Pyridostigmine Bromide: Package Insert and Label Information

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).

7 DRUG INTERACTIONS

7.1 Mefloquine

A potential interaction between the antimalarial drug mefloquine and pyridostigmine bromide exists through a possible additive effect on the gastrointestinal tract. The most common complaint about both drugs is loose bowels. It has been reported that simple additive effects on the atrial rate occur when mefloquine and pyridostigmine bromide are combined.

7.2 Other Anticholinesterase Drugs

Because anticholinesterase drugs are often used in the treatment of glaucoma, the use of pyridostigmine bromide in such situations 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. Atropine antagonizes the muscarinic effects of pyridostigmine, and this interaction is utilized to counteract the muscarinic symptoms of pyridostigmine 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.

7.5 Drugs Converted to Pantothenic Acid (e.g., Dexpanthenol)

Theoretically, drugs such as dexpanthenol, which are converted to pantothenic acid in vivo, may have additive effects with pyridostigmine by increasing production of acetylcholine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pyridostigmine produced no teratogenic effects in rats given up to 30 mg/kg/day and in rabbits given up to 45 mg/kg/day orally during the period of organogenesis. These doses are 3 and 10 times, respectively, the recommended human dose of 90 mg on a mg/m2 basis. In rats, a slight degree of delayed skeletal ossification was seen at 30 mg/kg, a dose which caused maternal toxicity, and a slight increase in the incidence of hydronephrosis was seen at all dose levels (lowest dose tested was 3 mg/kg). In rabbits, a slight increase in the incidence of hydronephrosis was seen at 45 mg/kg, a dose which caused maternal toxicity, and increased incidences of blood vessel variations were seen at all doses (lowest dose tested was 5 mg/kg). There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when pyridostigmine is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of pyridostigmine did not contain sufficient numbers of subjects aged 65 and over to determine whether they respond differently from 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.

In the elderly (71-85 years of age) the elimination half-life, volume of distribution (central and steady state) were comparable with the young (21-51 years of age). However, the systemic plasma clearance was significantly lower in the elderly compared to the young (6.7 ± 2.2 vs. 9.5 ± 2.7 ml/min/kg).

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, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Persons with 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. In anephric patients, a 3-fold increase in the elimination half-life and a 75% decrease in systemic clearance was observed [see Clinical Pharmacology (12.3)] It may be useful to monitor renal function.

8.7 Persons with Hepatic Impairment

No information is available on the pharmacokinetics of pyridostigmine in hepatic impaired patients.

9 DRUG ABUSE AND DEPENDENCE

9.2 Abuse

Although the abuse potential of pyridostigmine has not been specifically assessed, no abuse of, tolerance to, withdrawal from, or drug-seeking behavior was observed in patients who received pyridostigmine in clinical trials. Cholinesterase inhibitors are not believed to be associated with drug abuse.

10 OVERDOSAGE

As is true of all cholinergic drugs, overdosage of pyridostigmine bromide may result in cholinergic crisis, a state characterized by increasing muscle weakness that, through involvement of the muscles of respiration, may lead to death. Overdosage with pyridostigmine must be differentiated from the acute manifestations of nerve agent poisoning which may also be characterized by a cholinergic crisis. Atropine should be used to treat pyridostigmine overdosage.

In the treatment of pyridostigmine overdosage, maintaining adequate respiration is of primary importance. Tracheostomy, bronchial aspiration, and postural drainage may be required to maintain an adequate airway; respiration can be assisted mechanically if required. Supplemental oxygen may be necessary. Pyridostigmine should be discontinued immediately and 1-4 mg of atropine sulfate administered i.v. Additional doses of atropine may be given every 5-30 minutes as needed to control muscarinic symptoms. Atropine overdosage should be avoided, as tenacious secretions and bronchial plugs may result. It should be kept in mind that unlike muscarinic effects, the skeletal muscle effects and consequent respiratory paralysis (nicotinic effects) which can occur following pyridostigmine overdosage are not alleviated by atropine.

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