Protamine sulfate parenteral
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Injections containing protamine sulfate
Drugs List
Therapeutic Indications
Uses
Heparin toxicity (antidote)
Neutralisation of the anticoagulant effect of heparin in the following circumstances; before surgery, after renal dialysis, after open-heart surgery, if excessive bleeding occurs or inadvertent overdose.
Dosage
The dose is dependent on the amount and type of heparin to be neutralised, the route it was administered and the time elapsed since it was last given. Dose should be guided by blood coagulation studies or calculated from a protamine neutralisation test.
Carefully monitor patients using either the activated partial thromboplastin time or the activated coagulation time, 5 to 15 minutes after protamine sulfate administration. Further dose may be required as protamine sulfate is cleared from the blood faster than heparin.
Maximum rate of administration: 5mg/minute.
Maximum dose: 50mg.
Adults
Neutralisation of unfractionated (UF) heparin
1mg protamine sulfate will usually neutralise at least 100 international units (units) of mucous heparin or 80units of lung heparin. The dose of protamine sulphate should be reduced if more than 15 minutes have elapsed since intravenous injection.
For example, if 30 to 60 minutes have elapsed since heparin was injected intravenously, 500micrograms to 750micrograms protamine sulfate per 100units of mucous heparin is recommended. If two hours or more have elapsed, 250micrograms to 375micrograms per 100units of mucous heparin should be administered.
If the patient is receiving an intravenous infusion of heparin, the infusion should be stopped and 25mg to 50mg of protamine sulfate given by slow intravenous injection.
If heparin was administered subcutaneously, 1mg protamine sulfate should be given per 100units of mucous heparin, 25mg to 50mg by slow intravenous injection and the balance by intravenous infusion over 8 to 16 hours.
In the reversal of UF heparin following cardiopulmonary bypass, either a standard dose of protamine may be given, as above, or the dose may be titrated according to the activated clotting times.
Neutralisation of low molecular weight (LMW) heparins
A dose of 1mg per 100units is usually recommended but the manufacturer's own guidelines should be consulted.
The anti-Xa activity of LMW heparins may not be completely reversible with protamine sulfate and may persist for up to 24 hours after administration.
The longer half-life of LMW heparins (approximately twice that of UF heparins) should be borne in mind when estimating the required dose of protamine sulfate required in relation to the time which has elapsed since the last heparin dose.
Theoretically, the dose of protamine sulfate should be halved when one half-life has elapsed since LMW heparin administration. Intermittent intravenous injections or continuous intravenous infusion of protamine sulfate is recommended following subcutaneous administration of LMW heparin, as there may be continuing absorption from the subcutaneous depot.
Children
Overdosage with subcutaneous injection of low molecular weight heparin (unlicensed)
Give 1mg protamine sulfate to neutralise approximately 100units low molecular weight heparin by intermittent intravenous injection (not exceeding 5mg/minute) or by continuous intravenous infusion.
Overdosage with intravenous injection or intravenous infusion of unfractionated heparin (unlicensed)
If less than 30 minutes lapsed since overdose, give 1mg protamine sulfate by intravenous injection (not exceeding 5mg/minute) to neutralise each 100units of unfractionated heparin.
If 30 to 60 minutes has lapsed since overdose, give 500micrograms to 750micrograms protamine sulfate by intravenous injection (not exceeding 5mg/minute) to neutralise each 100units of unfractionated heparin.
If 60 to 120 minutes has lapsed since overdose, give 375micrograms to 500micrograms protamine sulfate by intravenous injection (not exceeding 5mg/minute) to neutralise each 100units of unfractionated heparin.
If over 120 minutes has lapsed since overdose, give 250micrograms to 375micrograms protamine sulfate by intravenous injection (not exceeding 5mg/minute) to neutralise each 100units of unfractionated heparin.
Overdosage with subcutaneous injection of unfractionated heparin (unlicensed)
Initial dose: Give 50% to 100% of the total dose by intravenous injection (not exceeding 5mg/minute).
Maintenance dose: Give any remainder of dose by intravenous infusion over 8 to 16 hours.
Administration
To be administered via slow intravenous injection over an approximate 10 minute period. No more than 50mg protamine sulfate may be given in any one dose.
Can also be administered via intravenous infusion.
Contraindications
Neonates under 1 month
Precautions and Warnings
Children 1 month to 18 years
Fish allergy
Male infertility
Prolonged procedures involving repeated doses
Breastfeeding
Diabetes mellitus previously treated with protamine insulins
Pregnancy
Resuscitation facilities must be immediately available
Rebound effect may occur upto 18hrs after a prolonged procedure
Too rapid administration of protamine sulfate may cause severe hypotension and anaphylactic reactions. Do not exceed a rate of 5mg/minute. Ensure facilities for resuscitation and treatment of shock are available.
Protamine sulfate is not suitable for reversing the effects of oral anticoagulants.
Protamine sulfate should not be used for bleeding that occurs without prior exposure to heparin.
Caution should be observed when administering protamine sulfate to patients who may be at increased risk of allergic reactions to protamine. These patients include those who have previously undergone procedures such as coronary angioplasty or cardiopulmonary bypass which may include the use of protamine; diabetics who have been treated with protamine insulin and men who have had a vasectomy and may have antibodies to protamine.
Patients undergoing prolonged procedures involving repeated doses of protamine sulfate should be subject to careful monitoring of clotting parameters.
Protamine sulfate has an anticoagulant effect when administered in the absence of heparin and in overdosage.
Pregnancy and Lactation
Pregnancy
Protamine should be used with caution during pregnancy.
At the time of writing, the safety of protamine has not been established during pregnancy (Briggs, 2011).
Neither human or animal reproduction studies have been conducted, and therefore protamine sulfate should only be used during pregnancy when clearly needed. Schaefer (2007) suggests that protamine may be used during pregnancy in the case of heparin or low molecular weight heparin overdose.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Use protamine with caution in breastfeeding.
At the time of writing, there is no published experience concerning the use of protamine during breastfeeding. It is not known whether protamine is excreted into human breast milk.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Side Effects
Anaphylactoid reaction
Anaphylaxis
Angioedema
Back pain
Bradycardia
Cardiovascular collapse
Death
Dyspnoea
Flushing
Hypersensitivity reactions
Hypertension
Hypotension
Lassitude
Nausea
Pulmonary hypertension
Pulmonary oedema
Rebound bleeding
Sensation of warmth
Vasoconstriction
Vomiting
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: July 2014
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.
Handbook on Injectable Drugs, 15th Edition, Trissel, L. American Society of Health-System Pharmacists.
Injectable Medicines Administration Guide, 3rd edition (2010) UCL NHS Foundation Trust. Wiley-Blackwell, Oxford.
Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.
Summary of Product Characteristics: Prosulf 10mg/ml solution for injection. Wockhardt UK Ltd. Revised September 2010.
Summary of Product Characteristics: Protamine sulphate BP 1% injection. Amdipharm Mercury Company Ltd. Revised April 2014.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 13 September 2017
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