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Drug class: Antiheparin Agents
CAS number: 9009-65-8

Medically reviewed by on Jun 9, 2022. Written by ASHP.


  • 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). Other possible risk factors include known sensitivity to fish, vasectomy, severe left ventricular dysfunction, and abnormal pulmonary hemodynamics. Weigh risk against anticipated benefit of protamine therapy in patients with risk factors. Administer only when facilities and equipment for treatment of such reactions are readily available. (See Sensitivity Reactions under Cautions.)

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


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


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 Xa activity is never completely neutralized. 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.


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.


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.


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


Heparin Overdosage

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†

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†

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). 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.

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

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

Prescribing Limits


Heparin Overdosage

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

Cautions for Protamine


  • Known hypersensitivity to protamine sulfate.



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


Category C.


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 for Protamine

Specific Drugs




Neutralization of anticoagulant activity of heparin


Prolongs absorption of insulin

LMW heparins

Incomplete neutralization of anticoagulant activity of LMW heparin

Protamine Pharmacokinetics



Neutralization of heparin occurs <5 minutes after IV administration.


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


Not known whether protamine sulfate is distributed into milk. (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. (See Effects on Hemostasis under Cautions.)


Without heparin in healthy individuals: Median 7.4 minutes.

Following cardiopulmonary bypass procedure with heparin: Median 4.5 minutes.




Solution for Injection

20–25°C; do not freeze.


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

Drug Compatibility

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

Admixture CompatibilityHID


Cimetidine HCl

Ranitidine HCl

Verapamil HCl


  • Neutralization of anticoagulant activity of heparin by complexing with heparin to form a stable salt. Protamine-heparin complex has no anticoagulant activity.

  • Does not bind to the low molecular weight fragments within LMW heparin preparations resulting in incomplete neutralization of anti-factor Xa activity when protamine is used to treat overdosage of LMW 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.)


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 2023, Selected Revisions June 19, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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