Introduction

Heparin antagonist; prepared from the sperm or mature testes of salmon or related species.

Uses for Protamine

Heparin Overdosage

Treatment of severe heparin overdosage.

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

Heparin Neutralization during Extracorporeal Circulation

Neutralization of heparin administered during extracorporeal circulation^{† [off-label]} in arterial and cardiac surgery or dialysis procedures.

Heparin Neutralization in Pregnant Women Near Delivery

Neutralization of anticoagulant effect of heparin to reduce risk of bleeding near delivery^{† [off-label]} in pregnant women receiving heparin therapy who go into spontaneous labor.

Low Molecular Weight Heparin Overdosage

Has been used for treatment of low molecular weight (LMW) heparin (e.g., dalteparin, enoxaparin, tinzaparin [no longer commercially available in the US]) overdosage^{† [off-label]}. However, neutralization of an LMW heparin is not complete even with multiple doses of protamine. (See Actions.)

Protamine Dosage and Administration

General

Heparin Overdosage

• With severe heparin overdosage, discontinue heparin and administer protamine sulfate immediately. Blood transfusions may be required for massive blood loss.

• Dose of protamine sulfate determined by dose of heparin received, route of administration, time elapsed since heparin was given, and blood coagulation studies. Generally, 1 mg of protamine sulfate will neutralize no less than 100 units of heparin sodium.

• Blood heparin concentrations decrease rapidly after IV administration of heparin; dose of protamine sulfate required in the treatment of IV heparin overdosage also decreases rapidly as time elapses.

• 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^{† [off-label]} in arterial and cardiac surgery or dialysis procedures) if indicated by coagulation studies. (See Effects on Hemostasis under Cautions.)

Low Molecular Weight Heparin Overdosage† [off-label]

• Dose of protamine sulfate determined by dose of LMW heparin received, the time elapsed since the drug was given, and blood coagulation studies.

• Following higher doses of protamine sulfate, aPTT may remain more prolonged than would be the case following treatment of heparin overdosage since anti-factor X_a activity is never completely neutralized. A maximum of about 60–75% or 60% of anti-factor X_a activity is neutralized with protamine sulfate administration for overdosage of dalteparin or enoxaparin, respectively.

Administration

IV Administration

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

Administer by very slow IV injection. (See Sensitivity Reactions under Cautions.)

Has been administered by continuous IV infusion^†.

Dilution

May be administered without further dilution at a concentration of 10 mg/mL. However, if more dilute infusion solution is desired, further dilution in 5% dextrose or 0.9% sodium chloride injection recommended. Contains no preservatives; discard unused portion.

Rate of Administration

Administer by very slow IV injection over 10 minutes.

Dosage

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

Adults

Heparin Overdosage

IV

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

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

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

Severe bleeding occurring after sub-Q injection of heparin: Some clinicians recommend 1–1.5 mg for every 100 units of heparin sodium; prolonged infusion may be required to neutralize sub-Q heparin dose. A 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 During Extracorporeal Circulation†

IV

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

Low Molecular Weight Heparin Overdosage†

IV

Severe bleeding within 8 hours of administration of an LMW heparin: 1 mg for every 100 anti-factor X_a units of LMW 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 LMW heparin administered.

Severe bleeding >8 hours after administration of an LMW heparin: 0.5 mg for every 100 anti-factor X_a units of LMW heparin administered.

Protamine sulfate administration may not be required if >12 hours has elapsed since administration of enoxaparin.

Prescribing Limits

Adults

Heparin Overdosage

IV

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

Contraindications

• Known hypersensitivity to protamine sulfate.

Warnings/Precautions

Warnings

Effects on Hemostasis

Heparin rebound (hyperheparinemia) with bleeding reported (e.g., after cardiac surgery, dialysis procedure).

Heparin rebound usually occurs several hours after heparin has been adequately neutralized by protamine sulfate but has been reported 0.5–18 hours following cardiopulmonary bypass procedure^†.

Precise cause unknown; may result from release of heparin from protamine-heparin complex or from extravascular compartments. (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. (See Boxed Warning.)

Patients at increased risk for development of antiprotamine antibodies and hypersensitivity reactions include infertile or vasectomized men, those with previous exposure to protamine-containing preparations (e.g., protamine-containing insulin, previous protamine sulfate therapy), or those with known hypersensitivity to fish.

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.

General

Heparin Overdosage

• With severe heparin overdosage, discontinue heparin and administer protamine sulfate immediately. Blood transfusions may be required for massive blood loss.

• Dose of protamine sulfate determined by dose of heparin received, route of administration, time elapsed since heparin was given, and blood coagulation studies. Generally, 1 mg of protamine sulfate will neutralize no less than 100 units of heparin sodium.

• Blood heparin concentrations decrease rapidly after IV administration of heparin; dose of protamine sulfate required in the treatment of IV heparin overdosage also decreases rapidly as time elapses.

• 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^{† [off-label]} in arterial and cardiac surgery or dialysis procedures) if indicated by coagulation studies. (See Effects on Hemostasis under Cautions.)

Low Molecular Weight Heparin Overdosage† [off-label]

• Dose of protamine sulfate determined by dose of LMW heparin received, the time elapsed since the drug was given, and blood coagulation studies.

• Following higher doses of protamine sulfate, aPTT may remain more prolonged than would be the case following treatment of heparin overdosage since anti-factor X_a activity is never completely neutralized. A maximum of about 60–75% or 60% of anti-factor X_a activity is neutralized with protamine sulfate administration for overdosage of dalteparin or enoxaparin, respectively.

Administration

IV Administration

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

Administer by very slow IV injection. (See Sensitivity Reactions under Cautions.)

Has been administered by continuous IV infusion^†.

Dilution

May be administered without further dilution at a concentration of 10 mg/mL. However, if more dilute infusion solution is desired, further dilution in 5% dextrose or 0.9% sodium chloride injection recommended. Contains no preservatives; discard unused portion.

Rate of Administration

Administer by very slow IV injection over 10 minutes.

Dosage

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

Adults

Heparin Overdosage

IV

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

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

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

Severe bleeding occurring after sub-Q injection of heparin: Some clinicians recommend 1–1.5 mg for every 100 units of heparin sodium; prolonged infusion may be required to neutralize sub-Q heparin dose. A 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 During Extracorporeal Circulation†

IV

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

Low Molecular Weight Heparin Overdosage†

IV

Severe bleeding within 8 hours of administration of an LMW heparin: 1 mg for every 100 anti-factor X_a units of LMW 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 LMW heparin administered.

Severe bleeding >8 hours after administration of an LMW heparin: 0.5 mg for every 100 anti-factor X_a units of LMW heparin administered.

Protamine sulfate administration may not be required if >12 hours has elapsed since administration of enoxaparin.

Prescribing Limits

Adults

Heparin Overdosage

IV

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