Protamine

Pharmacologic Category

Antidote

Dosing: Adult

Heparin overdose, following intravenous administration: IV: Initial: Protamine dosage is determined by the amount of heparin given; 1 mg of protamine neutralizes ~100 units of heparin; maximum single dose: 50 mg. Note: Because blood heparin concentrations decrease rapidly after heparin administration (half-life of heparin is ~60 to 90 minutes), may adjust the protamine dosage depending upon the duration of time since heparin administration. For example, if 2 hours has elapsed since heparin overdose, consider administering half of the calculated initial protamine dose; this is more conservative compared to product labeling, which suggests administering half of the calculated dose at 30 minutes after heparin administration. If patient is not bleeding, consider not administering protamine since risks may outweigh benefits of administration (Howland 2019).

Heparin overdose, 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). If patient is not bleeding, consider not administering protamine since risks may outweigh benefits of administration (Howland 2019).

Heparin neutralization (non-overdose) (off-label use): Initial: IV: Protamine dosage is determined by the dosage of heparin; 1 mg of protamine neutralizes ~100 units of heparin; maximum single dose: 50 mg. If the aPTT remains elevated, may repeat dose at 0.5 mg of protamine for every 100 units of heparin (NCS/SCCM [Frontera 2016]). Note: If heparin was given as a continuous IV infusion, only heparin given in the preceding 2 to 3 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]; NCS/SCCM [Frontera 2016]).

Cardiac surgery: Repeat dose: IV: After cardiopulmonary bypass, repeat doses of 25 to 50 mg may be given to reverse large doses of intraoperative heparin if 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).

Intracranial hemorrhage associated with heparin or low-molecular-weight heparin (off-label use): According to the Neurocritical Care Society/Society of Critical Care Medicine (NCS/SCCM [Frontera 2016]): IV:

Heparin-mediated (full dose infusions): 1 mg protamine for every 100 units of heparin administered in the previous 2 to 3 hours; administer by slow IV injection over ~10 minutes; maximum single dose: 50 mg. If the aPTT remains elevated, consider administering 0.5 mg protamine for every 100 units of heparin. Consider reversal for prophylactic subcutaneous doses of heparin when aPTT is significantly prolonged.

Low-molecular-weight heparin-mediated (full therapeutic dose): Note: In patients receiving low-molecular-weight heparin (LMWH) for prophylaxis (ie, not a full therapeutic dose), the NCS/SCCM guidelines suggest against reversal.

Enoxaparin: 1 mg protamine for every 1 mg of enoxaparin (if enoxaparin administered within 8 hours) or 0.5 mg protamine for every 1 mg of enoxaparin (if enoxaparin administered within 8 to 12 hours); administer by slow IV injection over ~10 minutes; maximum single dose: 50 mg. If life-threatening bleeding persists or patient has renal impairment, consider repeat dose of 0.5 mg protamine for every 1 mg of enoxaparin. Note: Protamine may not be needed if 3 to 5 half-lives have elapsed.

Dalteparin, nadroparin, and tinzaparin: 1 mg protamine for every 100 anti-Xa units of LMWH administered in the past 3 to 5 half-lives; administer by slow IV injection over ~10 minutes; maximum single dose: 50 mg. If life-threatening bleeding persists or patient has renal impairment, consider repeat dose of 0.5 mg protamine for every 100 anti-Xa units of LMWH.

Low-molecular-weight heparin overdose (off-label use): IV: Note: Anti-Xa activity is never completely neutralized (maximum: ~60% to 75%). Excessive protamine doses may worsen bleeding potential. If patient is not bleeding, consider not administering protamine since risks may outweigh benefits of administration (Howland 2019).

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.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

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

Dosing: Hepatic Impairment: Adult

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

Dosing: Pediatric

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

(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

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:

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: Pediatric

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

Dosing: Hepatic Impairment: Pediatric

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

Use: Labeled Indications

Heparin overdose: Treatment of heparin overdosage.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Heparin neutralization (non-overdose)Level of Evidence [C, G]

Clinical experience suggests the utility of protamine for patients when the anticoagulant effect of heparin needs to be neutralized, such as those receiving routine doses of heparin (eg, during continuous IV infusions of heparin) who may be bleeding or to prevent bleeding in patients receiving high heparin doses used during extracorporeal circulation (eg, cardiopulmonary bypass, hemodialysis) ^Ref.

Based on the 2011 Update to the Society of Thoracic Surgeons (STS) and the Society of Cardiovascular Anesthesiologists (SCA) Blood Conservation Clinical Practice Guidelines and the STS/SCA/American Society of Extracorporeal Technology (STS/SCA/AmSECT) 2018 Clinical Practice Guidelines for Anticoagulation during Cardiopulmonary Bypass, protamine titration may be considered at the end of cardiopulmonary bypass to reduce bleeding and blood transfusion requirements. In addition, the American College of Chest Physicians (ACCP) recommends the use of protamine to reverse the anticoagulant effect of heparin.

Intracranial hemorrhage associated with heparin or low-molecular-weight heparinLevel of Evidence [G]

Based on the Neurocritical Care Society and the Society of Critical Care Medicine guideline for reversal of antithrombotics in intracranial hemorrhage, protamine is recommended to reverse the anticoagulant effect following intracranial hemorrhage associated with heparin (full dose infusions; consider reversal for prophylactic subcutaneous doses when aPTT is significantly prolonged) or therapeutic doses of low-molecular-weight heparin (LMWH) (if given within 8 to 12 hours of enoxaparin or within 3 to 5 half-lives of dalteparin, nadroparin, or tinzaparin). In patients receiving LMWH for prophylaxis (ie, not a full therapeutic dose), the NCS/SCCM guidelines suggest against reversal.

Low-molecular-weight heparin overdoseLevel of Evidence [C, G]

There is no available agent for complete neutralization of LMWH. Data from in vitro and animal studies suggested that protamine may be beneficial for neutralizing the anticoagulant effects of LMWH ^Ref. However, in humans, incomplete neutralization occurs since protamine neutralizes a variable portion of LMWH anti-Xa activity ^Ref. Case reports have illustrated a failure of protamine to neutralize enoxaparin ^Ref. Additional data may be necessary to further define the role of protamine in the setting of LMWH overdose.

Based on the American College of Chest Physicians guidelines, protamine may be used to neutralize the anticoagulant effect of LMWH. In the context of intracranial hemorrhage due to heparin, the 2016 Neurocritical Care Society/Society of Critical Care Medicine guideline for the reversal of antithrombotics recommends administering IV protamine to reverse enoxaparin.

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Life-Threatening Hemorrhage:

AHA/ASA, “Guidelines for the Management of Spontaneous Intracerebral Hemorrhage,” July 2015

NCS/SCCM, “Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage,” 2016

Other:

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition), February 2012

STS/SCA, “Blood Conservation Clinical Practice Guideline,” March 2011

STS/SCA/AmSECT, “Clinical Practice Guidelines – Anticoagulation During Cardiopulmonary Bypass,” January 2018

Administration: 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.

Administration: Injectable Detail

pH: 6-7

Administration: Pediatric

Parenteral: IV: Administer undiluted slow IVP at a rate not to exceed 5 mg/minute (50 mg in any 10-minute period); rapid IV infusion causes hypotension

Storage/Stability

Store at 20°C to 25°C (68°F to 77°F). Do not freeze. Diluted solutions should not be stored.

Preparation for Administration: Adult

May be further diluted in D5W or NS.

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat heparin overdose.

Frequently reported side effects of this drug

• Loss of strength and energy

• Flushing

• Sensation of warmth

• Back pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Shortness of breath

• Slow heartbeat

• Severe dizziness

• Passing out

• Nausea

• Vomiting

• Bruising

• Bleeding

• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Contraindications

Hypersensitivity to protamine or any component of the formulation

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.

* See Cautions in AHFS Essentials for additional information.

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).

Breast-Feeding Considerations

It is not known if protamine is excreted in breast milk. The manufacturer recommends that caution be exercised when administering protamine to nursing women.

Briggs' Drugs in Pregnancy & Lactation

• Protamine

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

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

There are no known significant interactions.

Monitoring Parameters

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

Advanced Practitioners Physical Assessment/Monitoring

Obtain coagulation tests, aPTT, or ACT. Obtain cardiac monitor and blood pressure monitoring during administration. May be ineffective in some cardiac surgery patients.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Monitor cardiac status and blood pressure during infusion. Monitor infusion rate. Slowing infusion rate may improve hypotension.

Dosage Forms: US

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)

Dosage Forms: Canada

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)

Anatomic Therapeutic Chemical (ATC) Classification

• V03AB14

Generic Available (US)

Yes

Pricing: US

Solution (Protamine Sulfate Intravenous)

10 mg/mL (per mL): $2.09 - $2.95

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

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).

Pharmacodynamics/Kinetics

Onset of action: IV: Heparin neutralization: ~5 minutes

Half-life elimination: ~7 minutes

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

Administration reverses the effect of heparin anticoagulants to permit general surgical treatment (eg, abdominal or orthopedic surgery). Risk of bleeding is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility. The need to address the effects of anticoagulation for dental surgery is based on a complex risk to benefit assessment; medical consult is suggested.

Related Information

• Reversal of Oral Anticoagulants

Index Terms

Protamine Sulfate

FDA Approval Date

April 07, 1987

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Brand Names: International

Denpru (AR); Prosulf (GB); Protamina (ES); Protamina solfato (IT); Protamine Choay (FR); Protamine Sulfate Injection (AU); Protamine Sulphate (GB); Protamine Sulphate Injection BP (AU); Protamini Sulfas (FI); Protaminsulfat (NO); Protaminsulfat Novo (AT); Protaminsulfat ”Leo” (DE, DK); Protaminum Sulfuricum (PL)

Last Updated 12/30/19