily.
  • Men should apply 1 mL of 2% or 5% topical minoxidil solution to their scalp twice daily.
• Children: Use and dose must be determined by the doctor.

Minoxidil topical foam dosage form:

• Adults: Apply half a capful to the scalp two times a day.
  • Patients can apply a 5% aerosol formulation of topical minoxidil directly onto their scalp at a one-half capful dose. The medication should be used twice daily by male patients and once daily by female patients.
• Children: Use and dose must be determined by your doctor.

Scalp massage is not required following the application of minoxidil. Minoxidil uptake reaches approximately 50% within an hour and increases to 75% after 4 hours. Although certain practitioners use microneedling with topical minoxidil to potentially enhance minoxidil’s efficacy, further studies are necessary to evaluate the potential significance of this practice ³², ³³, ³⁴.

A 2% topical minoxidil solution is effective for male patients experiencing androgenic alopecia in their frontotemporal and vertex regions. However, the 5% topical minoxidil solution provides a more significant clinical benefit than the 2% solution. The clinical response to minoxidil is notably more pronounced when the onset of alopecia occurs within 5 years, primarily among young adults, and when the hair follicles are not extensively miniaturized ³⁵.

Oral minoxidil

Oral minoxidil is supplied in tablet formulations, with options of 2.5 mg and 10 mg doses. Although the U.S. Food and Drug Administration (FDA) does not approve the oral minoxidil for treating hair loss in individuals, clinical trials have demonstrated its effectiveness at dosages ranging from 0.25 to 2.5 mg daily for maintaining blood pressure levels in patients with resistant hypertension ³¹.

The recommended initial dosage of minoxidil for hypertensive therapy is 5 mg, administered once daily to patients younger than 12, which can be gradually escalated up to a maximum of 40 mg per day ²⁵. Higher doses should be equally divided and administered to individuals 2 or 3 times daily to prevent excessive hypotension. The maximum recommended dosage of oral minoxidil is 100 mg per day ⁵. As per the American Heart Association’s guidelines for managing resistant hypertension, minoxidil should be prescribed alongside a loop diuretic and a beta-blocker to reduce potential adverse effects in patients ¹.

The recommended off-label dosing of oral minoxidil for treating alopecia (hair loss) is 0.25 to 2.5 mg, administered once or twice daily in 1 or 2 equally divided doses.

What should I do if I forget a dose?

Skip the missed dose and continue your regular dosing schedule. Do not apply a double dose to make up for a missed one.

Minoxidil side effects

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

• scalp itching, dryness, scaling, flaking, irritation, or burning

Tell your doctor if you notice continued itching, redness, or burning of your scalp after you apply minoxidil. If the itching, redness, or burning is severe, wash the minoxidil off and check with your doctor before using it again.

Rare side effects:

• Minoxidil-induced telogen effluvium: The shortening of the telogen phase caused by minoxidil can result in excessive hair shedding in individuals.
• Skin irritation: This condition can lead to erythema, discomfort, and a burning sensation on the scalp.
• Scaly changes of the scalp: This condition can entail irritation or a potential worsening of seborrheic dermatitis.
• Isolated itch: appears in the area of application.
• Allergic contact dermatitis: This can lead to symptoms such as erythema, eczematous skin reactions, and pruritus. Minoxidil and propylene glycol are the primary allergens implicated in cases of allergic contact dermatitis. Patch testing can aid in identifying the underlying causative agent. If allergic contact dermatitis arises due to propylene glycol, topical minoxidil as a foam formulation can be used as an alternative option, as it does not contain propylene glycol.
• Acne at site of application
• Facial hair growth
• Inflammation or soreness at root of hair
• Reddened skin
• Swelling of face

Signs and symptoms of too much minoxidil topical being absorbed into your body:

• blurred vision or other changes in vision
• chest pain
• dizziness
• fainting
• fast or irregular heartbeat
• flushing
• headache
• lightheadedness
• numbness or tingling of hands, feet, or face
• swelling of face, hands, feet, or lower legs
• weight gain (rapid)

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

• new or worsening chest pain
• chest pain spreading to your jaw or shoulder
• fast or pounding heartbeats
• swelling in your legs, ankles, or feet
• rapid weight gain, especially in your face and midsection
• shortness of breath
• a light-headed feeling, like you might pass out
• fluid build-up in the lungs–pain when you breathe, feeling short of breath while lying down, wheezing, gasping for breath, cough with foamy mucus
• severe skin reaction–fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Oral minoxidil is also associated with significant adverse effects:

• Rare but severe reactions include pericarditis, pericardial effusion, cardiac tamponade, exacerbating congestive heart failure, and worsening angina.
• Oral minoxidil administration can lead to significant hypotension and potential complications such as thrombocytopenia and leukopenia in individuals taking the medication ³⁶.
• Breast tenderness and gynecomastia have also been reported as adverse effects of the medication ³⁷.
• Hypertrichosis, edema, tachycardia, and weight gain are also caused by oral minoxidil.

Patients using topical minoxidil should undergo regular monitoring for any alterations in the scalp and the occurrence of localized or generalized hypertrichosis (excessive hair growth over and above the normal for the age, sex and race of an individual) ³⁸. Both oral and topical minoxidil usage can lead to hypertrichosis. However, hypertrichosis is more frequently observed with the oral minoxidil formulation and when the 5% topical minoxidil solution is used compared to the 2% minoxidil solution. Research indicates that hypertrichosis is linked to minoxidil extending the anagen phase. In addition, cases of hypertrichosis have been documented in infants due to unintentional direct skin contact ³⁹.

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

Minoxidil Overdose

Minoxidil overdose is a rare occurrence following standard topical minoxidil application. In cases of significant oral minoxidil ingestion, there is currently no recognized antidote for minoxidil overdose. Unintentional oral consumption of minoxidil may lead to vomiting and, in rare instances, necessitate hospitalization. Instances of hypotension, tachycardia (fast heart beat) and changes in the electrocardiogram have been reported following accidental ingestion. Intravenous fluids and pharmaceutical vasopressors can address malignant hypotension. In substantial inadvertent minoxidil ingestion, gastric lavage technique and activated charcoal administration might be essential to avert systemic toxicity in patients ⁴⁰.

A case was reported where a young girl unintentionally ingested a topical solution of minoxidil prescribed to her father. After ingesting the medication, the girl encountered adverse effects such as hypotension and prolonged tachycardia ⁴¹. Intravenous fluids are essential in cases of oral minoxidil overdose, causing hypotension in individuals. Vasopressors should be administered to patients for hypotension that does not respond to standard treatment ⁴², ⁴³.

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26. Champaneria MK, Patel RS, Oroszi TL. When blood pressure refuses to budge: exploring the complexity of resistant hypertension. Front Cardiovasc Med. 2023 Jun 21;10:1211199. doi: 10.3389/fcvm.2023.1211199[↩]
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28. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-Himmelfarb CR, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American heart association. Hypertension. (2018) 72(5):e53–e90. 10.1161/HYP.0000000000000084[↩]
29. Ramírez-Marín HA, Tosti A. Role of Oral Minoxidil in Patterned Hair Loss. Indian Dermatol Online J. 2022 Oct 12;13(6):729-733. doi: 10.4103/idoj.idoj_246_22[↩][↩]
30. Gupta AK, Talukder M, Venkataraman M, Bamimore MA. Minoxidil: a comprehensive review. J Dermatolog Treat. 2022 Jun;33(4):1896-1906. doi: 10.1080/09546634.2021.1945527[↩]
31. Randolph M, Tosti A. Oral minoxidil treatment for hair loss: A review of efficacy and safety. J Am Acad Dermatol. 2021 Mar;84(3):737-746. doi: 10.1016/j.jaad.2020.06.1009[↩][↩]
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33. Sung CT, Juhasz ML, Choi FD, Mesinkovska NA. The Efficacy of Topical Minoxidil for Non-Scarring Alopecia: A Systematic Review. J Drugs Dermatol. 2019 Feb 1;18(2):155-160. https://jddonline.com/articles/the-efficacy-of-topical-minoxidil-for-non-scarring-alopecia-a-systematic-review-S1545961619P0155X[↩]
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Baclofen

Baclofen also known as beta‐4‐chlorophenyl‐gamma‐aminobutyric acid, sold by brand names Kemstro, Lioresal, Fleqsuvy, Lyvispah, Ozobax and Gablofen, is a prescription muscle relaxant drug that is used to treat pain and certain types of spasticity (muscle stiffness and tightness) most often used by people with multiple sclerosis, spinal cord injuries, or other spinal cord diseases ¹, ², ³, ⁴, ⁵, ⁶ . Baclofen reduces the number and severity of muscle spasms and relieves pain, clonus and muscle rigidity due to spasticity. Baclofen was approved for use in the United States in 1977 and is widely used with several million prescriptions filled yearly ⁷, ⁸.

Baclofen is a gamma-amino butyric acid type B (GABA_B) agonist that acts as an agonist of the GABA B receptor, thereby activating potassium channels and reducing calcium conductance leading to hypotonia and muscle relaxation ⁷. Baclofen acts on the nerves in the central nervous system (brain and spinal cord) primarily at the level of the spinal cord by stopping synaptic reflexes to reduce the messages that are sent out by the central nervous system (brain and spinal cord) to cause muscle contraction, therefore decreasing the number and severity of muscle spasms caused by multiple sclerosis or spinal cord conditions. Baclofen also relieves pain and improves muscle movement. Baclofen may also be used to relieve other conditions as determined by your doctor. Baclofen does not cure these problems, but it may allow other treatment, such as physical therapy, to be more helpful in improving your condition.

Baclofen is indicated primarily for treatment of spasticity from spinal cord injuries and multiple sclerosis. Baclofen has been used off label as add-on therapy to help people with alcohol use disorder with alcohol abstinence and withdrawal ³, ⁴, ⁵.

Baclofen comes as a tablet and a solution (liquid) to take by mouth. Baclofen is also available in various generic forms as well as under the brand names of Lioresal and Remular in tablets of 10 or 20 mg and in formulations for intrathecal injections of 0.5 mg/mL. The recommended adult dose for spasticity is 10 to 20 mg orally three to four times daily at evenly spaced intervals. The dose should be increased and tapered gradually.

Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take baclofen exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Use an oral syringe (measuring device) to accurately measure and take your dose of baclofen solution. Ask your pharmacist for an oral syringe if one is not included with your medication.

If baclofen tablets or liquid do not work well for you or your child, you may be prescribed a baclofen injection. This will be given by a specialist doctor in hospital. Baclofen can also be given through a pump that is fitted under the skin.

The most common side effects of baclofen are transient sedation, confusion, muscle weakness, vertigo, nausea, drowsiness, dizziness and fatigue ⁹.

Continue to take baclofen even if you feel well. Do not stop taking baclofen without talking to your doctor, especially if you have taken large doses for a long time. Abruptly stopping baclofen can cause seizures, fever, confusion, muscle stiffness, or hallucinations. Your doctor probably will want to decrease your baclofen dose gradually.

Baclofen key points to remember:

• Baclofen reduces pain and discomfort caused by muscle spasms.
• Baclofen is not recommended for use in patients with Parkinson disease and stroke due to a lack of reassuring data. In addition, baclofen is not indicated for skeletal muscle spasms associated with rheumatologic disorders.
• Baclofen tablets and liquid start to work after 1 hour after taking it. However, it might take a few days before you find the right dose to control your symptoms.
• Baclofen common side effects include feeling sleepy and feeling sick (nausea).
• Close supervision of patients being treated with baclofen who have depression or a history of previous suicide attempts is recommended.
• Recent coronial inquiries into 2 deaths have highlighted the need for health professionals to be alert to the well documented risk of overdose with baclofen ¹⁰.
• Do not stop taking baclofen without talking to your doctor. Abrupt discontinuation of oral baclofen therapy might cause seizures and hallucinations. Gradual dose reduction is recommended to prevent withdrawal symptoms ¹¹, ¹².
• If your doctor decides to stop your treatment, your dose will be reduced gradually over 1 to 2 weeks.
• It’s best not to drink alcohol while you are taking baclofen until you know how it affects you. There’s a risk alcohol may increase drowsy side effects and make you very sleepy.

How long does baclofen take to work?

Baclofen tablets and liquid start to work after 1 hour of taking it. However, it might take a few days before you find the right dose to control your symptoms. Baclofen is usually started at a low dose and slowly increased over a few days.

What will happen if I stop taking baclofen?

If your doctor decides to stop your treatment, your Baclofen dose will be reduced gradually over 1 to 2 weeks.

This will stop you getting withdrawal symptoms such as:

• feeling anxious or confused
• seeing things that are not there (hallucinations)
• seizures or fits
• changes in mood or behavior
• a fast heartbeat
• muscle spasms getting worse

Can I drive or ride a bike while taking baclofen?

Baclofen may make you feel tired, sleepy or dizzy and can affect your vision. It might be best to stop driving and cycling for the first few days of treatment until you know howBaclofen makes you feel.

It’s an offence to drive a car if your ability to drive safely is affected. It’s your responsibility to decide if it’s safe to drive.

Can I drink alcohol while taking baclofen?

Alcohol may increase the drowsy (sedative) effects of baclofen tablets and make you very sleepy. It’s best not to drink alcohol while you are taking baclofen until you know how the medicine makes you feel.

Will recreational drugs affect baclofen?

Using cannabis, heroin or methadone with baclofen will increase the drowsy effects of baclofen. It can make you go into a very deep sleep. There’s a risk you will not be able to breathe properly, and you may have difficulty waking up.

Using cocaine or other stimulants like MDMA (ecstasy) and amphetamines with baclofen can also make you drowsy.

Talk to your doctor if you think you might use recreational drugs while taking baclofen.

Is baclofen addictive?

Yes, Baclofen is addictive. Those who engage in baclofen abuse – including taking higher doses than prescribed or mixing it with alcohol or drugs – are at an increased risk of developing an addiction to the drug.

Usually, baclofen addiction begins with increased tolerance, which is when the person has to use more of the drug to experience the same effect. A patient who’s becoming tolerant to the drug may take more than their doctor prescribed to them to experience relief.

Eventually, physical dependence may occur, which is when the person experiences withdrawal symptoms when they aren’t taking the drug. Oftentimes, people who are physically dependent on a drug may keep taking it simply to avoid withdrawals.

After a while, however, their tolerance will continue to grow, and their drug use will become more severe. There are also some people who take baclofen to get high.

Like alcohol and other GABA agonists, baclofen can produce a high when taken in high enough doses, which can encourage further drug-taking behavior. As previously mentioned, there’s a high risk of baclofen overdose when the drug is consistently abused.

If you notice that your tolerance to baclofen has increased, speak to your doctor right away. Do not take higher doses than you’ve been prescribed.

Signs of Baclofen Abuse

People who abuse their prescription drugs may exhibit certain physical and behavioral signs. Some signs of baclofen abuse to look out for include:

• Doctor shopping (switching from one doctor to the next for prescriptions)
• Lying or stealing to get more of the drug
• Mood swings
• Decreased performance at school, work, or home
• Withdrawal from loved ones
• Lack of interest in activities they once liked
• Stupor
• Hallucinations
• Seizures
• Shock
• Difficulty breathing
• Cardiac arrest
• Coma
• Death

If you’re taking baclofen or any prescription muscle relaxers, be sure to take them exactly as prescribed. If you experience any adverse side effects while taking a prescription medication, speak to your doctor about adjusting your dose or other alternatives.

Will baclofen affect my contraception?

Baclofen does not affect any type of contraception, including the combined pill or emergency contraception.

However, if baclofen makes you sick (vomit) or have severe diarrhea for more than 24 hours, your contraceptive pills may not protect you from pregnancy. Check the pill packet to find out what to do.

Baclofen Mechanism of Action

Baclofen also known as beta‐4‐chlorophenyl‐gamma‐aminobutyric acid (GABA-B) is an agonist at the beta subunit of gamma-aminobutyric acid on mono and polysynaptic neurons at the spinal cord level and brain ¹³. The thinking is that baclofen reduces the release of excitatory neurotransmitters in the pre-synaptic neurons and stimulates inhibitory neuronal signals in the post-synaptic neurons with resultant relief of spasticity ¹⁴. Baclofen is also found to have an affinity for voltage-gated calcium channels. However, its clinical efficacy in this regard is still unclear ¹.

Baclofen has a 70% to 85% bioavailability and is rapidly absorbed through the gastrointestinal tract following oral administration. Peak plasma concentrations are generally observed 2 to 3 hours after ingestion. The absorption is dose-dependent and increases with higher doses. Due to the short half-life of 2 to 6 hours, baclofen should be administrated frequently to achieve optimal effect. Seventy percent of baclofen is eliminated in an unchanged form by renal excretion and the remaining via feces. Thereby, baclofen is a useful agent in patients with impaired hepatic function or a high potential for cytochrome P450-mediated drug-drug interactions. Research has observed significant inter-individual variability in baclofen’s absorption and elimination processes.

Baclofen special precautions

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if baclofen is working properly and to decide if you should continue to take it.

Do not suddenly stop using baclofen without checking first with your doctor. You may need to slowly decrease your dose before stopping it completely. Unwanted side effects (eg, hallucinations, seizures, high fever, rhabdomyolysis) may occur if baclofen is stopped suddenly.

Baclofen will add to the effects of alcohol and other central nervous system depressants (medicines that slow down the nervous system, possibly causing drowsiness). Some examples of central nervous system depressants are antihistamines or medicine for hay fever, other allergies, or colds, sedatives, tranquilizers, or sleeping medicine, prescription pain medicine or narcotics, medicine for seizures or barbiturates, other muscle relaxants, or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are using baclofen.

Baclofen may cause dizziness, drowsiness, vision problems, or clumsiness or unsteadiness in some people. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are not alert, well-coordinated, and able to see well.

Baclofen may affect blood sugar levels. If you notice a change in the results of your blood or urine sugar tests or if you have any questions, check with your doctor.

Using Baclofen while you are pregnant may cause neonatal withdrawal syndrome in your newborn babies. Tell your doctor right away if your baby has shakiness or tremors, seizures, or increased muscle tone.

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.

Before taking Baclofen:

• Use with caution when used in patients with urinary retention or respiratory disease.
• History of autonomic dysreflexia: Abrupt baclofen withdrawal or the presence of nociceptive stimuli can cause an autonomic dysreflexic episode.
• Gastrointestinal disorders: Use caution in patients with peptic ulcer disease, decreased GI motility, and/or GI obstructive disorders.
• Use caution in patients with confusional states, psychotic issues, or schizophrenia; it may cause exacerbation of the condition. In addition, patients treated with baclofen injection should be kept under surveillance because exacerbations of these conditions have been observed with oral administration.
• Use caution in patients with kidney impairment, as baclofen is primarily eliminated via the kidneys.
• Seizure disorder: Loss of seizure control is reported in patients treated with baclofen; monitor patients with a history of seizure disorder by checking electroencephalogram periodically.
• Co-administration of epidural morphine and baclofen injection is reported to cause dyspnea and hypotension.
  Because of the risk of sedation, patients should refrain from operating automobiles or other dangerous machinery, and activities made hazardous by decreased alertness. In addition, the central nervous system effects of baclofen may be additive to those of alcohol and other central nervous system (CNS) depressants.
• Tell your doctor and pharmacist if you are allergic to baclofen, any other medications, or any of the ingredients in baclofen tablets and oral solution. Ask your pharmacist for a list of the ingredients.
• Tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antidepressants, medications for anxiety, medications for mental illness, medications for seizures, sedatives, sleeping pills, or tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• Tell your doctor if you have or have ever had epilepsy, a stroke, a rheumatic disease, cerebral palsy, Parkinson’s disease, a psychiatric condition such as schizophrenia or a confusional state, or kidney disease.
• Tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking baclofen, call your doctor immediately.
• You should know that baclofen may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
• Ask your doctor about the safe use of alcoholic beverages while you are taking baclofen. Alcohol can make the side effects from baclofen worse.

In deciding to use a medicine, the risks of taking Baclofen must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Who can take baclofen?

Most adults and children aged 1 month and older can take baclofen tablets and liquid.

Baclofen injection can be given to adults and children aged 4 years and over.

How long to take baclofen for?

You may need to take baclofen for a long time to control muscle spasms.

If you’ve been having baclofen through an injection or pump for a long time, you may find that it stops working as well as it used to. You may need to stop having treatment for a short time to give your body a rest. Your doctor will be able to give you advice on this.

Stopping baclofen

If you stop taking baclofen suddenly, you may get withdrawal side effects such as:

• feeling anxious or confused
• seeing things that are not there (hallucinations)
• seizures or fits
• changes in mood or behavior
• a fast heartbeat
• muscle spasms getting worse

You doctor will reduce your dose gradually before stopping it completely. This will help prevent these side effects.

Who may not be able to take baclofen?

Baclofen is not suitable for some people. To make sure it’s safe for you, tell your doctor before taking Baclofen if you:

• have ever had an allergic reaction to baclofen or any other medicine
• have a stomach ulcer
• have lung, kidney or liver disease
• have a mental health condition
• have epilepsy
• have Parkinson’s disease
• have diabetes
• have ever had a stroke
• are being treated for high blood pressure
• have difficulty peeing
• have a rare blood disorder called porphyria
• are pregnant, trying to get pregnant or breastfeeding

Baclofen contraindications

Baclofen is contraindicated in patients with hypersensitivity to baclofen or any component of its formulation. The baclofen injection solution is not recommended for intravenous, subcutaneous, intramuscular, or epidural administration.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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.

Children

Appropriate studies have not been performed on the relationship of age to the effects of Baclofen oral liquid and granules in children younger than 12 years of age. Safety and efficacy have not been established.

Appropriate studies have not been performed on the relationship of age to the effects of Baclofen tablets in the pediatric population. Safety and efficacy have not been established..

Elderly people

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Baclofen oral liquid and granules in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require caution for patients receiving Baclofen.

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of baclofen tablet in the elderly. Side effects such as hallucinations, confusion or mental depression, other mood or mental changes, and severe drowsiness may be especially likely to occur in elderly patients, who are usually more sensitive than younger adults to the effects of Baclofen.

Balofen and pregnancy warnings

Baclofen should be used during pregnancy only if the benefit outweighs the risk.

• US FDA pregnancy category: Not Assigned. The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.
• Australian TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

Baclofen given orally in animal studies has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses at approximately 13 times on a mg/kg basis, or 3 times on a mg/m² basis, the maximum oral dose recommended for humans; this dose also caused reductions in food intake and weight gain in the dams. There are no controlled data in human pregnancy. It is not known whether this drug can cause fetal harm or adversely affect reproductive capacity in humans.

Baclofen and breastfeeding

There are no adequate studies in women for determining infant risk when using Baclofen during breastfeeding, but information shows that it passes into breast milk in small amounts. Weigh the potential benefits against the potential risks before taking Baclofen while breastfeeding.

Contact your pharmacist or doctor as soon as possible if your baby:

• is not feeding as well as usual or seems to have a dry mouth
• seems unusually sleepy
• is sweaty or develops a rash
• is being sick or has diarrhea
• is causing you any other concerns

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 Baclofen, it is especially important that your healthcare provider know if you are taking any of medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using Baclofen 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.

• Alfentanil
• Alprazolam
• Amifampridine
• Benzhydrocodone
• Bromazepam
• Buprenorphine
• Bupropion
• Butorphanol
• Calcium Oxybate
• Cannabidiol
• Cannabis
• Cetirizine
• Clobazam
• Clonazepam
• Codeine
• Daridorexant
• Dexmedetomidine
• Dihydrocodeine
• Donepezil
• Doxylamine
• Esketamine
• Fentanyl
• Flibanserin
• Gabapentin
• Gabapentin Enacarbil
• Hydrocodone
• Hydromorphone
• Ketamine
• Lacosamide
• Lemborexant
• Levocetirizine
• Levorphanol
• Lofexidine
• Loxapine
• Magnesium Oxybate
• Meperidine
• Methadone
• Metoclopramide
• Midazolam
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Oxycodone
• Oxymorphone
• Pentazocine
• Periciazine
• Phenobarbital
• Potassium Oxybate
• Pregabalin
• Primidone
• Remifentanil
• Remimazolam
• Ropeginterferon Alfa-2b-njft
• Scopolamine
• Sodium Oxybate
• Sufentanil
• Tapentadol
• Topiramate
• Tramadol
• Trazodone
• Zolpidem
• Zuranolone

Other Interactions

Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of Baclofen with alcohol or tobacco.

Mixing baclofen with herbal remedies and supplements

There’s not enough information to say that herbal remedies and supplements are safe to take with baclofen. They’re not tested in the same way as pharmacy and prescription medicines. They’re generally not tested for the effect they have on other medicines.

Other Medical Problems

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

• Autonomic dysreflexia, history of or
• Diabetes or
• Epilepsy or
• Mental illness or problems (eg, psychosis, schizophrenia) or
• Ovarian cysts or
• Posture or balance problems or
• Stroke, recent—Use with caution. May make these conditions worse.
• Kidney disease—The effects may be increased because of slower removal of Baclofen from the body.

Baclofen uses

Baclofen is a muscle relaxant that is used to relieve muscle spasms, cramping or tightness caused by conditions such as ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ¹⁹, ²⁰:

• Cerebral palsy. Baclofen is also considered for short-term treatment for spasticity associated with cerebral palsy in children and adolescents.
• Meningitis
• Motor neurone disease
• Multiple sclerosis (MS)
• Conditions affecting your brain, spinal cord and nervous system causing stiff limbs and/or some bladder dysfunctions.

Long-term (chronic) muscle stiffness can happen in conditions where the nerves that supply your muscles have been damaged. In these conditions, the muscles shorten (contract) tightly, and can then become stiff and harder to use. This is called muscle spasticity. Baclofen works by relaxing your muscles, which reduces pain and discomfort.

FDA-approved indications ²¹:

• Baclofen is FDA-approved for managing reversible spasticity, particularly to relieve flexor spasms, clonus, concomitant pain, common sequelae of spinal cord lesions, and multiple sclerosis.
• Intrathecal baclofen administration is FDA-approved for managing spasticity of cerebral origins, such as traumatic brain injury or severe spasticity of spinal cord origin that is unresponsive to treatment with maximum doses of oral baclofen, tizanidine, and/or dantrolene. However, intrathecal baclofen might be considered for patients who experience intolerable adverse effects or fail to respond to oral therapy.

Baclofen Off-labeled Uses ²², ¹³, ²³:

• Baclofen is currently prescribed off-label to treat alcohol use disorder²⁴, ²⁵, ²⁶:
  • Baclofen is used off-label to manage alcoholic liver disease.
  • Maintain alcohol abstinence by decreasing alcohol cravings and alcohol-related anxiety.
• Trigeminal neuralgia, gastroesophageal reflux disease, and hiccups.

Intrathecal baclofen

Baclofen is a muscle relaxant that works on the nerves in the brain and spinal cord, reducing the messages that are sent out by the nervous system to cause muscle contraction. It is used in children to treat severe muscle spasm (spasticity), due to cerebral palsy or other conditions that affect the brain or spinal cord. It acts on the whole body and does not target specific muscles.

The benefits of baclofen relaxing muscles include:

• Improved ability to move joints
• Less pain due to muscle spasm or cramps

Before you or your child’s doctors decide if intrathecal baclofen is right for you or your child, many specialists will thoroughly assess your child. You or your child may be seen by an orthopaedic surgeon, a neurosurgeon, different specialists, an occupational therapist and a physiotherapist.

There are many factors to consider when deciding who should have intrathecal baclofen treatment. Intrathecal baclofen does not suit every person or every family. You will need to live close to a medical center that can manage the baclofen therapy and you or your child will need to attend many appointments. All the people who help care for you or your child need to learn about baclofen and its side effects.

Once you or your child’s doctors and you have decided that intrathecal baclofen therapy might be right for you or your child, you will be booked in for a trial of the therapy, which will take place in hospital and involve a general anaesthetic. There are two types of trial:

• A bolus trial also called a single-dose test trial involves an injection of baclofen into the space surrounding your child’s spinal cord.
• A five-day catheter trial also called a tube trial involves an operation to have a tube placed in the spine. The tube is joined to an access port through which baclofen is delivered to your child’s spine.

The doctor will choose the most appropriate trial for you or your child. If you or your child responds well to the trial, you will have an appointment with a neurosurgeon to discuss the operation to insert the pump and how the pump works.

While your child is asleep (under a general anaesthetic), a neurosurgeon will implant the pump (about the size of a computer mouse) into you or your child’s abdomen on one side near the hip bone. Joined to the pump is a long catheter, which is inserted into the space surrounding your spinal cord. You or your child will be in the operating theatre for about two hours.
A very small computer, called a programmer, tells the pump how much medicine to release. The baclofen will last from one to six months, depending on you or your child’s dose. When the medicine is running low, you or your child will have an appointment to have you or your child’s pump refilled.

Intrathecal baclofen works differently for every person. Even though they have done a trial, your doctors cannot predict exactly how you or your child will respond to intrathecal baclofen therapy.

Complications of intrathecal baclofen therapy

Complications are rare, but it is important to know the possible side effects and what to do if something goes wrong. Side effects of baclofen may include constipation, nausea and blurred vision. These usually settle over time, but if they continue, they can be managed in various ways, which you can discuss with your child’s doctor.

Possible complications of intrathecal baclofen include:

• overdose of baclofen
• underdose (not enough) of baclofen
• infection of the site around the pump or tube
• infection of the wound from the surgery
• catheter kink (bent tubing), which prevents the flow of baclofen
• catheter break, causing a leak of baclofen
• catheter disconnection from pump, preventing baclofen from reaching spinal cord
• pump stops working properly.

Baclofen overdose primarily arises from drug screening before pump implantation or human error during pump refilling and programming. Baclofen overdose may cause altered mental status, somnolence, seizure, hypothermia, respiratory depression, and coma. In the presence of Baclofen overdose symptoms, the medical staff should empty the pump reservoir, and the patient should receive symptomatic management ²⁷. In patients when the lumbar puncture is not contraindicated, consider withdrawing 30-40 mL of CSF to reduce baclofen CSF concentration.

See your child’s baclofen doctor or take your child to the hospital emergency room if:

• your child has a temperature higher than 100.4 °F (38 ºC)
• there is redness or inflammation around the surgery site
• there is swelling around the pump area
• your child is drowsy or you can’t wake them
• your child has slow breathing
• you think your child is too ‘floppy’
• your child is unusually sweaty, itchy or grumpy
• your child’s muscles are tighter than usual
• you are concerned about the pump
• you hear beeping from the pump.

Monitoring

Administration of baclofen with any other central nervous system depressants requires close monitoring. Patients with epilepsy should be monitored with a regular electroencephalogram due to deterioration in seizure control when receiving baclofen ²⁸.

Monitor for signs and symptoms of baclofen withdrawal if the dose is reduced or discontinued ²⁹.

Intrathecal baclofen use requires careful attention to program the infusion pump and monitor its function, pump alarms, and refill schedules ³⁰.

Closely monitor when the initial phase of pump use and when adjusting the dosing rate and/or the concentration in the reservoir as small errors can result in subtherapeutic level or toxic levels.

Monitor for signs or symptoms of overdose which may occur suddenly, especially in the initial screening phase, dose-titration phase, and reintroduction of therapy after temporary cessation of treatment.

Baclofen dosage

Take Baclofen exactly as directed by your doctor. Do not take more of it, do not take it more often, or do not take it longer than your doctor ordered.

Baclofen comes with a patient information and instructions leaflet. Read and follow the instructions carefully. Ask your doctor if you have any questions.

To use Baclofen granules:

• Open the packet and empty all the granules directly into your mouth. The granules will dissolve in your mouth or can be swallowed. You may drink water after taking the medicine.
• You may mix the granules with 1 tablespoon (15 mL) of liquid (eg, apple juice or milk) or soft foods (eg, applesauce, pudding, or yogurt). Take this mixture within 2 hours of mixing.
• Baclofen can also be given using a nasogastric or gastric feeding tube. Mix the granules with 1 tablespoon (15 mL) of liquid (eg, apple juice or milk). Give this mixture within 2 hours of mixing. After Baclofen is given, flush the tube with an additional 1 tablespoon (15 mL) of water.
• Take all the contents of the packet to get a full dose. Do not take only part of this medicine. Do not save a portion for later use.

Measure the oral liquid with a marked measuring spoon, oral syringe, or medicine cup.

The dose of Baclofen 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 Baclofen. If your dose is different, do not change it unless your doctor tells you to do so.

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

Muscle relaxation

• For oral dosage form (granules):
  • Adults and children 12 years of age and older: At first, 5 milligrams (mg) 3 times a day for 3 days. Your doctor may increase your dose by 5 mg every 3 days as needed and tolerated. However, the dose is usually not more than 80 milligrams (mg) per day (20 mg four times a day).
  • Children younger than 12 years of age: Use and dose must be determined by your doctor.
• For oral dosage form (solution):
  • Adults and children 12 years of age and older: At first, 5 milliliters (mL) 3 times a day for 3 days. Your doctor may increase your dose by 5 mL every 3 days as needed and tolerated. However, the dose is usually not more than 80 milligrams (mg) per day (20 mg four times a day).
  • Children younger than 12 years of age: Use and dose must be determined by your doctor.
• For oral dosage form (tablets):
  • Adults and teenagers: At first, 5 milligrams (mg) 3 times a day. Your doctor may increase your dose by 5 mg every 3 days until the desired response is reached. However, the dose is not more than 80 mg per day.
  • Children: Use and dose must be determined by your doctor.

What should I do if I forget a dose?

If you miss a dose of Baclofen, take it as soon as possible. However, if it is almost time for your 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.

Baclofen side effects

Baclofen may cause 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 side effects:

• confusion
• constipation
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• headache
• increased need to urinate
• nausea
• passing urine more often
• sweating
• trouble sleeping
• unusual tiredness or weakness

Less common or rare side effects:

• diarrhea
• loss of appetite
• muscle or joint pain
• numbness or tingling in the hands or feet
• stomach pain or discomfort
• stuffy nose
• weight gain

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

Tell your doctor if any of these symptoms are severe or do not go away:

• dizziness
• weakness
• confusion
• headache
• nausea
• constipation
• difficulty falling asleep or staying asleep
• tiredness
• frequent urination

Some side effects can be serious. If you experience either of the following symptoms, see your doctor immediately:

• seeing things or hearing voices that do not exist (hallucinations)
• seizures

Baclofen overdose

The risks of Baclofen overdose are particularly pronounced when using high doses for off-label treatment of alcohol-use disorder. In case of Baclofen 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 for help.

Symptoms of Baclofen overdose may include:

• blurred vision or vision problems
• dizziness
• vomiting
• drowsiness
• irregular, fast or slow, or shallow breathing
• difficulty breathing
• lightheadedness
• loss of strength or energy
• muscle pain or weakness
• weak muscle tone
• pale or blue lips, fingernails, or skin
• seizures
• sleepiness or unusual drowsiness
• trouble breathing
• unusual weak feeling
• coma.

Overdosed on baclofen tablets has reported vomiting, drowsiness, muscular hypotonia, accommodation disorders, coma, respiratory depression, and seizures. When the patient is alert, consider vacating the stomach immediately by inducing emesis and then performing lavage. In the unconscious patients, do not induce vomiting. Before beginning lavage, secure the airway with an endotracheal tube. Avoid the use of respiratory stimulants and adequately maintain respiratory exchange.

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18. Xiao W, Naso L, Bennett GJ. Experimental studies of potential analgesics for the treatment of chemotherapy-evoked painful peripheral neuropathies. Pain Med. 2008 Jul-Aug;9(5):505-17. doi: 10.1111/j.1526-4637.2007.00301.x[↩]
19. Bauer MR, Hernández M, Kasten CR, Boehm SL 2nd. Systemic administration of racemic baclofen reduces both acquisition and maintenance of alcohol consumption in male and female mice. Alcohol. 2022 Sep;103:25-35. doi: 10.1016/j.alcohol.2022.06.003[↩][↩]
20. Johnstone A, Grigoras I, Petitet P, Capitão LP, Stagg CJ. A single, clinically relevant dose of the GABAB agonist baclofen impairs visuomotor learning. J Physiol. 2021 Jan;599(1):307-322. doi: 10.1113/JP280378[↩]
21. Ertzgaard P, Campo C, Calabrese A. Efficacy and safety of oral baclofen in the management of spasticity: A rationale for intrathecal baclofen. J Rehabil Med. 2017 Mar 6;49(3):193-203. doi: 10.2340/16501977-2211[↩]
22. Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, D’Angelo C, Caputo F, Zambon A, Haber PS, Gasbarrini G. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet. 2007 Dec 8;370(9603):1915-22. doi: 10.1016/S0140-6736(07)61814-5[↩]
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24. Agabio R, Sinclair JM, Addolorato G, Aubin HJ, Beraha EM, Caputo F, et al. Baclofen for the treatment of alcohol use disorder: the Cagliari Statement. Lancet Psychiatry. 2018;5(12):957–960. doi: 10.1016/S2215-0366(18)30303-1[↩]
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Procainamide

Procainamide is an oral antiarrhythmic agent (antiarrhythmic Class 1A) that has been in wide use for more than 60 years ¹, ². Procainamide is used to treat abnormal heart rhythms such as ventricular arrhythmias, supraventricular arrhythmias, atrial flutter, atrial fibrillation, and Wolf-Parkinson-White syndrome. Procainamide works by making your heart more resistant to abnormal activity by blocking open sodium channels and outward potassium channels. As a consequence, it decreases cardiac automaticity, increases refractory periods and slows conduction. Procainamide was approved for use in the United States in 1950, and current indications include suppression of symptomatic premature ventricular contractions and life threatening ventricular tachycardia, as well as maintenance of normal sinus rhythm after conversion of atrial fibrillation or flutter. Because of its safety profile, procainamide is now rarely used. Procainamide is available only with your doctor’s prescription.

The oral dosage forms of procainamide are no longer available in the United States but is available in Canada. Procainamide is available in capsules and tablets of 250, 375 and 500 mg generically as well as under the brand name Pronestyl; it is also available as extended release forms of 250, 500, 750 and 1,000 mg under the brand name Procanbid. Immediate-acting procainamide usually is taken every 3 or 4 hours. The long-acting product is usually taken every 6 or 12 hours. Do not cut, crush, or chew extended-release (long-acting) tablets; swallow them whole. You may see a waxy core in your stool if you are taking the extended-release product; this is normal. Procainamide is currently available in the United States as a solution for intravenous infusion. The usual maintenance dose in adults is 500 to 1000 mg every 4 to 6 hours.

Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take procainamide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Procainamide helps control your condition but will not cure it. Continue to take procainamide even if you feel well. Do not stop taking procainamide without talking to your doctor.

Procainamide is broken down by your liver via acetylation to form N-acetyl procainamide (NAPA) via a substrate of CYP2D6. This compound is then excreted as N-acetyl procainamide (NAPA). The half-life of procainamide is 2.5 to 5 hours, and the maximum dose in current recommendations is 17 mg/kg. As such, clinicians may consider decreasing the dosing or frequency of procainamide in cases of hepatic impairment ³.

Procainamide most common side effects include headache, nervousness, anxiety, nausea, decreased appetite, palpitations and disturbed sleep. Rare but potentially severe adverse effects include cardiac toxicity, bradycardia, hypotension, aplastic anemia, agranulocytosis, drug hypersensitivity reactions, induction of autoantibodies including antinuclear antibody and drug-induced lupus erythematosus-like syndrome ². QRS, QTc, and PR prolongation are the most potentially harmful cardiac side effects of procainamide and may become worse when levels of procainamide rise. Serial electrocardiograms are useful for monitoring these toxic effects during treatment with procainamide. Procainamide infusion may also increase the number of premature ventricular contractions in patients.

Another side effect of procainamide is hypotension, more commonly seen at doses of 20 mg/min. Drug-induced lupus erythematosus-like syndrome is rare and occurs due to the creation of positive ANA titers when taking the medication chronically. The symptoms of chronic use may include arthritis, arthralgias, and pleuritis and commonly resolve when usage stops.

Lastly, procainamide is known to cause certain blood dyscrasias. Procainamide has been known to cause bone marrow toxicity, leading to pancytopenia or agranulocytosis; this is usually due to hypersensitivity or varied immunologic mechanisms ⁴, ⁵.

Procainamide mechanism of action

Procainamide is an analogue of the local anesthetic procaine and has electrophysiological effects that resemble quinidine. Procainamide is a class 1A anti-arrhythmic that appears to act by blocking fast sodium channels and outward potassium channels inhibiting recovery after repolarization. Procainamide also prolongs the action potential and reduces the speed of impulse conduction. This action results in decreased myocardial excitability, slowed conduction velocity, and reduced myocardial contractility. It is possible that it acts as a negative inotrope and may cause peripheral vasodilation and hypotension, which may require cardioversion.

Procainamide special precautions

Before taking procainamide:

• tell your doctor and pharmacist if you are allergic to procainamide, anesthetics, aspirin, or any other drugs.
• tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially digoxin (Lanoxin) or drugs for high blood pressure, and vitamins.
• in addition to the condition listed in the IMPORTANT WARNING section, tell your doctor if you have or have ever had lupus, heart disease, high blood pressure, kidney or liver disease, or myasthenia gravis.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking procainamide, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking procainamide.
• you should know that this drug may make you dizzy. Do not drive a car or operate machinery until you know how this drug affects you.
• remember that alcohol can add to the dizziness caused by this drug.
• talk to your doctor about the use of cigarettes and caffeine-containing beverages. These products may increase the irritability of your heart and interfere with the action of procainamide.

It is important that your doctor check your progress carefully while you are receiving procainamide to make sure it is working properly. This will allow necessary changes in the amount of medicine you receive and may also help reduce side effects.

Dizziness or lightheadedness may occur with procainamide, especially in elderly patients and when large doses are used. Patients should use extra care to avoid falling. Make sure you know how you react to procainamide before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Procainamide in Pregnancy

Pregnancy Category C: 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.

Procainamide in 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.

Procainamide 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 procainamide, 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 procainamide 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
• Bepridil
• Cisapride
• Dronedarone
• Fingolimod
• Grepafloxacin
• Levomethadyl
• Mesoridazine
• Pimozide
• Piperaquine
• Saquinavir
• Sparfloxacin
• Terfenadine
• Thioridazine
• Vernakalant
• Ziprasidone

Using procainamide 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.

• Acecainide
• Ajmaline
• Alcuronium
• Alfuzosin
• Amiodarone
• Amitriptyline
• Amoxapine
• Anagrelide
• Apomorphine
• Aprindine
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Artemether
• Asenapine
• Astemizole
• Atracurium
• Azithromycin
• Buprenorphine
• Bupropion
• Buserelin
• Ceritinib
• Chloral Hydrate
• Chloroquine
• Chlorpromazine
• Ciprofloxacin
• Cisatracurium
• Citalopram
• Clarithromycin
• Clofazimine
• Clomipramine
• Clozapine
• Crizotinib
• Dabrafenib
• Dasatinib
• Degarelix
• Delamanid
• Desipramine
• Deslorelin
• Deutetrabenazine
• Disopyramide
• Dofetilide
• Dolasetron
• Domperidone
• Donepezil
• Doxacurium
• Doxepin
• Droperidol
• Efavirenz
• Eliglustat
• Encorafenib
• Enflurane
• Erythromycin
• Escitalopram
• Flecainide
• Fluconazole
• Fluoxetine
• Foscarnet
• Gallamine
• Gatifloxacin
• Gemifloxacin
• Glasdegib
• Gonadorelin
• Goserelin
• Granisetron
• Halofantrine
• Haloperidol
• Halothane
• Hexafluorenium
• Histrelin
• Hydroquinidine
• Hydroxychloroquine
• Hydroxyzine
• Ibutilide
• Iloperidone
• Imipramine
• Inotuzumab Ozogamicin
• Isoflurane
• Isradipine
• Ivabradine
• Ivosidenib
• Ketoconazole
• Lacosamide
• Lapatinib
• Leuprolide
• Levofloxacin
• Lidocaine
• Lidoflazine
• Lofexidine
• Lopinavir
• Lorcainide
• Lumefantrine
• Macimorelin
• Mefloquine
• Methadone
• Metocurine
• Metronidazole
• Mifepristone
• Mivacurium
• Moricizine
• Moxifloxacin
• Nafarelin
• Nalidixic Acid
• Nilotinib
• Norfloxacin
• Nortriptyline
• Octreotide
• Ofloxacin
• Ondansetron
• Osimertinib
• Paliperidone
• Pancuronium
• Pasireotide
• Pazopanib
• Pentamidine
• Pimavanserin
• Pipecuronium
• Pirmenol
• Pitolisant
• Posaconazole
• Prilocaine
• Probucol
• Promethazine
• Propafenone
• Protriptyline
• Quetiapine
• Quinidine
• Quinine
• Ribociclib
• Risperidone
• Rocuronium
• Salmeterol
• Sertindole
• Sertraline
• Sevoflurane
• Siponimod
• Sodium Phosphate
• Sodium Phosphate, Dibasic
• Sodium Phosphate, Monobasic
• Solifenacin
• Sorafenib
• Sotalol
• Spiramycin
• Succinylcholine
• Sulfamethoxazole
• Sulpiride
• Sultopride
• Sunitinib
• Tacrolimus
• Telavancin
• Telithromycin
• Tetrabenazine
• Tizanidine
• Toremifene
• Trazodone
• Triclabendazole
• Trifluoperazine
• Trimethoprim
• Trimipramine
• Triptorelin
• Tubocurarine
• Vandetanib
• Vardenafil
• Vasopressin
• Vecuronium
• Vemurafenib
• Vinflunine
• Voriconazole
• Zolmitriptan
• Zotepine
• Zuclopenthixol

Using procainamide 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.

• Cimetidine

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 procainamide. Make sure you tell your doctor if you have any other medical problems, especially:

• Heart block or
• Heart rhythm problem (e.g., QT prolongation) or
• Lupus erythematosus, history of—Should not use in patients with these conditions.
• Heart failure, congestive or
• Myasthenia gravis—May make these conditions worse.
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal from the body.

Procainamide contraindications

Hypersensitivity to procainamide, procaine, other ester-type local anesthetics, or any component of the formulation; complete heart block; second-degree AV block or various types of hemiblock (without a functional artificial pacemaker); systemic lupus erythematosus (SLE); Torsade de Pointes.

Use with caution in patients with heart failure, electrolyte imbalances (particularly hypokalemia and hypomagnesemia), myasthenia gravis patients, and in hepatic or renal impairment. Procainamide also crosses the placenta and may be present in the milk of breastfeeding mothers, and as such, chronic use requires caution in this population ⁶.

Canadian labeling: Additional contraindications (not in US labeling):

• Myasthenia gravis;
• Severe heart failure (IV);
• Renal failure (IV);
• Shock (IV).

Procainamide uses

Procainamide is used to treat abnormal heart rhythms. It works by making your heart more resistant to abnormal activity.

Ventricular arrhythmias: Intravenous: Treatment of life-threatening ventricular arrhythmias

Supraventricular arrhythmias: Oral [Canadian product]: Treatment of supraventricular arrhythmias.

Note: In the treatment of atrial fibrillation (AF), use only when preferred treatment is ineffective or cannot be used. Use in paroxysmal atrial tachycardia when reflex stimulation or other measures are ineffective.

Procainamide is indicated in patients with Wolf-Parkinson-White syndrome as it is important for acute termination of antidromic AV re-entrant tachycardia in stable patients ¹. In particular, because the use of an AV nodal blocking agent in this patient population may enhance conduction down the accessory pathway and therefore induce ventricular tachycardia or ventricular fibrillation ⁷.

Procainamide has also historically been used in diagnostic testing for Brugada syndrome; this was known as the “procainamide challenge,” which produces the standard Brugada-like pattern on ECG, which may have been otherwise unnoticed and thus identifying patients at risk for sudden cardiac death ¹. However, this usage has fallen out of favor, as it has low sensitivity for detecting Brugada-like patterns and may also put the patient at risk of going into ventricular arrhythmia ⁸.

Procainamide has been used for chemical cardioversion in atrial flutter and atrial fibrillation. These are common arrhythmias seen in emergency department patients, but there is no consensus for optimal management. Stiell et al. looked at the usage of IV procainamide in 341 patients over five years. Adverse events were infrequent and included hypotension, bradycardia, atrioventricular block, and ventricular tachycardia. There were no cases of torsades de pointes, cerebrovascular accidents, or death. Most patients (94.4%) received a discharge to home. IV procainamide had a 52% conversion rate of atrial fibrillation to normal sinus and a 28% conversion rate from atrial flutter to normal sinus ⁹.

Researchers have also studied the utility of procainamide compared to lidocaine in terminating sustained ventricular tachycardia in patients with structural heart defects. In this retrospective study from Circulation Journal, procainamide was found to be more effective than lidocaine in the termination of the arrhythmia ¹⁰.

One recent major study looked at the difference between amiodarone and procainamide in stable ventricular tachycardia. The PROCAMIO study ¹¹ has concluded that in patients with stable ventricular tachycardia, procainamide should be considered over the traditionally used amiodarone due to faster resolution of the arrhythmia, fewer major cardiac events, and is more efficacious in a subgroup of patients with structural heart disease.

Off Label Uses

Atrial fibrillation (preexcited)

Based on the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science and the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society Guideline (AHA/ACC/HRS) for the Management of Patients With Atrial Fibrillation (AF), procainamide may be considered for the treatment of hemodynamically stable preexcited AF with rapid ventricular response in adults with preserved left ventricular function.

Junctional tachycardia

Based on the American Heart Association, American College of Clinical Cardiology and Heart Rhythm Society Guideline for the Management of Patients with Supraventricular Tachycardia, procainamide may be considered for the treatment of hemodynamically, acute junctional tachycardia when beta-blocker therapy is ineffective. Dosing not specified.

Stable monomorphic ventricular tachycardia

Based on the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science, procainamide is an effective and recommended treatment alternative for hemodynamically stable monomorphic ventricular tachycardia in adults with preserved left ventricular function. Use should be avoided in those with a prolonged QT interval.

Procainamide dose

Procainamide is given IV or Oral with the onset of action in 10 to 30 minutes ¹. The loading dose of IV procainamide is 10 to 17 mg/kg and administered at a rate of 20 to 50 mg/min ¹. Alternatively, IV procainamide may be dosed at 100 mg every 5 minutes in adult patients. The administration of this maintenance dose is from 1 to 4 mg/minute; however, the manufacturer labeling recommends 2 to 6 mg/minute.

Administration of oral procainamide dosing for supraventricular arrhythmia is at 50 mg/kg/24 hours divided into doses every 6 hours.

In children, IV procainamide dosing divides into those less than 12 months in which a bolus dose of 7 to 10 mg/kg given over 15 to 30 minutes and those older than 12 months in which a bolus dose of 10 to 15 mg/kg is the regimen. An infusion rate of 20 to 50 mcg/kg/min follows the initial bolus ¹².

Adult dose for Arrhythmias

IV:

• Loading dose: 15 to 18 mg/kg administered as slow infusion over 25 to 30 minutes or 100 mg/dose at a rate not to exceed 50 mg/minute repeated every 5 minutes as needed to a total dose of 1 gram.
• Maintenance dose: 1 to 4 mg/minute by continuous infusion. Maintenance infusions should be reduced by one-third in patients with moderate renal or cardiac impairment and by two-thirds in patients with severe renal or cardiac impairment.

ACLS guidelines: Loading dose: Infuse 20 mg/minute (up to 50 mg/minute for more urgent situations) until arrhythmia is controlled, hypotension occurs, QRS complex widens by 50% of its original width, or total of 17 mg/kg is given. Note: Not recommended for use in ongoing ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) due to prolonged administration time and uncertain efficacy. Follow with maintenance dose as continuous infusion.

IM:

• 50 mg/kg divided into fractional amounts of 1/8 to 1/4 and injected every 3 to 6 hours or 0.5 to 1 gram every 4 to 8 hours.

Oral: ORAL procainamide is not available in the US but is available in Canada.

40 to 50 kg:

• Immediate-release: 250 mg orally every 3 hours.
• Sustained-release: 500 mg every 6 hours.
• Twice daily formulation: 1000 mg every 12 hours.

60 to 70 kg:

• Immediate-release: 375 mg every 3 hours.
• Sustained-release: 750 mg every 6 hours.
• Twice daily formulation: 1500 mg every 12 hours.

80 to 90 kg:

• Immediate-release: 500 mg every 3 hours.
• Sustained-release: 1000 mg every 6 hours.
• Twice daily formulation: 2000 mg every 12 hours.

100 kg or more

• Immediate-release: 625 mg every 3 hours.
• Sustained-release: 1250 mg every 6 hours.
• Twice daily formulation: 2500 mg every 12 hours.

Pediatric dose for Arrhythmias

Less than 1 month:

• Loading dose: 7 to 10 mg/kg IV infused over 60 minutes followed by a continuous IV infusion of 20 to 80 mcg/kg/minute; a retrospective study of 20 neonates (GA: 25 weeks or older) reported a mean loading dose of 9.6 ± 1.5 mg/kg and a mean continuous infusion rate of 37.56 ± 13.52 mcg/kg/minute.
• Note: Procainamide serum concentrations were supratherapeutic in five neonates studied; four of the five were less than 36 weeks GA and all five had Clcr less than 30 mL/minute/1.73 m2; these results indicate that doses may need to be decreased in preterm neonates and in those with renal impairment.

1 year or older:

• Oral: (ORAL procainamide is not available in the US but is available in Canada.)
• 15 to 50 mg/kg/day divided every 3 to 6 hours. Maximum 4 g/day.

IV:

• Loading dose: 3 to 6 mg/kg over 5 minutes (not to exceed 100 mg per dose), may repeat every 5 to 10 minutes to maximum total loading dose of 15 mg/kg; do not exceed 500 mg in 30 minutes.
• Maintenance dose: continuous IV infusion: 20 to 80 mcg/kg/minute; maximum dose: 2 g/day.

IM:

• 20 to 30 mg/kg/day divided every 4 to 6 hours. Maximum 4 g/day.

Stable wide complex tachycardia of unknown origin (atrial or ventricular) or SVT (PALS, 2010): Note: Avoid or use extreme caution when administering procainamide with other drugs that prolong QT interval (e.g., amiodarone); consider consulting with expert.

Loading dose: 15 mg/kg infused intravenously over 30 to 60 minutes; monitor ECG and blood pressure; stop the infusion if hypotension occurs or QRS complex widens by more than 50% of baseline

Renal Dose Adjustments

Oral:

• CrCl less than 10 mL/min: A dosing interval of every 8 to 24 hours is recommended.
• CrCl 10 to 50 mL/min: A dosing interval of every 6 to 12 hours is recommended.

IV:

• Reduce loading dose to 12 mg/kg in severe renal impairment.
• Maintenance infusions should be reduced by one-third in patients with moderate renal impairment and by two-thirds in patients with severe renal impairment.

Liver Dose Adjustments

A 50% reduction in the dose is recommended.

What should I do if I forget a dose?

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.

Procainamide side effects

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

• dizziness or lightheadedness
• loss of appetite
• upset stomach
• vomiting
• bitter taste

If you experience the following symptom or any of those listed in the IMPORTANT WARNING section, call your doctor immediately:

• irregular heartbeat

Less common

• fever and chills
• joint pain or swelling
• pains with breathing
• skin rash or itching

Rare

• Bleeding, blistering, burning, coldness, discoloration of skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, or warmth at the injection site
• Confusion
• Fever or sore mouth, gums, or throat
• Hallucinations (seeing, hearing, or feeling things that are not there)
• Mental depression
• Unusual bleeding or bruising
• Unusual tiredness or weakness

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of procainamide overdose

• decrease in urination
• dizziness (severe) or fainting
• drowsiness
• fast or irregular heartbeat
• nausea and vomiting

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

• diarrhea
• hardening or thickening of the skin where the needle is placed
• loss of appetite

Less common

• dizziness or lightheadedness

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

Procainamide injection 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 caregivers at once if you have a serious side effect such as:

• a new or a worsening irregular heartbeat pattern;
• chest pain, wheezing, trouble breathing;
• feeling like you might pass out;
• signs of infection such as fever, chills, sore throat, flu symptoms, pale skin, easy bruising or bleeding (nosebleeds, bleeding gums), loss of appetite, nausea and vomiting, sores in your mouth and throat, unusual weakness;
• depressed mood, hallucinations, severe dizziness;
• upper stomach pain, itching, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
• joint pain or swelling with fever, swollen glands, muscle pain or weakness, unusual thoughts or behavior, patchy skin color, red spots.

Less serious side effects may include:

• mild dizziness or tired feeling;
• flushing (warmth, redness, or tingly feeling); or
• mild itching or rash.

1. Pritchard B, Thompson H. Procainamide. [Updated 2023 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557788[↩][↩][↩][↩][↩]
2. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Procainamide. [Updated 2020 Jul 10]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548477[↩][↩]
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4. Lawson DH, Jick H. Adverse reactions to procainamide. Br J Clin Pharmacol. 1977 Oct;4(5):507-11. doi: 10.1111/j.1365-2125.1977.tb00777.x[↩]
5. Danielly J, DeJong R, Radke-Mitchell LC, Uprichard AC. Procainamide-associated blood dyscrasias. Am J Cardiol. 1994 Dec 1;74(11):1179-80. doi: 10.1016/0002-9149(94)90478-2[↩]
6. Pittard WB 3rd, Glazier H. Procainamide excretion in human milk. J Pediatr. 1983 Apr;102(4):631-3. doi: 10.1016/s0022-3476(83)80210-8[↩]
7. Correction to: 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2016 Sep 13;134(11):e232-3. doi: 10.1161/CIR.0000000000000447. Erratum for: Circulation. 2016 Apr 5;133(14):e471-505.[↩]
8. Obeyesekere MN, Klein GJ. Preventing Sudden Death in Asymptomatic Wolf-Parkinson-White Patients. JACC Clin Electrophysiol. 2018 Apr;4(4):445-447. doi: 10.1016/j.jacep.2017.11.014[↩]
9. Stiell IG, Sivilotti MLA, Taljaard M, Birnie D, Vadeboncoeur A, Hohl CM, McRae AD, Rowe BH, Brison RJ, Thiruganasambandamoorthy V, Macle L, Borgundvaag B, Morris J, Mercier E, Clement CM, Brinkhurst J, Sheehan C, Brown E, Nemnom MJ, Wells GA, Perry JJ. Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation (RAFF2): a partial factorial randomised trial. Lancet. 2020 Feb 1;395(10221):339-349. doi: 10.1016/S0140-6736(19)32994-0[↩]
10. Komura S, Chinushi M, Furushima H, Hosaka Y, Izumi D, Iijima K, Watanabe H, Yagihara N, Aizawa Y. Efficacy of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Circ J. 2010 May;74(5):864-9. doi: 10.1253/circj.cj-09-0932[↩]
11. Ortiz M, Martín A, Arribas F, Coll-Vinent B, Del Arco C, Peinado R, Almendral J; PROCAMIO Study Investigators. Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study. Eur Heart J. 2017 May 1;38(17):1329-1335. doi: 10.1093/eurheartj/ehw230[↩]
12. Guerrier K, Shamszad P, Czosek RJ, Spar DS, Knilans TK, Anderson JB. Variation in Antiarrhythmic Management of Infants Hospitalized with Supraventricular Tachycardia: A Multi-Institutional Analysis. Pediatr Cardiol. 2016 Jun;37(5):946-52. doi: 10.1007/s00246-016-1375-x[↩]

Flecainide

Flecainide is an oral antiarrhythmic agent (antiarrhythmic Class 1C) that is used in certain situations to prevent or treat certain types of life-threatening irregular heartbeats (arrhythmias) that include paroxysmal supraventricular tachycardias (PSVTs), atrioventricular nodal re-entrant tachycardia (AVNRT), AV re-entrant tachycardia (AVRT), and paroxysmal atrial fibrillation or atrial flutter in patients who do not have structural heart disease and arrhythmic long QT syndromes (LQTS), as well as the Ca²⁺-mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT) ¹, ². However, flecainide can also exert pro‐arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome ¹. Flecainide works by slowing electrical signals in the heart to stabilize the heart rhythm. Flecainide appears to act by blocking open sodium channels and outward potassium channels ³, ⁴, ⁵, ⁶, ⁷. As a consequence, it decreases cardiac automaticity, increases refractory periods and slows conduction. Flecainide was approved for use in the United States in 1985. Flecainide current indications include prevention and treating life-threatening ventricular arrhythmias and conversion of paroxysmal supraventricular tachycardia (PSVTs), Wolf-Parkinson-White syndrome, atrioventricular nodal re-entrant tachycardia (AVNRT), AV re-entrant tachycardia (AVRT), and atrial fibrillation/atrial flutter in patients who do not have structural heart disease, in whom other agents were unsuccessful.

Flecainide is available only with your doctor’s prescription.

Flecainide is a benzamide derivative analogue of the local anesthetic procaine and has electrophysiological effects that resemble quinidine. Flecainide appears to act by blocking open sodium channels and outward potassium channels ⁸. As a consequence, it decreases cardiac automaticity, increases refractory periods and slows conduction.

Oral bioavailability of Flecainide is nearly 100% but decreases when administered with milk ². Flecainide is 40% protein-bound, and half-life elimination varies across age groups. In newborns: less than 28 hours, 3 months: 11 to 12 hours, 12 months: 6 hours. In children: 8 hours, adolescents 12 to 15 years: approximately 11 hours, adults: 12 to 24 hours. It takes 1 to 6 hours to peak in serum after administration. Flecainide is metabolized by your liver via the CYP450 system; specifically, it is a CYP2D6 substrate. Flecainide is excreted in the urine (30%) and, to a lesser extent, the feces (5%) ⁹, ¹⁰, ¹¹. Its half-life is approximately 20 hours ¹².

Flecainide is available in tablets of 50, 100 and 150 mg generically to be taken by mouth and under the brand name Tambocor. The usual maintenance dose in adults is 50 to 200 mg twice daily (once every 12 hours). Some people may take flecainide once every 8 hours if they experience side effects or if their condition cannot be controlled by taking flecainide every 12 hours. Take flecainide at around the same times 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 flecainide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

You may be hospitalized when you begin your treatment with flecainide. Your doctor will monitor you carefully during this time and for as long as you continue to take flecainide. Your doctor will probably start you on a low dose of flecainide and gradually increase your dose, not more than once every 4 days. Your doctor may also decrease your dose once your condition is controlled.

Flecainide may control your condition, but will not cure it. Continue to take flecainide even if you feel well. Do not stop taking flecainide without talking to your doctor. If you suddenly stop taking flecainide, your condition may become worse.

Flecainide most common side effects include dizziness, visual blurring, headache, fatigue, anxiety, gastrointestinal upset and nausea.

How long does it take for flecainide to work?

Time to Peak

• Serum: ~3 hours (range: 1 to 6 hours)

Half-Life Elimination

• Newborns: Up to ≤29 hours; 3 months: 11 to 12 hours; 12 months: 6 hours
• Children: ~8 hours
• Adolescents 12 to 15 years: ~11 to 12 hours
• Adults: ~20 hours (range: 12 to 27 hours); increased in patients with heart failure (NYHA Class III) or renal dysfunction

After administration of one XL capsule, plasma flecainide concentrations gradually increase after a lag time of 2 to 3 hours to reach a peak between the 21st and 25th hour and remain at plateau levels until after the 30th hour. After reaching the steady state concentration (3-5days), it exerts maximum action.

Flecainide mechanism of action

Flecainide acts on the fast-inward sodium (Na⁺) ion channel and has a high affinity to activated or open sodium (Na⁺) channels ². Flecainide prolongs depolarization and increases refractoriness due to slow release from its binding site. Flecainide potently acts on the His-Purkinje system. It also works by inhibiting rapid delayed rectifier (IKr) channels, delaying potassium rectifier current resulting in prolongation of action potential duration in both ventricular and atrial muscle fibers ¹³. Flecainide is shown to block ryanodine receptor opening, which reduces calcium release from sarcoplasmic reticulum resulting after depolarization and triggered activity ¹⁴. Hence, indications for flecainide include catecholaminergic polymorphic ventricular tachycardia (CPVT).

Flecainide contraindications

According to the American College of Cardiology/American Heart Association/European Society of Cardiology, the use of flecainide is considered contraindicated in patients with structural heart disease. Other contraindications include hypersensitivity, documented second or third-degree AV block, sick sinus syndrome, bundle branch block, cardiogenic shock, and acquired/congenital QT prolongation with a history of Torsades de Pointes.

Caution is also advised in myocardial dysfunction, congestive heart failure, QT prolongation, electrolyte abnormalities, and pacemaker use ¹⁵.

Significant drug interactions include ritonovir, cisapride, despiramine, dronedarone, quinidine, saquinavir, and tipranavir. Concurrent use with these agents is contraindicated. It interacts with many other drugs where therapy modification may be necessary, so thorough medication reconciliation is necessary with flecainide, as with all drugs.

Flecainide special precautions

Before taking flecainide:

• tell your doctor and pharmacist if you are allergic to flecainide or any other medications.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: acetazolamide (Diamox); amiodarone (Cordarone, Pacerone); ammonium chloride; antacids; beta blockers such as atenolol (Tenormin), labetalol (Trandate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), and propranolol (Inderal); carbamazepine (Carbatrol, Tegretol); cimetidine (Tagamet); clozapine (Clozaril); dichlorphenamide; digoxin (Lanoxin); diltiazem (Cardizem, Tiazac); disopyramide (Norpace); methazolamide; nifedipine (Adalat, Procardia); phenytoin (Dilantin); phenobarbital; quinidine; sodium bicarbonate (baking soda, Citrocarbonate, Soda Mint); and verapamil (Calan, Verelan). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have heart block (condition in which electrical signals are not passed normally from the upper chambers of the heart to the lower chambers). Your doctor may tell you not to take flecainide.
• tell your doctor if you have a pacemaker (device that is surgically placed under the skin to control irregular heartbeats) and if you have or have ever had a heart attack, heart failure, or any type of heart disease; low or high levels of potassium in the blood; or liver or kidney disease. Also tell your doctor if you follow a strict vegetarian diet.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking flecainide, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking flecainide.
• if you are giving this medication to an infant, be sure to talk to the doctor if there will be any major changes in the amount of milk the infant drinks. Milk can affect how the medication is absorbed in the body.

It is important that your doctor check your progress at regular visits to make sure the medicine is working properly. This will allow for changes to be made in the amount of medicine you are taking, if necessary.

Check with your doctor right away if you develop any of the following:

• chest pain;
• shortness of breath;
• swelling of your hands, ankles, or feet; or weight gain.

These may be symptoms of heart failure.

This medicine can cause changes in your heart rhythm, such as conditions called PR, QRS, or QT prolongation. It may cause fainting or serious side effects in some patients. Contact your doctor right away if your symptoms do not improve or if they become worse.

Your doctor may want you to carry a medical identification card or bracelet stating that you are using flecainide.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking flecainide.

Flecainide may cause some people to become dizzy, lightheaded, or less alert than they are normally. Make sure you know how you react to flecainide before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert.

If you have been using flecainide regularly for several weeks, do not suddenly stop using it. Check with your doctor for the best way to gradually reduce the amount you are taking before stopping 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.

Pregnancy

Pregnancy Category C: 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.

Using flecainide during pregnancy may pose some risk to the fetus, so clinicians must perform a risk/benefit analysis. Fetal risks include fetal heart rate variability, acceleration impairment, and QT interval abnormalities ¹⁶. Fetuses may also experience neonatal hyperbilirubinemia, although this data is unclear.

Breastfeeding

Flecainide is present in breast milk; the relative infant dose is 8% when the maternal dosing is 200mg/day. The relative infant dosing is calculated using the highest average breast milk concentration compared to the maternal dosage. Breastfeeding is acceptable as long as relative infant dosing is under 10% ¹⁶.

Flecainide 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 flecainide, 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 flecainide 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
• Bepridil
• Cisapride
• Dronedarone
• Levomethadyl
• Mesoridazine
• Pimozide
• Piperaquine
• Ritonavir
• Saquinavir
• Sparfloxacin
• Terfenadine
• Thioridazine
• Tipranavir
• Vernakalant
• Ziprasidone

Using flecainide 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.

• Acecainide
• Ajmaline
• Alfuzosin
• Amiodarone
• Amitriptyline
• Amoxapine
• Anagrelide
• Apomorphine
• Aprindine
• Arbutamine
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Artemether
• Asenapine
• Astemizole
• Azimilide
• Azithromycin
• Bedaquiline
• Bendroflumethiazide
• Boceprevir
• Bretylium
• Buprenorphine
• Bupropion
• Buserelin
• Ceritinib
• Chloral Hydrate
• Chloroquine
• Chlorothiazide
• Chlorpromazine
• Chlorthalidone
• Ciprofloxacin
• Citalopram
• Clarithromycin
• Clofazimine
• Clomipramine
• Clozapine
• Cobicistat
• Crizotinib
• Cyclobenzaprine
• Dabrafenib
• Darifenacin
• Dasabuvir
• Dasatinib
• Degarelix
• Delamanid
• Delavirdine
• Desipramine
• Deslorelin
• Deutetrabenazine
• Dibenzepin
• Disopyramide
• Dofetilide
• Dolasetron
• Domperidone
• Donepezil
• Droperidol
• Duloxetine
• Efavirenz
• Encorafenib
• Enflurane
• Erythromycin
• Escitalopram
• Etravirine
• Fingolimod
• Fluconazole
• Fluoxetine
• Foscarnet
• Gatifloxacin
• Gemifloxacin
• Glasdegib
• Gonadorelin
• Goserelin
• Granisetron
• Halofantrine
• Haloperidol
• Halothane
• Histrelin
• Hydrochlorothiazide
• Hydroflumethiazide
• Hydroquinidine
• Hydroxychloroquine
• Hydroxyzine
• Ibutilide
• Iloperidone
• Imipramine
• Inotuzumab Ozogamicin
• Isoflurane
• Isradipine
• Ivabradine
• Ivosidenib
• Ketoconazole
• Lacosamide
• Lapatinib
• Leuprolide
• Levofloxacin
• Lidocaine
• Lidoflazine
• Lofexidine
• Lorcainide
• Lumefantrine
• Macimorelin
• Mefloquine
• Methadone
• Metolazone
• Metronidazole
• Mifepristone
• Moxifloxacin
• Nafarelin
• Nilotinib
• Norfloxacin
• Nortriptyline
• Octreotide
• Ofloxacin
• Ombitasvir
• Ondansetron
• Osimertinib
• Paliperidone
• Panobinostat
• Paritaprevir
• Pasireotide
• Pazopanib
• Peginterferon Alfa-2b
• Pentamidine
• Pimavanserin
• Pirmenol
• Pitolisant
• Polythiazide
• Posaconazole
• Prajmaline
• Prilocaine
• Probucol
• Procainamide
• Prochlorperazine
• Promethazine
• Propafenone
• Protriptyline
• Quetiapine
• Quinidine
• Ranolazine
• Ribociclib
• Risperidone
• Salmeterol
• Sematilide
• Sertindole
• Sertraline
• Sevoflurane
• Simeprevir
• Siponimod
• Sodium Phosphate
• Sodium Phosphate, Dibasic
• Sodium Phosphate, Monobasic
• Solifenacin
• Sorafenib
• Sotalol
• Spiramycin
• Sulfamethoxazole
• Sulpiride
• Sultopride
• Sunitinib
• Tacrolimus
• Tedisamil
• Telaprevir
• Telavancin
• Telithromycin
• Tetrabenazine
• Tizanidine
• Toremifene
• Trazodone
• Trichlormethiazide
• Triclabendazole
• Trifluoperazine
• Trimethoprim
• Trimipramine
• Triptorelin
• Vandetanib
• Vardenafil
• Vasopressin
• Vemurafenib
• Vinflunine
• Voriconazole
• Zolmitriptan
• Zotepine
• Zuclopenthixol

Using flecainide 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.

• Cimetidine
• Digoxin
• Paroxetine
• Propranolol
• Verapamil

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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using flecainide with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use flecainide, or give you special instructions about the use of food, alcohol, or tobacco.

• Milk

Using flecainide 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 flecainide, 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 flecainide. Make sure you tell your doctor if you have any other medical problems, especially:

• AV block (type of abnormal heart rhythm), with no pacemaker or
• Bundle branch block (heart rhythm problem), with no pacemaker or
• Cardiogenic shock (shock caused by heart attack) or
• Chronic atrial fibrillation or
• Heart attack, recent—Should not be used in patients with these conditions.
• Congestive heart failure (severe) or
• Heart disease (e.g., cardiomyopathy) or
• Sick sinus syndrome (type of abnormal heart rhythm)—Use with caution. May make these conditions worse.
• Electrolyte imbalance (e.g., high or low potassium in the blood)—Should be corrected first before using flecainide.
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
• If you have a permanent pacemaker—Use with caution. Flecainide may interfere with the pacemaker and require more careful follow-up by the doctor.

What is flecainide used for?

Flecainide is used to prevent  or treat certain types of life-threatening irregular heartbeats (arrhythmias) such as paroxysmal supraventricular tachycardia (PSVT) and paroxysmal atrial fibrillation/flutter (PAF). Flecainide is also used to prevent life-threatening sustained ventricular tachycardia (sustained VT). Flecainide is in a class of medications called antiarrhythmics. It works by slowing electrical signals in the heart to stabilize the heart rhythm.

There is a chance that flecainide may cause new or make worse existing heart rhythm problems when it is used. Since it has been shown to cause severe problems in some patients, it is only used to treat serious heart rhythm problems. Discuss this possible effect with your doctor.

Flecainide dose

The dose of flecainide 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 flecainide. If your dose is different, do not change it unless your doctor tells you to do so.

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

For oral dosage form (tablets) per American College of Cardiology, American Heart Association and Heart Rhythm Society guidelines:

• For paroxysmal supraventricular tachycardia (PSVT) and paroxysmal atrial fibrillation/atrial flutter:
  • Adults: 50 to 300 milligrams (mg) daily by mouth divided into 8 to 12-hour intervals. Start with 50 mg orally every 12 hours, then increase 100 mg per day every four days. The maximum dose is 300 mg daily. Dose adjustment is made based on serum levels. Your doctor may increase your dose as needed.
  • Children: Use and dose must be determined by your doctor. Dose is based on body size and must be determined by your child’s doctor. The starting dose is 100 milligrams (mg) per square meter (m²) per day for infants 6 months and older and 50 mg/m² per day in infants younger than 6 months. Doses are divided into two or three equal doses per day.
• For sustained ventricular tachycardia (sustained VT) prophylaxis:
  • Adults: 100 to 400 milligrams (mg) daily by mouth, divided into 8 or 12-hour intervals. Start 100 mg daily every 12 hours, and increase dosing by 100 mg per day every four days. The maximum dose is 400 mg daily. Dose adjustment is made based on serum levels. Your doctor may increase your dose as needed. However, the dose is usually not more than 400 mg per day.
  • Children: Use and dose must be determined by your doctor. Dose is based on body size and must be determined by your child’s doctor. The starting dose is 100 milligrams (mg) per square meter (m²) per day for infants 6 months and older and 50 mg/m² per day in infants younger than 6 months. Doses are divided into two or three equal doses per day.

No dosage changes are necessary for liver disease, as per the manufacturer. With kidney disease and CrCl less than 35ml/min/1.73m², caution is necessary when increasing the dose at 4-day intervals.

There are an increased response and a steep relationship between dose and concentration. Plasma levels require monitoring in patients with severe kidney failure or hepatic disease. Drug overdose could be fatal with flecainide. The prescriber should adjust dosing based on clinical response ¹².

In patients with renal failure or hepatic impairment, it is prudent to monitor EKG and blood pressure and to obtain periodic serum trough concentration. Therapeutic trough concentration is between 0.2 to 1 mcg/ml. Lower trough concentration is sufficient in pediatric patients.

Consult facility guidelines or manufacturer prescribing data for pediatric dose regimens.

Adult dose for Ventricular Tachycardia

• Initial dose: 100 mg orally every 12 hours.
• Maintenance dose: May be increased in increments of 50 mg bid every 4 days until efficacy is achieved. Most patients with SUSTAINED VT do not require more than 150 mg every 12 hours (300 mg/day), and the maximum dose recommended is 400 mg/day.

Adult dose for Atrial Fibrillation

• Initial dose: 50 mg orally every 12 hours.
• Maintenance dose: May be increased in increments of 50 mg bid every 4 days until efficacy is achieved.

Adult dose for Atrial Flutter

• Initial dose: 50 mg orally every 12 hours.
• Maintenance dose: May be increased in increments of 50 mg bid every 4 days until efficacy is achieved.

Adult dose for Wolff-Parkinson-White Syndrome

• Initial dose: 50 mg orally every 12 hours.
• Maintenance dose: May be increased in increments of 50 mg bid every 4 days until efficacy is achieved.

Adult dose for Paroxysmal Supraventricular Tachycardia

• Initial dose: 50 mg orally every 12 hours.
• Maintenance dose: May be increased in increments of 50 mg bid every 4 days until efficacy is achieved.

Pediatric dose for Supraventricular Tachycardia

Less than 1 month:

• Supraventricular tachycardia: Limited data available: Initial: 2 mg/kg/day orally divided every 12 hours; titrate to clinical response, monitor serum concentration; mean dose required to suppress SVT: 3.35 ± 1.35 mg/kg/day in 17 neonates (n=20 treated neonates; mean PNA: 11.5 days; mean GA: 36.8 weeks; mean birthweight: 2.8 kg); study did not report resultant serum concentrations.

1 month or older:

• Initial: 1 to 3 mg/kg/day orally or 50 to 100 mg/m²/day orally in 3 divided doses; usual: 3 to 6 mg/kg/day or 100 to 150 mg/m²/day in 3 divided doses; up to 8 mg/kg/day or 200 mg/m²/day for uncontrolled patients with subtherapeutic levels; higher doses have been reported, however they may be associated with an increased risk of proarrhythmias; a review of world literature reports the average effective dose to be 4 mg/kg/day or 140 mg/m²/day.

Renal Dose Adjustments

• CrCl=35 mL/min or less: Initial dose: 100 mg orally once a day or 50 mg twice a day. It may take longer than 4 days before a new steady-state plasma level is reached following a dosage change.
• In patients with less severe renal dysfunction: Initial dose: 100 mg every 12 hours.

Liver Dose Adjustments

Flecainide should not be used in patients with significant liver dysfunction unless the potential benefits clearly outweigh the risks, as elimination from plasma can be markedly slower in patients with significant hepatic impairment. If it is deemed necessary, frequent and early plasma level monitoring is required to guide dosage and dosage increases should be made very cautiously when plasma levels have plateaued (after more than four days).

What should I do if I forget a dose?

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.

Flecainide side effects

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

• dizziness
• changes in vision
• headache
• weakness
• uncontrollable shaking of a part of your body
• constipation
• stomach pain

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

• fast, pounding, or irregular heartbeat
• chest pain
• shortness of breath
• extreme tiredness
• nausea
• loss of appetite
• persistent cough with blood-tinged mucus
• swelling of the hands, feet, ankles, or lower legs
• confusion
• unusual bleeding or bruising
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• flu-like symptoms

More common

• difficult or labored breathing
• dizziness, fainting, or lightheadedness
• fast, irregular, pounding, or racing heartbeat or pulse
• shortness of breath
• tightness in the chest
• wheezing

Less common

• burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
• chest pain
• fainting
• feeling of warmth
• fever
• increased sweating
• partial or slight paralysis
• redness of the face, neck, arms, and occasionally, upper chest
• shakiness and unsteady walk
• shakiness in the legs, arms, hands, or feet
• swelling of the feet or lower legs
• trembling or shaking of the hands or feet
• unsteadiness, trembling, or other problems with muscle control or coordination

Rare

• arm, back, or jaw pain
• black, tarry stools
• bleeding gums
• blood in the urine or stools
• blurred vision
• chest discomfort
• chest tightness or heaviness
• chills
• confusion
• convulsions
• cough
• decrease in the frequency of urination
• decrease in urine volume
• difficulty in passing urine (dribbling)
• difficulty with breathing
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• frequent urination
• general feeling of discomfort or illness
• headache
• increased volume of pale, dilute urine
• nausea
• nervousness
• noisy breathing
• painful or difficult urination
• pinpoint red spots on the skin
• pounding in the ears
• sensation of pins and needles
• slow or fast heartbeat
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stabbing pain
• sweating
• swollen glands
• thickening of bronchial secretions
• troubled breathing
• unusual bleeding or bruising
• unusual tiredness or weakness
• yellow eyes or skin

Flecainide may cause other side effects. Call your doctor if you have any unusual problems while taking flecainide.

Flecainide toxicity

Broadly speaking, flecainide like other sodium channel blockers cause metabolic, cardiac, and neurologic symptoms. This leads to hemodynamic compromise and metabolic acidosis, potentiating the effects of the medications and causing further sodium blockade ¹⁷. Patients with potential flecainide toxicity require an immediate electrocardiogram (ECG). Flecainide toxicity leads to a widening of the QRS complex, lengthening of the QT interval, a new right axis deviation, bradydysrhythmias, ventricular tachycardia, ventricular fibrillation or torsades des pointes ¹⁸. Brugada phenocopy, a sodium channelopathy disorder, can also be seen during acute toxicity ¹⁹.

Symptoms of flecainide toxicity may include:

• nausea
• vomiting
• seizures
• slow, fast, or irregular heartbeat
• loss of consciousness
• sudden death

Sodium channel blockers cross the blood-brain barrier and act through multiple mechanisms. They inhibit the gamma-aminobutyric acid (GABA) system (primarily lidocaine), activate the sodium ouabain-sensitive current, stimulate 5-TH2C receptors, antagonize H1 receptors and block all noradrenaline activating effect. It is through these actions that adrenergic stimulation occurs. These medications in large doses are also pro-convulsant through the above mechanisms ²⁰.

Co-ingestion of other drugs can alter the elimination kinetics. A recent case report describes how propafenone delayed the metabolism of metoprolol by inhibition of CYP2D. This interaction of the two medications led to a more profound toxicity, and in this case cardiovascular collapse ²¹.

It is vital to consider and evaluate for any other co-ingestion.

Obtain electrolyte, renal and hepatic profiles, acetaminophen level, salicylate level, arterial or venous blood gas, drug screen, and a complete blood count. Evaluate for an anion gap, and osmolal gap as this could indicate coingestants not detectable on standard testing.

Flecainide toxicity management

Immediate initial management must begin with an assessment of airway, breathing, and circulation. Many patients present with hypotension, bradycardia or tachycardia and altered mental status. An endotracheal tube or other advanced airways should be placed in patients who are unable to protect their airway.

The cornerstone of treatment is the administration of sodium bicarbonate. It is indicated for patients with an ECG demonstrating a QRS duration >100 ms or any suspicious QT prolongation or dysrhythmia ²². Sodium bicarbonate is beneficial in raising the serum pH and increasing the extracellular sodium. Alkalinization leads to an increase of the electrochemical gradient across cell membranes which helps to offload sodium channels. It might also increase the protein binding of the offending agent. Patients should be given 1-2mEq/kg as a bolus dose ¹⁷. Bolus doses can be administered until the QRS duration is less than 100 ms. This can be followed with a continuous infusion of sodium bicarbonate of 2-3 50mEq ampules in one liter of D5W (5% dextrose in water) ²². Hypertonic saline has been used but is not routinely recommended; it remains an option in dire circumstances as reported in a case of flecainide overdose ²³.

Management of hypotension requires a combination of volume resuscitation and vasopressor and inotropic support. Use of inotropic agents such as dobutamine helps increase cardiac output while the effects of the toxicity dissipate. Addition of vasopressors such as norepinephrine, vasopressin, or epinephrine might be considered for hemodynamic support. These agents lead to vasoconstriction and an increase in the systemic vascular resistance, resulting in increased systemic blood pressure.

Patients with sodium channel blocker toxicity from lidocaine have benefitted from the administration of 20% lipid emulsion if they are hemodynamically unstable ²⁴. The mechanism of action of lipid emulsion is unclear; however, it is hypothesized that it acts as a lipid sink, with an electrochemical gradient drawing the lidocaine into the lipid. Patients should be given a 1.5mL/kg bolus followed by a 0.25mL/kg infusion ²⁵. Few studies exist on lipid emulsion for other sodium channel toxicities.

Extracorporeal membrane oxygenation (ECMO) has been used in a refractory case with reported survival ²³. In general, the drugs which cause sodium channel blockade toxicity are highly lipophilic, have a wide volume of distribution, and are not dialyzable.

Seizure management is accomplished with benzodiazepine medications, such as lorazepam and midazolam. For refractory seizures, loading of antiepileptic medications such as levetiracetam is recommended. Phenytoin and its derivatives should be avoided in this situation as phenytoin is itself a sodium channel blocker and will likely lead to clinical deterioration. Intubation and sedation with propofol should be considered for seizures refractory to other management.

Flecainide toxicity prognosis

Complications of sodium channel blocker toxicity include cardiogenic shock, hypotension, bradycardia or tachycardia, cardiovascular collapse, respiratory depression, encephalopathy, status epilepticus, and death.

Class I antiarrhythmic toxicity is associated with a significantly higher mortality rate (22.5%) compared with other drugs (1%) ¹⁹. Prompt recognition and treatment are vital to minimize morbidity and mortality.

1. Salvage SC, Chandrasekharan KH, Jeevaratnam K, Dulhunty AF, Thompson AJ, Jackson AP, Huang CL. Multiple targets for flecainide action: implications for cardiac arrhythmogenesis. Br J Pharmacol. 2018 Apr;175(8):1260-1278. doi: 10.1111/bph.13807[↩][↩]
2. Arunachalam K, Alzahrani T. Flecainide. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542291[↩][↩][↩]
3. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Flecainide. [Updated 2018 Jan 24]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548023[↩]
4. Paul AA, Witchel HJ, Hancox JC. Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine. Br J Pharmacol. 2002 Jul;136(5):717-29. doi: 10.1038/sj.bjp.0704784[↩]
5. Rolf S, Haverkamp W, Borggrefe M, Musshoff U, Eckardt L, Mergenthaler J, Snyders DJ, Pongs O, Speckmann EJ, Breithardt G, Madeja M. Effects of antiarrhythmic drugs on cloned cardiac voltage-gated potassium channels expressed in Xenopus oocytes. Naunyn Schmiedebergs Arch Pharmacol. 2000 Jul;362(1):22-31. doi: 10.1007/s002100000257[↩]
6. Liu N, Denegri M, Ruan Y, Avelino-Cruz JE, Perissi A, Negri S, Napolitano C, Coetzee WA, Boyden PA, Priori SG. Short communication: flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity. Circ Res. 2011 Jul 22;109(3):291-5. doi: 10.1161/CIRCRESAHA.111.247338[↩]
7. Nagatomo T, January CT, Makielski JC. Preferential block of late sodium current in the LQT3 DeltaKPQ mutant by the class I(C) antiarrhythmic flecainide. Mol Pharmacol. 2000 Jan;57(1):101-7.[↩]
8. Dokken K, Fairley P. Sodium Channel Blocker Toxicity. [Updated 2018 Nov 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534844[↩]
9. Holmes B, Heel RC. Flecainide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs. 1985 Jan;29(1):1-33. doi: 10.2165/00003495-198529010-00001[↩]
10. Roden DM, Woosley RL. Drug therapy. Flecainide. N Engl J Med. 1986 Jul 3;315(1):36-41. doi: 10.1056/NEJM198607033150106[↩]
11. Conard GJ, Ober RE. Metabolism of flecainide. Am J Cardiol. 1984 Feb 27;53(5):41B-51B. doi: 10.1016/0002-9149(84)90501-0[↩]
12. Tamargo J, Le Heuzey JY, Mabo P. Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. Eur J Clin Pharmacol. 2015 May;71(5):549-67. doi: 10.1007/s00228-015-1832-0[↩][↩]
13. Salvage, S.C., Chandrasekharan K.H., Jeevaratnam K., Dulhunty A.F., Thompson A.J., Jackson A.P., and Huang C.L.H.. 2018. Multiple targets for flecainide action: Implications for cardiac arrhythmogenesis. Br. J. Pharmacol. 175:1260–1278. 10.1111/bph.13807[↩]
14. Bannister ML, MacLeod KT, George CH. Moving in the right direction: elucidating the mechanisms of interaction between flecainide and the cardiac ryanodine receptor. Br J Pharmacol. 2022 Jun;179(11):2558-2563. doi: 10.1111/bph.15718[↩]
15. Rivner H, Lambrakos LK. Flecainide Toxicity Leading to Loss of Pacemaker Capture and Cardiac Arrest. JACC Case Rep. 2021 Jan 27;3(4):586-590. doi: 10.1016/j.jaccas.2020.11.030[↩]
16. Tamirisa KP, Elkayam U, Briller JE, Mason PK, Pillarisetti J, Merchant FM, Patel H, Lakkireddy DR, Russo AM, Volgman AS, Vaseghi M. Arrhythmias in Pregnancy. JACC Clin Electrophysiol. 2022 Jan;8(1):120-135. doi: 10.1016/j.jacep.2021.10.004[↩][↩]
17. Mirrakhimov AE, Ayach T, Barbaryan A, Talari G, Chadha R, Gray A. The Role of Sodium Bicarbonate in the Management of Some Toxic Ingestions. Int J Nephrol. 2017;2017:7831358[↩][↩]
18. Di Grande A, Giuffrida C, Narbone G, Le Moli C, Nigro F, Di Mauro A, Pirrone G, Tabita V, Alongi B. Management of sodium-channel blocker poisoning: the role of hypertonic sodium salts. Eur Rev Med Pharmacol Sci. 2010 Jan;14(1):25-30.[↩]
19. Arı ME, Ekici F. Brugada-Phenocopy Induced by Propafenone Overdose and Successful Treatment: A Case Report. Balkan Med J. 2017 Sep 29;34(5):473-475[↩][↩]
20. Grant AO. On the mechanism of action of antiarrhythmic agents. Am. Heart J. 1992 Apr;123(4 Pt 2):1130-6[↩]
21. Kacirova I, Grundmann M, Kolek M, Vyskocilova-Hrudikova E, Urinovska R, Handlos P. Lethal suicide attempt with a mixed-drug intoxication of metoprolol and propafenone – A first pediatric case report. Forensic Sci. Int. 2017 Sep;278:e34-e40[↩]
22. Kacirova I, Grundmann M, Kolek M, Vyskocilova-Hrudikova E, Urinovska R, Handlos P. Lethal suicide attempt with a mixed-drug intoxication of metoprolol and propafenone – A first pediatric case report. Forensic Sci. Int. 2017 Sep;278:e34-e40.[↩][↩]
23. Szadkowski M, Drapkin Z, Hewes H, Caravati EM, Plumb J. A Teenager With Seizures and Cardiac Arrest After Drug Overdose: Are We Numb to the Danger? Pediatr Emerg Care. 2017 Sep;33(9):657-659[↩][↩]
24. Rothschild L, Bern S, Oswald S, Weinberg G. Intravenous lipid emulsion in clinical toxicology. Scand J Trauma Resusc Emerg Med. 2010 Oct 05;18:51[↩]
25. Vu NM, Hill TE, Summers MR, Vranian MN, Faulx MD. Management of life-threatening flecainide overdose: A case report and review of the literature. HeartRhythm Case Rep. 2016 May;2(3):228-231[↩]

What is propylene glycol

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

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

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

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

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

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

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

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

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

Propylene glycol allergy

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

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

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

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

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

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

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

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

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

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

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

Is propylene glycol safe?

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

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

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

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

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

Absorption, distribution, metabolism and elimination

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

Acute toxicity

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

Subacute, subchronic toxicity studies

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

Genotoxicity

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

Developmental and reproductive toxicity

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

How might I be exposed to propylene glycol?

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

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

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

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

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

How likely is propylene glycol to cause cancer?

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

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

Propylene glycol in medicinal products for children

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

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

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

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

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

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

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

Propylene glycol uses

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

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

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

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

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

Propylene glycol toxicity

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

Airways and lungs

• Rapid breathing
• No breathing

Bladder and kidneys

• Blood in urine
• No urine output or decreased urine output

Eyes, Ears, Nose, and Throat

• Blurred vision
• Blindness

Heart and blood

• Rapid heartbeat
• Low blood pressure

Muscles and joints

• Leg cramps

Nervous system

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

Skin

• Blue lips and fingernails

Stomach and gastrointestinal tract

• Nausea and vomiting

Home Care

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

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

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

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

What to Expect at the Emergency Room

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

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

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

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

Propylene glycol side effects

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

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

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

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What is calcium gluconate

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

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

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

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

Table 1: Recommended Dietary Allowances (RDAs) for Calcium

Footnotes:

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

* Adequate Intake (AI)

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

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

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

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

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

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

Table 2: Selected Food Sources of Calcium

Footnotes:

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

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

Calcium and Health

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

Bone health and osteoporosis

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

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

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

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

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

Cancer of the colon and rectum

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

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

Cancer of the prostate

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

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

Cardiovascular disease

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

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

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

Blood pressure and hypertension

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

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

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

Preeclampsia

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

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

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

Kidney stones

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

Weight management

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

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

Calcium gluconate vs calcium chloride

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

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

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

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

Based on the American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care ⁵⁵ and the American Academy of Pediatrics Committee on Drugs, calcium chloride, although based on limited evidence, is an effective and recommended treatment in the setting of calcium channel blocker overdose.

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

Calcium chloride is contraindications

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

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

Calcium chloride dosage

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

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

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

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

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

Calcium gluconate uses

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

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

Calcium gluconate precautions and warnings

Calcium Gluconate Injection Contraindications

Calcium Gluconate Injection is contraindicated in:

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

Arrhythmias with concomitant cardiac glycoside use

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

End-Organ damage due to intravascular ceftriaxone-calcium precipitates

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

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

Tissue Necrosis and Calcinosis

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

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

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

Hypotension, bradycardia, and cardiac arrhythmias with rapid administration

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

Aluminum Toxicity

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

Drug Incompatibilities

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

Calcium gluconate in pregnancy

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

Risk summary

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

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

Clinical Considerations

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

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

Calcium gluconate in breastfeeding

Risk summary

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

Calcium gluconate for pediatric use

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

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

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

Calcium gluconate for geriatric use

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

Calcium gluconate in people with kidney impairment

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

Calcium Gluconate in people with liver impairment

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

Calcium gluconate dose

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

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

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

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

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

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

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

Calcium Gluconate Injection Dosage and Administration

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

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

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

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

Important Administration Instructions

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

For bolus intravenous administration:

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

For continuous intravenous infusion:

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

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

Serum Calcium Monitoring

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

Dosage in Renal Impairment

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

Adult dose for hypocalcemia

Calcium gluconate intravenous:

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

Calcium gluconate oral:

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

Adult dose for hypermagnesemia

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

Adult dose for hyperkalemia

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

Adult dose for exchange transfusion

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

Adult dose for osteoporosis

1000 to 1500 mg/day orally in divided doses.

Pediatric dose for hypocalcemia

Neonatal:

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

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

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

IV or intraosseous IO:

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

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

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

Dose expressed in mg of calcium gluconate:

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

Hypocalcemia secondary to citrated blood infusion:

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

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

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

Dosing: Usual

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

Oral:

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

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

Oral:

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

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

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

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

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

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

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

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

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

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

Hypocalcemia secondary to citrated blood infusion:

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

Tetany:

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

Daily maintenance calcium:

IV:

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

Renal dose adjustments

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

Liver dose adjustments

Data not available

Dialysis

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

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

Calcium gluconate side effects

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

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

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

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

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

Common side effects may include:

• upset stomach, gas; or
• constipation.

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

Call your doctor for medical advice about side effects.

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

Psychiatric

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

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

Genitourinary

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

Cardiovascular

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

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

Renal

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

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

Nervous system

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

Calcium gluconate antidote

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

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

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

Management of severe toxicity

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

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

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What is magnesium oxide

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

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

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

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

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

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

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

Table 1: Recommended Dietary Allowances (RDAs) for Magnesium

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

Table 2: Selected food sources of magnesium

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

Magnesium oxide supplement

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

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

Magnesium oxide vs Magnesium citrate

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

Magnesium oxide uses

What is magnesium oxide used for

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

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

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

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

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

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

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

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

Magnesium benefits

Magnesium for ADHD

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

Magnesium for osteoporosis

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

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

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

Magnesium for migraines and headaches

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

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

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

Magnesium for hypertension and cardiovascular disease

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

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

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

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

Magnesium for type 2 diabetes

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

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

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

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

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

Magnesium oxide dosage

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

Take magnesium oxide with a full glass of water.

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

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

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

Store at room temperature away from moisture and heat.

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

Adult dose for dyspepsia

Uses: Acid indigestion, upset stomach

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

Comments:

• May have a laxative effect.

Adult dose for constipation

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

Adult dose for vitamin/mineral supplementation during pregnancy/lactation

Recommended dietary intake:

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

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

Pediatric dose for constipation

500 mg caplets:

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

Comments:

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

Pediatric dose for vitamin/mineral supplementation

Recommended dietary intakes:

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

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

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

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

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

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

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

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

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

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

Magnesium oxide side effects

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

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

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

• cramping
• diarrhea

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

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

Interactions with Medications

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

Bisphosphonates

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

Antibiotics

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

Diuretics

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

Proton pump inhibitors

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

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What is potassium chloride

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Potassium chloride medication

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

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

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

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

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

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

How should I take potassium chloride?

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

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

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

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

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

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

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

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

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

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

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

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

Potassium in food

What is potassium chloride used for?

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

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

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

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

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

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

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

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

Potassium chloride dosage

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

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

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

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

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

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

Usual Adult Dose for Hypokalemia (low blood potassium)

Oral:

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

Parenteral (must be diluted prior to administration):

Dose and rate of administration are dependent on patient condition

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

Maximum daily dose: 200 mEq

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

Maximum daily dose: 400 mEq

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

Comments:

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

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

Oral:

Typical dose: 20 mEq, orally, daily

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

Parenteral (must be diluted prior to administration):

Dose and rate of administration are dependent on patient condition

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

Maximum daily dose: 200 mEq

Comments:

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

Usual Pediatric Dose for Hypokalemia (low blood potassium)

Birth to 16 years:

Oral solution:

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

Maximum daily dose: 100 mEq

Parenteral (must be diluted prior to administration):

Dose and rate of administration are dependent on patient condition

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

Maximum daily dose: 200 mEq

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

Maximum daily dose: 400 mEq

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

Comments:

• Never give injectable potassium chloride undiluted

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

Birth to 16 years:

Oral solution:

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

Intravenous (must be diluted prior to administration):

Dose and rate of administration are dependent on patient condition

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

Maximum daily dose: 200 mEq

Comments:

• Never give injectable potassium chloride undiluted

Potassium chloride side effects

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

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

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

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

Potassium chloride overdose

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

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

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

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

Treatment measures for hyperkalemia include the following:

Basic life support measures are essential in severely poisoned patients:

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

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

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

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

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