PYRIDOSTIGMINE BROMIDE

Pyridostigmine bromide is an orally active, reversible cholinesterase inhibitor. Pyridostigmine bromide is a white or almost white, crystalline, deliquescent powder, very soluble in water and alcohol, and practically insoluble in ether. CAS registration number is 101-26-8. Pyridostigmine bromide has a molecular formula of C 9 H 13 BrN 2 O 2 , with a molecular weight of 261.12. Its chemical name is 3-hydroxy-1-methylpyridinium bromide dimethylcarbamate, and its structural formula is: Pyridostigmine bromide extended-release tablets contain 105 mg of pyridostigmine bromide (equivalent to 72.87 mg of pyridostigmine base) for oral administration. The inactive ingredients included in the tablet formula are ammonia methacrylate copolymer, ammonium hydroxide, black iron oxide, calcium carbonate, colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, mannitol, propylene glycol, shellac glaze, sodium bicarbonate, succinic acid, talc, titanium dioxide, and triethyl citrate. structural formula

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 )

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 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.

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 )

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 (suggesting a seizure event). 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.

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.