Protamine

Black Box Warnings

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, 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 should not be given when bleeding occurs without prior heparin use

Contraindications

Hypersensitivity

Cautions

Heparin rebound causing bleeding may occur 8-9 hr after protamine administration

May be ineffective in cardiac surgery patients despite adequate dose

Rapid infusion reactions can cause severe hypotensive reactions

IV Incompatibilities

Additive: cephalosporins, penicillins

Syringe: diatrizoate meglumine 52%, diatrizoate sodium, ioxaglate meglumine 39.3%, ioxaglate sodium 19.6%

IV Preparation

Reconstitute with 5 mL sterile water

Resulting solution equals 10 mg/mL

IV Administration

Inject without further dilution over 1-3 min; maximum of 50 mg in any 10 min period

For IV use only

Administer slow IVP (50 mg over 10 min)

Rapid IV infusion causes hypotension

Storage

Refrigerate

Avoid freezing

Protamine is part of the drug class:

• Antidotes

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about protamine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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 protamine. 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 protamine.

Review Date: October 4, 2017

• Antidote

Hypersensitivity to protamine or any component of the formulation

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.

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. If the aPTT remains elevated, may repeat dose at 0.5 mg of protamine for every 100 units of heparin. In cardiac surgery, a maximum dose of 3 mg/kg may be required to reverse large doses of heparin administered intraoperatively (Kincaid 2014; NCS/SCCM [Frontera 2016]).

Note: When heparin is 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]).

Intracranial hemorrhage associated with heparin or LMWH (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.

LMWH-mediated (full therapeutic dose): Note: In patients receiving 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.

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.

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):

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).

Applies to protamine: injectable solution

Hematologic

It has been postulated that the heparin-protamine complex may be acted upon by fibrinolysin, thus freeing heparin. Clinical monitoring of coagulation parameters such as the heparin titration test with protamine and plasma thrombin time is recommended to determine subsequent protamine dosage requirements.[Ref]

Hematologic adverse effects such as bleeding and elevated plasma heparin concentrations resulting from rebound anticoagulation have occurred 30 minutes to 18 hours following cardiac surgery despite complete protamine neutralization of heparin.[Ref]

Immunologic

Immune responses, some life-threatening and fatal, have occurred and are thought to be related to previous protamine exposure such as prior heparin neutralization or use of protamine-containing insulin. Severe reactions may occur in the absence of local or systemic allergic reactions to protamine-containing insulin injections and fatal anaphylaxis without a prior allergy history has been reported. Data suggest that vasectomized men may be at increased risk for protamine-induced immunologic reactions.[Ref]

Vasectomy disrupts the normal blood-testes barrier allowing systemic absorption of sperm and the potential for antibody formation. Data concerning vasectomized men have reported the appearance of human protamine-specific IgG antibodies in 22% to 33% within one year after vasectomy. A study revealed antiprotamine IgE antibodies in 35% of vasectomized men compared to 0% in nonvasectomized controls. Cross-reactivity has been demonstrated between human and salmon protamine.[Ref]

Cardiovascular

Cardiovascular symptoms of hypotension and bradycardia have occurred following intravenous (IV) administration of protamine. Reduced cardiac output, myocardial failure, and irreversible circulatory collapse can occur.[Ref]

Respiratory

Respiratory adverse effects resulting in high-protein, noncardiogenic pulmonary edema have been reported in patients on cardiopulmonary bypass undergoing cardiovascular surgery. The role of protamine is not completely understood, but may be related to an immune-mediated response. However, this effect has been observed with administration of certain blood products, drugs, cardiopulmonary by-pass alone, and in the presence of other etiologic factors.

Respiratory side effects have also included reports of severe pulmonary hypertension.[Ref]

Dermatologic

Dermatologic effects, primarily associated with allergic reactions, have been characterized by urticaria, erythema, or edema.[Ref]

Some side effects of protamine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.