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Class: Antiheparin Agents
CAS Number: 9009-65-8

Medically reviewed by Last updated on June 9, 2020.


  • Possible severe hypotension, cardiovascular collapse, noncardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction, and pulmonary hypertension with rapid IV injection, high doses, repeated doses, or previous exposure to protamine or protamine-containing drugs (e.g., insulin).100 Other possible risk factors include known sensitivity to fish, vasectomy, severe left ventricular dysfunction, and abnormal pulmonary hemodynamics.100 Weigh risk against anticipated benefit of protamine therapy in patients with risk factors.100 Administer only when facilities and equipment for treatment of such reactions are readily available.100 (See Sensitivity Reactions under Cautions.)

  • Protamine should not be used for bleeding that occurs without prior exposure to heparin.100


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 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 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.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


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 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†

  • 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 Xa activity is never completely neutralized.114 115 A maximum of about 60–75% or 60% of anti-factor Xa activity is neutralized with protamine sulfate administration for overdosage of dalteparin or enoxaparin, respectively.114 115


IV Administration

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

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

Has been administered by continuous IV infusion.117


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


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


Heparin Overdosage

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†

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†

Severe bleeding within 8 hours of administration of an LMW heparin: 1 mg for every 100 anti-factor Xa units of LMW heparin (e.g., enoxaparin sodium, dalteparin sodium, tinzaparin sodium) administered (e.g., 1 mg of enoxaparin sodium has an anti-factor Xa 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 Xa 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 Xa 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


Heparin Overdosage

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

Cautions for Protamine


  • Known hypersensitivity to protamine sulfate.100



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


Category C.100


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

Interactions for Protamine

Specific Drugs




Neutralization of anticoagulant activity of heparin100 117 123


Prolongs absorption of insulin123

LMW heparins

Incomplete neutralization of anticoagulant activity of LMW heparin114 115 117 121

Protamine Pharmacokinetics



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


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


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



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.)


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

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




Solution for Injection

20–25°C; do not freeze.100


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

Drug Compatibility

Incompatible with some anti-infective agents, including some cephalosporins and penicillins.100

Admixture CompatibilityHID


Cimetidine HCl

Ranitidine HCl

Verapamil HCl


  • 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 Xa 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.)


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.

Protamine Sulfate


Dosage Forms


Brand Names



Injection, for IV use only

10 mg/mL

Protamine Sulfate Injection (preservative-free; available as single-dose vials)


AHFS DI Essentials™. © Copyright 2021, Selected Revisions June 19, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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


Only references cited for selected revisions after 1984 are available electronically.

8. Caplan SN, Berkman EM. Protamine sulfate and fish allergy. N Engl J Med. 1976; 295:172.

10. Lakin JD, Blocker TJ, Strong DM et al. Anaphylaxis to protamine sulfate mediated by a complement-dependent IgG antibody. J Allergy Clin Immunol. 1978; 61:102-7.

100. APP. Protamine sulfate injection prescribing information. Schaumberg, IL; 2008 Jan.

101. Lake CL, Arnold WP, Epstein RM. Vasectomy and health. JAMA. 1985; 253:1723.

102. Watson RA, Ansbacher R, Barry M et al. Allergic reaction to protamine: a late complication of elective vasectomy? Urology. 1983; 22:493-5.

103. Alexander NJ, Anderson DJ. Vasectomy: consequences of autoimmunity to sperm antigens. Fertil Steril. 1979; 32:253-60.

104. Samuel T, Kolk AHJ, Rümke P. Studies on the immunogenicity of protamines in humans and experimental animals by means of a micro-complement fixation test. Clin Exp Immunol. 1978; 33:252-60.

105. Hellema HWJ, Rümke P. Sperm autoantibodies as a consequence of vasectomy. I. Within 1 year post-operation. Clin Exp Immunol. 1978; 31:18-29.

106. Samuel T. Antibodies reacting with salmon and human protamines in sera from infertile men and from vasectomized men and monkeys. Clin Exp Immunol. 1977; 30:181-7.

107. Samuel T, Kolk AHJ, Rümke P et al. Autoimmunity to sperm antigens in vasectomized men. Clin Exp Immunol. 1975; 21:65-74.

108. Samuel T, Linnet L, Rümke P. Post-vasectomy antoimmunity to protamines in relation to the formation of granulomas and sperm agglutinating antibodies. Clin Exp Immunol. 1978; 33:261-9.

109. Sharath MD, Metzger WJ, Richerson HB et al. Protamine-induced fatal anaphylaxis: prevalence of antiprotamine immunoglobulin E antibody. J Thorac Cardiovasc Surg. 1985; 90:86-90.

110. Weiler JM, Freiman P, Sharath MD et al. Serious adverse reactions to protamine sulfate: are alternatives needed? J Allergy Clin Immunol. 1985; 75:297-303.

111. Olinger GN, Becker RM, Bonchek LI. Noncardiogenic pulmonary edema and peripheral vascular collapse following cardiopulmonary bypass: rare protamine reaction? Ann Thorac Surg. 1980; 29:20-5.

112. Holland CL, Singh AK, McMaster PR et al. Adverse reactions to protamine sulfate following cardiac surgery. Clin Cardiol. 1984; 7:157-62.

113. Stewart WJ, McSweeney SM, Kellett MA et al. Increased risk of severe protamine reactions in NPH insulin-dependent diabetics undergoing cardiac catheterization. Circulation. 1984; 70:788-92.

114. Aventis Pharmaceuticals. Lovenox (enoxaparin sodium) injection prescribing information. Bridgewater, NJ; 2007 Oct

115. Eisai. Fragmin (dalteparin sodium) injection prescribing information. Woodcliff, NJ; 2007 Apr.

116. APP Pharmaceuticals. Heparin sodium injection prescribing information. Schaumburg, IL; 2007 Dec.

117. Hirsh J, Bauer KA, Donati MB et al. Parenteral anticoagulants: American College of Chest Physicians evidenced-based clinical practice guidelines (8th ed). Chest. 2008; 133 (Suppl):141S-59S.

118. Butterworth J, Lin YA, Prielipp R et al. The pharmacokinetics and cardiovascular effects of a single intravenous dose of protamine in normal volunteers. Anesth Analg. 2002; 94:514-22.

119. Butterworth J, Lin YA, Prielipp RC et al. Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass. Ann Thorac Surg. 2002; 74:1589-95.

120. Jaques LB. Protamine-antagonist to heparin. Can Med Assoc J. 1973; 108:1291-5.

121. Celgene. Innohep (tinzaparin sodium) injection prescribing information. Boulder, CO; 2008 Apr.

122. Pretorius M, Scholl FG, McFarlane JA et al. A pilot study indicating that bradykinin β2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass. Clin Pharmacol Ther. 2005; 78:477-85.

123. Lindblad B. Protamine sulphate: A review of its effects: hypersensitivity and toxicity. Eur J Vasc Surg. 1989; 3:195-201.

124. Carr JA, Silverman N. The heparin-protamine interaction. J Cardiovasc Surg. 1999; 40:659-66.

125. Bates SM, Greer I, Pabinger I et al. Venous thromboembolism, thrombophilia, antithrombotic therapy and pregnancy: American College of Chest Physicians evidenced-based clinical practice guidelines (8th ed). Chest. 2008; 133(Suppl):844S-86S.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1432-3.

a. AHFS Drug Information 2010. McEvoy GK, ed. Protamine. Bethesda, MD: American Society of Health-System Pharmacists; 2010:1601-3.