Medically reviewed by Drugs.com. Last updated on Sep 18, 2020.
(PROE ta meen)
- Protamine Sulfate
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)
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
Use: Labeled Indications
Heparin neutralization: Treatment of heparin overdosage.
Off Label Uses
Low-molecular-weight heparin neutralization
There is no available agent for complete neutralization of low-molecular-weight heparin (LMWH). Data from in vitro and animal studies suggested that protamine may be beneficial for neutralizing the anticoagulant effects of LMWH [Lindblad 1987], [Massonnet-Castel 1986]. However, in humans, incomplete neutralization occurs since protamine neutralizes a variable portion of LMWH anti-factor Xa activity [Massonnet-Castel 1986]. Case reports have illustrated a failure of protamine to neutralize enoxaparin [Chawla 2004], [Makris 2000].
The American College of Chest Physicians guidelines recommend protamine when the anticoagulant effect of LMWH requires neutralization [ACCP [Garcia 2012]]. Based on the American Heart Association/American Stroke Association guidelines for the management of spontaneous intracerebral hemorrhage (ICH) and the 2016 Neurocritical Care Society/Society of Critical Care Medicine guideline for the reversal of antithrombotics, protamine may be used to neutralize the anticoagulant effect of LMWH in the setting of ICH [AHA/ASA [Hemphill 2015]], [NCS [Frontera 2016]].
Hypersensitivity to protamine or any component of the formulation
The adult dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editor: Edith A Nutescu, PharmD, MS, FCCP.
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).
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).
Refer to adult dosing.
Heparin or enoxaparin neutralization: Limited data available: Infants, Children, and Adolescents: IV: Protamine dosage is determined by the most recent dosage of heparin or low molecular weight heparin (LMWH); 1 mg of protamine sulfate neutralizes ~100 units of heparin or 1 mg of enoxaparin; maximum protamine dose: 50 mg/dose. Dosing extrapolated from experience in adult patients (ACCP [Mongale 2012]; Lovenox prescribing information 2013; Park 2014). Note: When heparin is given as a continuous IV infusion, only heparin given in the preceding several hours (eg, 2 hours) should be considered when administering protamine (ACCP [Monagle 2012]).
Heparin overdosage following intravenous administration: Limited data available (ACCP [Monagle 2012): Infants, Children, and Adolescents: Since blood heparin concentrations decrease rapidly after heparin administration, adjust the protamine dosage depending upon the duration of time since heparin administration as follows (see table):
Time Since Last Heparin Dose
Dose of Protamine (mg) to Neutralize
100 units of Heparin
30 to 60
0.5 to 0.75
60 to 120
0.375 to 0.5
0.25 to 0.375
Heparin overdosage following subcutaneous administration: Limited data available: Infants, Children, and Adolescents: 1 to 1.5 mg protamine per 100 units heparin; this may be done by administering a portion of the protamine dose (eg, 25 to 50 mg) slowly IV 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); dosing extrapolated from experience in adult patients (ACCP [Monagle 2012]; Park 2014)
LMWH overdosage (enoxaparin, dalteparin): Limited data available: Infants, Children, and Adolescents: Note: Anti-Xa activity is never completely neutralized (maximum: ~60% to 75%). Excessive protamine doses may worsen bleeding potential; dosing extrapolated from experience in adult patients (ACCP [Monagle 2012])
Enoxaparin dose administered ≤8 hours: IV: Dose of protamine should equal the dose of enoxaparin administered; therefore, 1 mg protamine sulfate neutralizes per 1 mg of enoxaparin (Lovenox prescribing information 2013)
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 (Lovenox prescribing information 2013)
Dalteparin: IV: 1 mg protamine for each 100 anti-Xa units of dalteparin; if PTT 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 2010).
May be further diluted in D5W or NS.
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.
There are no known significant interactions.
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
ALERT: U.S. Boxed WarningHypersensitivity reactions:
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.
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.
• Cardiac surgery patients: May be ineffective in some patients following cardiac surgery despite adequate doses.
Coagulation test, aPTT or ACT, cardiac monitor and blood pressure monitor required during administration
Pregnancy Risk Factor
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).
What is this drug used for?
• It is used to treat heparin overdose.
All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
• Loss of strength and energy
• Sensation of warmth
• Back pain
WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
• Shortness of breath
• Slow heartbeat
• Severe dizziness
• Passing out
• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
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