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(PROE ta meen)

Index Terms

  • Protamine Sulfate

Dosage Forms

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)

Pharmacologic Category

  • Antidote


Combines with strongly acidic heparin to form a stable complex (salt) neutralizing the anticoagulant activity of both drugs

Onset of Action

IV: Heparin neutralization: ~5 minutes

Half-Life Elimination

~7 minutes

Use: Labeled Indications

Treatment of heparin overdosage; neutralize heparin during surgery or dialysis procedures

Use: Unlabeled

Treatment of low molecular weight heparin (LMWH) overdose


Hypersensitivity to protamine or any component of the formulation

Dosing: Adult

Heparin neutralization: IV: Protamine dosage is determined by the dosage of heparin; 1 mg of protamine neutralizes ~100 units of heparin; maximum dose: 50 mg

Note: When heparin is given as a continuous IV infusion, only heparin given in the preceding several hours should be considered when administering protamine. For example, a patient receiving heparin at 1250 units/hour will require ~30 mg of protamine for reversal of heparin given in the last 2-2.5 hours (Garcia, 2012).

Heparin overdosage, following intravenous administration: IV: Since blood heparin concentrations decrease rapidly after administration, adjust the protamine dosage depending upon the duration of time since heparin administration as follows: See table.

Time Elapsed

Dose of Protamine (mg) to Neutralize 100 units of Heparin



30-60 min


>2 h


Table has been converted to the following text.

Dose of Protamine Needed to Neutralize 100 Units of Heparin

Time elapsed: Immediate: 1-1.5 mg

Time elapsed: 30-60 minutes: 0.5-0.75 mg

Time elapsed: >2 hours: 0.25-0.375 mg

Heparin overdosage, following SubQ injection: IV: 1-1.5 mg protamine per 100 units heparin; this may be done by a portion of the dose (eg, 25-50 mg) given slowly IV followed by the remaining portion as a continuous infusion over 8-16 hours (the expected absorption time of the SubQ heparin dose) (Caravati 2004).

LMWH overdose (off-label use): IV: Note: Anti-Xa activity is never completely neutralized (maximum: ~60% to 75%). Excessive protamine doses may worsen bleeding potential.

Enoxaparin (Lovenox® prescribing information, 2011):

Enoxaparin administered in ≤8 hours: Dose of protamine should equal the dose of enoxaparin administered. Therefore, 1 mg of protamine sulfate neutralizes 1 mg of enoxaparin.

Enoxaparin administered in > 8 hours or if it has been determined that a second dose of protamine is required (eg, if aPTT measured 2-4 hours after the first dose remains prolonged or if bleeding continues): 0.5 mg of protamine sulfate for every 1 mg of enoxaparin administered

Dalteparin or tinzaparin (Fragmin® prescribing information, 2010; Innohep® prescribing information, 2010): 1 mg protamine for each 100 anti-Xa units of dalteparin or tinzaparin; if PTT prolonged 2-4 hours after first dose (or if bleeding continues), consider additional dose of 0.5 mg for each 100 anti-Xa units of dalteparin or tinzaparin.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling.


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.


Stable in D5W, NS.

Compatibility in syringe: Incompatible with furosemide, ioxaglate meglumine 39.3%, ioxaglate sodium 19.6%.


Refrigerate; do not freeze. Stable for at least 2 weeks at room temperature. Preservative-free formulation does not require refrigeration.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Frequency not defined.

Cardiovascular: Sudden fall in blood pressure, bradycardia, flushing, hypotension

Central nervous system: Lassitude

Gastrointestinal: Nausea, vomiting

Hematologic: Hemorrhage

Respiratory: Dyspnea, pulmonary hypertension

Miscellaneous: Hypersensitivity reactions

ALERT: U.S. Boxed Warning

Hypersensitivity 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.

Special populations:

• Cardiac surgery patients: May be ineffective in some patients following cardiac surgery despite adequate doses.

Monitoring Parameters

Coagulation test, aPTT or ACT, cardiac monitor and blood pressure monitor required during administration

Pregnancy Risk Factor


Pregnancy Considerations

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).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience loss of strength and energy, flushing, sensation of warmth, or back pain. Have patient report immediately to prescriber shortness of breath, bradycardia, severe dizziness, passing out, nausea, vomiting, bruising, or bleeding (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.