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Drug Reference

protamine sulfate

heparin antagonist· Brands: ProtamineIV

Mechanism of action
Protamine sulfate is a highly basic protein rich in arginine that binds electrostatically to the acidic glycosaminoglycan chains of heparin, forming a stable, inactive complex. This neutralises the anticoagulant effect of unfractionated heparin and partially reverses low molecular weight heparin activity.
Pharmacokinetics
After intravenous administration, protamine sulfate has a rapid onset of action, within 5 minutes, and the effect lasts approximately 2 hours. It is distributed throughout the extracellular fluid and is cleared by the reticuloendothelial system. The half-life is short, about 7 minutes, but the neutralising effect is prolonged due to the stability of the protamine-heparin complex. It is not systemically metabolised.
Indications & dosing

Reversal of heparin anticoagulation (e.g., bleeding or after surgery)

Slow IV injection. Dose based on amount of heparin given in the last 3-4 hours; maximum 50 mg per dose.

  • adult · IV: 1–1.5 mg/100 units once · Slow IV injection. Dose based on amount of heparin given in the last 3-4 hours; maximum 50 mg per dose.

Neutralisation of heparin after cardiopulmonary bypass

Administer by slow IV injection; maximum 50 mg. Titrate to clinical effect and ACT.

  • adult · IV: 1–1.5 mg/100 units once · Administer by slow IV injection; maximum 50 mg. Titrate to clinical effect and ACT.

Reversal of low molecular weight heparin (e.g., enoxaparin) overdoseoff-label

Partial neutralisation only; anti-Xa activity may remain. Dose based on amount given in last 8 hours; maximum 50 mg.

  • adult · IV: 1 mg/mg enoxaparin once · Partial neutralisation only; anti-Xa activity may remain. Dose based on amount given in last 8 hours; maximum 50 mg.

Reversal of heparin anticoagulation (paediatric)

Dose based on amount of heparin given; maximum 50 mg per dose.

  • pediatric · IV: 1–1.5 mg/100 units once · Dose based on amount of heparin given; maximum 50 mg per dose.
Contraindications & precautions
  • Known hypersensitivity to protamine or previous anaphylactoid reaction · Contraindicated in patients with a history of severe adverse reaction to protamine.
  • Fish allergy · Protamine is derived from fish sperm; caution is advised as there may be cross-reactivity.
  • Previous exposure to protamine-containing insulin (e.g., NPH insulin) · Prior exposure increases the risk of hypersensitivity reactions.
  • Administer slowly intravenously and monitor blood pressure and pulse closely, as rapid administration can cause hypotension and bradycardia.
  • Use with caution in patients with fish allergy, previous exposure to protamine-containing insulin, or a history of vasectomy, as these increase the risk of hypersensitivity reactions.
  • Ensure that resuscitation equipment and trained staff are available immediately, as severe anaphylactoid reactions can occur.
  • Dose carefully based on the amount of heparin given, and monitor coagulation parameters (e.g., activated clotting time) to avoid over-dosage and subsequent anticoagulant effects.
Adverse effects
  • Hypotensionserious
  • Bradycardiaserious
  • Nausea and vomiting
  • Dyspnoeaserious
  • Flushing
  • Anaphylaxisserious
  • Pulmonary hypertensionserious
  • Cardiovascular collapseserious
  • Bleeding due to anticoagulant effect of protamine (when given in excess)serious
Monitoring, pregnancy & toxicity
  • Activated clotting time (ACT) · 15 minutes after dose
  • aPTT · 15 minutes after dose
  • Blood pressure · During and after infusion
  • Heart rate · During and after infusion
  • Signs of hypersensitivity · Monitor throughout
  • Pregnancy: Protamine should be used in pregnancy only when clearly needed; limited human data available.
  • Toxicity: Hypotension and bradycardia from rapid infusion · Slow the infusion rate; treat hypotension with IV fluids and vasopressors; give atropine for bradycardia.
  • Toxicity: Anaphylaxis, especially in patients with previous exposure or fish allergy · Stop infusion; give immediate IM adrenaline (epinephrine); follow with antihistamine and corticosteroid.
  • Toxicity: Pulmonary hypertension and acute respiratory distress · Stop infusion; provide supportive care with oxygen and ventilatory support as needed.
  • Toxicity: Paradoxical anticoagulation in overdose · Stop protamine; monitor coagulation and manage bleeding with supportive measures; consider factor replacement if necessary.
Clinical notes
Protamine sulfate is used to reverse heparin anticoagulation, such as after cardiopulmonary bypass surgery or in heparin overdose. The dose should be based on the amount of heparin administered; for unfractionated heparin, approximately 1 mg of protamine is required per 100 units of heparin. It must be given by slow intravenous injection over 10 minutes to prevent hypotension and bradycardia. Rapid administration may trigger anaphylactoid reactions, particularly in patients previously exposed to protamine, including those using insulin containing protamine. Blood coagulation parameters, such as activated partial thromboplastin time, should be monitored to ensure adequate reversal. Excess protamine can paradoxically cause anticoagulation.

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BNF; local formulary