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Protamine

Pronunciation

(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

Pharmacology

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 antifactor Xa activity of LMWH (Makris 2000; Massonnet-Castel 1986; Racanelli 1985).

Onset of Action

IV: Heparin neutralization: ~5 minutes

Half-Life Elimination

~7 minutes

Use: Labeled Indications

Heparin overdose: Treatment of heparin overdosage

Use: Unlabeled

Treatment of low molecular weight heparin (LMWH) overdose

Contraindications

Hypersensitivity to protamine or any component of the formulation

Dosing: Adult

Heparin overdosage, following intravenous administration (off-label dosing): IV: Because 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.

Neutralization Dose of Protamine for IV Heparin Overdosage (Caravati 2014)

Time Elapsed

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

Immediate

1 to1.5

30 to 60 min

0.5 to 0.75

>2 h

0.25 to 0.375

Table has been converted to the following text.

Dose of Protamine Needed to Neutralize 100 Units of Heparin

Time elapsed: Immediate: 1 to 1.5 mg

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

Time elapsed: >2 hours: 0.25 to 0.375 mg

Heparin overdosage, following SubQ injection (off-label dosing) IV: 1 to 1.5 mg protamine per 100 units heparin; this may be done by a portion of the dose (eg, 25 to 50 mg) given 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).

Heparin neutralization (off-label use): IV: Protamine dosage is determined by the dosage of heparin; 1 mg of protamine neutralizes ~100 units of heparin; maximum dose: 50 mg. In cardiac surgery, a maximum dose of 3 mg/kg may be required to reverse large doses of heparin administered intraoperatively (Kincaid 2014).

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 1,250 units/hour will require ~30 mg of protamine for reversal of heparin given in the last 2 to 2.5 hours (ACCP [Garcia 2012]).

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 to 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 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 or tinzaparin.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Heparin or enoxaparin neutralization (off-label use): 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 [Monagle 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 (off-label use): Limited data available (ACCP [Monagle 2012]): Infants, Children, and Adolescents: Because 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):

Neutralization Dose of Protamine for IV Heparin Overdosage in Pediatric Patients (Monagle 2012)

Time Since Last Heparin Dose (min)

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

<30

1

30 to 60

0.5 to 0.75

60 to 120

0.375 to 0.5

>120

0.25 to 0.375

Table has been converted to the following text.

Time since last heparin dose: <30 minutes

Dose: 1 mg protamine needed to neutralize 100 units of heparin

Time since last heparin dose: 30 to 60 minutes

Dose: 0.5 to 0.75 mg protamine needed to neutralize 100 units of heparin

Time since last heparin dose: 60 to 120 minutes

Dose: 0.375 to 0.5 mg protamine needed to neutralize 100 units of heparin

Time since last heparin dose: >120 minutes

Dose: 0.25 to 0.375 mg protamine needed to neutralize 100 units of heparin

Heparin overdosage following SubQ administration (off-label use): 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) (off-label use): 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:

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).

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.

Administration

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.

Compatibility

Stable in D5W, NS.

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

Storage

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: 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 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.

Warnings/Precautions

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

C

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.

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