Drug information of Protamine sulfat

Protamine sulfat

Drug group:

Protamine sulfate is a drug that reverses the anticoagulant effects of heparin by binding to it. It was originally isolated from the sperm of salmon and other species of fish but is now produced primarily through recombinant biotechnology. Protamine sulfate was approved for medical use in the United States in 1969.

Mechanism of effect

It is a highly cationic peptide that binds to either heparin or low molecular weight heparin (LMWH) to form a stable ion pair, which does not have anticoagulant activity. The ionic complex is then removed and broken down by the reticuloendothelial system. In large doses, protamine sulfate may also have an independent—however weak—anticoagulant effect.


Protamine sulphate 1% demonstrates activity neutralising anticoagulant properties of heparin, creating the complex heparin/protamine. Activity of protamine (towards heparin) takes place within five minutes after intravenous injection of the preparation.


Half-life elimination: 7 min

Onset: 5 min

Duration: 2 hr

Vd: 5.4 L

Metabolism: Unknown

Clearance: 1.4 L/min



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 hr

In accidental overdoses of heparin, consider t1/2 heparin 60-90 min

Complex of protamine and heparin may degrade over time requiring further doses

Dalteparin or Tinzaparin Overdose

1 mg protamine for 100 units dalteparin or tinzaparin; if PTT prolonged 4hr 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 hr); if >8 hr of overdose or bleeding continues after 4 hr after first dose, give 0.5 mg protamine per mg enoxaparin

Time Elapsed Since Heparin Dose

Dose of protamine (mg) to neutralize 100 units of heparin

  • <1/2 hr: 1-1.5 mg/100 units of heparin
  • 30-120 min: 0.5-0.75 mg/100 units of heparin
  • >2 hr: 0.25-0.375 mg/100 units of heparin


IV solution

  • 10 mg/mL

Heparin Neutralization (Off-label)

~1 mg protamine neutralizes 100 units of heparin; not to exceed 50 mg/dose

Monagle P, et al. Chest 2008:133(6 Suppl):S887-S968

Time elapsed since heparin dose

  • Protamine dose to neutralize 100 units of heparin
  • <1/2 hr: 1 mg
  • 30-120 min: 0.5-0.75 mg
  • >2 hr: 0.25-0.375 mg

Drug contraindications

hypersensitivity to this drug

Side effects

nausea , vomiting


Black Box Warnings

  • 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, 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 should not be given when bleeding occurs without prior heparin use

Points of recommendation

  • This medicine may cause very low blood pressure or very bad heart or lung problems. Sometimes, these may be deadly. Tell your doctor if you have heart or lung problems, if you have had a vasectomy, or if you have an allergyto fish. Talk with your doctor.
  • This medicine is not for use when bleeding happens without heparin use. Talk with the doctor.
  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.
  • Importance of informing patients of other important precautionary information. 
  • It is given as a shot into a vein over a period of time.
  • You will be watched closely by your doctor.

Pregnancy level


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