Protopam

Manifestations of Overdosage

Observed in normal subjects only: dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, slight tachycardia. In therapy it has been difficult to differentiate side effects due to the drug from those due to the effects of the poison.

If possible, before you receive pralidoxime, tell your doctor if you have kidney disease, or if you are allergic to any drugs.

Also tell your doctor if you are pregnant or breast-feeding.

In an emergency situation it may not be possible before you are treated to tell your caregivers about your health conditions or if you are pregnant or breast-feeding. Make sure any doctor caring for you afterward knows that you have received this medication.

The principal action of pralidoxime chloride is to reactivate cholinesterase (mainly outside of the central nervous system) which has been inactivated by phosphorylation due to an organophosphate pesticide or related compound. The destruction of accumulated acetylcholine can then proceed, and neuromuscular junctions will again function normally. Pralidoxime chloride also slows the process of “aging” of phosphorylated cholinesterase to a nonreactivatable form, and detoxifies certain organophosphates by direct chemical reaction. The drug has its most critical effect in relieving paralysis of the muscles of respiration. Because pralidoxime chloride is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site. Pralidoxime chloride relieves muscarinic signs and symptoms, salivation, bronchospasm, etc., but this action is relatively unimportant since atropine is adequate for this purpose.

Protopam Chloride has been studied in animals as an antidote against numerous organophosphate pesticides, chemicals, and drugs (see Animal Pharmacology and Toxicology). Regardless of whether or not animal studies suggest that the organophosphate poison to which a particular patient has been exposed is amenable to treatment with pralidoxime chloride, the use of pralidoxime chloride should, nevertheless, be considered in any life-threatening situation resulting from poisoning by these compounds, since the limited and arbitrary conditions of pharmacologic screening do not always accurately reflect the usefulness of pralidoxime chloride in the clinical situation.

There are no adequate and well controlled clinical studies that establish the effectiveness of pralidoxime chloride as a treatment for poisoning with organophosphates having anticholinesterase activity. However, its use has been considered to be successful against poisoning with numerous pesticides, chemicals, and drugs.

Pharmacokinetics

Animal studies suggest that the minimum therapeutic concentration of pralidoxime in plasma is 4 µg/mL; this level is reached in about 16 minutes after a single injection of 600 mg pralidoxime chloride. In one study of healthy adult volunteers and patients self-poisoned with organophosphate compounds, a single intramuscular injection of 1000 mg of pralidoxime chloride resulted in mean peak plasma levels of 7.5 ± 1.7 µg/mL and 9.9 ± 2.4 µg/mL, respectively. Time to reach the mean peak plasma levels in both groups was similar, 34 minutes in healthy adults and 33 minutes in poisoned patients. Mean half-life was about 3 hours in both groups.

Some evidence suggests that a loading dose followed by continuous intravenous infusion of pralidoxime chloride may maintain therapeutic levels longer than short intermittent infusion therapy. In a cross-over study of seven healthy adults (18 – 50 years) a short intravenous infusion dose of 16 mg/kg over 30 minutes was compared to an intravenous loading dose of 4 mg/kg over 15 minutes, followed by 3.2 mg/kg/hr for 3.75 hours (for a total dose of 16 mg/kg). Results showed that the mean time over which plasma levels were maintained above 4 µg/mL was prolonged in the volunteers who received a loading dose followed by continuous infusion as compared to those who received short infusion therapy (257.5 ± 50.5 min vs. 118.0 ± 52.1 min). Use of continuous intravenous infusion in adult patients with organophosphate poisoning has been described in several case reports, with and without loading doses. Infusion rates ranged from 400 – 600 mg/hr. In one case the blood levels were 11.6 – 13.7 µg /mL when given 400 mg/hr over 5 days (measured at 5, 10 and 18 hours). In another case following an initial loading dose of 1000 mg, blood levels were 11.79 µg /mL when given 500 mg/hr and 17.26 µg /mL when given 600 mg/hr. In the latter case the pralidoxime elimination half-life was 4 hours. In two other cases blood levels were not measured.

Pralidoxime chloride is distributed throughout the extracellular water; its apparent volume of distribution at steady state has been reported to range from 0.60 to 2.7 L/kg. Pralidoxime chloride is not bound to plasma protein.

Pralidoxime chloride is relatively short acting and repeated doses may be needed, unless continuous intravenous infusion is selected. Simulations suggest that after a dose of 1000 mg given intravenously, concentrations fall below 4 µg/mL in about 1.5 hours. The short duration of action of pralidoxime chloride and the necessity for repeated doses should be considered especially where there is any evidence of continuing absorption of the poison. The apparent half-life of pralidoxime chloride is 74 to 77 minutes. The drug is rapidly excreted in the urine by renal tubular secretion, partly unchanged, and partly as a metabolite produced by the liver. After intramuscular administration of 1000 mg of pralidoxime chloride, the renal clearance has been reported to be 7.2 ± 2.9 mL/min/kg in healthy volunteers and 3.6 ± 1.5 mL/min/kg in organophosphate-poisoned patients.

In one study of 11 organophosphate-poisoned pediatric patients (age, 0.8 to 18 years), an intravenous loading dose of 15-50 mg/kg (mean 29 mg/kg) of pralidoxime chloride followed by a continuous infusion of 10-16 mg/kg/hr (mean 14 mg/kg/hr) over 12 to 43 hours (mean 27 ± 8 hours) resulted in an average steady state plasma concentration of 22.2 mg/L (6.9 to 47.4 mg/L) and an average body clearance of 0.88 L/kg/hr (0.28 to 2.20 L/kg/hr). After the continuous infusion was discontinued, determinations of the apparent volume of distribution and half-life ranged from 1.7 to 13.8 L/kg and from 2.4 to 5.3 hours, respectively.

Protopam Chloride is not subject to abuse and possesses no known potential for dependence.

Manifestations of Overdosage

Observed in normal subjects only: dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, slight tachycardia. In therapy it has been difficult to differentiate side effects due to the drug from those due to the effects of the poison.

Applies to pralidoxime: injection injectable, injection powder for solution

Along with its needed effects, pralidoxime (the active ingredient contained in Protopam Chloride) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking pralidoxime:

• Blurred or double vision
• change in near or distance vision
• difficult or rapid breathing
• difficulty in focusing the eyes
• difficulty with speaking
• dizziness
• fast, pounding, or irregular heartbeat or pulse
• muscle stiffness or weakness
• pain at the injection site (after injection into a muscle)

• Deep or fast breathing with dizziness
• numbness of the feet, hands, and around the mouth

Some side effects of pralidoxime may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Drowsiness
• headache
• nausea

Applies to pralidoxime: intravenous powder for injection

General

Pralidoxime has been well tolerated in most cases; however, it should be considered that the desperate condition of the organophosphate-poisoned patient generally masks the minor signs and symptoms noted in normal subjects who have not been exposed to anticholinesterase poisons. Many of the signs and symptoms of organophosphate poisoning are similar to the side effects of pralidoxime (the active ingredient contained in Protopam Chloride) It may be difficult to ascertain which effects are due to the drug and which are toxic symptoms produced by atropine or the organophosphate compounds.[Ref]

Cardiovascular

Cardiovascular side effects have included tachycardia and increased systolic and diastolic blood pressure in normal subjects. Tachycardia has also occurred after excessively rapid infusions. Asystole and cardiac arrest have been reported; however, causality is unclear due to the presence of atropine and an organophosphate insecticide.[Ref]

Musculoskeletal

Musculoskeletal side effects have included muscle weakness in normal subjects. Laryngospasm and muscle rigidity have occurred after excessively rapid infusions.[Ref]

Nervous system

Nervous system side effects have included dizziness, headache, and drowsiness in normal subjects.[Ref]

Respiratory

Respiratory side effects have included hyperventilation in normal subjects.[Ref]

Ocular

Ocular side effects have included blurred vision, diplopia, and impaired accommodation in normal subjects.[Ref]

Gastrointestinal

Gastrointestinal side effects have included nausea in normal subjects.[Ref]

Metabolic

Metabolic side effects have included transient elevations of creatine phosphokinase in all normal subjects.

Hepatic

Hepatic side effects have included elevations of AST and/or ALT in normal subjects.[Ref]

Elevated AST and/or ALT were reported in 1 of 6 normal subjects given 1200 mg intramuscularly and 4 of 6 normal subjects given 1800 mg intramuscularly. Levels returned to normal in about 2 weeks.[Ref]

Local

Local side effects have included mild to moderate injection site pain, 40 to 60 minutes after intramuscular injection.[Ref]

Some side effects of Protopam Chloride may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.