Protamine sulfate, which is prepared from the sperm or mature testes of salmon or related species and is composed of arginine, proline, serine, and valine, acts as a heparin antagonist.
Protamine sulfate is used in the treatment of severe heparin sodium overdosage.100, 116 Protamine sulfate should not be used if only minor bleeding occurs during heparin therapy, since withdrawal of heparin will usually correct minor overdosage or bleeding within a few hours.123 However, if severe overdosage or bleeding occurs during heparin therapy, heparin should be discontinued and protamine sulfate administered immediately. Blood transfusions may be required in patients with massive blood loss. (See Heparin 20:12.04.16.)
Heparin Neutralization during Extracorporeal Circulation
Protamine sulfate is also used to neutralize heparin administered during extracorporeal circulation† in arterial and cardiac surgery or dialysis procedures.100, 122
Heparins Neutralization in Pregnant Women Near Delivery
Protamine sulfate has been used to neutralize the 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
Protamine sulfate has been used in the treatment of low molecular weight heparin (e.g., dalteparin, enoxaparin, tinzaparin [no longer commercially available in the US]) overdosage†.114, 115, 121 However, unlike treatment of overdosage of conventional unfractionated heparin, neutralization of the effects of a low molecular weight heparin is not complete even with multiple doses of protamine sulfate.114, 115, 121 (See Pharmacology.)
Protamine sulfate is administered by very slow IV injection. The drug has also been administered by continuous IV infusion†.117 Protamine sulfate injection is intended for administration without further dilution at a concentration of 10 mg of protamine sulfate per mL.100 However, if further dilution is desired, 5% dextrose or 0.9% sodium chloride injection may be used.100 Diluted solutions of protamine sulfate should not be stored since they contain no preservative.100, 117
Protamine sulfate usually is administered by very slow IV injection over 10 minutes.100 116 No more than 50 mg of the drug should be administered in any 10-minute period.100, 116 (See Cautions: Precautions and Contraindications.)
Dosage of protamine sulfate should be determined by the dose of heparin received, route of administration, the time elapsed since heparin was given, and by blood coagulation studies.100, 116, 117 Generally, 1 mg of protamine sulfate will neutralize no less than 100 units of heparin sodium.100, 117
Since blood heparin concentrations decrease rapidly after IV administration of heparin, the dose of protamine sulfate required in the treatment of IV heparin overdosage also decreases rapidly as time elapses. If only a few minutes have elapsed since heparin was administered by IV injection, most clinicians recommend that 1 mg of protamine sulfate be given for every 100 units of heparin sodium administered.100, 116, 117 If 30 minutes have elapsed since IV injection of heparin, 0.5 mg of protamine sulfate should be given for every 100 units of heparin sodium100 and, if 2 hours or more have elapsed since IV injection of heparin, 0.25-0.375 mg of protamine sulfate should be given for every 100 units of heparin sodium administered. If heparin was administered by IV infusion, some clinicians recommend that a dose of 25-50 mg of protamine sulfate be given after stopping the infusion.
If heparin was administered by deep subcutaneous injection, some clinicians recommend that 1-1.5 mg of protamine sulfate be given IV for each 100 units of heparin sodium. Some clinicians have suggested that a loading dose of 25-50 mg of protamine sulfate may be administered by slow IV injection and the rest of the calculated dose administered by continuous IV infusion over 8-16 hours or the expected duration of absorption of heparin.
Heparin Neutralization during Extracorporeal Circulation
To neutralize heparin administered during extracorporeal circulation†, 1.5 mg of protamine sulfate is usually given for each 100 units of heparin sodium administered. Alternatively, some clinicians recommend that protamine sulfate dosage be determined using sequential activated coagulation time (ACT) and a dose-response curve which correlates results of the coagulation tests and the amount of heparin remaining in the body. (See Cautions: Precautions and Contraindications.)
Low Molecular Weight Heparin Overdosage
To largely neutralize the effects of low molecular weight heparins following overdosage†, the dose of protamine sulfate is determined by the administered dose of the low molecular weight heparin, the time elapsed since the drug was given, and blood coagulation studies.114, 115, 121
For severe bleeding or low molecular weight heparin overdosage, 1 mg of protamine sulfate should be given for every 100 anti-factor Xa units of low molecular weight heparin (e.g., dalteparin sodium, enoxaparin sodium [1 mg of enoxaparin sodium has an anti-factor Xa activity of approximately 100 units], tinzaparin sodium [no longer commercially available in the US]) if the low molecular weight heparin was administered in the previous 8 hours.114, 115, 117 If the activated partial thromboplastin time (aPTT) measured 2-4 hours after the first protamine sulfate infusion remains prolonged or if bleeding continues, a second dose of 0.5 mg of protamine sulfate may be given for every 100 anti-factor Xa units of low molecular weight heparin administered.114, 115, 117, 121
If more than 8 hours has elapsed since the low molecular weight heparin was administered, an infusion of 0.5 mg of protamine sulfate may be given for every 100 anti-factor Xa units of low molecular weight heparin administered.114, 117
However, even after higher dosages of protamine sulfate, the aPTT may remain more prolonged than would be the case following treatment of overdosage of conventional unfractionated heparin 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
Protamine administration may not be required if more than 12 hours has elapsed since administration of enoxaparin.114
Rapid IV injection or high doses of protamine sulfate have caused severe hypotension, bradycardia, pulmonary hypertension, pulmonary vasoconstriction, dyspnea, transient flushing, and a feeling of warmth.100, 114, 115, 116, 117, 118, 119, 121, 122, 123, 124 (See Cautions: Precautions and Contraindications.)
Hypersensitivity reactions including urticaria, angioedema, acute pulmonary hypertension, anaphylaxis, and anaphylactoid reactions have occurred occasionally after administration of protamine sulfate. Anaphylaxis occurring with protamine sulfate administration also has been associated with severe respiratory distress and capillary leak. Complement activation by the heparin-protamine complexes, release of lysosomal enzymes from neutrophils, and prostaglandin and thromboxane generation have been associated with the development of anaphylactoid reactions. Severe and potentially irreversible circulatory collapse associated with myocardial failure and reduced cardiac output also can occur. The mechanism(s) of this reaction is unclear, as is the role played by concurrent factors. High-protein, noncardiogenic pulmonary edema associated with the use of protamine sulfate has been reported in patients on cardiopulmonary bypass who are undergoing cardiovascular surgery. The etiologic role of protamine sulfate in the pathogenesis of this condition is uncertain, and multiple factors have been present in most cases. The condition has been reported in association with administration of certain blood products, other drugs, cardiopulmonary bypass alone, and other etiologic factors. It is difficult to treat and can be life-threatening.
Hypersensitivity reactions to the drug have been reported in several individuals who were also hypersensitive to fish, and the drug probably should be used with caution in patients with a history of allergy to fish. Several fatalities temporally associated with apparent protamine sulfate-induced reactions have been reported,100, 109, 110, 111, 112, 113 including at least one patient with evidence of antiprotamine IgE-mediated anaphylaxis.109 In at least 2 of these patients, death occurred following intentional109 or unintentional113 rechallenge in patients who had previously developed a serious immediate reaction (hypotension, cardiovascular collapse) following administration of protamine sulfate.
Previous exposure to protamine from use of protamine sulfate for the management of heparin overdosage or from use of protamine-containing insulin may predispose susceptible individuals to the development of severe hypersensitivity reactions (e.g., anaphylaxis) or other life-threatening reactions during subsequent use of protamine sulfate.10, 100, 109, 110, 112, 113 In one study, about 50% of patients who used isophane (neutral protamine Hagedorn, NPH) insulin had high serum levels of antiprotamine IgE.109 In another study, patients with a history of isophane insulin use appeared to be at substantially increased risk of developing a serious adverse reaction (i.e., hypotension and other manifestations suggestive of anaphylaxis) to protamine sulfate than patients with no history of isophane insulin use.113
Severe reactions to protamine can occur in the absence of local or systemic allergic reactions to protamine-containing insulin.100 Fatal anaphylaxis has been reported in at least one patient with no prior history of allergies.100
Antiprotamine antibodies are present in the serum of some infertile or vasectomized men,100, 101, 102, 103, 104, 105, 106, 107, 108, 117, 123 and the presence of these antibodies potentially may predispose individuals to protamine sulfate-induced hypersensitivity reactions.100, 101, 102, 104, 106, 107, 108 About 22-33% of vasectomized males have been reported to develop antibodies (e.g., IgG) to human protamine.101, 102, 107, 108 Cross-reactivity between these antibodies and protamines from other species (e.g., salmon) can occur,101, 102, 104, 106, 108 particularly when relatively high levels of antibody to human protamine are present.108 An immediate anaphylactoid reaction has occurred in at least one vasectomized male following administration of a dose of protamine sulfate; pretreatment with a corticosteroid and antihistamine prevented recurrence of the reaction during subsequent administration of protamine sulfate.102 Vasectomy history should be determined prior to administration of protamine sulfate in males, and the possibility of protamine sensitivity should be considered.100, 101, 102 Some clinicians suggest that vasectomized males should be pretreated with a corticosteroid and antihistamine prior to administration of protamine sulfate in an attempt to ameliorate or prevent such reactions.101, 115 Males undergoing vasectomy should be advised of the potential risk of developing protamine antibodies.102
Systemic hypertension, nausea, vomiting, and lassitude have occurred in patients receiving protamine sulfate. Back pain has been reported rarely in conscious patients undergoing procedures such as cardiac catheterization.
Heparin rebound with anticoagulation and bleeding has been reported occasionally several hours after heparin has been adequately neutralized by protamine sulfate.100, 123 This effect occurs most frequently when protamine sulfate is used to neutralize heparin administered during extracorporeal circulation† in arterial and cardiac surgery or dialysis procedures. Heparin rebound, when it occurs, usually is evident within 8-9 hours after protamine sulfate administration but has been reported 30 minutes to 18 hours after cardiopulmonary bypass† despite complete neutralization of heparin by adequate doses of protamine sulfate at the end of the operation.100 The precise cause is unknown but this effect presumably results from release of heparin from the protamine-heparin complex or release of heparin from extravascular compartments.119, 123
Because protamine sulfate is a weak anticoagulant, overdosage theoretically may result in bleeding. However, in one study, overdosage of 600-800 mg of IV protamine sulfate had only minimal, transient effects on blood coagulation tests.
Precautions and Contraindications
Either the activated partial thromboplastin time (aPTT) or the activated coagulation time (ACT) should be used to monitor the effect of protamine sulfate in neutralizing heparin, and additional doses of protamine sulfate should be administered if necessary.100, 117 Coagulation tests are usually performed 5-15 minutes after administration of protamine sulfate. Repeat coagulation tests are not usually necessary; however, because heparin rebound has been reported (e.g., after cardiac surgery, dialysis procedure) another test in 2-8 hours may be desirable. It is important to keep the patient under close observation following cardiac surgery; additional doses of protamine sulfate should be administered if indicated by coagulation studies (e.g., heparin titration test with protamine, plasma thrombin time, ACT, aPTT).100, 117, 119, 123
Severe hypotension and potentially fatal anaphylactoid reactions have been reported in patients receiving protamine sulfate, particularly with large doses or too-rapid administration of the drug.100, 109, 110, 111, 112, 113, 114, 115, 116, 121, 122, 123 Particular care should be taken to avoid overdosage with protamine sulfate.114, 115, 121
The risk of a hypersensitivity reaction to protamine sulfate should be considered in patients with known sensitivity to fish,8, 100, 113 vasectomized or infertile males,100, 101, 104, 106, 107, 108 and patients who have received protamine-containing insulin100, 109, 110, 113 or previous protamine sulfate therapy.10, 100, 109, 110, 112, 113 (See Cautions: Adverse Effects.) Because fatal anaphylactic and anaphylactoid reactions have been reported following administration of protamine sulfate,100, 109, 110, 111, 112, 113 the drug should be given only when facilities and equipment for the treatment of such reactions are readily available.100 Protamine sulfate should not be used for bleeding that occurs without prior exposure to heparin.100 Protamine sulfate is contraindicated in patients with a history of intolerance to the drug.100
Safety and efficacy of protamine sulfate in children have not been established.100
Mutagenicity and Carcinogenicity
Studies to determine the mutagenic or carcinogenic potential of protamine sulfate have not been performed to date.100
Pregnancy, Fertility, and Lactation
Animal reproduction studies have not been performed with protamine sulfate.100 It is not known whether protamine sulfate can cause fetal harm when administered to pregnant women or can affect reproduction capacity.100 The drug should be used during pregnancy only when clearly needed.100
Studies have not been performed to date with protamine sulfate to determine the effect of the drug on fertility.
Since it is not known whether protamine sulfate is distributed into human milk, the drug should be used with caution in nursing women.100
The median lethal dose (LD50) of protamine sulfate in mice is 100 mg/kg.100 Overdosage of protamine sulfate may theoretically result in hemorrhage because of the slight anticoagulant effect of the drug; however, in one study, overdosage with 600-800 mg of IV protamine sulfate resulted in only minimal, transient effects on blood coagulation.
If overdosage of the drug occurs, the patient should be monitored with coagulation tests and symptomatic treatment instituted if necessary.
Protamine sulfate, which is strongly basic, acts as a heparin antagonist in vitro and in vivo by complexing with strongly acidic heparin to form a stable salt; the protamine-heparin complex has no anticoagulant activity.100, 117, 123, 124 Protamine does not bind to the low molecular weight fragments within low molecular weight heparin preparations,117 resulting in incomplete neutralization of anti-factor Xa activity when protamine sulfate is used to treat overdosage of low molecular weight heparins.114, 115, 117, 121
When administered alone, protamine sulfate is also a weak anticoagulant as a result of inhibition of platelet aggregation; interaction with many proteins, including fibrinogen;100, 120, 123 and inhibition of thromboplastin generation and thromboplastin activity, which prevents the conversion of prothrombin to thrombin.
Protamine reduces systolic and diastolic blood pressure, increases pulmonary artery pressure, and decreases heart rate and systemic vascular resistance.123, 124 Vasoactive effects of protamine are associated with release of vasoactive mediators (e.g., histamine, bradykinin, thromboxane, nitric oxide), complement activation, and antibody production.120, 122, 123
Protamine sulfate has a rapid onset of action.100 Following IV administration of an appropriate dose of protamine sulfate, neutralization of heparin occurs within 5 minutes.100 Protamine has a variable duration of action that presumably results from release of heparin from the protamine-heparin complex or extravascular compartments.118, 119, 120, 123 (See Pharmacokinetics: Elimination.)
It is not known whether protamine sulfate is distributed into human milk.100 (See Cautions: Pregnancy, Fertility, and Lactation.)
Although the metabolic fate of the protamine-heparin complex has not been elucidated, it appears that the protamine in the heparin-protamine complex may be partially metabolized or attacked by fibrinolysin, thus freeing heparin.100 (See Cautions: Precautions and Contraindications.)
Following IV administration of protamine sulfate in healthy individuals who were not recieving heparin, a median elimination half-life of 7.4 minutes has been reported.117, 118 Following IV administration of protamine sulfate in patients undergoing a cardiopulmonary bypass proceedure who received heparin, a median elimination half-life of 4.5 minutes was reported.119
Protamines are simple, low molecular weight, cationic proteins that occur in the sperm of salmon and certain other species of fish. Commercially available protamine sulfate is prepared from the sperm or mature testes of salmon or related species and is composed of arginine, proline, serine, and valine. Protamine sulfate occurs as a fine, white or off-white, amorphous or crystalline powder and is sparingly soluble in water and very slightly soluble in alcohol.
Protamine sulfate injection is a colorless, sterile solution which has been made isotonic with 0.9% sodium chloride; sodium phosphate and/or sulfuric acid may have been added to adjust the pH to 6-7.100
Protamine sulfate injection should be stored at 20-25°C; freezing of the injection should be avoided.100 Protamine sulfate is potentially physically and/or chemically incompatible with some anti-infective agents, including some cephalosporins and penicillins.100 Specialized references should be consulted for specific compatibility information.
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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Bulk | Powder | |||
Parenteral | Injection, for IV use only | 10 mg/mL* | Protamine Sulfate Injection (preservative-free; available as single-dose vials) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
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100. APP Pharmaceuticals. Protamine sulfate injection prescribing information. Schaumberg, IL; 2008 Jan.
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115. Eisai. Fragmin® (dalteparin sodium) injection prescribing information. Woodcliff, NJ; 2007 Apr.
116. APP Pharmaceuticals. Heparin sodium injection prescribing information. Schaumburg, IL; 2007 Dec.
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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.