Protamine Sulfate

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# Black Box Warning

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

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
- Protamine Sulfate Injection, USP is indicated in the treatment of heparin overdosage.

# Dosage
- 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 (see WARNINGS).
- 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 Sulfate in adult patients.

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

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Protamine Sulfate in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

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

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

# Contraindications
- Protamine sulfate is contraindicated in patients who have shown previous intolerance to the drug.

# Warnings
- 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.

# Adverse Reactions

## Clinical Trials 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: (1) Anaphylaxis that resulted in severe respiratory distress, circulation collapse and capillary leak.  Fatal anaphylaxis has been reported in one patient with no prior history of allergies; (2) Anaphylactoid reactions with circulatory collapse, capillary leak, and noncardiogenic pulmonary edema; acute pulmonary hypertension.
- Complement activation by the heparin-protamine complexes, release of lysosomal enzymes from neutrophils, and prostaglandin and thomboxane generation have been associated with the development of anaphylactoid reactions.
- 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.

## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Protamine Sulfate in the drug label.

# Drug Interactions
- Protamine sulfate has been shown to be incompatible with certain antibiotics, including several of the cephalosporins and penicillins

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category CAnimal 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 Sulfate in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Protamine Sulfate 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 Sulfate with respect to geriatric patients.

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

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

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

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

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Protamine Sulfate in women of reproductive potentials and males.

### Immunocompromised Patients
- There is no FDA guidance one the use of Protamine Sulfate in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intravenous

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

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

# Overdosage

# Overdosage
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.
- Rapid administration of protamine is more likely to result in bradycardia, dyspnea, a sensation of warmth, flushing, and severe hypotension.  Hypertension has also occurred.
- 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.
Treatment
- 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.
- Replace blood loss with blood transfusions or fresh frozen plasma.
- If the patient is hypotensive, consider fluids, epinephrine, dobutamine or dopamine.

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

## Mechanism of Action
There is limited information regarding Protamine Sulfate Mechanism of Action 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.

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

## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Protamine Sulfate in the drug label.

## 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 Sulfate in the drug label.

# How Supplied
- This image is provided by the National Library of Medicine.

## Storage
- Store at 20 to 25C (68 to 77F) .  Do not permit to freeze.

# Images

## Drug Images

## Package and Label Display Panel

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

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

# Brand Names
- PROTAMINE SULFATE 

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price