For Intravenous Use

Rx only

Protamines are simple proteins of low molecular weight that are rich in arginine and strongly basic. They occur in the sperm of salmon and certain other species of fish.

Protamine sulfate occurs as fine white or off-white amorphous or crystalline powder. It is sparingly soluble in water. The pH is between 6.0 and 7.0. The cationic hydrogenated protamine at a pH of 6.8 to 7.1 reacts with anionic heparin at a pH of 5.0 to 7.5 to form an inactive complex.

Protamine Sulfate Injection, USP is a sterile, isotonic solution of protamine sulfate. It acts as a heparin antagonist. It is also a weak anticoagulant.

Each mL contains: Protamine sulfate 10 mg; sodium chloride 9 mg; Water for Injection q.s. Sulfuric acid and/or dibasic sodium phosphate (heptahydrate) may have been added for pH adjustment.

The preparation is preservative free.

Protamine sulfate is administered intravenously.

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 and the anticoagulant activity of both drugs is lost.

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

Protamine Sulfate Injection, USP is indicated in the treatment of heparin overdosage.

Protamine sulfate is contraindicated in patients who have shown previous intolerance to the drug.

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.

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.

Each mg of protamine sulfate, calculated on the dried basis, neutralizes not less than 100 USP Heparin Units.

Protamine sulfate injection should be given by very slow intravenous injection over a 10-minute period in doses not to exceed 50 mg (see WARNINGS).

Protamine sulfate is intended for injection without further dilution; however, if further dilution is desired, D5-W or normal saline may be used. Diluted solutions should not be stored since they contain no preservative.

Protamine sulfate should not be mixed with other drugs without knowledge of their compatibility, because protamine sulfate 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 sulfate required also decreases rapidly with the time elapsed following intravenous injection of heparin. For example, if the protamine sulfate is administered 30 minutes after the heparin, one-half the usual dose may be sufficient.

The dosage of protamine sulfate 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.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not permit to freeze.

CAUTION: The total dose of protamine sulfate contained in product No. 22925 and 22930 (250 mg in 25 mL) is 5 times greater than in product No. 22905 and product No. RF22905 (50 mg in 5 mL).

The large size 25 mL vials are designed for antiheparin treatment only when large doses of heparin have been given during surgery and are to be neutralized by large doses of protamine sulfate after surgical procedures.

www.fresenius-kabi.com/us

45848J

November 2024

NDC 65219-646-02           RF22905

Protamine

Sulfate

Injection, USP

50 mg per 5 mL

(10 mg per mL)

For Intravenous

Use Only

           Rx only

5 mL Single Dose Vial

NDC 65219-646-05           RF22905

Protamine

Sulfate

Injection, USP

50 mg per 5 mL

(10 mg per mL)

For Intravenous

Use Only

           Rx only

25 x 5 mL Single Dose Vials