Pyridostigmine Bromide

PYRIDOSTIGMINE BROMIDE- pyridostigmine bromide tablet
Valeant Canada Limited

  • Pyridostigmine bromide is for use as a pretreatment for exposure to the chemical nerve agent Soman. Pyridostigmine alone will not protect against exposure to soman. The efficacy of pyridostigmine is dependent upon the rapid use of atropine and pralidoxime (2-PAM) after Soman exposure. [See Dosage and Administration (2)]
  • 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 and on the antidotes atropine and pralidoxime (2-PAM) to provide complete protection from poisoning by the chemical nerve agent Soman.
  • Pyridostigmine must not be taken after exposure to Soman. If pyridostigmine 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 Clinical Pharmacology (12.2)]

FOR MILITARY MEDICAL USE ONLY

1 INDICATIONS AND USAGE

Pyridostigmine bromide is indicated for pretreatment against the lethal effects of Soman nerve agent poisoning. Pyridostigmine is intended for use in conjunction with protective garments, including a mask. At the first sign of nerve agent poisoning, pyridostigmine should be stopped, and atropine and pralidoxime therapy started immediately.

The evidence for the effectiveness of pyridostigmine as pretreatment against Soman-induced toxicity was derived from animal studies alone [see Nonclinical Toxicology (13.2)].

FOR MILITARY MEDICAL USE ONLY

2 DOSAGE AND ADMINISTRATION

PYRIDOSTIGMINE BROMIDE IS FOR USE AS A PRETREATMENT FOR EXPOSURE TO THE CHEMICAL NERVE AGENT SOMAN. PYRIDOSTIGMINE ALONE WILL NOT PROTECT AGAINST EXPOSURE TO SOMAN. THE EFFICACY OF PYRIDOSTIGMINE IS DEPENDENT UPON THE RAPID USE OF ATROPINE AND PRALIDOXIME (2-PAM) AFTER SOMAN EXPOSURE.

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, AND THE ANTIDOTES ATROPINE AND PRALIDOXIME (2-PAM) TO PROVIDE COMPLETE PROTECTION FROM POISONING BY THE CHEMICAL NERVE AGENT SOMAN.

PYRIDOSTIGMINE MUST NOT BE TAKEN AFTER EXPOSURE TO SOMAN. IF PYRIDOSTIGMINE 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 Clinical Pharmacology (12.2)].

The dose of pyridostigmine is one 30 mg tablet every 8 hours, started at least several hours prior to exposure to Soman. At the first sign of nerve agent poisoning, pyridostigmine should be discontinued and treatment with atropine and pralidoxime should be instituted immediately.

There is no known advantage to taking pyridostigmine just prior to or concurrent with Soman exposure. According to the mechanism of action of pyridostigmine described below [See Clinical Pharmacology (12.2)], pyridostigmine should be effective when it is given sufficiently in advance of Soman poisoning to provide a pool of protected enzyme. Therefore, it is expected that pyridostigmine will not be effective if administered just prior to or during exposure to Soman.

The benefits and risks of use beyond 14 consecutive days have not been definitively established, therefore, continued use beyond 14 consecutive days should be evaluated in the context of the likelihood of exposure to Soman nerve agent.

3 DOSAGE FORMS AND STRENGTHS

Pyridostigmine Bromide Tablets, USP, 30 mg, are round, white and imprinted with the letters “PBT”

4 CONTRAINDICATIONS

  • Mechanical intestinal or urinary obstruction
  • Known hypersensitivity to anticholinesterase agents

5 WARNINGS AND PRECAUTIONS

5.1 Stopping Pyridostigmine and Using Atropine and 2-PAM in the Event of Soman Exposure

See Dosage and Administration (2) and Boxed Caution statement (at beginning of Full Prescribing Information).

Pyridostigmine 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. Pyridostigmine should be discontinued at the first sign of nerve agent poisoning since it may exacerbate the effects of a sub-lethal exposure to Soman.

5.2 Individuals at Increased Risk of Anticholinergic Adverse Reactions

Pyridostigmine should be used with caution in persons with bronchial asthma, chronic obstructive pulmonary disease, bradycardia, cardiac arrhythmias, and, for example, in people being treated for hypertension or glaucoma with beta adrenergic receptor blockers.

5.3 Use in Bromide-Sensitive Individuals

Caution should be taken when administering pyridostigmine bromide to individuals with known bromide sensitivity. The risks and benefits of administration must be weighed against the potential for rash or other adverse reactions in these individuals. [See Adverse Reactions (6)]

5.4 Action in Case of Serious Adverse Reactions

If personnel experience serious adverse reactions such as difficult breathing, severe dizziness, or loss of consciousness as a result of ingestion of pyridostigmine bromide, they should be advised to temporarily discontinue use of product and seek immediate medical attention. Serious adverse events should be reported to their commander and responsible medical officer.

6 ADVERSE REACTIONS

The most common adverse reactions (≥ 3% ) are diarrhea, abdominal pain, dysmenorrhea, and twitch.

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.

Pyridostigmine 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.

Extremely high doses may produce CNS symptoms of agitation, restlessness, confusion, visual hallucinations, and paranoid delusions. Electrolyte abnormalities, possibly resulting from high serum bromide concentrations, also have been reported. Death may result from cardiac arrest or respiratory paralysis and pulmonary edema.

As with any compound containing bromide, a skin rash may be observed in an occasional patient, which usually subsides promptly upon discontinuance of the medication.

6.1 Clinical Studies Experience

In a controlled study of 90 healthy volunteers comparing pyridostigmine 30 mg every 8 hours to placebo for 21 days, the following incidence of adverse reactions was reported.

Table 1 Incidence of Adverse Reactions ≥ 2%
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, 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).

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