Protamine Sulfate

Reviewed on 1/6/2022

What Is Protamine and How Does It Work?

Protamine is a prescription medication used to treat Heparin Neutralization, Dalteparin or Tinzaparin Overdose, and Enoxaparin Overdose. 

  • Protamine is available under the following different brand names: Protamine

What Are Dosages of Protamine?

Adult dosage

IV solution

  • 10 mg/mL

Heparin Neutralization

  • 1-1.5 mg per 100 USP units of Heparin; not to exceed 50 mg
  • Monitor APTT 5-15 min after dose then in 2-8 hours
  • In accidental overdoses of Heparin, consider t1/2 Heparin 60-90 minutes
  • In setting without bleeding complications, consider observation, rather than reversal of anticoagulation with protamine (avoids ADR’s)
  • Complex of Protamine and Heparin may degrade over time requiring further doses
  • Time Elapsed Since Heparin Dose
  • Less than ½ hour: 1-1.5 mg/100 units of Heparin
  • 30-120 minutes: 0.5-0.75 mg/100 units of Heparin
  • Over 2 hours: 0.25-0.375 mg/100 units of Heparin 

Dalteparin or Tinzaparin Overdose

Adult dosage

  • 1 mg protamine for 100 units dalteparin or tinzaparin; if PTT prolonged 4 hours after protamine overdose administer 0.5 mg per 100 units of dalteparin or tinzaparin

Enoxaparin Overdose

  • 1 mg per mg enoxaparin (if enoxaparin overdose given within 8 hours); if more than 8 hours of overdose or bleeding continues after 4 hours after first dose, give 0.5 mg protamine per mg enoxaparin

Dosage Considerations – Should be Given as Follows: 

  • See "Dosages."

What Are Side Effects Associated with Using Protamine?

Common side effects of Protamine include:

  • sudden fall in blood pressure, 
  • slow heart rate, 
  • pulmonary hypertension
  • shortness of breath, 
  • temporary flushing, and
  • feeling of warmth

Serious side effects of Protamine include:

  • hives, 
  • rash, 
  • swelling in the face, tongue, and throat, 
  • dizziness, 
  • difficulty breathing, 
  • high blood pressure
  • nausea, 
  • vomiting, 
  • fatigue, and 
  • back pain

Rare side effects of Protamine include:

  • none 
This is not a complete list of side effects and other serious side effects or health problems may occur as a result of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

What Other Drugs Interact with Protamine?

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them.  Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.

  • Protamine has severe interactions with the following drugs:
  • Protamine has serious interactions with at least 52 other drugs.
  • Protamine has moderate interactions with at least 89 other drugs.
  • Protamine has minor interactions with at least 17 other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drugs interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use.  Keep a list of all your medications with you, and share this information with your doctor and pharmacist.  Check with your health care professional or doctor for additional medical advice, or if you have health questions, concerns.

What Are Warnings and Precautions for Protamine?


  • Hypersensitivity 
  • Previous intolerance to drug

Effects of drug abuse

  • None

Short-Term Effects

  • See “What Are Side Effects Associated with Using Protamine?”

Long-Term Effects

  • See “What Are Side Effects Associated with Using Protamine?”


  • Heparin rebound causing bleeding may occur 8-9 hours after protamine administration
  • May be ineffective in cardiac surgery patients despite adequate dose
  • Rapid infusion reactions can cause severe hypotensive reactions
  • Because of anticoagulant effect of the drug, it is unwise to give more than 50 mg over a short period unless a larger dose is clearly needed
  • Patients with history of allergy to fish may develop hypersensitivity reactions to drug, although no relationship established to date between allergic reactions to protamine and fish allergy
  • Prior exposure
    • Previous exposure to protamine can induce a humoral immune response and predispose susceptible individuals to development of untoward reactions from subsequent use of drug
    • Patients exposed to protamine through 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 absence of local or systemic allergic reactions to subcutaneous injection of protamine-containing insulin
    • Reports of presence of antiprotamine antibodies in sera of infertile or vasectomized men suggest that some of these individuals may react to use of protamine sulfate
    • Fatal anaphylaxis has been reported in one patient with no prior history of allergies
  • Bleeding risk
    • Hyperheparinemia or bleeding reported 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 end of operation
    • Important to keep patient under close observation after cardiac surgery; administer additional doses of protamine sulfate if indicated by coagulation studies, such as heparin titration test with protamine and determination of plasma thrombin time

Pregnancy and Lactation

  • Use with caution if benefits outweigh risks in pregnancy. 
  • Not known if excreted in breast milk.
Medscape. Protamine.

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