Pyridostigmine bromide

1 INDICATIONS AND USAGE Pyridostigmine bromide is indicated for pretreatment against the lethal effects of soman nerve agent poisoning in adults. Pyridostigmine bromide is intended for use in conjunction with protective garments, including a mask. At the first sign of nerve agent poisoning, pyridostigmine bromide should be stopped, and atropine and pralidoxime therapy started immediately. The evidence for the effectiveness of pyridostigmine bromide as pretreatment against soman-induced toxicity was derived from animal studies alone [see Clinical Studies (14) ]. FOR MILITARY MEDICAL USE ONLY Pyridostigmine bromide is a cholinesterase inhibitor indicated for pretreatment against the lethal effects of soman nerve agent poisoning in adults. ( 1 ) Pyridostigmine bromide is for use in conjunction with Protective garments, including a gas mask, and Immediate atropine and pralidoxime therapy at the first sign of nerve agent poisoning. ( 1 )

2 DOSAGE AND ADMINISTRATION 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 ) At the first sign of soman nerve agent poisoning, discontinue pyridostigmine and administer atropine and pralidoxime immediately. ( 2.2 ) Evaluate use beyond 14 consecutive days in the context of the likelihood of soman exposure. ( 2.2 ) 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. Administration with Food Take 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 Alcohol Pyridostigmine bromide 105 mg extended-release tablets should not be taken with alcohol [see Clinical Pharmacology (12.3) ] . 2.2 Recommended Dosage, Administration, and Duration Dosage The 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 Treatment Timing Pyridostigmine 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. 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 miss…

5 WARNINGS AND PRECAUTIONS At the first sign of soman poisoning pyridostigmine must be stopped, and atropine and 2-PAM must be administered immediately. ( 5.1 ) Use with caution in persons with increased risk of anticholinergic reactions, such as persons with bronchial asthma, chronic obstructive pulmonary disease, bradycardia, cardiac arrhythmias, beta blocker treatment (increased risk of anticholinergic reactions). ( 5.2 ) Use with caution in persons with bromide sensitivity. ( 5.3 ) In case of serious adverse reactions, advise personnel to temporarily discontinue pyridostigmine and seek immediate medical attention. ( 5.4 ) 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. A skin rash may be observed in bromide-sensitive patients, which usually subsides 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 rea…

4 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. ( 4 ) Known hypersensitivity to pyridostigmine or other anticholinesterase agents. ( 4 )

7 DRUG INTERACTIONS Mefloquine: Additive effect on gastrointestinal tract and atrial rate. ( 7.1 ) Anticholinesterase drugs for glaucoma treatment: Additive effect. ( 7.2 ) Narcotics: Exacerbation of bradycardia possible. ( 7.3 ) Depolarizing neuromuscular blocking agents: Increased effect. ( 7.4 ) Non-depolarizing neuromuscular blocking agents: Dose may need to be increased. ( 7.4 ) Aminoglycoside antibiotics, local and some general anesthetics, antiarrhythmic agents, and other drugs that interfere with neuromuscular transmission should be used cautiously, if at all. ( 7.4 ) Drugs converted to pantothenic acid (e.g., dexpanthenol): Additive effect. ( 7.5 ) 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 non-depolarizing 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/m 2 ) 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.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Risk of Improper Use of Pyridostigmine Bromide [see Warnings and Precautions (5.1) ] Individuals at Increased Risk of Anticholinergic Adverse Reactions [see Warnings and Precautions (5.2) ] Use in Bromide-Sensitive Individuals [see Warnings and Precautions (5.3) ] Serious Adverse Reactions, Such as Difficulty Breathing, Severe Dizziness, Loss of Consciousness [see Warnings and Precautions (5.4) ] Most common adverse reactions ( ≥ 3% ) are diarrhea, abdominal pain, dysmenorrhea, and twitch. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 immediate-release pyridostigmine bromide 30 mg every 8 hours, which provides exposures comparable to pyridostigmine bromide 105 mg extended-release tablets once daily, 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. Table 1: Incidence of Adverse Reactions ≥ 2% Adverse Reaction Pyridostigmine N = 60 % Placebo N = 30 % Diarrhea 7 0 Abdominal pain 7 0 Dysmenorrhea 5 0 Twitch 3 0 Myalgia 2 0 Dry skin 2 0 Urinary frequency 2 0 Epistaxis 2 0 Amblyopia 2 0 Hypesthesia 2 0 Neck pain 2 0 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 of immediate release pyridostigmine bromide 30 mg every 8 hours, which provides exposures comparable to pyridostigmine bromide 105 mg extended-release tablets once daily, there were two reports of loss of consciousness, one of which 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 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.