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PROTAMINE SULPHATE BP 1% INJECTION

Active substance(s): PROTAMINE SULPHATE / PROTAMINE SULPHATE / PROTAMINE SULPHATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT
Protamine Sulphate BP 1% Injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Protamine Sulphate BP 1% Injection
Each ampoule contains protamine sulphate 10 mg/ml in sodium chloride 0.9% w/v.
For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM
Clear, colourless, sterile solution for injection.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications
Protamine sulphate is indicated in adults.
It 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
Posology
For intravenous injection
Adults:
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 continuously
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 clotting 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, 0.50.75 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
clotting 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.
Older people:

There is no current evidence for alteration of the recommended dose.
Paediatric population:
Safety and efficacy in children have not been established. Not recommended.
Method of administration
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.

4.3.

Contraindications
Protamine Sulphate Injection is contraindicated in patients who are known to be
hypersensitive to protamine or to any of the excipients listed in section 6.1.

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.
Protamine sulfate should not be used for bleeding that occurs without prior exposure to
heparin. 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.

Interactions with other medicinal products and other forms of interaction
Protamine sulfate should not be mixed with other drugs without knowledge of their
compatibility, because protamine sulphate has been shown to be incompatible with
certain antibiotics, including several of the cephalosporins and penicillins
Protamine sulphate may increase the magnitude and/or duration of action of nondepolarising neuromuscular blocking agents.

4.6.

Fertility, pregnancy and lactation
Pregnancy
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.
Breast-feeding
The safety of protamine sulphate during lactation has not been established. It is not known
whether protamine sulphate is distributed into breast milk and the drug should be used with
caution during lactation.
Fertility
Studies have not been performed to date with protamine sulphate to determine the effect
of the drug on fertility.

4.7.

Effects on ability to drive and use machines
No adverse effects known.

4.8.

Undesirable effects

Blood and lymphatic system disorders

Anticoagulant effect (when used at doses
in excess of that required to neutralise the
anticoagulant effect of heparin).

Immune system disorders

Hypersensitivity
reactions,
including
angioedema anaphylactoid reactions and
fatal anaphylaxis have been reported.

Cardiac disorders

Bradycardia,

Vascular disorders

Sudden fall in blood pressure,
Pulmonary and systemic hypertension,
transitory flushing and a feeling of
warmth severe, acute pulmonary
vasoconstriction with cardiovascular
collapse

Respiratory, thoracic and mediastinal
disorders:

Dyspnoea,
there have been rare instances of
noncardiogenic pulmonary oedema with
prolonged hypotension, with significant

morbidity and mortality.
Gastrointestinal disorders
Musculoskeletal and connective tissue
disorders
General disorders and administration site
conditions

4.9.

Nausea and vomiting
Back pain
Lassitude

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme, www.mhra.gov.uk/yellowcard.
Overdose
Symptoms
Protamine sulphate has weak anticoagulating properties and if given in the absence of
heparin, or at doses in excess of those required to neutralise the anticoagulant effect of
heparin, exerts its own anticoagulant effect
Hypotension, bradycardia, dyspnoea nausea, vomiting, lassitude, transitory flushing and/
or a sensation of warmth may also occur.
Management
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
ATC code: V03AB
Pharmacotherapeutic group: Antidotes,
Mechanism of action
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
Absorption
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
3 years

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:

6.6.

6 x 10 ml ampoules.
5 x 10 ml ampoules.

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
Amdipharm UK Limited
Capital House, 85 King William Street,
London EC4N 7BL, UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 20072/0227

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
29/08/2006

10

DATE OF REVISION OF THE TEXT
03/04/2014

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Source: Medicines and Healthcare Products Regulatory Agency

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