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.
Note: 1 mg of protamine sulfate neutralizes ~100 units of heparin or 1 mg of enoxaparin (ACCP [Monagle 2012]).
Heparin (intravenous) neutralization/reversal: Limited data available:
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 (ACCP [Monagle 2012]; Park 2021).
|
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 |
Enoxaparin (intravenous or subcutaneous) neutralization/reversal: Limited data available; dosing based on experience in adult patients (ACCP [Monagle 2012]; Park 2021): Note: Anti-Xa activity is never completely neutralized (maximum: ~60%).
Enoxaparin last administered in ≤8 hours: IV: Dose of protamine sulfate should equal the dose of enoxaparin administered; therefore, 1 mg protamine neutralizes 1 mg enoxaparin (Lovenox prescribing information).
Enoxaparin last administered in >8 hours or if it has been determined that 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 per 1 mg enoxaparin (Lovenox prescribing information). One report of a 10-fold enoxaparin overdose in a neonate (40 mg dose of enoxaparin administered) described using smaller protamine aliquots (10 mg) of the total protamine dose every 2 to 3 hours until the anti-Xa level was <2 units/mL to avoid potential protamine toxicity from administration of a large single dose (Wiernikowski 2007).
Note: 1 mg of protamine sulfate neutralizes ~100 units of heparin or 1 mg of enoxaparin (ACCP [Monagle 2012]; Park 2021).
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 (ACCP [Monagle 2012]; Park 2021).
|
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 (ACCP [Monagle 2012]; Howland 2019; Park 2021):
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 (Lovenox prescribing information; Park 2021).
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 (Lovenox prescribing information).
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 (Howland 2019; Lovenox prescribing information).
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 (Fragmin prescribing information).
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Protamine sulfate: Drug information")
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 (manufacturer's labeling); if aPTT remains elevated, may repeat 0.5 mg of protamine for every 100 units of heparin (NCS/SCCM [Frontera 2016]).
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 (Howland 2019). 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 (ACCP [Garcia 2012]; NCS/SCCM [Frontera 2016]). If patient is not bleeding, consider not administering protamine since risks may outweigh benefits (Howland 2019).
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 (Kincaid 2014). For heparin rebound, may consider protamine 25 mg/hour continuous IV infusion for 6 hours following the initial dose (Teoh 2004).
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 (Howland 2019; NCS/SCCM [Frontera 2016]).
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) (Caravati 2004). If patient is not bleeding, consider not administering protamine since risks may outweigh benefits (Howland 2019).
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 (Howland 2019).
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 (Lovenox prescribing information).
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 (Lovenox prescribing information).
Enoxaparin administered ≥12 hours ago (Lovenox prescribing information) or if 3 to 5 half-lives have elapsed (NCS/SCCM [Frontera 2016]): 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 (NCS/SCCM [Frontera 2016]; Fragmin prescribing information; Fraxiparine prescribing information; Innohep prescribing information).
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
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
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)
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.
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.
Store at 20°C to 25°C (68°F to 77°F). Do not freeze. Diluted solutions should not be stored.
Treatment of heparin overdosage (FDA approved in adults); has also been used as antidote for low molecular weight heparin (LMWH) overdose or reversal.
Protamine may be confused with ProAmatine, Protonix, Protopam
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined.
Cardiovascular: Bradycardia, flushing, hypotension, sudden decrease of blood pressure
Central nervous system: Lassitude
Gastrointestinal: Nausea, vomiting
Hematologic & oncologic: Hemorrhage
Hypersensitivity: Hypersensitivity reaction
Respiratory: Dyspnea, pulmonary hypertension
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.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program
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).
Coagulation tests, aPTT or activated clotting time (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
Solution (Protamine Sulfate Intravenous)
10 mg/mL (per mL): $2.35 - $3.23
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