pyridostigmine bromide 180 MG Extended Release Oral Tablet [Mestinon]

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 )

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 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.

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. 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.

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 )

CLINICAL PHARMACOLOGY REGONOL ® (pyridostigmine bromide injection, USP) an analogue of neostigmine, facilitates the transmission of impulses across the myoneural junction by inhibiting the destruction of acetylcholine by cholinesterase. Currently available data indicate that pyridostigmine may have a significantly lower degree and incidence of bradycardia, salivation and gastrointestinal stimulation than does neostigmine. Animal studies using the injectable form of pyridostigmine and human studies using the oral preparation have indicated that pyridostigmine has a longer duration of action than does neostigmine measured under similar circumstances. 1,2 REGONOL ® is effective in reversing the neuromuscular blocking effects of nondepolarizing muscle relaxants. Anticholinesterase agents such as REGONOL ® and neostigmine may produce depolarization block when administered at doses above their recommended therapeutic ranges. The therapeutic index of REGONOL ® (ratio of reversal dose to blocking dose) is approximately 1:6 (see OVERDOSAGE ). 3 The antagonism of neuromuscular blockade by anticholinesterase agents may be influenced by the degree of spontaneous recovery achieved when the reversal agent is administered, by the particular relaxant administered, acid-base balance, body temperature, electrolyte imbalance, concomitant medications such as potent inhalational anesthetics, antibiotics or other drugs which enhance or antagonize the action of nondepolarizing muscle relaxants. 4 The use of peripheral nerve stimulation to determine the degree of neuromuscular blockade is recommended in evaluating the effects of the reversal agents. Failure of anticholinesterase agents to produce prompt (within 30 minutes) reversal of neuromuscular blockade may occur in the presence of extreme debilitation, carcinomatosis, and with concomitant use of certain broad-spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular blockade or cause respiratory depression through their own pharmacologic actions. As with other anticholinesterase agents, the administration of REGONOL® may be associated with muscarinic and nicotinic side effects, notably bradycardia and excessive bronchial secretions; the use of glycopyrrolate or atropine sulfate simultaneously with or prior to administration of REGONOL® is recommended to counteract these side effects (see DOSAGE AND ADMINISTRATION ). 5 Pharmacokinetics It has been postulated that the clearance of pyridostigmine is almost equally dependent on metabolism and on urinary elimination of the unchanged drug. 6 Other studies in man indicated that approximately 75 percent of the plasma clearance of pyridostigmine is dependent on renal excretion and the remainder on nonrenal mechanisms. 7