Version May 2024
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, and 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 sulfate should not be given when bleeding occurs without prior heparin use.
The adult dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editor: Edith A Nutescu, PharmD, MS, FCCP.
Heparin neutralization:
Following IV heparin administration: IV: Initial: Protamine dosage is determined by the amount of heparin administered; 1 mg of protamine neutralizes ~100 units of heparin; administer by slow IV injection over ~10 minutes; maximum single dose: 50 mg (Ref); if aPTT remains elevated, may repeat 0.5 mg of protamine for every 100 units of heparin (Ref).
Note: Because heparin concentration decreases rapidly after administration (half-life of heparin is ~60 to 90 minutes), adjust protamine dosage depending on duration of time since heparin administration. For example, if 2 hours has elapsed since a heparin overdose, administer half of the calculated initial protamine dose (Ref). If heparin was administered as a continuous IV infusion, calculate protamine dose based on heparin administered in the preceding 2 to 3 hours. For example, a patient receiving heparin 1,250 units/hour will require ~30 mg of protamine to neutralize heparin (Ref). If patient is not bleeding, consider not administering protamine since risks may outweigh benefits (Ref).
Cardiac surgery patients: After cardiopulmonary bypass, repeat protamine doses of 25 to 50 mg may be given to reverse large doses of intraoperative heparin if activated clotting time (ACT) remains elevated or if heparin rebound is a concern; maximum total dose: 3 mg/kg (Ref). For heparin rebound, may consider protamine 25 mg/hour continuous IV infusion for 6 hours following the initial dose (Ref).
Following SUBQ heparin injection: Note: May consider protamine to neutralize prophylactic SUBQ doses of heparin when aPTT is significantly prolonged and patient has clinically significant bleeding (Ref).
IV: Initial: Protamine dosage is determined by the amount of heparin administered; 1 mg of protamine neutralizes ~100 units of heparin; administer by slow IV injection over ~10 minutes; maximum single dose: 50 mg.
Note: Consider heparin absorption via SUBQ route when determining protamine dose. A portion of the protamine dose may be given IV over 10 minutes followed by the remaining portion as a continuous infusion over 8 to 16 hours (the expected absorption time of the SUBQ heparin dose) (Ref). If patient is not bleeding, consider not administering protamine since risks may outweigh benefits (Ref).
Low-molecular-weight heparin neutralization (off-label use): Note: Protamine will not completely neutralize anti-factor Xa activity (maximum: ~60% to 75%). Excessive protamine doses may worsen bleeding (Lovenox prescribing information). Consider using in patients with clinically significant bleeding. If patient is not bleeding, consider not administering protamine since risks may outweigh benefits (Ref).
IV:
Enoxaparin:
Enoxaparin administered in ≤8 hours: Dose of protamine should equal the dose of enoxaparin administered. Administer 1 mg of protamine to neutralize 1 mg of enoxaparin; administer by slow IV injection over ~10 minutes; maximum single dose: 50 mg (Ref).
Enoxaparin administered >8 hours to <12 hours ago or if a second dose of protamine is required (eg, clinically significant bleeding continues): Administer 0.5 mg of protamine for every 1 mg of enoxaparin administered; administer by slow IV injection over ~10 minutes; maximum single dose: 50 mg (Ref).
Enoxaparin administered ≥12 hours ago (Ref) or if 3 to 5 half-lives have elapsed (Ref): Protamine administration may not be required.
Dalteparin, nadroparin, or tinzaparin: 1 mg of protamine for every 100 anti-factor Xa units of low-molecular-weight heparin (LMWH) administered within the past 3 to 5 half-lives; administer by slow IV injection over ~10 minutes; maximum single dose: 50 mg. If clinically significant bleeding persists or patient has renal impairment, consider repeat dose of 0.5 mg of protamine for every 100 anti-factor Xa units of LMWH (Ref).
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
Refer to adult dosing.
(For additional information see "Protamine sulfate: Pediatric drug information")
Note: 1 mg of protamine sulfate neutralizes ~100 units of heparin or 1 mg of enoxaparin (Ref).
Heparin (intravenous) neutralization/reversal: Limited data available:
Infants, Children, and Adolescents: IV: Note: Since heparin disappears rapidly from the circulation, the dose of protamine is adjusted based upon the time since heparin administration (see table). If given as a continuous IV infusion, only heparin given in the preceding 2 to 4 hours should be considered when administering protamine (Ref).
|
Time Since Last Heparin Dose |
Dose of Protamine |
|---|---|
|
<30 minutes |
IV: 1 mg of protamine per 100 units of heparin; maximum dose: 50 mg/dose |
|
30 to 60 minutes |
IV: 0.5 to 0.75 mg of protamine per 100 units of heparin; maximum dose: 50 mg/dose |
|
60 to 120 minutes |
IV: 0.375 to 0.5 mg of protamine per 100 units of heparin; maximum dose: 50 mg/dose |
|
>120 minutes |
IV: 0.25 to 0.375 mg of protamine per 100 units of heparin; maximum dose: 50 mg/dose |
Low molecular weight heparin (LMWH) neutralization/reversal (enoxaparin, dalteparin):
Note: Protamine will not completely neutralize the anti-Xa activity (maximum: ~60% to 75%). Protamine dosage is determined by the most recent dosage of LMWH (Ref):
Enoxaparin (intravenous and subcutaneous) neutralization/reversal: Limited data available: Dosing extrapolated from experience in adult patients:
Infants, Children, and Adolescents: IV: Protamine dosage is determined by the most recent dosage and time of administration of enoxaparin (Ref).
Enoxaparin dose administered ≤8 hours: IV: Dose of protamine should equal the dose of enoxaparin administered; therefore, 1 mg protamine sulfate neutralizes 1 mg of enoxaparin (Ref).
Enoxaparin administered >8 hours prior or if it has been determined that a second dose of protamine is required (eg, if aPTT measured 2 to 4 hours after the first dose remains prolonged or if bleeding continues): IV: 0.5 mg protamine sulfate for every 1 mg enoxaparin (Ref).
Dalteparin (subcutaneous) neutralization/reversal:
Infants, Children, and Adolescents: IV: 1 mg protamine for each 100 anti-Xa units of dalteparin; if aPTT prolonged 2 to 4 hours after first dose (or if bleeding continues), consider additional dose of 0.5 mg for each 100 anti-Xa units of dalteparin (Ref).
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions are derived from product labeling unless otherwise specified.
Frequency not defined:
Cardiovascular: Flushing
Gastrointestinal: Nausea, vomiting
Local: Localized warm feeling
Nervous system: Lassitude
Respiratory: Dyspnea
Postmarketing:
Cardiovascular: Bradycardia (McDonald 2020), circulatory shock, hypotension (McDonald 2020), right heart failure (right ventricular failure) (Pannu 2016), severe hypotension (Leung 2019, Pannu 2016), ventricular fibrillation (Leung 2019)
Hematologic & oncologic: Immune thrombocytopenia (Singla 2013)
Hypersensitivity: Hypersensitivity reaction (including anaphylactic shock, anaphylaxis, angioedema) (Doolan 1981, Roelofse 1991), nonimmune anaphylaxis
Neuromuscular & skeletal: Back pain
Respiratory: Noncardiogenic pulmonary edema (Kindler 1996), pulmonary complications (pulmonary vasoconstriction) (Lowenstein 1983), pulmonary hypertension (can be acute) (Pannu 2016)
Hypersensitivity to protamine or any component of the formulation
Concerns related to adverse effects:
• Heparin rebound: Heparin rebound associated with anticoagulation and bleeding has been reported to occur occasionally; symptoms typically occur 8-9 hours after protamine administration, but may occur as long as 18 hours later.
• Hypersensitivity reactions: May cause hypersensitivity reaction in patients (have epinephrine 1 mg/mL and resuscitation equipment available). [US Boxed Warning]: Hypotension, cardiovascular collapse, noncardiogenic pulmonary edema, pulmonary vasoconstriction, and pulmonary hypertension may occur. Risk factors for such events include use of high doses or overdose, repeated doses, previous protamine administration (including protamine-containing drugs), fish allergy, vasectomy, severe left ventricular dysfunction, and abnormal preoperative pulmonary hemodynamics.
• Infusion reactions: Too rapid administration can cause severe hypotensive and anaphylactoid-like reactions.
Special populations:
• Cardiac surgery patients: May be ineffective in some patients following cardiac surgery despite adequate doses.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous, as sulfate:
Generic: 10 mg/mL (5 mL, 25 mL)
Solution, Intravenous, as sulfate [preservative free]:
Generic: 10 mg/mL (5 mL, 25 mL)
Yes
Solution (Protamine Sulfate Intravenous)
10 mg/mL (per mL): $2.68 - $3.72
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous, as sulfate:
Generic: 10 mg/mL (5 mL, 25 mL)
IV: For IV use only. Administer slow IVP (50 mg over 10 minutes). Rapid IV infusion causes hypotension; maximum of 50 mg in any 10-minute period.
Parenteral: IV: Administer undiluted (preferred) by slow IVP at a rate not to exceed 5 mg/minute (maximum rate: 50 mg in any 10-minute period); may be administered as diluted solution. Note: Rapid IV infusion causes hypotension.
Heparin neutralization: Treatment of heparin overdosage.
Low-molecular-weight heparin neutralization
Protamine may be confused with ProAmatine, Protonix, Protopam
None known.
There are no known significant interactions.
Animal reproduction studies have not been conducted. In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey, 2003). Protamine sulfate may be used during delivery to reduce the risk of bleeding following maternal use of heparin or low molecular weight heparin (LMWH) (Bates, 2012).
It is not known if protamine is excreted in breast milk. The manufacturer recommends that caution be exercised when administering protamine to nursing women.
Coagulation test, aPTT or ACT, cardiac monitor and blood pressure monitor required during administration
Protamine, a highly alkaline protein molecule with a large positive charge, has weak anticoagulant activity when administered alone. When protamine is given in the presence of heparin (strongly acidic and negatively charged), a stable salt is formed and the anticoagulant activity of both drugs is nullified (Pai 2012). In the presence of LMWH, protamine incompletely reverses the anti-factor Xa activity of LMWH (Makris 2000; Massonnet-Castel 1986; Racanelli 1985).
Onset of action: IV: Heparin neutralization: ~5 minutes
Half-life elimination: ~7 minutes
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