Regonol (Page 2 of 3)

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Experience concerning injection of quinidine during recovery from use of nondepolarizing muscle relaxants suggest that recurrent paralysis may occur. This possibility must be considered when administering anticholinesterase agents to antagonize neuromuscular blockade induced by nondepolarizing muscle relaxants.

Electrolyte imbalance and diseases which lead to electrolyte imbalance, such as adrenal cortical insufficiency, have been shown to alter neuromuscular blockade. Depending on the nature of the imbalance, either enhancement or inhibition may be expected. Magnesium salts, administered for the management of toxemia of pregnancy, may enhance the neuromuscular blockade. The possibility that such circumstances may interfere with the restoration of neuromuscular function should be considered when administering REGONOL®.

Interactions with Laboratory Tests

None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential or impairment of fertility.

Pregnancy

It is not known whether REGONOL® (pyridostigmine bromide injection, USP) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. REGONOL® should be given to a pregnant woman only if the administering clinician decides that the benefits outweigh the risks.

Pediatric Use

Safety and efficacy in pediatric patients have not been established.

Benzyl alcohol, a component of this drug product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

ADVERSE REACTIONS

The side effects of pyridostigmine bromide are most commonly related to overdosage and generally are of two varieties, muscarinic and nicotinic. Among those in the former group are nausea, vomiting, diarrhea, abdominal cramps, increased peristalsis, increased salivation, increased bronchial secretions, miosis, and diaphoresis. Nicotinic side effects are comprised chiefly of muscle cramps, fasciculation, and weakness. Muscarinic side effects can usually be counteracted by atropine. As with any compound containing the bromide radical, a skin rash may be seen in an occasional patient. Such reactions usually subside promptly upon discontinuance of the medication. Thrombophlebitis has been reported subsequent to intravenous administration.

OVERDOSAGE

THE POSSIBILITY OF IATROGENIC OVERDOSAGE CAN BE MINIMIZED BY CAREFULLY MONITORING THE MUSCLE TWITCH RESPONSE TO PERIPHERAL NERVE STIMULATION. Should overdosage occur, ventilation should be supported by artificial means until the adequacy of spontaneous respiration is assured, and cardiac function should be monitored.

Respiratory depression following administration of nondepolarizing neuromuscular blocking agents may be due either wholly or in part to other drugs used during the conduct of general anesthesia, such as narcotics, thiobarbiturates and other central nervous system depressants. A peripheral nerve stimulator may be used to assess the degree of residual neuromuscular blockade and to help differentiate residual neuromuscular blockade from other causes of decreased respiratory reserve.

DOSAGE AND ADMINISTRATION

REGONOL® (pyridostigmine bromide injection, USP) 2 mL single-dose ampule is for intravenous use only. This drug should be administered by or under the supervision of experienced clinicians familiar with the use of agents which reverse or antagonize the effects of neuromuscular blocking agents. Dosage must be individualized in each case. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

NOTE: CONTAINS BENZYL ALCOHOL (see PRECAUTIONS)

Reversal doses of REGONOL® range from 0.1 to 0.25 mg/kg.5,10,11,12,13 The onset time to peak effect is dose-dependent; return of twitch height to 90% of control occurs within approximately 6 minutes following administration of a 0.25 mg/kg dose of REGONOL®.5,12 At lower doses, full recovery usually occurs within 15 minutes in most patients, although others may require a half-hour or more.

When REGONOL® is given intravenously to reverse the action of muscle relaxant drugs, it is recommended that atropine sulfate (0.6 to 1.2 mg) or an equipotent dose of glycopyrrolate be given immediately prior to or simultaneously with the administration of REGONOL®. Side effects, notably excessive secretions and bradycardia are thereby minimized. Please refer to the appropriate prescribing information prior to the use of glycopyrrolate or atropine sulfate.

To obtain maximum clinical benefits of REGONOL® and to minimize the possibility of overdosage, the monitoring of muscle twitch response to peripheral nerve stimulation is advised. REGONOL® should be administered after spontaneous recovery of neuromuscular function has begun.

Satisfactory reversal can be evident by adequate voluntary respiration, respiratory measurements and use of a peripheral nerve stimulator device. It is recommended that the patient be well-ventilated and a patent airway maintained until complete recovery of normal respiration is assured. Once satisfactory reversal has been attained following administration of REGONOL® , recurrence of paralysis is unlikely to occur.

Inadequate reversal of neuromuscular blockade by anticholinesterase drugs is possible with all curariform drugs, and is managed by manual or mechanical ventilation until recovery is judged adequate. The administration of additional doses of anticholinesterase reversal agents is not recommended since excessive dosages of such drugs may produce depolarizing block through their own pharmacological actions.

Use in Pediatrics

The safety and efficacy of REGONOL® (pyridostigmine bromide injection, USP) in pediatric patients have not been established, therefore no dosing recommendations can be made (see PRECAUTIONS).

HOW SUPPLIED

REGONOL® (pyridostigmine bromide injection USP) for injection is available as 2 mL single-dose ampule containing 10 mg pyridostigmine bromide (5 mg/mL) and supplied as:

NDC 0781-3040-95 — box of 10 x 2 mL Single-Dose Ampules

CONTAINS BENZYL ALCOHOL.

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) (see USP Controlled Room Temperature). Protect from light.

REFERENCES

1.
Baker PR, Calvey TN, Chan K, Macnee CM, Taylor K. Plasma clearance of neostigmine and pyridostigmine in the dog. Br J Pharmacol 1978;63:509-512.
2.
Cronnelly R, Stanski DR, Miller RD, Sheiner LB. Pyridostigmine kinetics with and without renal function. Clin Pharmacol & Ther 1980;28:78-81.
3.
Katz RL. Pyridostigmine (Mestinon) as an antagonist of d-tubocurarine. Anesthesiology 1967;28:528-534.
4.
Miller RD. Antagonism of neuromuscular blockade. Anesthesiology 1967; 44: 318-329.
5.
Gyermek L. Clinical studies on the reversal of the neuromuscular blockade produced by pancuronium bromide. 1. The effects of glycopyrrolate and pyridostigmine. Curr Ther Res 1975; 18:20-23.
6.
Williams ME, Calvey TN, Chan K. Plasma concentration of pyridostigmine during the antagonism of neuromuscular block. Br J Anesth 1983; 55:27-30.
7.
Miller RD. Pharmacodynamics and pharmacokinetics of anticholinesterase. In: Ruegheimer E, Zindler M, eds., Anaesthesiology , Amsterdam, Netherlands: Excerpta Medica 1981: 222-223.
8.
Breyer-Pfaff U, Maier U, Brinkmann AM, Schumm F. Pyridostigmine kinetics in healthy subjects and patients with myasthenia gravis. Clin Pharmacol Ther 1985;5:494-501.
9.
Miller RD, Booij LH, Agoston S, Crul JF. 4-aminopyridine potentiates neostigmine and pyridostigmine in man. Anesthesiology 1979;50:416-420.
10.
Gyermek L. The Glycopyrrolate-Pyridostigmine Combination. Anesthesiology Review 1978;5:19-22.
11.
Zsigmond EK. New Safe and Effective Antagonist of Pancuronium Bromide: Pyridostigmine Bromide. A Scientific Exhibit Presented at the American Medical Association Annual Convention in New York City, NY; June 23-27, 1973.
12.
Rusin WD. Comparison of Neostigmine and Pyridostigmine as Antagonists of Pancuronium Neuromuscular Blockade. ASA Clinical Papers , 299-300, 1976.
13.
Katz R. Pyridostigmine as an Antagonist of d-Tubocurarine. Anesthesiology 1967;3:528-534.
14.
Miller RD, Van Nyhuis LS, Eger EI, Vitez TS, Way WL. Comparative Times to Peak Effect and Durations of Action of Neostigmine and Pyridostigmine. Anesthesiology 1974;41:27-33.
15.
Fogdall RP, Miller RD. Antagonism of d-Tubocurarine and Pancuronium Induced Neuromuscular Blockades by Pyridostigmine in Man. Anesthesiology 1973;39:504-509.

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