Pralidoxime Chloride

PROTOPAM Chloride is indicated as an antidote: (1) in the treatment of poisoning due to those pesticides and chemicals (e.g., nerve agents) of the organophosphate class which have anticholinesterase activity and (2) in the control of overdosage by anticholinesterase drugs used in the treatment of myasthenia gravis. The principal indications for the use of PROTOPAM Chloride are muscle weakness and respiratory depression. In severe poisoning, respiratory depression may be due to muscle weakness.

There are no known absolute contraindications for the use of PROTOPAM Chloride (see PRECAUTIONS, Drug Interactions and DOSAGE AND ADMINISTRATION ). Relative contraindications include known hypersensitivity to the drug and other situations in which the risk of its use clearly outweighs possible benefit.

PROTOPAM Chloride is not effective in the treatment of poisoning due to phosphorus, inorganic phosphates, or organophosphates not having anticholinesterase activity. PROTOPAM Chloride is not indicated as an antidote for intoxication by pesticides of the carbamate class since it may increase the toxicity of carbaryl.

General PROTOPAM Chloride has been well tolerated in most cases, but it must be remembered that the desperate condition of the organophosphate-poisoned patient will generally mask such minor signs and symptoms as have been noted in normal subjects. Intravenous administration of PROTOPAM Chloride should be carried out slowly and, preferably, by continuous or intermittent infusion, since temporary worsening of cholinergic manifestations (i.e. tachycardia, cardiac arrest, laryngospasm, and muscle rigidity or paralysis) may occur if PROTOPAM Chloride is infused too rapidly. The intermittent infusion rate should not exceed 200 mg/minute. If intravenous administration is not feasible, intramuscular or subcutaneous injection should be used (see DOSAGE AND ADMINISTRATION ). PROTOPAM Chloride should be used with great caution in treating organophosphate overdosage in cases of myasthenia gravis since it may precipitate a myasthenic crisis. Because pralidoxime is excreted in the urine, a decrease in renal function will result in increased blood levels of the drug. Thus, the dosage of PROTOPAM Chloride should be reduced in the presence of renal insufficiency. Laboratory Tests Treatment of organophosphate poisoning should be instituted without waiting for the results of laboratory tests. Red blood cell, plasma cholinesterase, and urinary paranitrophenol measurements (in the case of parathion exposure) may be helpful in confirming the diagnosis and following the course of the illness, although such tests may be normal in the face of clinically significant organophosphate poisoning. A reduction in red blood cell cholinesterase concentration to below 50% of normal has been seen only with organophosphate ester poisoning. Drug Interactions When atropine and pralidoxime chloride are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime chloride has been delayed. The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime chloride: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. Prolonged paralysis has been reported in patients when succinylcholine is given with drugs having anticholinesterase activity; therefore, it should be used with caution. Carcinogenesis, Mutagenesis, Impairment of Fertility Because pralidoxime chloride is indicated for short-term emergency use only, no investigations of its potential for carcinogenesis, mutagenesis, or impairment of fertility have been conducted by the manufacturer, or reported in the literature. Pregnancy Teratogenic Effects: Animal reproduction studies have not been conducted with pralidoxime chloride. It is also not known whether pralidoxime chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pralidoxime chloride should be given to a pregnant woman only if clearly needed. 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 pralidoxime chloride is administered to a nursing woman. Pediatric Use There are no adequate and well-controlled clinical trials that establish the effectiveness of pralidoxime chloride in pediatric patients. Efficacy has been extrapolated from the adult population and is supported by nonclinical studies, pharmacokinetic studies in adults and experience in the pediatric population (see DOSAGE AND ADMINISTRATION ). As in adults, laryngospasm, cardiac arrest, tachycardia, and muscle rigidity or paralysis have been reported following rapid intravenous injection. Muscle fasciculations, apnea, and convulsions have also been reported. Geriatric Use Clinical studies of PROTOPAM Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Forty to 60 minutes after intramuscular injection, mild to moderate pain may be experienced at the site of injection. Pralidoxime chloride may cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure, hyperventilation, and muscular weakness when given parenterally to normal volunteers who have not been exposed to anticholinesterase poisons. In patients, it is very difficult to differentiate the toxic effects produced by atropine or the organophosphate compounds from those of the drug. Elevations in SGOT and/or SGPT enzyme levels were observed in 1 of 6 normal volunteers given 1200 mg of pralidoxime chloride intramuscularly, and in 4 of 6 volunteers given 1800 mg intramuscularly. Levels returned to normal in about 2 weeks. Transient elevations in creatine phosphokinase were observed in all normal volunteers given the drug. When atropine and pralidoxime chloride are used together, the signs of atropinization may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime chloride has been delayed. Excitement and manic behavior immediately following recovery of consciousness have been reported in several cases. However, similar behavior has occurred in cases of organophosphate poisoning that were not treated with pralidoxime chloride.

When atropine and pralidoxime chloride are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime chloride has been delayed. The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime chloride: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. Prolonged paralysis has been reported in patients when succinylcholine is given with drugs having anticholinesterase activity; therefore, it should be used with caution.

Teratogenic Effects: Animal reproduction studies have not been conducted with pralidoxime chloride. It is also not known whether pralidoxime chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pralidoxime chloride should be given to a pregnant woman only if clearly needed.

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 pralidoxime chloride is administered to a nursing woman.

There are no adequate and well-controlled clinical trials that establish the effectiveness of pralidoxime chloride in pediatric patients. Efficacy has been extrapolated from the adult population and is supported by nonclinical studies, pharmacokinetic studies in adults and experience in the pediatric population (see DOSAGE AND ADMINISTRATION ). As in adults, laryngospasm, cardiac arrest, tachycardia, and muscle rigidity or paralysis have been reported following rapid intravenous injection. Muscle fasciculations, apnea, and convulsions have also been reported.

Clinical studies of PROTOPAM Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.