1. Name Of The Medicinal Product
Protamine Sulphate Injection BP 1%
2. Qualitative And Quantitative Composition
Protamine Sulphate Injection BP 1% contains protamine sulphate 10 mg/ml in sodium chloride 0.9% w/v.
3. Pharmaceutical Form
Sterile solution for injection.
4. Clinical Particulars
4.1 Therapeutic Indications
Protamine sulphate neutralises the anticoagulant action of heparin: before surgery; after renal dialysis; after open-heart surgery, if excessive bleeding occurs and when an overdose has inadvertently been given.
4.2 Posology And Method Of Administration
For intravenous injection
Adults:
Protamine sulphate should be administered by slow intravenous injection over a period of ten minutes. Not more than 50 mg of protamine sulphate should be given in any one dose.
The dose is dependent on the amount and type of heparin to be neutralised, its route of administration and the time elapsed since it was last given, since heparin is continously being excreted. Ideally, the dose required to neutralise the action of heparin should be guided by blood coagulation studies or calculated from a protamine neutralisation test.
Patients should be carefully monitored using either the activated partial thromboplastin time or the activated coagulation time, carried out 5-15 minutes after protamine sulphate administration. Further doses may be needed because protamine is cleared from the blood more rapidly than heparin, especially low molecular weight heparin.
In gross excess, protamine itself acts as an anticoagulant.
Neutralisation of unfractionated (UF) heparins:
1 mg of protamine sulphate will usually neutralise at least 100 international units of mucous heparin or 80 units of lung heparin. The dose of protamine sulphate should be reduced if more than 15 minutes have elapsed since intravenous injection.
For example, if 30-60 minutes have elapsed since heparin was injected intravenously, 0.5-0.75 mg protamine sulphate per 100 units of mucous heparin is recommended. If two hours or more have elapsed, 0.25-0.375 mg per 100 units of mucous heparin should be administered.
If the patient is receiving an intravenous infusion of heparin, the infusion should be stopped and 25-50 mg of protamine sulphate given by slow intravenous injection.
If heparin was administered subcutaneously, 1 mg protamine sulphate should be given per 100 units of mucous heparin – 25-50 mg by slow intravenous injection and the balance by intravenous infusion over 8-16 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 doffing time.
Neutralisation of low molecular weight (LMW) heparins:
A dose of 1 mg per 100 units 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 sulphate and may persist for up to 24 hours after administration.
The longer half-life of LMW heparins (approximately twice that of UF heparin) should also be borne in mind when estimating the dose of protamine sulphate required in relation to the time which has elapsed since the last heparin dose.
Theoretically, the dose of protamine sulphate should be halved when one half-life has elapsed since the last LMW heparin dose. Intermittent injections or continuous infusion of protamine sulphate have been recommended for the neutralisation of LMW heparin following subcutaneous administration, as there may be continuing absorption from the subcutaneous depot.
Elderly:
There is no current evidence for alteration of the recommended dose.
Children:
Safety and efficacy in children have not been established. Not recommended.
4.3 Contraindications
Protamine Sulphate Injection is contra-indicated in patients who are known to be hypersensitive to protamine.
4.4 Special Warnings And Precautions For Use
Too rapid administration of protamine sulphate may cause severe hypotension and anaphylactoid reactions. Facilities for resuscitation and treatment of shock should be available.
Protamine sulphate is not suitable for reversing the effects of oral anticoagulants. Caution should be observed when administering protamine sulphate 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 by-pass which may include the use of protamine; diabetics who have been treated with protamine insulin, patients who are allergic to fish and men who have had a vasectomy or are infertile and may have antibodies to protamine.
Patients undergoing prolonged procedures involving repeated doses of protamine should be subject to careful monitoring of clotting parameters. A rebound bleeding effect may occur up to 18 hours post-operatively which responds to further doses of protamine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Protamine sulphate may increase the magnitude and/or duration of action of non-depolarising neuromuscular blocking agents.
4.6 Pregnancy And Lactation
The safety of protamine sulphate during pregnancy and lactation has not been established.
Neither animal nor human reproduction studies have been conducted, and therefore the drug should only be used during pregnancy when clearly needed. It is not known whether protamine sulphate is distributed into breast milk and the drug should be used with caution during lactation.
4.7 Effects On Ability To Drive And Use Machines
No adverse effects known.
4.8 Undesirable Effects
When used at doses in excess of that required to neutralise the anticoagulant effect of heparin, protamine sulphate exerts its own anticoagulant effect. Following injection of protamine sulphate, the following effects have been observed: a sudden fall in blood pressure, bradycardia, pulmonary and systemic hypertension, dyspnoea, transitory flushing and a feeling of warmth, back pain, nausea and vomiting, and lassitude. Hypersensitivity reactions, including angioedema and fatal anaphylaxis have been reported. There have been rare instances of noncardiogenic pulmonary oedema with prolonged hypotension, with significant morbidity and mortality.
4.9 Overdose
Symptoms: Overdose may cause hypotension, bradycardia and dyspnoea with a sensation of warmth, nausea, vomiting, lassitude and transitory flushing.
Treatment: Includes monitoring of coagulation tests, respiratory ventilation and symptomatic treatment. If bleeding is a problem, fresh frozen plasma or fresh whole blood should be given.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Protamine sulphate is strongly basic and acts as a heparin antagonist by complexing with the strongly acidic heparin sodium or heparin calcium to form a stable complex.
5.2 Pharmacokinetic Properties
Protamine sulphate has a rapid onset of action. Following intravenous administration, neutralisation of heparin occurs within 5 minutes. Although the metabolic fate of the protamine-heparin complex is not known, it appears that the complex is partially degraded, thus freeing heparin.
5.3 Preclinical Safety Data
Not applicable.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Water for injections, sodium chloride for injections, sodium hydroxide and/or hydrochloric acid as pH adjusters.
6.2 Incompatibilities
Protamine sulphate is incompatible with certain antibiotics, including several penicillins and cephalosporins.
6.3 Shelf Life
36 months
6.4 Special Precautions For Storage
Store at 15 to 25ºC. Do not refrigerate.
6.5 Nature And Contents Of Container
One point cut ampoule.
Pack sizes: 6x10 ml ampoules
5x10 ml ampoules.
6.6 Special Precautions For Disposal And Other Handling
None.
Administrative Data
7. Marketing Authorisation Holder
Waymade PLC
Trading as: Sovereign Medical
Sovereign House
Miles Gray Road
Basildon, Essex, SS14 3FR
United Kingdom
8. Marketing Authorisation Number(S)
PL 06464/0903
9. Date Of First Authorisation/Renewal Of The Authorisation
29/08/2006
10. Date Of Revision Of The Text
29/08/2006
11 Legal Category
POM
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