Pyridostigmine Bromide Prescribing Information
- Pyridostigmine bromide is for use as a pretreatment for exposure to soman nerve agent. Pyridostigmine bromide alone will not protect against exposure to soman. The efficacy of pyridostigmine bromide is dependent upon the rapid use of atropine and pralidoxime (2-PAM) after soman exposure [seeand
2.1 Important Administration InformationFor Military Medical Use Only.Treatment and Protection for Soman ExposurePyridostigmine bromide is for use as a pretreatment for exposure to soman nerve agent (see Treatment Timing). Pyridostigmine bromide alone will not protect against exposure to soman.
Atropine and PralidoximeThe efficacy of pyridostigmine bromide is dependent upon the rapid use of atropine and pralidoxime (2-PAM) after soman exposure.
Primary ProtectionThe primary protection against exposure to chemical nerve agents consists of wearing protective garments including masks, hoods, and overgarments designed specifically for this use.
Do not rely solely upon pretreatment with pyridostigmine bromide and the antidotes atropine and pralidoxime to provide complete protection from poisoning by soman nerve agent.
Treatment TimingPyridostigmine bromide is to be administered as pretreatment before exposure to soman nerve agent
[see Dosage and Administration (2.2)].If pyridostigmine bromide is taken immediately before exposure (e.g., when the gas attack alarm is given) or at the same time as poisoning by soman, it is not expected to be effective and may exacerbate the effects of a sublethal exposure to soman[see Clinical Pharmacology (12.2)]. Do not take pyridostigmine bromide after exposure to soman.Administration with FoodTake pyridostigmine bromide 105 mg extended-release tablets with either a medium fat, medium calorie or high fat, high calorie meal to maintain efficacious pyridostigmine levels
[see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)].Administration with AlcoholPyridostigmine bromide 105 mg extended-release tablets should not be taken with alcohol
[see Clinical Pharmacology (12.3)].].5.1 Risk of Improper Use of Pyridostigmine BromideRisk of Not Stopping Pyridostigmine Bromide and Using Atropine and Pralidoxime in the Event of Soman ExposurePyridostigmine bromide is for use as pretreatment for exposure to soman nerve agent and must not be taken after exposure to soman nerve agent
[see Dosage and Administration (2.1, 2.2)].Pyridostigmine bromide pretreatment offers no benefit against the nerve agent soman unless the nerve agent antidotes, atropine and pralidoxime (2-PAM), are administered once symptoms of poisoning appear.Discontinue pyridostigmine at the first sign of nerve agent poisoning because it may exacerbate the effects of a sub-lethal exposure to soman if taken immediately before exposure (e.g., when the gas attack alarm is given) or at the same time as poisoning by soman
[see Clinical Pharmacology (12.2)].Signs of nerve agent poisoning can include runny nose; watery eyes; small, pinpoint pupils; eye pain; blurred vision; drooling and excessive sweating; cough; chest tightness; rapid breathing; diarrhea; increased urination; confusion; drowsiness; weakness; headache; nausea, vomiting, and/or abdominal pain; slow or fast heart rate; and/or abnormally low or high blood pressure.Risk of Not Wearing Protective GarmentsPyridostigmine bromide is not the primary protection against exposure to soman nerve agent.
The primary protection against exposure to chemical nerve agents is the wearing of protective garments including masks, hoods, and overgarments designed specifically for this use. Individuals must not rely solely upon pretreatment with pyridostigmine bromide and on the antidotes, atropine and pralidoxime (2-PAM), to provide complete protection from poisoning by soman nerve agent.
Always Use Protective Garment(s) - Primary protection against exposure to chemical nerve agents is the wearing of protective garments including masks, hoods, and overgarments designed specifically for this use. Individuals must not rely solely upon pretreatment with pyridostigmine bromide and on the antidotes atropine and pralidoxime (2-PAM) to provide complete protection from poisoning by soman nerve agent [see.]
2.1 Important Administration InformationFor Military Medical Use Only.Treatment and Protection for Soman ExposurePyridostigmine bromide is for use as a pretreatment for exposure to soman nerve agent (see Treatment Timing). Pyridostigmine bromide alone will not protect against exposure to soman.
Atropine and PralidoximeThe efficacy of pyridostigmine bromide is dependent upon the rapid use of atropine and pralidoxime (2-PAM) after soman exposure.
Primary ProtectionThe primary protection against exposure to chemical nerve agents consists of wearing protective garments including masks, hoods, and overgarments designed specifically for this use.
Do not rely solely upon pretreatment with pyridostigmine bromide and the antidotes atropine and pralidoxime to provide complete protection from poisoning by soman nerve agent.
Treatment TimingPyridostigmine bromide is to be administered as pretreatment before exposure to soman nerve agent
[see Dosage and Administration (2.2)].If pyridostigmine bromide is taken immediately before exposure (e.g., when the gas attack alarm is given) or at the same time as poisoning by soman, it is not expected to be effective and may exacerbate the effects of a sublethal exposure to soman[see Clinical Pharmacology (12.2)]. Do not take pyridostigmine bromide after exposure to soman.Administration with FoodTake pyridostigmine bromide 105 mg extended-release tablets with either a medium fat, medium calorie or high fat, high calorie meal to maintain efficacious pyridostigmine levels
[see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)].Administration with AlcoholPyridostigmine bromide 105 mg extended-release tablets should not be taken with alcohol
[see Clinical Pharmacology (12.3)].Pyridostigmine Bromide as Pretreatment Only - Pyridostigmine bromide must not be taken after exposure to soman. If pyridostigmine bromide is taken immediately before exposure (e.g., when the gas attack alarm is given) or at the same time as poisoning by soman, it is not expected to be effective and may exacerbate the effects of a sub-lethal exposure to soman [see].
12.2 PharmacodynamicsThe mechanism of soman-induced death is reasonably well understood. Death is believed to result primarily from respiratory failure due to irreversible inhibition of the enzyme acetylcholinesterase and the consequent increase in the level of the neurotransmitter acetylcholine 1) at nicotinic receptors at the neuromuscular junction, resulting in pathological stimulation and ultimate failure of the muscles of respiration, 2) at muscarinic receptors in secretory glands and smooth muscle, resulting in excessive respiratory secretions and bronchoconstriction, and 3) at cholinergic receptors in the brain, resulting in central respiratory depression.
The effect of pyridostigmine is presumed to result from its reversible inhibition of a critical number of acetylcholinesterase active sites in the peripheral nervous system, protecting them from irreversible inhibition by soman. (Pyridostigmine bromide is not thought to enter the brain in significant amounts.) When the pyridostigmine bromide-induced inhibition of the enzyme is subsequently reversed, there is a small residual amount of enzyme activity that is adequate to sustain life (provided atropine and 2-PAM are subsequently administered). An implication of this presumed mechanism is that it is not helpful to give pyridostigmine bromide either just before or during exposure to soman
[see Dosage and Administration (2.1, 2.2)].
Contraindications (
Pyridostigmine bromide extended-release tablets are contraindicated in patients with:
- Mechanical intestinal or urinary obstruction
- Known hypersensitivity to pyridostigmine or other anticholinesterase agents
- Mechanical intestinal or urinary obstruction.
- Known hypersensitivity to pyridostigmine or other anticholinesterase agents.
Warnings and Precautions (
Drugs that increase cholinergic activity, including pyridostigmine bromide, should be used with caution in persons with bronchial asthma or chronic obstructive pulmonary disease.
Because pyridostigmine bromide increases cholinergic activity, it may have vagotonic effects on heart rate, which can lead to bradycardia or cardiac arrhythmias.
Drugs that increase cholinergic agents, including pyridostigmine bromide, could cause symptoms in persons susceptible to genitourinary tract or gastrointestinal tract obstruction.
Pyridostigmine bromide should be used with caution in people being treated for hypertension or glaucoma with beta adrenergic receptor blockers
Pyridostigmine bromide is indicated for
The evidence for the effectiveness of pyridostigmine bromide as pretreatment against soman-induced toxicity was derived from animal studies alone
The effectiveness of pyridostigmine bromide as a pretreatment against the lethal effects of soman nerve agent poisoning has not been determined in humans because adequate and well-controlled field trials have not been feasible and inducing soman nerve agent poisoning in humans to study the drug’s efficacy is not ethical. Therefore, the effectiveness of pyridostigmine bromide as a pretreatment for against the lethal effects of soman nerve agent poisoning was established based on the results of the following adequate and well-controlled animal efficacy studies.
Evidence of the effectiveness of pyridostigmine bromide as a pretreatment for soman poisoning was obtained from studies in animals alone, because it is unethical to perform such studies in humans. While the results of these animal studies cannot be extrapolated to humans with certainty, the extrapolation is supported by the reasonably well understood pathophysiologic mechanisms of the toxicity of soman and the mechanism of the protective effect of pyridostigmine bromide pretreatment, as examined in various animal species. In addition, the results of these animal studies establish that pyridostigmine bromide is reasonably likely to produce clinical benefit in humans. The section below explains the current understanding of the mechanism of soman toxicity and the beneficial effect of pyridostigmine bromide pretreatment, as well as the basis for extrapolating the animal findings to humans.
Pyridostigmine bromide pretreatment has been shown in animals to decrease the lethality of the soman nerve agent, provided atropine and pralidoxime (2-PAM) are administered immediately after exposure to soman.
Rhesus monkeys were given oral doses of pyridostigmine bromide every 8 hours for a total of 6 doses and were challenged with soman given intramuscularly 5 hours after the last pyridostigmine bromide dose. Two dosage groups of pyridostigmine bromide were used: a low-dose group given 1.2 mg/kg for all 6 doses and a high-dose group given 1.2 and 1.8 mg/kg for the first and second doses, respectively, and 2.4 mg/kg for the final 4 doses. These animals were also given atropine and 2-PAM after exposure to soman. An untreated control group and a group given atropine and 2-PAM (but not pyridostigmine bromide) were also used. The primary endpoint in this study was a decrease in the lethality of soman expressed as an increase in the LD50 (the dose of soman that killed 50% of the animals). The atropine/2-PAM control group showed a small but statistically significant 1.6-fold increase in the soman LD50 compared to the untreated control group. The groups given pyridostigmine bromide as well as atropine and 2-PAM showed increases in the soman LD50 of at least 40-fold compared to the untreated control group and at least 25-fold compared to the atropine/2-PAM group. The two dose levels of pyridostigmine bromide showed similar effectiveness.
Additional studies in rhesus monkeys and guinea pigs also showed effectiveness of pyridostigmine bromide (in the presence of post-soman administration of atropine and 2-PAM). The magnitude of effect in guinea pigs was smaller than that in monkeys (soman LD50 increased 4 to 7-fold compared to untreated control and 2- to 4-fold compared to atropine/2-PAM alone).
Pyridostigmine bromide produced only small and inconsistent effects in studies in rats, mice, and rabbits. It is thought that the effect of pyridostigmine bromide in rats and mice is masked by high blood levels of the enzyme carboxylesterase, which eliminates soman from blood and makes those species highly resistant to soman. In a study in which rats were given an inhibitor of carboxylesterase, pretreatment with pyridostigmine bromide plus atropine and 2-PAM increased the LD50 of soman 8.5-fold compared to untreated controls. Humans have little or no carboxylesterase in blood.
Animal studies have shown that pyridostigmine bromide pretreatment was effective only when animals were given atropine and 2-PAM after exposure to soman.
- The recommended dosage is 105 mg orally once daily, started at least several hours prior to exposure to soman. Do not take on an empty stomach. Take with a medium-fat medium-calorie meal (e.g., meal with 650 calories, 40% fat) or a high-fat high-calorie meal (e.g., meal with 1,000 calories, 50% fat). Do not take with a low-fat low-calorie meal (e.g., meal with 400 calories, 25% fat) ()
2.2 Recommended Dosage, Administration, and DurationDosageThe recommended dosage of pyridostigmine bromide is 105 mg orally once daily with food, started at least several hours prior to exposure to soman. Do not take on an empty stomach. Take with a medium-fat medium-calorie meal (e.g., meal with 650 calories, 40% fat) or a high-fat high-calorie meal (e.g., meal with 1,000 calories, 50% fat). Do not take with a low-fat low-calorie meal (e.g., meal with 400 calories, 25% fat)
[see Clinical Pharmacology (12.3)].Timing and Duration of TreatmentTimingPyridostigmine bromide is a pretreatment for exposure to soman nerve agent.
There is no known advantage to taking pyridostigmine bromide just prior to, or concurrent with, soman exposure. According to the mechanism of action of pyridostigmine bromide
[see Clinical Pharmacology (12.1, 12.2)], pyridostigmine bromide is effective when it is given sufficiently in advance of soman poisoning to provide a pool of protected enzyme. Therefore, it is expected that pyridostigmine bromide will not be effective if administered just prior to or during exposure to soman.DurationAt the first sign of nerve agent poisoning, discontinue pyridostigmine bromide and administer pretreatment with atropine and pralidoxime immediately
[see Warnings and Precautions (5.1)].The benefits and risks of use beyond 14 consecutive days have not been definitively established; therefore, evaluate continued use beyond 14 consecutive days in the context of the likelihood of exposure to soman nerve agent.
Missed DoseIf a dose is missed, take the missed dose as soon as possible. Resume dosing at 24-hour intervals from the time the missed dose was taken. Do not take double or extra doses.
- At the first sign of soman nerve agent poisoning, discontinue pyridostigmine and administer atropine and pralidoxime immediately. ()
2.2 Recommended Dosage, Administration, and DurationDosageThe recommended dosage of pyridostigmine bromide is 105 mg orally once daily with food, started at least several hours prior to exposure to soman. Do not take on an empty stomach. Take with a medium-fat medium-calorie meal (e.g., meal with 650 calories, 40% fat) or a high-fat high-calorie meal (e.g., meal with 1,000 calories, 50% fat). Do not take with a low-fat low-calorie meal (e.g., meal with 400 calories, 25% fat)
[see Clinical Pharmacology (12.3)].Timing and Duration of TreatmentTimingPyridostigmine bromide is a pretreatment for exposure to soman nerve agent.
There is no known advantage to taking pyridostigmine bromide just prior to, or concurrent with, soman exposure. According to the mechanism of action of pyridostigmine bromide
[see Clinical Pharmacology (12.1, 12.2)], pyridostigmine bromide is effective when it is given sufficiently in advance of soman poisoning to provide a pool of protected enzyme. Therefore, it is expected that pyridostigmine bromide will not be effective if administered just prior to or during exposure to soman.DurationAt the first sign of nerve agent poisoning, discontinue pyridostigmine bromide and administer pretreatment with atropine and pralidoxime immediately
[see Warnings and Precautions (5.1)].The benefits and risks of use beyond 14 consecutive days have not been definitively established; therefore, evaluate continued use beyond 14 consecutive days in the context of the likelihood of exposure to soman nerve agent.
Missed DoseIf a dose is missed, take the missed dose as soon as possible. Resume dosing at 24-hour intervals from the time the missed dose was taken. Do not take double or extra doses.
- Evaluate use beyond 14 consecutive days in the context of the likelihood of soman exposure. ()
2.2 Recommended Dosage, Administration, and DurationDosageThe recommended dosage of pyridostigmine bromide is 105 mg orally once daily with food, started at least several hours prior to exposure to soman. Do not take on an empty stomach. Take with a medium-fat medium-calorie meal (e.g., meal with 650 calories, 40% fat) or a high-fat high-calorie meal (e.g., meal with 1,000 calories, 50% fat). Do not take with a low-fat low-calorie meal (e.g., meal with 400 calories, 25% fat)
[see Clinical Pharmacology (12.3)].Timing and Duration of TreatmentTimingPyridostigmine bromide is a pretreatment for exposure to soman nerve agent.
There is no known advantage to taking pyridostigmine bromide just prior to, or concurrent with, soman exposure. According to the mechanism of action of pyridostigmine bromide
[see Clinical Pharmacology (12.1, 12.2)], pyridostigmine bromide is effective when it is given sufficiently in advance of soman poisoning to provide a pool of protected enzyme. Therefore, it is expected that pyridostigmine bromide will not be effective if administered just prior to or during exposure to soman.DurationAt the first sign of nerve agent poisoning, discontinue pyridostigmine bromide and administer pretreatment with atropine and pralidoxime immediately
[see Warnings and Precautions (5.1)].The benefits and risks of use beyond 14 consecutive days have not been definitively established; therefore, evaluate continued use beyond 14 consecutive days in the context of the likelihood of exposure to soman nerve agent.
Missed DoseIf a dose is missed, take the missed dose as soon as possible. Resume dosing at 24-hour intervals from the time the missed dose was taken. Do not take double or extra doses.
Extended-Release Tablets: 105 mg, peach, oval, coated, unscored, biconvex tablets imprinted with “A2 463” on one side and plain on the other side. A hole may be visible on one side of the tablet.
Renal impairment: Increased risk of side effects; careful dose selection. In persons with renal impairment, renal function monitoring may be useful. (
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Caution should be observed, and dosage be selected carefully, when administering pyridostigmine bromide to patients with impaired renal function.