Dosing and uses of Protamine
Adult dosage forms and strengths
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
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
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
Pediatric dosage forms and strengths
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
Protamine adverse (side) effects
Frequency not defined
Anaphylaxis
Hypotension
N/V
Decreased O2 consumption
Flushing
Pulmonary hypertension
Uncontrollable bleeding
Circulatory collapse
Pulmonary edema
Warnings
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
Contraindications
Hypersensitivity
Cautions
Heparin rebound causing bleeding may occur 8-9 hr after protamine administration
May be ineffective in cardiac surgery patients despite adequate dose
Rapid infusion reactions can cause severe hypotensive reactions
Pregnancy and lactation
Pregnancy category: C
Lactation: not known if excreted in breast milk
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Protamine
Mechanism of action
Protamine that is strongly basic combines with acidic heparin forming a stable complex and neutralizes the anticoagulant activity of both drugs
Pharmacokinetics
Half-life elimination: 7 min
Onset: 5 min
Duration: 2 hr
Vd: 5.4 L
Metabolism: Unknown
Clearance: 1.4 L/min
Administration
IV Incompatibilities
Additive: cephalosporins, penicillins
Syringe: diatrizoate meglumine 52%, diatrizoate sodium, ioxaglate meglumine 39.3%, ioxaglate sodium 19.6%
IV Preparation
Reconstitute with 5 mL sterile water
Resulting solution equals 10 mg/mL
IV Administration
Inject without further dilution over 1-3 min; maximum of 50 mg in any 10 min period
For IV use only
Administer slow IVP (50 mg over 10 min)
Rapid IV infusion causes hypotension
Storage
Refrigerate
Avoid freezing
