PROTAMINE SULFATE

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration.
Intravenous Administration
Dilution:
-The manufacturer recommends protamine be given without further dilution. If further dilution is desired, dilute in NS or D5W. Do not store diluted solutions because they do not contain preservatives.

Intravenous injection:
-Inject via very slow IV injection over 10 minutes, not to exceed 5 mg/min. No more than 50 mg should be administered in a 10-minute period. Bradycardia, severe hypotension and anaphylactoid reactions have resulted from too-rapid administration of protamine.
-Protamine has exhibited incompatibilities with several penicillins and cephalosporins and should not be administered through the same infusion line as these agents.

Severe hypotension, sinus bradycardia, pulmonary hypertension, flushing, dyspnea, and rash have been reported following protamine administration. These adverse reactions have been potentiated by rapid infusion of protamine and can be minimized by adherence to recommended dosing guidelines. Systemic hypertension, back pain, nausea, vomiting, and fatigue (reported as lassitude) also have occurred during therapy with protamine. Intravenous administration of protamine has been associated with serious hypersensitivity reactions or anaphylaxis, including fatal reactions. Reactions have included angioedema, urticaria, acute bronchospasm or wheezing, and anaphylactic shock. Potential risk factors for protamine reactions include insulin-dependent diabetes mellitus, fish allergy, prior exposure to protamine sulfate, and the rate of IV infusion. Pulmonary edema has also been reported in patients on cardiopulmonary bypass undergoing cardiovascular surgery. The precise mechanism of protamine in potentiating this condition is unknown; however, multiple contributing factors have been implicated. Severe and possibly irreversible circulatory collapse associated with reduced cardiac output and heart failure may also occur with the administration of protamine sulfate. The mechanism of this reaction is not known. In a 6 week old infant, pulmonary hypertension and severe hemorrhagic pulmonary edema occurred after protamine administration for heparin neutralization following cardiac surgery. Two doses of protamine were given to the infant; initially 50 mg of protamine was administered over 3 minutes and then a dose of protamine 26 mg was given over 3 minutes. Both doses exceeded the maximum infusion rate of 5 mg/minute.

Hyperheparinemia (heparin rebound) and bleeding have been reported 30 minutes to18 hours after cardiac surgery despite complete neutralization of heparin by adequate doses of protamine sulfate. This reaction results from release of heparin from the protamine/heparin complex. It has been observed most frequently when protamine is used following extracorporeal circulation in dialysis or arterial and cardiac surgery. Additionally, an overdose of protamine may cause bleeding due to the weak anticoagulant effect that can occur due to an interaction with platelets and proteins.

Protamine administration has a risk of serious hypersensitivity reactions or anaphylaxis manifesting as severe hypotension, cardiovascular collapse, pulmonary edema, pulmonary vasoconstriction, and pulmonary hypertension. Risk factors for these events include high doses or overdose, rapid IV administration, previous exposure, repeated doses, and current or previous use of protamine-containing drugs (e.g., NPH insulin, protamine zinc insulin, and certain beta-blockers). Fish hypersensitivity, severe left ventricular dysfunction, and abnormal preoperative pulmonary hemodynamics may also be risk factors. Carefully consider the risks and benefits of use in patients with any of these risk factors. Administration requires a specialized care setting as vasopressors and resuscitation equipment should be immediately available in case of a severe reaction. Do not give protamine when bleeding occurs without prior heparin use.

Description: Protamine sulfate, a protein derived from the sperm of salmon and other fish species, is a chemical antagonist of heparin. Clinically, protamine is indicated for heparin overdose and is commonly used to neutralize heparin after cardiac surgery. Due to the anticoagulant effect of protamine, doses greater than 50 mg should not be given over a short period of time unless a larger dose is clearly needed. Protamine was approved by the FDA in December 1948. Although not FDA-approved, protamine has been used off-label in pediatric patients as young as neonates.

For the treatment of unfractionated heparin toxicity*, or for hemorrhage* associated with unfractionated heparin (UFH) therapy:
Intravenous dosage:
Neonates, Infants, Children, and Adolescents: If immediate unfractionated heparin (UFH) reversal is required, the dose of protamine is based on the amount of UFH received in the previous 2 hours. If less than 30 minutes has lapsed since UFH administration, then administer 1 mg protamine/100 units heparin received. If 30 to 60 minutes has elapsed since UFH administration, administer 0.5 to 0.75 mg protamine/100 units heparin received. If 60 to 120 minutes has elapsed since UFH administration, administer 0.375 to 0.5 mg protamine/100 units heparin received. If greater than 120 minutes has elapsed since UFH administration, administer 0.25 to 0.375 mg protamine/100 units heparin received.

For the neutralization of UFH following cardiac surgery* (i.e., cardiopulmonary bypass surgery):
Intravenous dosage:
Infants and Children <= 6 years of age: 1 to 1.3 mg protamine IV for every 100 units of heparin has been administered for unfractionated heparin reversal at the completion of cardiopulmonary bypass. 1 to 2 mg protamine IV for every 100 units of heparin has been administered for unfractionated heparin reversal during cardiopulmonary bypass, titrating to the desired activated clotting time (ACT). In studies, when patients continued to bleed after protamine administration, other reversal agents (e.g., aprotinin, tranexamic acid) or blood products were administered.

Maximum Dosage Limits:
-Neonates
Must individualize dosage; do not exceed 50 mg/dose.
-Infants
Must individualize dosage; do not exceed 50 mg/dose.
-Children
Must individualize dosage; do not exceed 50 mg/dose.
-Adolescents
Must individualize dosage; do not exceed 50 mg/dose.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Protamine possesses weak anticoagulant effects when administered alone; however, upon contact with heparin, it forms a salt, neutralizing the anticoagulant effect of both drugs. Protamine, a strongly basic compound, forms complexes with heparin sodium or heparin calcium, which are acidic compounds. Formation of this complex can result in disruption of the heparin-antithrombin III complex responsible for the anticoagulant activity of heparin. The protamine-heparin complex does not possess anticoagulant properties. Protamine's anticoagulant effect usually is clinically insignificant and is likely the result of thromboplastin inhibition, which diminishes thrombin activity.

Pharmacokinetics: Protamine is administered via intravenous infusion. The onset of action is rapid, with neutralization of heparin evident within 5 minutes. The duration of action can persist up to 2 hours, depending on body temperature. The fate of the heparin-protein complex is unknown, but it appears to be metabolized or partially degraded by fibrinolysin, with the release of heparin.

Affected cytochrome P450 isoenzymes: none