Protamine sulfate, a protein derived from fish sperm, is a chemical antagonist of heparin. Clinically, protamine is indicated for heparin overdose and is commonly used to neutralize heparin during extracorporeal circulation following dialysis, and arterial or cardiac surgery. Dosage is guided by blood coagulation studies, with each mg of protamine sulfate neutralizing not less than 100 USP heparin units. Protamine must be administered via slow intravenous injection at a rate not to exceed 50 mg over a 10 minute period. High doses and rapid administration may result in severe hypotension, cardiovascular collapse, pulmonary edema, pulmonary vasoconstriction, and pulmonary hypertension.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Ensure ready access to vasopressors and resuscitation equipment in cases of severe reaction.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration.
Intravenous Administration
-Administer protamine 10 mg/mL solution undiluted via slow intravenous injection. The administration rate MUST NOT exceed 50 mg over a 10 minute period. High doses and rapid administration may result in severe hypotension, cardiovascular collapse, pulmonary edema, pulmonary vasoconstriction, and pulmonary hypertension.
-Dilution is not recommended; however if desired, the product may be added to 5% Dextrose in Water or 0.9% Sodium Chloride for Injection. If diluted, the product must be used immediately as it does not contain preservatives.
-Do not administer with other medications without ensuring compatibility. Protamine has exhibited incompatibilities with certain antibiotics, including some penicillins and cephalosporins.
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, vasectomy, 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.
Severe and possibly irreversible circulatory collapse associated with reduced cardiac output and heart failure may occur with the administration of protamine sulfate. The mechanism of this reaction is not known.
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, vasectomy, 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.
Protamine is classified as FDA pregnancy risk category C. It is not known if protamine can cause fetal harm when administered to a pregnant woman. Use protamine during pregnancy only if clearly needed.
According to the manufacturer, it is unknown whether protamine is excreted into human breast milk. Protamine should be administered during breast-feeding only when clearly needed. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the treatment of low-molecular weight heparin (LMWH) or unfractionated heparin toxicity, or for hemorrhage associated with unfractionated heparin (UFH) or LMWH therapy:
-for UFH toxicity or hemorrhage associated with UFH therapy:
Intravenous dosage:
Adults: 1 mg IV for every 100 units of heparin to be neutralized or as indicated by coagulation studies. The appropriate dose can be calculated based on a 60-minute half-life for heparin. Example: For a patient receiving 1,500 units/hour of heparin by continuous IV infusion who had not recently received bolus heparin: this patient would require enough protamine to neutralize all the heparin received in the last hour (1,500 units), plus half the dose in the preceding hour (750 units), plus a quarter of the dose received the hour before that (375 units). Thus, this patient would require 26.25 mg of protamine to neutralize a total of 2,625 units of heparin. The maximum recommended dose within a 2-hour period is 100 mg unless a larger quantity is indicated through confirmation by coagulation tests.
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 more 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 during extracorporeal circulation in cardiac surgery or dialysis procedures:
Intravenous dosage:
Adults: 1.5 mg IV for every 100 units of heparin administered. Dosage may also be determined by using the sequential activated coagulation time (ACT) and a dose-response curve which correlates the coagulation test values with the amount of heparin in the body. Increased levels of heparin and bleeding complications have occurred up to 18 hours after cardiac surgery, despite complete neutralization of heparin by protamine. The patient should be monitored to verify the need for additional doses of protamine.
Infants* and Children 6 years and younger*: 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.
-for LMWH toxicity or hemorrhage associated with enoxaparin therapy:
Intravenous dosage:
Adults: If enoxaparin was administered in the previous 8 hours, give protamine 1 mg IV for every 1 mg of enoxaparin. If enoxaparin was administered greater than 8 hours previous to the protamine dose or if a second dose is needed, give protamine 0.5 mg IV for every 1 mg of enoxaparin. A second dose of protamine may be administered if the aPTT measured at 2 to 4 hours after the initial infusion remains prolonged. However, even with higher doses of protamine, the aPTT may remain more prolonged than would usually be found with protamine treatment following unfractionated heparin. In all cases, the anti-Xa activity is never completely neutralized (maximum 60% to 75%).
-for LMWH toxicity or hemorrhage associated with dalteparin or tinzaparin therapy:
Intravenous dosage:
Adults: In general, protamine 1 mg IV for every 100 anti-Xa international units of dalteparin or tinzaparin is given. A second infusion of protamine 0.5 mg IV for every 100 anti-Xa international units of dalteparin or tinzaparin may be administered if the aPTT measured at 2 to 4 hours after the initial infusion remains prolonged. However, even with higher doses of protamine, the aPTT may remain more prolonged than would usually be found with protamine treatment following unfractionated heparin. In all cases, the anti-Xa activity is never completely neutralized (maximum 60% to 75%).
Maximum Dosage Limits:
-Adults
100 mg IV within a 2-hour period unless a larger quantity is indicated through confirmation by coagulation tests.
-Geriatric
100 mg IV within a 2-hour period unless a larger quantity is indicated through confirmation by coagulation tests.
-Adolescents
Must individualize dosage; do not exceed 50 mg/dose.
-Children
Must individualize dosage; do not exceed 50 mg/dose.
-Infants
Must individualize dosage; do not exceed 50 mg/dose.
-Neonates
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
Heparin: (Contraindicated) Upon contact with heparin, protamine 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. Protamine is used therapeutically to reverse the activity of heparins.
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.
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 partially degraded, with the release of heparin.
Affected cytochrome P450 isoenzymes: none