2.1 Important Administration Information

For Military Medical Use Only.

Treatment and Protection for Soman Exposure

Pyridostigmine 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 Pralidoxime

The efficacy of pyridostigmine bromide is dependent upon the rapid use of atropine and pralidoxime (2-PAM) after soman exposure.

Primary Protection

The 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 Timing

Pyridostigmine 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.

2.2 Recommended Dosage, Administration, and Duration

Dosage

The recommended dosage of pyridostigmine bromide is one 30-mg tablet by mouth every 8 hours, started at least several hours prior to exposure to soman.

Timing and Duration of Treatment

Timing

Pyridostigmine 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.

Duration

At 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 Dose

If a dose is missed, take the missed dose as soon as possible. Do not take double or extra doses.

5.1 Risk of Improper Use of Pyridostigmine Bromide

Risk of Not Stopping Pyridostigmine Bromide and Using Atropine and Pralidoxime in the Event of Soman Exposure

Pyridostigmine 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 sublethal 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 Garments

Pyridostigmine 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.

5.2 Increased Risk of Anticholinergic Adverse Reactions in Individuals with Certain Conditions

Pulmonary Conditions

Drugs that increase cholinergic activity, including pyridostigmine bromide, should be used with caution in persons with bronchial asthma or chronic obstructive pulmonary disease.

Cardiovascular Conditions

Because pyridostigmine bromide increases cholinergic activity, it may have vagotonic effects on heart rate, which can lead to bradycardia or cardiac arrhythmias.

Genitourinary Tract or Gastrointestinal Tract Obstruction

Drugs that increase cholinergic agents, including pyridostigmine bromide, could cause symptoms in persons susceptible to genitourinary tract or gastrointestinal tract obstruction.

Conditions Treated with Beta Adrenergic Receptor Blockers

Pyridostigmine bromide should be used with caution in people being treated for hypertension or glaucoma with beta adrenergic receptor blockers [see Drug Interactions (7.2)].

5.3 Use in Bromide-Sensitive Individuals

Caution should be taken when administering pyridostigmine bromide to individuals with known bromide sensitivity. As with any compound containing bromide, a skin rash may be observed in bromide-sensitive patients, which usually subsides promptly upon discontinuance of the medication.

The risks and benefits of administration must be weighed against the potential for rash or other adverse reactions in these individuals.

5.4 Serious Adverse Reactions, Such as Difficulty Breathing, Severe Dizziness, Loss of Consciousness

Pyridostigmine bromide can cause serious adverse reactions such as difficulty breathing, severe dizziness, or loss of consciousness. If these adverse reactions occur, patients should temporarily discontinue use of pyridostigmine bromide and seek immediate medical attention. Personnel should report serious adverse events to their commander and responsible medical officer.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The adverse reactions to pyridostigmine bromide are typically of two varieties: muscarinic and nicotinic. Muscarinic adverse reactions include abdominal cramps, bloating, flatulence, diarrhea, emesis, increased peristalsis, nausea, hypersalivation, urinary incontinence, increased bronchial secretion, diaphoresis, miosis, and lacrimation. Nicotinic adverse reactions are comprised chiefly of muscle cramps, fasciculations, and weakness.

In a controlled study of 90 healthy volunteers comparing pyridostigmine bromide 30 mg every 8 hours to placebo for 21 days, the adverse reactions that were reported in 2% or more of subjects is included in Table 1. The most common adverse reactions (≥ 3%) are diarrhea, abdominal pain, dysmenorrhea, and twitch.

Other less common adverse reactions seen during controlled and uncontrolled clinical trials for pyridostigmine include the following:

• Pulmonary: Exacerbation of acute bronchitis and asthma
• Cardiovascular: Elevated blood pressure, decreased heart rate (4-6 beats per minute), chest tightness
• Eyes: Change in vision, eye pain
• Neurologic: Headache, hypertonia, difficulty in concentrating, confusion, disturbed sleep, tingling of extremities, numbness of the tongue
• Skin: Increased sweating, rash, alopecia
• Digestive: Vomiting, borborygmi, nausea, bloating, flatulence
• General: Warm sensation, lethargy/drowsiness, depressed mood

During safety studies at the recommended dosage, there were two reports of loss of consciousness, one of which was suggestive of a seizure event as it also included urinary and fecal incontinence, stiffness of the upper torso and arms, post-syncopal skin pallor, post-syncopal confusion, and post-syncopal weakness.

Central Nervous System Adverse Reactions

Pyridostigmine bromide is a quaternary ammonium compound and does not readily cross the blood-brain barrier. Compared to the peripheral effects of pyridostigmine bromide, central nervous system (CNS) manifestations are less frequent and less serious, primarily consisting of headache and vertigo, with minor and clinically insignificant changes in heart rate, blood pressure, and respiratory function.

7.1 Mefloquine

Concomitant use of mefloquine and pyridostigmine bromide may have additive effects on the gastrointestinal tract, the most common of which is loose bowels. Additive effects on the atrial rate may also occur with concomitant use of mefloquine and pyridostigmine bromide.

7.2 Other Anticholinesterase Drugs

Concomitant use of anticholinesterase drugs used in the treatment of glaucoma and pyridostigmine bromide may have an additive effect that may cause or exacerbate problems with night vision.

7.3 Narcotics

The bradycardia associated with the use of narcotics may exacerbate pyridostigmine-induced bradycardia.

7.4 Drugs that Interfere with Neuromuscular Transmission

Particular caution should be observed in the administration of depolarizing neuromuscular blocking agents (e.g., succinylcholine) during surgery since the degree of neuromuscular blockade that ensues may be enhanced by previously administered pyridostigmine bromide. Doses of nondepolarizing neuromuscular blocking agents (e.g., pancuronium bromide) may need to be increased in patients previously administered pyridostigmine bromide. Atropine antagonizes the muscarinic effects of pyridostigmine bromide, and this interaction is utilized to counteract the muscarinic symptoms of pyridostigmine bromide toxicity. Anticholinesterase agents are sometimes effective in reversing neuromuscular block induced by aminoglycoside antibiotics. However, aminoglycoside antibiotics, local and some general anesthetics, antiarrhythmic agents, and other drugs that interfere with neuromuscular transmission should be used cautiously, if at all, during treatment with pyridostigmine bromide.

7.5 Drugs Converted to Pantothenic Acid

Concomitant use of drugs that are converted to pantothenic acid in vivo (e.g., dexpanthenol) and pyridostigmine bromide may have additive effects by increasing production of acetylcholine.

8.1 Pregnancy

Risk Summary

Available data from case reports and case series over decades of use with pyridostigmine bromide have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Treatment with pyridostigmine bromide for soman nerve agent poisoning during pregnancy should not be delayed because exposure to soman during pregnancy may increase the risk of maternal and fetal morbidity and mortality.

In animal studies, oral administration of pyridostigmine during organogenesis resulted in adverse developmental effects (increased embryofetal mortality and fetal structural abnormalities) at clinically relevant doses (see Data).

The background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Oral administration of pyridostigmine to pregnant rats during organogenesis resulted in increases in embryofetal deaths and incidences of fetal skeletal variations at the highest dose tested (30 mg/kg/day), which was also maternally toxic. A slight increase in the incidence of hydronephrosis was observed at all dose levels (lowest dose tested was 3 mg/kg/day). A no-effect dose for adverse effects on embryofetal development in the rat was not identified. The lowest dose tested (3 mg/kg/day) is less than the recommended human dose (105 mg) on a body surface area (mg/m2) basis.

Oral administration of pyridostigmine to pregnant rabbits during organogenesis resulted in an increase in the incidence of visceral variations at the highest dose tested (45 mg/kg/day), which was also maternally toxic. An increased incidence of blood vessel variations was observed at all doses (lowest dose tested was 5 mg/kg/day). A no-effect dose for adverse effects on embryofetal development in the rabbit was not identified. The lowest dose tested (5 mg/kg/day) is less than the recommended human dose on a body surface area (mg/m2) basis.

8.2 Lactation

Risk Summary

Pyridostigmine bromide is present in human milk. Based on limited data, pyridostigmine bromide was not detected in the plasma of infants who were breastfed by mothers taking pyridostigmine bromide. There are no data on the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pyridostigmine bromide and any potential adverse effects on the breastfed infant from pyridostigmine bromide or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of pyridostigmine bromide did not contain sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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. Because elderly patients are more likely to have decreased renal function [see Clinical Pharmacology (12.3)], care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Impairment

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 [see Clinical Pharmacology (12.3)]. It may be useful to monitor renal function.

12.1 Mechanism of Action

Pyridostigmine is a reversible cholinesterase inhibitor.

12.2 Pharmacodynamics

The 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)].

12.3 Pharmacokinetics

Absorption

Pyridostigmine bromide is poorly absorbed from the gastrointestinal tract with an absolute bioavailability of 10% to 20%. Following a single oral dose of 30 mg pyridostigmine bromide in the fasting state, the Tmax was 2.2 ± 1.0 hours. The pharmacokinetics of pyridostigmine bromide is linear over the dose range of 30 mg to 60 mg. Following multiple doses of pyridostigmine bromide (30 mg every 8 hours for 21 days), the average steady-state trough concentration of pyridostigmine bromide was about ¼ of the peak concentration after a single dose.

Distribution

The volume of distribution was about 19 ± 12 liters, indicating that pyridostigmine bromide distributes into tissues. No information on protein binding of pyridostigmine bromide is available.

Elimination

Metabolism

Pyridostigmine bromide undergoes hydrolysis by cholinesterases and is metabolized in the liver.

Excretion

Pyridostigmine bromide is excreted in the urine as both unchanged drug and its metabolites. The systemic clearance of pyridostigmine bromide is 830 mL/min and the elimination half-life of pyridostigmine bromide is approximately 3 hours.

Specific Populations

Patients with Renal Impairment: In anephric patients (n = 4), the elimination half-life increased 3-fold and the systemic clearance decreased by 75% [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment: No information is available on the pharmacokinetics of pyridostigmine bromide in hepatic impaired patients.

Male and Female Patients: The clearance of pyridostigmine bromide is not influenced by sex.

Geriatric Patients: In a pyridostigmine bromide study in elderly subjects (71 to 85 years of age), the elimination half-life and volume of distribution (central and steady-state) of pyridostigmine were comparable with younger subjects (21 to 51 years of age). However, the systemic plasma clearance was 30% lower in the elderly compared to younger subjects (6.7 ± 2.2 vs. 9.5 ± 2.7 mL/min/kg) [see Use in Specific Populations (8.5)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Studies to evaluate the carcinogenic potential of pyridostigmine bromide have not been conducted.

Mutagenicity

Pyridostigmine bromide was negative in in vitro (bacterial reverse mutation, mammalian gene mutation in Chinese hamster ovary (CHO) cells, clastogenicity in CHO cells) and in vivo (mouse micronucleus) assays. Pyridostigmine bromide was mutagenic and clastogenic in an in vitro mammalian gene mutation assay in mouse lymphoma cells, in the presence of metabolic activation.

Impairment of Fertility

Pyridostigmine bromide did not impair fertility in male or female rats given oral doses of up to 45 mg/kg/day (5 times the recommended human daily dose of 90 mg on a mg/m2 basis) beginning at 10 (males) or 2 (females) weeks prior to mating.

16.1 How Supplied

Pyridostigmine bromide tablets, USP, 30 mg, are round, white tablets imprinted with the letters "PBT."

Immediate Container: Individually sealed blister or strip package containing twenty-one (21) tablets which is supplied in a protective sleeve.

NDC 72458-128-03

Secondary Container: A protective foil overwrap containing ten (10) immediate containers (sleaved blister of strip packages) containing 210 tablets total.

NDC 72458-128-04

  NSN 6505-01-178-7903. The NSN refers to the secondary container unit that is ordered from supply (1 of this stock number is one foil overwrap of 10 blister packs).

Shipping Carton Contents: Ten (10) foil overwrap packages containing ten (10) blister or strip packages containing 2,100 tablets total.

16.2 Storage and Handling

Store refrigerated between 2°C to 8°C (36°F to 46°F) in carton or foil overwrap to protect from light until the expiration date. Once removed from refrigerator, store at 20°C to 25°C (68°F to 77°F) [see USP controlled room temperature] in carton or foil overwrap for up to 5 years minus half of the time spent under refrigerated storage or until the expiration date, whichever comes first. Following removal of the blister packages from the foil overwrap, discard the contents of the blister package after 14 months or after the expiration date, whichever comes first.