5.1 Stopping Pyridostigmine Bromide 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).

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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. Pyridostigmine should be discontinued at the first sign of nerve agent poisoning (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) because it may exacerbate the effects of a sub-lethal exposure to soman.

5.2 Individuals at Increased Risk of Anticholinergic Adverse Reactions

Pyridostigmine bromide should be used with caution in persons with bronchial asthma, chronic obstructive pulmonary disease, bradycardia, or 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 temporarily discontinue use of product and seek immediate medical attention. Personnel should report serious adverse events to their commander and responsible medical officer.

6.1 Clinical Studies Experience

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

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).

7.1 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 (eg, 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 (eg, 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 (e.g., Dexpanthenol)

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

8.1 Pregnancy

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 bromide 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 bromide did not contain sufficient numbers of subjects aged 65 and over to determine whether they respond differently than 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 to 85 years of age) the elimination half-life, volume of distribution (central and steady state) were comparable with the young (21to 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 were 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 bromide in hepatic impaired patients.

9.2 Abuse

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

12.1 Mechanism of Action

Pyridostigmine is a reversible cholinesterase inhibitor.

12.2 Pharmacodynamics

The mechanism of soman-induced death is reasonably well understood. Death is believed to result primarily from respiratory failure due to irreversible inhibition of the enzyme acetylcholinesterase and the consequent increase in the level of the neurotransmitter acetylcholine 1) at nicotinic receptors at the neuromuscular junction, resulting in pathological stimulation and ultimate failure of the muscles of respiration, 2) at muscarinic receptors in secretory glands and smooth muscle, resulting in excessive respiratory secretions and bronchoconstriction, and 3) at cholinergic receptors in the brain, resulting in central respiratory depression.

The effect of pyridostigmine is presumed to result from its reversible inhibition of a critical number of acetylcholinesterase active sites in the peripheral nervous system, protecting them from irreversible inhibition by soman. (Pyridostigmine bromide is not thought to enter the brain in significant amounts.) When the pyridostigmine bromide-induced inhibition of the enzyme is subsequently reversed, there is a small residual amount of enzyme activity that is adequate to sustain life (provided atropine and 2-PAM are subsequently administered). An implication of this presumed mechanism is that it is not helpful to give pyridostigmine bromide either just before or during exposure to soman.

12.3 Pharmacokinetics

Pyridostigmine bromide is poorly absorbed from the gastrointestinal tract with an absolute bioavailability of 10% to 20%. Following a single oral dose of 30 mg pyridostigmine bromide in the fasting state, the TMAX was 2.2 ± 1.0 hours. The pharmacokinetics of pyridostigmine bromide is linear over the dose range of 30 mg to 60 mg. Following multiple doses of pyridostigmine bromide (30 mg every 8 hours for 21 days), the average steady-state trough concentration of pyridostigmine bromide was about ¼ of the peak concentration after a single dose.

The volume of distribution was about 19 ± 12 liters, indicating that pyridostigmine bromide distributes into tissues. No information on protein binding of pyridostigmine bromide is available.

Pyridostigmine bromide undergoes hydrolysis by cholinesterases and is metabolized in the liver. It is excreted in the urine as both unchanged drug and its metabolites. The systemic clearance of pyridostigmine bromide is 830 mL/min and the elimination half-life of pyridostigmine bromide is approximately 3 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Evidence of the effectiveness of pyridostigmine bromide as a pretreatment for soman poisoning was obtained from studies in animals alone, because it is unethical to perform such studies in humans. While the results of these animal studies cannot be extrapolated to humans with certainty, the extrapolation is supported by the reasonably well understood pathophysiologic mechanisms of the toxicity of soman and the mechanism of the protective effect of pyridostigmine bromide pretreatment, as examined in various animal species. In addition, the results of these animal studies establish that pyridostigmine bromide is reasonably likely to produce clinical benefit in humans. The section below explains the current understanding of the mechanism of soman toxicity and the beneficial effect of pyridostigmine bromide pretreatment, as well as the basis for extrapolating the animal findings to humans.

Pyridostigmine bromide pretreatment has been shown in animals to decrease the lethality of the soman nerve agent, provided atropine and pralidoxime (2-PAM) are administered immediately after exposure to soman.

Rhesus monkeys were given oral doses of pyridostigmine bromide every 8 hours for a total of 6 doses and were challenged with soman given intramuscularly 5 hours after the last pyridostigmine bromide dose. Two dosage groups of pyridostigmine bromide were used: a low-dose group given 1.2 mg/kg for all 6 doses and a high-dose group given 1.2 and 1.8 mg/kg for the first and second doses, respectively, and 2.4 mg/kg for the final 4 doses. These animals were also given atropine and 2-PAM after exposure to soman. An untreated control group and a group given atropine and 2-PAM (but not pyridostigmine bromide) were also used. The primary endpoint in this study was a decrease in the lethality of soman expressed as an increase in the LD50 (the dose of soman that killed 50 % of the animals). The atropine/2-PAM control group showed a small but statistically significant 1.6-fold increase in the soman LD50 compared to the untreated control group. The groups given pyridostigmine bromide as well as atropine and 2 PAM showed increases in the soman LD50 of at least 40-fold compared to the untreated control group and at least 25 fold compared to the atropine/2-PAM group. The two dose levels of pyridostigmine bromide showed similar effectiveness.

Additional studies in rhesus monkeys and guinea pigs also showed effectiveness of pyridostigmine bromide (in the presence of post-soman administration of atropine and 2-PAM). The magnitude of effect in guinea pigs was smaller than that in monkeys (soman LD50 increased 4 to 7 fold compared to untreated control and 2- to 4-fold compared to atropine/ 2-PAM alone).

Pyridostigmine bromide produced only small and inconsistent effects in studies in rats, mice, and rabbits. It is thought that the effect of pyridostigmine bromide in rats and mice is masked by high blood levels of the enzyme carboxylesterase, which eliminates soman from blood and makes those species highly resistant to soman. In a study in which rats were given an inhibitor of carboxylesterase, pretreatment with pyridostigmine bromide plus atropine and 2 PAM increased the LD50 of soman 8.5-fold compared to untreated controls. Humans have little or no carboxylesterase in blood.

Animal studies have shown that pyridostigmine bromide pretreatment was effective only when animals were given atropine and 2-PAM after exposure to soman.

Storage

Store in refrigerator (2° to 8°C) (36 to 46°F). Protect from light.

Discard the contents of the blister package after removal from refrigerator for more than a total of 3 months. Do not use after the 10-year expiration date provided on the package.

17.1 Indication and Conditions of Use

• Pyridostigmine bromide is approved as a pretreatment for protection against the chemical nerve agent soman (GD). PB has not been approved for use against other chemical nerve agents including Sarin (GB), Tabun (GA), and VX. [See Indications and Usage (1).]
  The approval is based on safety studies in humans and effectiveness studies conducted in animals. The FDA has approved pyridostigmine bromide based only on animal studies of effectiveness because it is not ethical to do these studies in humans. Human studies would require exposing people to the deadly effects of nerve agents, risking poisoning them or even killing them. Studies in monkeys and guinea pigs show that pretreatment with pyridostigmine bromide makes the antidotes (atropine and 2-PAM) work better against soman (GD). [See Nonclinical Toxicology (13.2).]
• The main protection against chemical weapons is the chemical protective mask and battle dress overgarments. [See boxed WARNINGS and Dosage and Administration (2).]
• Pyridostigmine bromide is used as a pretreatment against a soman nerve agent attack. Based on the animal studies, it is thought that any potential benefits from use of pyridostigmine bromide occur only if:

  (1)

  It is taken within 8 hours before, but not right before, exposure to the nerve agent soman. If it is taken right before (when the nerve gas attack alarm is given) or during nerve agent exposure, it may not work and may make the effects of soman worse.

  (2)

  Atropine and 2-PAM are used when symptoms of nerve agent poisoning occur. The two antidotes are part of the ATNAA (Antidote Treatment – Nerve Agent Autoinjector). See Dosage and Administration (2).

17.2 Dosage and Administration

• The chain of command will tell personnel when it is time to take pyridostigmine bromide, based on the threat of exposure to soman nerve agents.
• One tablet must be taken every 8 hours until the chain of command tells personnel to stop taking pyridostigmine bromide.
• Pyridostigmine bromide tablets must not be taken more often. The dose must not be doubled if a dose has been missed.
• There is no known advantage to taking extra pyridostigmine bromide right before soman exposure.
• No further pyridostigmine bromide should be taken after nerve agent exposure has occurred, instead:
• Persons experiencing most or all of the MILD symptoms of nerve agent poisoning (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) should IMMEDIATELY AVOID INHALATION (hold their breath) AND PUT ON THEIR PROTECTIVE MASK. Then atropine and 2 PAM (one ATNAA) must be administered.
  See Dosage and Administration (2).
  Personnel should contact their unit medical officer if adverse reactions from pyridostigmine bromide continue and limit duty performance.

17.3 Contraindications and Precautions

Pyridostigmine bromide must not be taken by persons with any of the following:

• Mechanical bowel or bladder obstruction
• Hypersensitivity to anticholinesterase medicines (certain drugs used during surgery like physostigmine, edrophonium, neostigmine, and ambenonium)
  See Contraindications (4).

Personnel should be instructed to inform their doctor or medic before taking pyridostigmine bromide if they:

• Are pregnant
• Have asthma
• Are allergic to bromide
• Take a beta blocker (a medicine to treat, eg, high blood pressure)
• Have high eye pressure (glaucoma)
• Have any other medical condition, including heart problems or reflux esophagitis (GERD)

See Warnings and Precautions (5.2).

17.4 Side Effects (Adverse Reactions)

The following adverse reactions are possible (this list of adverse reactions is not complete.):

• Stomach cramps
• Gas
• Diarrhea
• Nausea
• Frequent urination
• Increased salivation
• Sweating
• Headaches
• Dizziness
• Watery eyes
• Blurred vision
• Runny nose
• Difficulty or tightness in breathing
• Acid stomach (including heartburn or reflux)
• Tingling of fingers, toes, arms, and legs
• Muscle twitching or weakness
• Muscle cramps

See Adverse Reactions (6).

Most side effects are mild and will disappear without treatment.

Pyridostigmine bromide has been safely used and has been FDA approved for over 40 years in the US to treat a disease called myasthenia gravis (MG). Human studies of pyridostigmine bromide at doses intended for military use have found pyridostigmine bromide to be generally safe.

Personnel should contact their unit medical officer if side effects from pyridostigmine bromide continue and limit duty performance.

17.5 Collection of Information

The Department of Defense (DoD) may collect information on the use of pyridostigmine bromide to help decide how best to protect deployed forces in the future. Information that identifies individual persons will remain confidential. However, the FDA may review any data collected by DoD for the purpose of evaluating pyridostigmine bromide.

17.6 Questions and Requests for Information

Questions about personnel rights and welfare should be directed to the unit medical officer, or e-mailed to usamrmcregulatoryaffairs@mail.mil.

Personnel can receive information about pyridostigmine bromide from unit medical officers or medics. Questions about pyridostigmine bromide can also be e-mailed directly to the US Army Medical Research and Materiel Command at address usarmy.detrick.medcom-usammda.mbx.usamrmc-regulatory-affairs@mail.mil.