Protamine

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Protamine
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi

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Black Box Warning

BOXED WARNING
See full prescribing information for complete Boxed Warning.
* Protamine sulfate can cause severe hypotension, cardiovascular collapse, noncardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction, and pulmonary hypertension. Risk factors include high dose or overdose, rapid administration, repeated doses, previous administration of protamine, and current or previous use of protamine-containing drugs (NPH insulin, protamine zinc insulin, and certain beta-blockers). Allergy to fish, previous vasectomy, and severe left ventricular dysfunction and abnormal preoperative pulmonary hemodynamics also may be risk factors. In patients with any of these risk factors, the risk to benefit of administration of protamine sulfate should be carefully considered. Vasopressors and resuscitation equipment should be immediately available in case of a severe reaction to protamine. Protamine sulfate should not be given when bleeding occurs without prior heparin use.

Overview

Protamine is a heparin antagonist that is FDA approved for the {{{indicationType}}} of heparin overdosage. There is a Black Box Warning for this drug as shown here. Common adverse reactions include flushing, dyspnea, nausea, and vomiting.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Heparin Overdosage
  • Dosing Information
  • Each mg of protamine sulfate, calculated on the dried basis, neutralizes not less than 100 USP Heparin Units.
  • Protamine sulfate injection should be given by very slow intravenous injection over a 10-minute period in doses not to exceed 50 mg.
  • Protamine sulfate is intended for injection without further dilution; however, if further dilution is desired, D5-W or normal saline may be used. Diluted solutions should not be stored since they contain no preservative.
  • Protamine sulfate should not be mixed with other drugs without knowledge of their compatibility, because protamine sulfate has been shown to be incompatible with certain antibiotics, including several of the cephalosporins and penicillins.
  • Because heparin disappears rapidly from the circulation, the dose of protamine sulfate required also decreases rapidly with the time elapsed following intravenous injection of heparin. For example, if the protamine sulfate is administered 30 minutes after the heparin, one-half the usual dose may be sufficient.
  • The dosage of protamine sulfate should be guided by blood coagulation studies.
  • Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Protamine in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Protamine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

  • Safety and effectiveness in children have not been established.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Protamine in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Protamine in pediatric patients.

Contraindications

  • Protamine sulfate is contraindicated in patients who have shown previous intolerance to the drug.

Warnings

BOXED WARNING
See full prescribing information for complete Boxed Warning.
* Protamine sulfate can cause severe hypotension, cardiovascular collapse, noncardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction, and pulmonary hypertension. Risk factors include high dose or overdose, rapid administration, repeated doses, previous administration of protamine, and current or previous use of protamine-containing drugs (NPH insulin, protamine zinc insulin, and certain beta-blockers). Allergy to fish, previous vasectomy, and severe left ventricular dysfunction and abnormal preoperative pulmonary hemodynamics also may be risk factors. In patients with any of these risk factors, the risk to benefit of administration of protamine sulfate should be carefully considered. Vasopressors and resuscitation equipment should be immediately available in case of a severe reaction to protamine. Protamine sulfate should not be given when bleeding occurs without prior heparin use.
  • Hyperheparinemia or bleeding has been reported in experimental animals and in some patients 30 minutes to 18 hours after cardiac surgery (under cardiopulmonary bypass) in spite of complete neutralization of heparin by adequate doses of protamine sulfate at the end of the operation. It is important to keep the patient under close observation after cardiac surgery. Additional doses of Protamine sulfate should be administered if indicated by coagulation studies, such as the heparin titration test with protamine and the determination of plasma thrombin time.
  • Too-rapid administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Facilities to treat shock should be available.

Precautions

  • Because of the anticoagulant effect of protamine, it is unwise to give more than 50 mg over a short period unless a larger dose is clearly needed.
  • Patients with a history of allergy to fish may develop hypersensitivity reactions to protamine, although to date no relationship has been established between allergic reactions to protamine and fish allergy.
  • Previous exposure to protamine can induce a humoral immune response and predispose susceptible individuals to the development of untoward reactions from the subsequent use of this drug. Patients exposed to protamine through the use of protamine-containing insulin or during heparin neutralization may experience life-threatening reactions and fatal anaphylaxis upon receiving large doses of protamine intravenously. Severe reactions to intravenous protamine can occur in the absence of local or systemic allergic reactions to subcutaneous injection of protamine-containing insulin. Reports of the presence of antiprotamine antibodies in the sera of infertile or vasectomized men suggest that some of these individuals may react to the use of protamine sulfate.
  • Fatal anaphylaxis has been reported in one patient with no prior history of allergies.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Protamine in the drug label.

Postmarketing Experience

  • The intravenous administration of protamine sulfate may cause a sudden fall in blood pressure and bradycardia. Other reactions include transitory flushing and feeling of warmth, dyspnea, nausea, vomiting and lassitude. Back pain has been reported in conscious patients undergoing such procedures as cardiac catheterization.
  • Severe adverse reactions have been reported including:
  • Severe and potentially irreversible circulatory collapse associated with myocardial failure and reduced cardiac output can also occur. The mechanism(s) of this reaction and the role played by concurrent factors are unclear.
  • High-protein, noncardiogenic pulmonary edema associated with the use of protamine has been reported in patients on cardiopulmonary bypass who are undergoing cardiovascular surgery. The etiologic role of protamine 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 it can be life-threatening. Because fatal anaphylactic and anaphylactoid reactions have been reported after the administration of protamine sulfate, the drug should be given only when resuscitation techniques and treatment of anaphyactic and anaphylactoid shock are readily available.

Drug Interactions

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category C
  • Animal reproduction studies have not been conducted with protamine sulfate. It is also not known whether protamine sulfate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Protamine sulfate should be given to a pregnant woman only if clearly needed.


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Protamine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Protamine during labor and delivery.

Nursing Mothers

  • It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when protamine sulfate is administered to a nursing woman.

Pediatric Use

  • Safety and effectiveness in children have not been established.

Geriatic Use

There is no FDA guidance on the use of Protamine with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Protamine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Protamine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Protamine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Protamine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Protamine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Protamine in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Intravenous

Monitoring

There is limited information regarding Monitoring of Protamine in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Protamine in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

  • Overdose of protamine sulfate may cause bleeding. Protamine has a weak anticoagulant effect due to an interaction with platelets and with many proteins including fibrinogen. This effect should be distinguished from the rebound anticoagulation that may occur 30 minutes to 18 hours following the reversal of heparin with protamine.
  • The median lethal dose of protamine sulfate is 50 mg/kg in mice. Serum concentrations of protamine sulfate are not clinically useful. Information is not available on the amount of drug in a single dose that is associated with overdosage or is likely to be life-threatening.

Management

  • To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs and unusual drug kinetics in your patient.

Chronic Overdose

There is limited information regarding Chronic Overdose of Protamine in the drug label.

Pharmacology

There is limited information regarding Protamine Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Mechanism of Action of Protamine in the drug label.

Structure

  • Protamines are simple proteins of low molecular weight that are rich in arginine and strongly basic. They occur in the sperm of salmon and certain other species of fish.
  • Protamine sulfate occurs as fine white or off-white amorphous or crystalline powder. It is sparingly soluble in water. The pH is between 6.0 and 7.0. The cationic hydrogenated protamine at a pH of 6.8 to 7.1 reacts with anionic heparin at a pH of 5.0 to 7.5 to form an inactive complex.
  • Protamine Sulfate Injection, USP is a sterile, isotonic solution of protamine sulfate. It acts as a heparin antagonist. It is also a weak anticoagulant.
  • Each mL contains: Protamine sulfate 10 mg; sodium chloride 9 mg; Water for Injection q.s. Sulfuric acid and/or dibasic sodium phosphate (heptahydrate) may have been added for pH adjustment.
  • The preparation is preservative free.
  • Protamine sulfate is administered intravenously.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Protamine in the drug label.

Pharmacokinetics

  • When administered alone, protamine has an anticoagulant effect. However, when it is given in the presence of heparin (which is strongly acidic), a stable salt is formed and the anticoagulant activity of both drugs is lost.
  • Protamine sulfate has a rapid onset of action. Neutralization of heparin occurs within five minutes after intravenous administration of an appropriate dose of protamine sulfate. Although the metabolic fate of the heparin-protamine complex has not been elucidated, it has been postulated that protamine sulfate in the heparin-protamine complex may be partially metabolized or may be attacked by fibrinolysin, thus freeing heparin.

Nonclinical Toxicology

  • Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Studies have not been performed to determine potential for carcinogenicity, mutagenicity or impairment of fertility.

Clinical Studies

There is limited information regarding Clinical Studies of Protamine in the drug label.

How Supplied

  • Protamine Sulfate Injection, USP, 50 mg (10 mg/mL, 5 mL) in a single dose flip-top vial, in packages of 25.
  • Protamine Sulfate Injection, USP, 250 mg (10 mg/mL, 25 mL) in a single dose flip-top vial, packaged individually.
  • Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not permit to freeze.
  • CAUTION: The total dose of protamine sulfate contained in product No. 22930 (250 mg in 25 mL) is 5 times greater than in product No. 22905 (50 mg in 5 mL).
  • The large size 25 mL vials are designed for antiheparin treatment only when large doses of heparin have been given during surgery and are to be neutralized by large doses of protamine sulfate after surgical procedures.

Storage

There is limited information regarding Protamine Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Protamine in the drug label.

Precautions with Alcohol

  • Alcohol-Protamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

  • Protamine sulfate®[1]

Look-Alike Drug Names

  • protamine — Protonix®[2]

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ "PROTAMINE SULFATE injection, solution".
  2. ↑ "http://www.ismp.org". External link in |title= (help)


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