Protamine (Monograph)

Drug class: Antiheparin Agents

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Heparin antagonist; prepared from the sperm or mature testes of salmon or related species.¹⁰⁰

Uses for Protamine

Heparin Overdosage

Treatment of severe heparin overdosage.^{100 116}

Do not use for minor bleeding during heparin therapy.¹²³ (See Boxed Warning.) Heparin withdrawal usually corrects minor overdosage or bleeding within a few hours.¹²³

Heparin Neutralization during Extracorporeal Circulation

Neutralization of heparin administered during extracorporeal circulation^{† [off-label]} in arterial and cardiac surgery or dialysis procedures.^{100 122}

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.¹²⁵

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]}.^{114 115 121} However, neutralization of an LMW heparin is not complete even with multiple doses of protamine.^{114 115 121} (See Actions.)

Protamine Dosage and Administration

General

Heparin Overdosage

• With severe heparin overdosage, discontinue heparin and administer protamine sulfate immediately.^a Blood transfusions may be required for massive blood loss.^{100 a}

• Dose of protamine sulfate determined by dose of heparin received, route of administration, time elapsed since heparin was given, and blood coagulation studies.^{100 116 117} Generally, 1 mg of protamine sulfate will neutralize no less than 100 units of heparin sodium.^{100 117}

• 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.¹⁰⁰

• Monitor therapeutic response through coagulation studies (aPTT, activated coagulation time [ACT], heparin titration test with protamine, plasma thrombin time).^{100 117 a}

• 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.^{100 119 123 a} (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.^{114 115 121}

• 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.^{114 115} 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.^{114 115}

Administration

IV Administration

Administer by very slow IV injection.¹⁰⁰ (See Sensitivity Reactions under Cautions.)

Has been administered by continuous IV infusion^†.¹¹⁷

Dilution

May be administered without further dilution at a concentration of 10 mg/mL.¹⁰⁰ However, if more dilute infusion solution is desired, further dilution in 5% dextrose or 0.9% sodium chloride injection recommended.¹⁰⁰ Contains no preservatives; discard unused portion.¹⁰⁰

Rate of Administration

Administer by very slow IV injection over 10 minutes.^{100 116}

Dosage

Available as protamine sulfate; dosage expressed in terms of the salt.¹⁰⁰

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.^{100 116 117}

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

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

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 A loading dose of 25–50 mg by slow IV infusion suggested by some clinicians,^a with remainder of calculated dose administered by continuous IV infusion^† over 8–16 hours or expected duration of absorption of heparin.^a

Heparin Neutralization During Extracorporeal Circulation†

IV

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

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).^{114 115 117} 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.^{114 115 117 121}

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.^{114 117}

Protamine sulfate administration may not be required if >12 hours has elapsed since administration of enoxaparin.¹¹⁴

Prescribing Limits

Adults

Heparin Overdosage

IV

Maximum 50 mg administered in any 10-minute period, unless larger dose clearly needed.^{100 116} (See Sensitivity Reactions under Cautions.)

Cautions for Protamine

Contraindications

• Known hypersensitivity to protamine sulfate.¹⁰⁰

Warnings/Precautions

Warnings

Effects on Hemostasis

Heparin rebound (hyperheparinemia) with bleeding reported (e.g., after cardiac surgery, dialysis procedure).^{100 123}

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^†.^{100 123}

Precise cause unknown; may result from release of heparin from protamine-heparin complex or from extravascular compartments.^{119 123} (See Metabolism under Pharmacokinetics.)

Monitor patients closely following cardiac surgery; administer additional doses of protamine sulfate if indicated by coagulation studies.^{100 117 119 123}

Sensitivity Reactions

Severe hypotension and potentially fatal anaphylactoid reactions reported, particularly with large doses or too-rapid administration.^{100 109 110 111 112 113 114 115 116 121 122 123} Take particular care to avoid overdosage with protamine.^{114 115 121} (See Boxed Warning.)

Patients at increased risk for development of antiprotamine antibodies and hypersensitivity reactions include infertile or vasectomized men,^{100 101 102 103 104 105 106 107 108 117 123} those with previous exposure to protamine-containing preparations (e.g., protamine-containing insulin, previous protamine sulfate therapy),^{10 100 109 110 112 113} or those with known hypersensitivity to fish.^{8 100 113}

Severe reactions to IV protamine can occur in absence of local or systemic allergic reactions to sub-Q protamine-containing insulin.¹⁰⁰ Fatal anaphylaxis reported in at least 1 patient with no prior history of allergies.¹⁰⁰

Minimize these adverse effects by administering drug slowly.^{100 117 123} (See IV Administration under Dosage and Administration.) Administer only when medical facilities equipped to provide resuscitation and treat shock available.¹⁰⁰ Patients at risk for protamine allergy can be pretreated with corticosteroids and antihistamines.¹¹⁷ (See Actions.)

Specific Populations

Pregnancy

Category C.¹⁰⁰

Lactation

Not known whether protamine sulfate is distributed into milk.¹⁰⁰ Use caution.¹⁰⁰

Pediatric Use

Safety and efficacy not established in children.¹⁰⁰

Common Adverse Effects

Decreased BP or hypotension,^{100 117 123} bradycardia,^{100 117} skin reactions (e.g., flushing, feeling of warmth, urticaria, edema),^{120 123} dyspnea,¹⁰⁰ nausea,¹⁰⁰ vomiting,¹⁰⁰ lassitude,¹⁰⁰ back pain.¹⁰⁰

Drug Interactions

Specific Drugs

Protamine Pharmacokinetics

Absorption

Onset

Neutralization of heparin occurs <5 minutes after IV administration.¹⁰⁰

Duration

Variable duration presumably results from release of heparin from protamine-heparin complex or extravascular compartments.^{118 119 120 123} (See Metabolism under Pharmacokinetics.)

Distribution

Not known whether protamine sulfate is distributed into milk.¹⁰⁰ (See Lactation under Cautions.)

Elimination

Metabolism

Metabolic fate of the protamine-heparin complex has not been elucidated; however, protamine-heparin complex may be partially metabolized or attacked by fibrinolysin, freeing heparin.¹⁰⁰ (See Effects on Hemostasis under Cautions.)

Half-life

Without heparin in healthy individuals: Median 7.4 minutes.^{117 118}

Following cardiopulmonary bypass procedure^† with heparin: Median 4.5 minutes.¹¹⁹

Stability

Storage

Parenteral

Solution for Injection

20–25°C; do not freeze.¹⁰⁰

Actions

• Neutralization of anticoagulant activity of heparin by complexing with heparin to form a stable salt.^{100 117 123 124} Protamine-heparin complex has no anticoagulant activity.^{100 117 123 124}

• Does not bind to the low molecular weight fragments within LMW heparin preparations¹¹⁷ resulting in incomplete neutralization of anti-factor X_a activity when protamine is used to treat overdosage of LMW heparins.^{114 115 117 121}

• Has weak anticoagulant activity as a result of inhibition of platelet aggregation and interaction of many proteins, including fibrinogen,^{100 120 123} and inhibition of thromboplastin generation and activity, which prevents conversion of prothrombin to thrombin.^a

• Reduces systolic and diastolic BP, increases pulmonary artery pressure, and decreases heart rate and systemic vascular resistance.^{123 124}

• Vasoactive effects associated with release of vasoactive mediators (e.g., histamine, bradykinin, thromboxane, nitric oxide), complement activation, and antibody production.^{120 122 123}

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.¹⁰⁰

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.¹⁰⁰

• Importance of informing patients of other important precautionary information.¹⁰⁰ (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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