Hypersensitivity to protamine or any component of the formulation Absolute
Adverse Reactions
Very Common >10%Common 1–10%Uncommon 0.1–1%Rare 0.01–0.1%Very Rare <0.01%Not Known
Cardiac disorders (4)
Not Known
Bradycardia · flushing · hypotension · sudden decrease of blood pressure
Nervous system disorders (1)
Not Known
Lassitude
Blood and lymphatic system disorders (1)
Not Known
Hemorrhage
Immune system disorders (1)
Not Known
Hypersensitivity reaction
Gastrointestinal disorders (2)
Not Known
Nausea · vomiting
Respiratory, thoracic and mediastinal disorders (2)
Not Known
Dyspnea · pulmonary hypertension
Dosing
Source: Lexicomp
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 2004) 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 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
(For additional information see "Protamine sulfate: Pediatric drug information") 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 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 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).
Refer to adult dosing.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
Warnings & Precautions
Source: Lexicomp
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.
Pregnancy & Lactation
Pregnancy
FDA category CTeratogenic
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).
Lactation
It is not known if protamine is excreted in breast milk. The manufacturer recommends that caution be exercised when administering protamine to nursing women.
Monitoring
Clinical pearl
Coagulation test, aPTT or ACT, cardiac monitor and blood pressure monitor required during administration