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Protamine Side Effects

Medically reviewed by Last updated on Jun 9, 2022.

Applies to protamine: parenteral solution for injection.


  • 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

Side effects include:

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

For Healthcare Professionals

Applies to protamine: injectable solution.


It has been postulated that the heparin-protamine complex may be acted upon by fibrinolysin, thus freeing heparin. Clinical monitoring of coagulation parameters such as the heparin titration test with protamine and plasma thrombin time is recommended to determine subsequent protamine dosage requirements.[Ref]

Hematologic adverse effects such as bleeding and elevated plasma heparin concentrations resulting from rebound anticoagulation have occurred 30 minutes to 18 hours following cardiac surgery despite complete protamine neutralization of heparin.[Ref]


Immune responses, some life-threatening and fatal, have occurred and are thought to be related to previous protamine exposure such as prior heparin neutralization or use of protamine-containing insulin. Severe reactions may occur in the absence of local or systemic allergic reactions to protamine-containing insulin injections and fatal anaphylaxis without a prior allergy history has been reported. Data suggest that vasectomized men may be at increased risk for protamine-induced immunologic reactions.[Ref]

Vasectomy disrupts the normal blood-testes barrier allowing systemic absorption of sperm and the potential for antibody formation. Data concerning vasectomized men have reported the appearance of human protamine-specific IgG antibodies in 22% to 33% within one year after vasectomy. A study revealed antiprotamine IgE antibodies in 35% of vasectomized men compared to 0% in nonvasectomized controls. Cross-reactivity has been demonstrated between human and salmon protamine.[Ref]


Cardiovascular symptoms of hypotension and bradycardia have occurred following intravenous (IV) administration of protamine. Reduced cardiac output, myocardial failure, and irreversible circulatory collapse can occur.[Ref]


Respiratory adverse effects resulting in high-protein, noncardiogenic pulmonary edema have been reported in patients on cardiopulmonary bypass undergoing cardiovascular surgery. The role of protamine is not completely understood, but may be related to an immune-mediated response. However, this effect has been observed with administration of certain blood products, drugs, cardiopulmonary by-pass alone, and in the presence of other etiologic factors.

Respiratory side effects have also included reports of severe pulmonary hypertension.[Ref]


Dermatologic effects, primarily associated with allergic reactions, have been characterized by urticaria, erythema, or edema.[Ref]


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Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.