Protamine Sulfate 10 mg/mL Injection, Solution — NDC 63323-229-15 (Billing 63323-0229-15)

WARNINGS: 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 sulfate at the end of the operation. It is important to keep the patient under close observation after cardiac surgery. Additional doses of protamine sulfate 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 sulfate can cause severe hypotensive and anaphylactoid reactions (see DOSAGE AND ADMINISTRATION and WARNINGS ). Facilities to treat shock should be available.

ADVERSE REACTIONS: To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The intravenous administration of protamine sulfate may cause a sudden fall in blood pressure and bradycardia. Other reactions include transitory flushing and feeling of warmth, dyspnea, nausea, vomiting and lassitude.

Back pain has been reported in conscious patients undergoing such procedures as cardiac catheterization. Severe adverse reactions have been reported including: (1) Anaphylaxis that resulted in severe respiratory distress, circulation collapse and capillary leak (see PRECAUTIONS ). Fatal anaphylaxis has been reported in one patient with no prior history of allergies; (2) Anaphylactoid reactions with circulatory collapse, capillary leak, and noncardiogenic pulmonary edema; acute pulmonary hypertension.

Complement activation by the heparin-protamine complexes, release of lysosomal enzymes from neutrophils, and prostaglandin and thomboxane generation have been associated with the development of anaphylactoid reactions. Severe and potentially irreversible circulatory collapse associated with myocardial failure and reduced cardiac output can also occur. The mechanism(s) of this reaction and the role played by concurrent factors are unclear.

High-protein, noncardiogenic pulmonary edema associated with the use of protamine has been reported in patients on cardiopulmonary bypass who are undergoing cardiovascular surgery. The etiologic role of protamine in the pathogenesis of this condition is uncertain, and multiple factors have been present in most cases. The condition has been reported in association with administration of certain blood products, other drugs, cardiopulmonary bypass alone, and other etiologic factors.

It is difficult to treat, and it can be life-threatening. Because fatal anaphylactic and anaphylactoid reactions have been reported after the administration of protamine sulfate, the drug should be given only when resuscitation techniques and treatment of anaphylactic and anaphylactoid shock are readily available.

PRECAUTIONS: General Because of the anticoagulant effect of protamine, it is unwise to give more than 50 mg over a short period unless a larger dose is clearly needed. 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. Previous exposure to protamine can induce a humoral immune response and predispose susceptible individuals to the development of untoward reactions from the subsequent use of this drug.

Patients exposed to protamine through the use of protamine-containing insulin or during heparin neutralization may experience life-threatening reactions and fatal anaphylaxis upon receiving large doses of protamine intravenously. Severe reactions to intravenous protamine can occur in the absence of local or systemic allergic reactions to subcutaneous injection of protamine-containing insulin. Reports of the presence of antiprotamine antibodies in the sera of infertile or vasectomized men suggest that some of these individuals may react to the use of protamine sulfate.

Fatal anaphylaxis has been reported in one patient with no prior history of allergies. Drug Interactions Protamine sulfate has been shown to be incompatible with certain antibiotics, including several of the cephalosporins and penicillins (see DOSAGE AND ADMINISTRATION ). Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been performed to determine potential for carcinogenicity, mutagenicity or impairment of fertility.

Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with protamine sulfate. It is also not known whether protamine sulfate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Protamine sulfate 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 protamine sulfate is administered to a nursing woman. Pediatric Use Safety and effectiveness in children have not been established.

General Because of the anticoagulant effect of protamine, it is unwise to give more than 50 mg over a short period unless a larger dose is clearly needed. 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. Previous exposure to protamine can induce a humoral immune response and predispose susceptible individuals to the development of untoward reactions from the subsequent use of this drug.

Patients exposed to protamine through the use of protamine-containing insulin or during heparin neutralization may experience life-threatening reactions and fatal anaphylaxis upon receiving large doses of protamine intravenously. Severe reactions to intravenous protamine can occur in the absence of local or systemic allergic reactions to subcutaneous injection of protamine-containing insulin. Reports of the presence of antiprotamine antibodies in the sera of infertile or vasectomized men suggest that some of these individuals may react to the use of protamine sulfate.

Fatal anaphylaxis has been reported in one patient with no prior history of allergies.

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

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

Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with protamine sulfate. It is also not known whether protamine sulfate can cause fetal harm when administered to a pregnant woman or can affect repro… [Excerpted — this section continues on DailyMed.]