protamine sulfate

Antidotes, Systemic

Ensure ready access to vasopressors and resuscitation equipment in cases of severe reaction.
Visually inspect parenteral products for particulate matter and discoloration prior to administration.

Administer protamine 10 mg/mL solution undiluted via slow intravenous injection. The administration rate MUST NOT exceed 50 mg over a 10 minute period. High doses and rapid administration may result in severe hypotension, cardiovascular collapse, pulmonary edema, pulmonary vasoconstriction, and pulmonary hypertension.
Dilution is not recommended; however if desired, the product may be added to 5% Dextrose in Water or 0.9% Sodium Chloride for Injection. If diluted, the product must be used immediately as it does not contain preservatives.
Do not administer with other medications without ensuring compatibility. Protamine has exhibited incompatibilities with certain antibiotics, including some penicillins and cephalosporins.

bradycardia / Rapid / Incidence not known
serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known
pulmonary hypertension / Delayed / Incidence not known
pulmonary edema / Early / Incidence not known
anaphylactic shock / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
bronchospasm / Rapid / Incidence not known
heart failure / Delayed / Incidence not known

hypotension / Rapid / Incidence not known
dyspnea / Early / Incidence not known
wheezing / Rapid / Incidence not known
bleeding / Early / Incidence not known

urticaria / Rapid / Incidence not known
flushing / Rapid / Incidence not known
back pain / Delayed / Incidence not known
rash / Early / Incidence not known
fatigue / Early / Incidence not known

Protamine administration has a risk of serious hypersensitivity reactions or anaphylaxis manifesting as severe hypotension, cardiovascular collapse, pulmonary edema, pulmonary vasoconstriction, and pulmonary hypertension. Risk factors for these events include high doses or overdose, rapid IV administration, previous exposure, repeated doses, and current or previous use of protamine-containing drugs (e.g., NPH insulin, protamine zinc insulin, and certain beta-blockers). Fish hypersensitivity, vasectomy, severe left ventricular dysfunction, and abnormal preoperative pulmonary hemodynamics may also be risk factors. Carefully consider the risks and benefits of use in patients with any of these risk factors. Administration requires a specialized care setting as vasopressors and resuscitation equipment should be immediately available in case of a severe reaction. Do not give protamine when bleeding occurs without prior heparin use.

Rx

Heparin antagonist; derived from fish sperm
For heparin overdose and is used to neutralize heparin during extracorporeal circulation following dialysis and arterial or cardiac surgery
Must be given at a rate not to exceed 50 mg over a 10 minute period

1.5 mg IV for every 100 units of heparin administered. Dosage may also be determined by using the sequential activated coagulation time (ACT) and a dose-response curve which correlates the coagulation test values with the amount of heparin in the body. Increased levels of heparin and bleeding complications have occurred up to 18 hours after cardiac surgery, despite complete neutralization of heparin by protamine. The patient should be monitored to verify the need for additional doses of protamine.

1 to 1.3 mg protamine IV for every 100 units of heparin has been administered for unfractionated heparin reversal at the completion of cardiopulmonary bypass. 1 to 2 mg protamine IV for every 100 units of heparin has been administered for unfractionated heparin reversal during cardiopulmonary bypass, titrating to the desired activated clotting time (ACT). In studies, when patients continued to bleed after protamine administration, other reversal agents (e.g. aprotinin, tranexamic acid) or blood products were administered.

1 mg IV for every 100 units of heparin to be neutralized or as indicated by coagulation studies. The appropriate dose can be calculated based on a 60-minute half-life for heparin. Example: For a patient receiving 1,500 units/hour of heparin by continuous IV infusion who had not recently received bolus heparin: this patient would require enough protamine to neutralize all the heparin received in the last hour (1,500 units), plus half the dose in the preceding hour (750 units), plus a quarter of the dose received the hour before that (375 units). Thus, this patient would require 26.25 mg of protamine to neutralize a total of 2,625 units of heparin. The maximum recommended dose within a 2-hour period is 100 mg unless a larger quantity is indicated through confirmation by coagulation tests.

If immediate unfractionated heparin (UFH) reversal is required, the dose of protamine is based on the amount of UFH received in the previous 2 hours.  If less than 30 minutes has lapsed since UFH administration, then administer 1 mg protamine/100 units heparin received. If 30 to 60 minutes has elapsed since UFH administration, administer 0.5 to 0.75 mg protamine/100 units heparin received. If 60 to 120 minutes has elapsed since UFH administration, administer 0.375 to 0.5 mg protamine/100 units heparin received. If more than 120 minutes has elapsed since UFH administration, administer 0.25 to 0.375 mg protamine/100 units heparin received.

If enoxaparin was administered in the previous 8 hours, give protamine 1 mg IV for every 1 mg of enoxaparin. If enoxaparin was administered greater than 8 hours previous to the protamine dose or if a second dose is needed, give protamine 0.5 mg IV for every 1 mg of enoxaparin. A second dose of protamine may be administered if the aPTT measured at 2 to 4 hours after the initial infusion remains prolonged. However, even with higher doses of protamine, the aPTT may remain more prolonged than would usually be found with protamine treatment following unfractionated heparin. In all cases, the anti-Xa activity is never completely neutralized (maximum 60% to 75%).

In general, protamine 1 mg IV for every 100 anti-Xa international units of dalteparin or tinzaparin is given. A second infusion of protamine 0.5 mg IV for every 100 anti-Xa international units of dalteparin or tinzaparin may be administered if the aPTT measured at 2 to 4 hours after the initial infusion remains prolonged. However, even with higher doses of protamine, the aPTT may remain more prolonged than would usually be found with protamine treatment following unfractionated heparin. In all cases, the anti-Xa activity is never completely neutralized (maximum 60% to 75%).

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Heparin: (Contraindicated) Upon contact with heparin, protamine forms a salt, neutralizing the anticoagulant effect of both drugs. Protamine, a strongly basic compound, forms complexes with heparin sodium or heparin calcium, which are acidic compounds. Formation of this complex can result in disruption of the heparin-antithrombin III complex responsible for the anticoagulant activity of heparin. Protamine is used therapeutically to reverse the activity of heparins.

Protamine Sulfate Intravenous Inj Sol: 1mL, 10mg

100 mg IV within a 2-hour period unless a larger quantity is indicated through confirmation by coagulation tests.

100 mg IV within a 2-hour period unless a larger quantity is indicated through confirmation by coagulation tests.

Must individualize dosage; do not exceed 50 mg/dose.

Must individualize dosage; do not exceed 50 mg/dose.

Must individualize dosage; do not exceed 50 mg/dose.

Must individualize dosage; do not exceed 50 mg/dose.

Protamine possesses weak anticoagulant effects when administered alone; however, upon contact with heparin, it forms a salt, neutralizing the anticoagulant effect of both drugs. Protamine, a strongly basic compound, forms complexes with heparin sodium or heparin calcium, which are acidic compounds. Formation of this complex can result in disruption of the heparin-antithrombin III complex responsible for the anticoagulant activity of heparin. The protamine-heparin complex does not possess anticoagulant properties. Protamine's anticoagulant effect usually is clinically insignificant and is likely the result of thromboplastin inhibition, which diminishes thrombin activity.

Protamine is administered via intravenous infusion. The onset of action is rapid, with neutralization of heparin evident within 5 minutes. The duration of action can persist up to 2 hours, depending on body temperature. The fate of the heparin-protein complex is unknown, but it appears to be partially degraded, with the release of heparin.
 
Affected cytochrome P450 isoenzymes: none

Protamine is classified as FDA pregnancy risk category C. It is not known if protamine can cause fetal harm when administered to a pregnant woman. Use protamine during pregnancy only if clearly needed.

According to the manufacturer, it is unknown whether protamine is excreted into human breast milk. Protamine should be administered during breast-feeding only when clearly needed. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.