Protamine Sulfate Injection

PROTAMINE SULFATE INJECTION

Pharmaceutical Partners

Heparin Antagonist

Action And Clinical Pharmacology: When administered alone, protamine has an anticoagulant effect. However, when it is given in the presence of heparin (which is strongly acidic), a stable salt is formed which results in the loss of anticoagulant activity of both drugs.

Protamine has a rapid onset of action. Neutralization of heparin occurs within 5 minutes after i.v. administration. Although the metabolic fate of the heparin-protamine complex has not been elucidated, it has been postulated that protamine in the heparin-protamine complex may be partially metabolized or may be attacked by fibrinolysin, thus freeing heparin.

Indications And Clinical Uses: Treatment of heparin overdosage.

Contra-Indications: Patients who have shown previous intolerance to the drug.

Manufacturers’ Warnings In Clinical States: Hyperheparinemia or bleeding has been reported in experimental animals and in some patients 30 minutes to 18 hours after cardiac surgery (under cardiopulmonary bypass) in spite of complete neutralization of heparin by adequate doses of protamine at the end of the operation.

Therefore, it is important to keep the patient under close observation after cardiac surgery. Additional doses of protamine should be administered if indicated by coagulation studies; such as the heparin titration test with protamine and the determination of plasma thrombin time.

Too rapid administration of protamine can cause severe hypotensive and anaphylactoid-like reactions (see Dosage). Facilities to treat shock should be available.

Precautions: General: Because of the anticoagulant effect of protamine, it is unwise to give more than 100 mg over a short period unless there is certain knowledge of a larger requirement.

Previous exposure to protamine through use of protamine-containing insulins or during heparin neutralization may predispose susceptible individuals to the development of untoward reactions from the subsequent use of this drug. Reports of the presence of antiprotamine antibodies in the serums of infertile or vasectomized men suggest that some of these individuals may react to the use of protamine.

Patients with a history of allergy to fish may develop hypersensitivity reactions to protamine, although to date no relationship has been established between allergic reactions to protamine and fish allergy.

Drug Interactions: Protamine has been shown to be incompatible with certain antibiotics, including several of the cephalosporins and penicillins (see Dosage).

Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies have not been performed to determine potential for carcinogenicity, mutagenicity or impairment of fertility.

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

Lactation: 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 protamine is administered to a nursing woman.

Children: Safety and effectiveness in children have not been established.

Adverse Reactions: I.V. injections of protamine may cause a sudden fall in blood pressure, bradycardia, pulmonary hypertension, dyspnea, or transitory flushing and a feeling of warmth. There have been reports of anaphylaxis that resulted in respiratory embarrassment (see Precautions). Other reported adverse reactions include systemic hypertension, nausea, vomiting and lassitude. Back pain has been reported rarely in conscious patients undergoing such procedures as cardiac catheterization.

Because fatal reactions often resembling anaphylaxis have been reported after administration of protamine, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Because of the anticoagulant effect of protamine, overdosage of this drug may theoretically result in hemorrhage. However, in one study, overdosage of 600 to 800 mg of i.v. protamine had only minimal, transient effects on blood coagulation tests. The patient should be followed with coagulation studies and treated symptomatically.

The LD50 of protamine is 100 mg/kg in mice.

Dosage And Administration: Each mg of protamine will neutralize approximately 90 USP units of heparin activity derived from beef lung tissue or about 115 USP units of heparin activity derived from porcine intestinal mucosa.

Protamine sulfate injection should be given by very slow i.v. injection in doses not to exceed 50 mg of protamine in any 10 minute period (see Warnings).

Protamine is intended for injection without further dilution; however, if further dilution is desired, 5% Dextrose Injection or 0.9% Sodium Chloride Injection may be used. Diluted solutions should not be stored since they contain no preservative.

Protamine should not be mixed with other drugs without knowledge of their compatibility, because protamine has been shown to be incompatible with certain antibiotics, including several of the cephalosporins and penicillins.

Because heparin disappears rapidly from the circulation, the dose of protamine required also decreases rapidly with the time elapsed following i.v. injection of heparin. For example, if the protamine is administered 30 minutes after the heparin, one-half the usual dose may be sufficient.

The dosage of protamine should be guided by blood coagulation studies (see Warnings).

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.

Availability And Storage: Each mL of sterile, nonpyrogenic, isotonic solution contains: protamine sulfate 10 mg, sodium chloride 9 mg and water for injection q.s. Sulfuric acid and/or dibasic sodium phosphate (heptahydrate) may have been added for pH adjustment. Preservative-free. Flip-top vials of 5 mL, packages of 25. Individually packaged flip-top vials of 30 mL with 25 mL fill. Store at controlled room temperature 15 to 30°C. Do not freeze. Discard unused portion.

Note: The 25 mL vials are designed for antiheparin treatment in certain cases in which large doses of heparin have been given during surgery and are to be neutralized by large doses of protamine after surgical procedures.

PROTAMINE SULFATE INJECTION Pharmaceutical Partners Heparin Antagonist

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