Protamine sulfate is used as an antidote in patients with heparin overdose. It may also be used to partially reverse the effects of LMWH (low molecular weight heparin) and fondaparinux. It is administered as an intravenous infusion, however, rapid administration of the drug should be avoided as it may cause life-threatening hypotension and anaphylactic reactions.

It may also be used as an off-label medicine in the following situations:

• Heparin neutralization
• Intracranial hemorrhage associated with the use of enoxaparin or other LMWH or unfractionated heparin.
• LMWH overdose.

Protamine sulfate dose in Adults

Protamine sulfate dose in patients with heparin overdosage (following intravenous administration):

IV Administration:

• Adjust protamine dosage based on time elapsed since heparin administration:
  • Immediate: 1 to 1.5 mg protamine per 100 units of heparin
  • 30 to 60 minutes: 0.5 to 0.75 mg protamine per 100 units of heparin
  • More than 2 hours: 0.25 to 0.375 mg protamine per 100 units of heparin

Subcutaneous (SubQ) Injection:

• IV administration of 1 to 1.5 mg protamine per 100 units of heparin.
• It can be administered partially as a slow IV dose (e.g., 25 to 50 mg) followed by the remaining as a continuous infusion over 8 to 16 hours.

Heparin Neutralization:

• Initial IV dosage of protamine is determined by the heparin dosage.
• 1 mg of protamine neutralizes approximately 100 units of heparin.
• Maximum single dose: 50 mg.
• If the activated partial thromboplastin time (aPTT) remains elevated, may repeat the dose at 0.5 mg of protamine for every 100 units of heparin.

Heparin neutralization after Cardiac surgery:

Repeat Dose After Cardiopulmonary Bypass:

• IV Administration:
  • Administer repeat doses of 25 to 50 mg after cardiopulmonary bypass to reverse large intraoperative heparin doses if activated clotting time (ACT) remains elevated or if heparin rebound is a concern.
  • Maximum total dose: 3 mg/kg.

For Heparin Rebound:

• Consider continuous IV infusion of protamine sulfate at 25 mg/hour for 6 hours following the initial dose.

Note:

• When heparin is administered as a continuous IV infusion, only consider the heparin given in the preceding 2 to 3 hours when administering protamine.
• For instance, a patient receiving heparin at a rate of 1,250 units/hour will require approximately 30 mg of protamine to reverse the effects of heparin administered in the last 2 to 2.5 hours.

Protamine sulfate dose in patients with intracranial hemorrhage associated with heparin or LMWH (off-label):

Heparin-Mediated Intracranial Hemorrhage:

• Full Dose Infusions:
  • IV Administration:
    • 1 mg protamine for every 100 units of heparin administered in the previous 2 to 3 hours.
    • Administer slowly over approximately 10 minutes.
    • Maximum single dose: 50 mg.
    • Consider administering 0.5 mg protamine for every 100 units of heparin if the activated partial thromboplastin time (aPTT) remains elevated.
• Prophylactic Subcutaneous Heparin:
  • Consider reversal when aPTT is significantly prolonged.

LMWH-Mediated Intracranial Hemorrhage:

• Enoxaparin:
  • Administer 1 mg protamine for every 1 mg of enoxaparin if enoxaparin was administered within 8 hours.
  • Administer 0.5 mg protamine for every 1 mg of enoxaparin if enoxaparin was administered within 8 to 12 hours.
  • Maximum single dose: 50 mg.
  • Consider repeat dose if life-threatening bleeding persists or if the patient has renal impairment.
• Dalteparin, Nadroparin, and Tinzaparin:
  • Administer 1 mg protamine for every 100 anti-Xa units of LMWH administered in the past 3 to 5 half-lives.
  • Maximum single dose: 50 mg.
  • Consider repeat dose if life-threatening bleeding persists or if the patient has renal impairment.

LMWH Overdose:

• Enoxaparin:
  • Administer equal doses of protamine sulfate to enoxaparin administered within 8 hours.
  • Administer 0.5 mg protamine sulfate for every 1 mg of enoxaparin administered if more than 8 hours have passed or if a second dose of protamine is required.
• Dalteparin or Tinzaparin:
  • Administer 1 mg protamine for each 100 anti-Xa units of dalteparin or tinzaparin.
  • Consider additional dose if prolonged partial thromboplastin time (PTT) persists or bleeding continues.

Protamine sulfate dose in Childrens

Protamine Sulfate Dosing for Heparin or Enoxaparin Neutralization

Infants, Children, and Adolescents

Heparin Overdosage Following Intravenous Administration:

• Adjust protamine dosage based on time since last heparin dose:
  • Less than 30 minutes: 1 mg protamine to neutralize 100 units of heparin
  • 30 to 60 minutes: 0.5 to 0.75 mg protamine to neutralize 100 units of heparin
  • 60 to 120 minutes: 0.375 to 0.5 mg protamine to neutralize 100 units of heparin
  • More than 120 minutes: 0.25 to 0.375 mg protamine to neutralize 100 units of heparin

Heparin Overdosage Following Subcutaneous Administration:

• Administer 1 to 1.5 mg protamine per 100 units of heparin.
• Consider administering a portion of the protamine dose slowly intravenously followed by the remaining portion as a continuous infusion over 8 to 16 hours.

LMWH Overdosage (Enoxaparin, Dalteparin):

• Enoxaparin:
  • Administer equal doses of protamine sulfate to enoxaparin administered within 8 hours.
  • Administer 0.5 mg protamine sulfate for every 1 mg of enoxaparin if administered more than 8 hours prior or if a second dose of protamine is required.
• Dalteparin:
  • Administer 1 mg protamine for each 100 anti-Xa units of dalteparin.
  • Consider additional dose if prolonged partial thromboplastin time (PTT) persists or bleeding continues.

Pregnancy Risk Factor C

• Protamine sulfate is considered safe for use during delivery to prevent bleeding in pregnant women who have received heparin or low molecular weight heparin (LMWH).
• Although animal studies regarding its safety in pregnancy haven't been conducted, antidotes like protamine sulfate should be given to pregnant women if there's a clear need, without withholding due to concerns about potential harm to the fetus.
• It's important to consider the mother's health and prognosis when deciding on medication use during pregnancy, as per guidelines by Bailey (2003) and Bates (2012).

Protamine sulfate use during breastfeeding:

• The presence of protamine sulfate in breast milk is uncertain.
• As a precaution, the manufacturer advises caution when giving protamine to nursing mothers.

Protamine sulfate dose in kidney disease:

• The manufacturer's labeling does not include specific dosage adjustments for individuals with renal impairment.
• This means that there are no recommended changes in the dosage of protamine sulfate based solely on the presence of renal impairment.

Protamine sulfate dose in liver disease:

• The manufacturer's labeling does not include specific dosage adjustments for individuals with hepatic impairment.
• This indicates that there are no recommended changes in the dosage of protamine sulfate based solely on the presence of hepatic impairment.

Protamine sulfate side effects:

• 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

Protamine sulfate contraindications:

• People who have a known hypersensitivity (allergic reaction) to protamine or any component of the formulation should not use protamine sulfate.

Warnings and Precautions

Heparin rebound:

• Occasionally, heparin rebound may occur, causing anticoagulation and bleeding symptoms to reappear.
• Symptoms typically manifest 8-9 hours post-protamine administration, but may occur up to 18 hours later.

Hypersensitivity reactions:

• Protamine sulfate may trigger hypersensitivity reactions in some patients.
• Have epinephrine 1 mg/mL and resuscitation equipment readily available.
• Serious adverse effects may include hypotension, cardiovascular collapse, pulmonary edema, vasoconstriction, and pulmonary hypertension.
• Risk factors include high doses, repeated doses, previous protamine exposure, fish allergy, vasectomy, severe heart dysfunction, and abnormal preoperative pulmonary hemodynamics.

Infusion Reactions:

• Rapid administration can lead to severe hypotensive and anaphylactoid-like reactions.
• Caution should be exercised to avoid such reactions.

Monitor:

Safety Monitoring During Protamine Sulfate Administration

• Coagulation Test:
  • Regular monitoring of coagulation parameters, such as activated partial thromboplastin time (aPTT) or activated clotting time (ACT), is essential during protamine sulfate administration.
• Cardiac Monitor:
  • Continuous cardiac monitoring should be employed throughout the administration of protamine sulfate to promptly identify any potential cardiac abnormalities or arrhythmias.
• Blood Pressure Monitor:
  • Monitoring blood pressure is crucial to detect any changes or fluctuations, particularly hypotension, which can occur as a side effect of protamine sulfate administration.

These monitoring measures are necessary to ensure the safety of the patient and to promptly identify and manage any adverse reactions or complications that may arise during the administration of protamine sulfate.

How to administer Protamine sulfate?

• Route of Administration:
  • Protamine sulfate is designated for intravenous (IV) use only.
• Administration Method:
  • Administer slowly via intravenous push (IVP).
  • Infuse 50 mg over a period of 10 minutes.
  • Rapid IV infusion can lead to hypotension.
• Dosage Limitation:
  • Do not exceed a maximum of 50 mg in any 10-minute period to mitigate the risk of adverse effects.

These guidelines are crucial for safe and effective administration of protamine sulfate, minimizing the risk of complications and ensuring patient safety.

Protamine sulfate mechanism of action:

• Protamine is a protein molecule that's very basic and carries a big positive charge.
• On its own, it doesn't have much ability to prevent blood clotting.
• However, when it's given alongside heparin, which is strongly acidic and has a negative charge, they form a stable salt.
• This neutralizes the blood-thinning effects of both drugs.
• With low molecular weight heparin (LMWH), protamine doesn't completely reverse its blood-thinning effects, only partly reducing its activity against factor Xa, an enzyme involved in blood clotting.

Onset of Action (IV, Heparin Neutralization):

• It typically takes around 5 minutes for protamine sulfate to neutralize the effects of heparin when administered intravenously.

Half-life Elimination:

• Protamine sulfate has a relatively short half-life of approximately 7 minutes. This means that it is rapidly eliminated from the body.

Protamine sulfate brand name (international):

• Denpru
• Prosulf
• Protamina
• Protamina solfato
• Protamine Choay
• Protamine Sulfate Injection
• Protamine Sulphate
• Protamine Sulphate Injection BP
• Protamini Sulfas
• Protaminsulfat
• Protaminsulfat Novo
• Protaminsulfat ”Leo”

Protamine sulfate Brand Names in Pakistan: