Generic Name: protamine

Uses

Heparin Overdosage

Treatment of severe heparin sodium overdosage.

Do not use for minor bleeding during heparin therapy. Heparin withdrawal usually corrects minor overdosage or bleeding within a few hours.

Heparin Neutralization After Extracorporeal Circulation

Neutralization of heparin at the end of arterial or cardiac surgery with extracorporeal circulation† or dialysis procedures†.

Heparin Neutralization in Pregnant Women Near Delivery

Neutralization of anticoagulant effect to reduce risk of bleeding near delivery† in pregnant women receiving heparin therapy.

Low Molecular Weight Heparins Overdosage

Treatment of overdosage of low molecular weight heparins†. (See Actions.)

Dosage and Administration

General

• With severe heparin overdosage, discontinue heparin and administer protamine sulfate immediately. Blood transfusions may be required for massive blood loss.
• Dosage of protamine sulfate determined by dosage of heparin sodium or low molecular weight heparin† received, route of administration, time elapsed since administration, and blood coagulation studies.
• Monitor therapeutic response through coagulation studies (aPTT, activated coagulation time [ACT], heparin titration test with protamine, plasma thrombin time).
• Additional doses of protamine sulfate may be required in patients with heparin rebound (e.g., as may occur during extracorporeal circulation† in arterial and cardiac surgery or dialysis procedures) if indicated by coagulation studies. (See Effects on Hemostasis under Cautions.)

Administration

IV Administration

For solution and drug compatibility information, see Stability: Compatibility.

Administer by very slow IV injection over 10 minutes. (See Sensitivity Reactions under Cautions.) Available in single-use vials at a concentration of 10 mg/mL; no further dilution necessary.

Has been administered by continuous IV infusion†.

Dilution

If more dilute infusion solutions desired, further dilution in 5% dextrose or 0.9% sodium chloride injection recommended. Contains no preservatives; discard unused portion.

Dosage

Available as protamine sulfate; dosage expressed in terms of protamine sulfate.

Adults

Heparin Overdosage

IV

Severe bleeding occurring only a few minutes after heparin IV injection: 1 mg protamine sulfate for every 100 units of heparin sodium administered.

Severe bleeding occurring 30 minutes after heparin IV injection: 0.5 mg protamine sulfate for every 100 units of heparin sodium administered.

Severe bleeding occurring ≥2 hours after heparin IV injection: 0.25–0.375 mg protamine sulfate for every 100 units of heparin sodium administered.

Sub-Q heparin overdosage: Some clinicians recommend administering 1–1.5 mg protamine sulfate for each 100 units of heparin sodium; may require prolonged infusion to neutralize sub-Q heparin sodium dose. Protamine sulfate loading dose of 25–50 mg by slow IV infusion suggested by some clinicians, with remainder of calculated dose administered by continuous IV infusion† over 8–16 hours or expected duration of absorption of heparin.

Heparin Neutralization After Extracorporeal Circulation

IV

1.5 mg protamine sulfate for each 100 units of heparin sodium administered. Alternatively, determine dosage by using sequential ACT determinations and dose-response curve which correlates results with amount of heparin remaining in body.†

Low Molecular Weight Heparin Overdosage

IV

Severe bleeding within previous 8 hours of administration of a low molecular weight heparin: 1 mg protamine sulfate for every 100 anti-factor X_a units of low molecular weight heparin (e.g., enoxaparin sodium, dalteparin sodium, tinzaparin sodium) administered (e.g., 1 mg of enoxaparin sodium has an anti-factor X_a activity of approximately 100 units). If aPTT measured 2–4 hours after first infusion of protamine sulfate remains prolonged or if bleeding continues, may administer a second dose of 0.5 mg protamine sulfate for every 100 anti-factor X_a units of low molecular weight heparin administered.†

Severe bleeding >8 hours after administration of a low molecular weight heparin: 0.5 mg protamine sulfate for every 100 anti-factor X_a units of low molecular weight heparin administered.†

Manufacturer of enoxaparin states that protamine sulfate may not be required if ≥12 hours has elapsed since administration of enoxaparin.†

Prescribing Limits

Adults

Heparin Overdosage

IV

≤50 mg protamine sulfate in any 10-minute period, unless larger dose clearly needed. (See Sensitivity Reactions under Cautions.)

Cautions

Contraindications

• Known hypersensitivity to protamine sulfate.

Warnings/Precautions

Warnings

Effects on Hemostasis

Heparin rebound (hyperheparinemia) with bleeding reported occasionally, 0.5–18 hours following complete neutralization with protamine sulfate at end of cardiopulmonary bypass procedure†. (See Metabolism under Pharmacokinetics.) Monitor patients closely following cardiac surgery; administer additional doses of protamine sulfate if indicated by coagulation studies.

Sensitivity Reactions

Severe hypotension and potentially fatal anaphylactoid reactions reported, particularly with large doses or too-rapid administration. Take particular care to avoid overdosage with protamine.

Patients at increased risk for development of antiprotamine antibodies and hypersensitivity reactions include infertile or vasectomized men or those with previous exposure to protamine-containing preparations or known hypersensitivity to fish (protamine sulfate is prepared from sperm or mature testes of salmon or related species).

Severe reactions to IV protamine can occur in absence of local or systemic allergic reactions to sub-Q protamine-containing insulin. Fatal anaphylaxis reported in at least 1 patient with no prior history of allergies.

Minimize these adverse effects by administering drug slowly. (See IV Administration under Dosage and Administration.) Administer only when medical facilities equipped to provide resuscitation and treat shock available. Patients at risk for protamine allergy can be pretreated with corticosteroids and antihistamines. (See Actions.)

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether protamine sulfate is distributed into milk. Use caution.

Pediatric Use

Safety and efficacy not established in children.

Common Adverse Effects

Decreased BP or hypotension, bradycardia, skin reactions (e.g., flushing, feeling of warmth, urticaria, edema), dyspnea, nausea, vomiting, lassitude, back pain.

Interactions

Specific Drugs

Pharmacokinetics

Absorption

Onset

<5 minutes after IV administration.

Duration

Variable duration presumably results from release of heparin from protamine-heparin complex or extravascular compartments. (See: Metabolism under Pharmacokinetics.)

Distribution

Not known whether protamine sulfate is distributed into milk. (See Lactation under Cautions.)

Elimination

Metabolism

Protamine-heparin complex partially metabolized by fibrinolysin, freeing heparin. (See Effects on Hemostasis under Cautions.)

Half-life

Without heparin in healthy individuals: Median 7.4 minutes.

Following cardiopulmonary bypass procedure† with heparin: Median 4.5 minutes.

Stability

Storage

Parenteral

Solution for Injection

20–25°C; do not freeze.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Drug Compatibility

Incompatible with some anti-infective agents, including some cephalosporins and penicillins.

Actions

• Neutralization of anticoagulant activity of heparin by complexing with heparin to form a stable salt.
• Formation of protamine-heparin complex influenced by molecular weight of heparin. Reduced binding to low molecular weight heparins compared with heparin results in incomplete neutralization of anti-factor X_a activity (60–75%) when protamine is used to treat overdosage of low molecular weight heparins.
• Has weak anticoagulant activity as a result of inhibition of platelet aggregation and interaction of many proteins, including fibrinogen, and inhibition of thromboplastin generation and activity, which prevents conversion of prothrombin to thrombin.
• Reduces systolic and diastolic BP, increases pulmonary artery pressure, and decreases heart rate and systemic vascular resistance.
• Vasoactive effects associated with release of vasoactive mediators (e.g., histamine, bradykinin, thromboxane, nitric oxide), complement activation, and antibody production.

Advice to Patients

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.
• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions June 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.