INFORMATION FOR HEALTH PROFESSIONALS
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Heparin sodium (mucous) 5,000 I.U./ml (25,000 I.U. in 5ml)
For excipients see List of Excipients.
Solution for injection or concentrate for solution for infusion
A colourless or straw-coloured liquid, free from turbidity and from matter that deposits on standing.
Route of administration
By continuous intravenous infusion in 5% glucose or 0.9% sodium chloride or by intermittent intravenous injection, or by subcutaneous injection.
The intravenous injection volume of Multiparin should not exceed 15ml.
As the effects of heparin are short-lived, administration by intravenous infusion or subcutaneous injection is preferable to intermittent intravenous injections.
Recommended dosage
Prophylaxis of deep vein thrombosis and pulmonary embolism:
Adults:
2 hours pre-operatively: 5,000 units subcutaneously
followed by: 5,000 units subcutaneously every 8-12 hours, for 7-10 days or until the patient is fully ambulant.
No laboratory monitoring should be necessary during low dose heparin prophylaxis. If monitoring is considered desirable, anti-Xa assays should be used as the activated partial thromboplastin time (APTT) is not significantly prolonged.
During pregnancy: 5,000 - 10,000 units every 12 hours, subcutaneously, adjusted according to APTT or anti-Xa assay.
Elderly:
Dosage reduction and monitoring of APTT may be advisable.
Children:
No dosage recommendations.
Treatment of deep vein thrombosis, pulmonary embolism, unstable angina pectoris, acute peripheral arterial occlusion:
Adults:
Loading dose: 5,000 units intravenously (10,000 units may be required in severe pulmonary embolism)
Maintenance: 1,000-2,000 units/hour by intravenous infusion,
or 10,000-20,000 units 12 hourly subcutaneously,
or 5,000-10,000 units 4-hourly by intravenous injection.
Elderly:
Dosage reduction may be advisable.
Children and small adults:
Loading dose: 50 units/kg intravenously
Maintenance: 15-25 units/kg/hour by intravenous infusion,
or 250 units/kg 12 hourly subcutaneously
or 100 units/kg 4-hourly by intravenous injection
Daily laboratory monitoring (ideally at the same time each day, starting 4-6 hours after initiation of treatment) is essential during full-dose heparin treatment, with adjustment of dosage to maintain an APTT value 1.5-2.5 x midpoint of normal range or control value.
Adults:
12,500 units 12 hourly subcutaneously for at least 10 days.
Elderly:
Dosage reduction may be advisable
In extracorporeal circulation and haemodialysis
Adults:
Cardiopulmonary bypass:
Initially 300 units/kg intravenously, adjusted thereafter to maintain the activated clotting time (ACT) in the range 400-500 seconds.
Initially 1-5,000 units,
Maintenance: 1-2,000 units/hour, adjusted to maintain clotting time >40 minutes.
Known hypersensitivity to heparin or any of the other ingredients.
Patients who consume large amounts of alcohol, who are sensitive to the drug, who are actively bleeding or who have haemophilia or other bleeding disorders, severe liver disease (including oesophageal varices), purpura, severe hypertension, active tuberculosis or increased capillary permeability.
Patients with present or previous thrombocytopenia. The rare occurrence of skin necrosis in patients receiving heparin contra-indicates the further use of heparin either by subcutaneous or intravenous routes because of the risk of thrombocytopenia. Because of the special hazard of post-operative haemorrhage heparin is contra-indicated during surgery of the brain, spinal cord and eye, and in patients undergoing lumbar puncture or regional anaesthetic block.
The relative risks and benefits of heparin should be carefully assessed in patients with a bleeding tendency or those patients with an actual or potential bleeding site eg. hiatus hernia, peptic ulcer, neoplasm, bacterial endocarditis, retinopathy, bleeding haemorrhoids, suspected intracranial haemorrhage, cerebral thrombosis or threatened abortion.
Menstruation is not a contra-indication.
Platelet counts should be measured in patients receiving heparin treatment for longer than 5 days and the treatment should be stopped immediately in those who develop thrombocytopenia.
In patients with advanced renal or hepatic disease, a reduction in dosage may be necessary. The risk of bleeding is increased with severe renal impairment and in women over 60 years of age.
Although heparin hypersensitivity is rare, it is advisable to give a trial dose of 1,000 I.U. in patients with a history of allergy. Caution should be exercised in patients with known hypersensitivity to low molecular weight heparins. Multiparin contains benzyl alcohol and methyl parahydroxybenzoate as preservatives. Caution should be used if prescribing Multiparin to susceptible patients as benzyl alcohol may increase the risk of jaundice in neonates and cause toxic reactions in infants and children up to three years old. Methyl parahydroxybenzoate may cause allergic reactions (possibly delayed).
In most patients, the recommended low-dose regimen produces no alteration in clotting time. However, patients show an individual response to heparin, and it is therefore essential that the effect of therapy on coagulation time should be monitored in patients undergoing major surgery.
Caution is recommended in spinal or epidural anaesthesia (risk of spinal haematoma).
Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and in all patients treated for more than 7 days.
Drugs that interfere with platelet aggregation eg. aspirin and other NSAIDs, dextran solutions, dipyridamole or any other drug which may interfere with coagulation, should be used with care.
Hyperkalaemia may occur with concomitant ACE inhibitors.
Reduced activity of heparin has been reported with simultaneous intravenous glyceryl trinitrate infusion.
Interference with diagnostic tests may be associated with pseudo-hypocalcaemia (in haemodialysis patients), artefactual increases in total thyroxine and triiodothyronine, simulated metabolic acidosis and inhibition of the chromogenic lysate assay for endotoxin. Heparin may interfere with the determination of aminoglycosides by immunoassays.
Heparin is not contraindicated in pregnancy. Heparin does not cross the placenta or appear in breast milk. The decision to use heparin in pregnancy should be taken after evaluation of the risk/benefit in any particular circumstances.
Reduced bone density has been reported with prolonged heparin treatment during pregnancy.
Haemorrhage may be a problem during pregnancy or after delivery.
None stated.
Haemorrhage (see also Special Warnings and Precautions and Overdosage Information).
Thrombocytopenia has been observed occasionally (see also Special Precautions and Warnings). Two types of heparin-induced thrombocytopenia have been defined. Type I is frequent, mild (usually >50 x 109/L) and transient, occurring within 1-5 days of heparin administration. Type II is less frequent but often associated with severe thrombocytopenia (usually <50 x 109/L). It is immune-mediated and occurs after a week or more (earlier in patients previously exposed to heparin). It is associated with the production of a platelet-aggregating antibody and thromboembolic complications which may precede the onset of thrombocytopenia. Heparin should be discontinued immediately.
There is some evidence that prolonged dosing with heparin (ie. over many months) may cause alopecia and osteoporosis. Significant bone demineralisation has been reported in women taking more than 10,000 I.U. per day of heparin for at least 6 months.
Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium. Rarely, clinically significant hyperkalemia may occur particularly in patients with chronic renal failure and diabetes mellitus (see Warnings and Precautions).
Hypersensitivity reactions to heparin are rare. They include urticaria, conjunctivitis, rhinitis, asthma, cyanosis, tachypnoea, feeling of oppression, fever, chills, angioneurotic oedema and anaphylactic shock. In some instances the precipitating agent will prove to be the preservative rather than the heparin itself.
Local irritation and skin necrosis may occur but are rare. Erythematous nodules, or infiltrated and sometimes eczema-like plaques, at the site of subcutaneous injections are common, occurring 3-21 days after starting heparin treatment.
Priapism has been reported. Increased serum transaminase values may occur but usually resolve on discontinuation of heparin. Heparin administration is associated with release of lipoprotein lipase into the plasma; rebound hyperlipidaemia may follow heparin withdrawal.
A potential hazard of heparin therapy is haemorrhage, but this is usually due to overdosage and the risk is minimised by strict laboratory control. Slight haemorrhage can usually be treated by withdrawing the drug. If bleeding is more severe, clotting time and platelet count should be determined. Prolonged clotting time will indicate the presence of an excessive anticoagulant effect requiring neutralisation by intravenous protamine sulphate, at a dosage of 1 mg for every 100 I.U. of heparin to be neutralised. The bolus dose of protamine sulphate should be given slowly over about 10 minutes and not exceed 50 mg. If more than 15 minutes have elapsed since the injection of heparin, lower doses of protamine will be necessary.
Pharmacodynamic Properties
Heparin is an anticoagulant and acts by inhibiting thrombin and by potentiating the naturally occurring inhibitors of activated Factor X (Xa).
Pharmacokinetic Particulars
As heparin is not absorbed from the gastrointestinal tract and sublingual sites it is administered by injection. After injection heparin extensively binds to plasma proteins.
Heparin is metabolised in the liver and the inactive metabolic products are excreted in the urine.
The half life of heparin is dependent on the dose.
Pre-clinical Safety Data
There are no pre-clinical data of relevance to the prescriber which are additional to those already included in other sections.
PHARMACEUTICAL PARTICULARS
List of Excipients
Benzyl alcohol
Methyl parahydroxybenzoate (E218)
Water for injections
Sodium hydroxide solution
Hydrochloric acid
Incompatibilities
Heparin is incompatible with many injectable preparations e.g. some antibiotics, opioid analgesics and antihistamines.
Dobutamine hydrochloride and heparin should not be mixed or infused through the same intravenous line, as this causes precipitation.
Heparin and reteplase are incompatible when combined in solution.
If reteplase and heparin are to be given through the same line this, together with any Y-lines, must be thoroughly flushed with a 0.9% saline or a 5% glucose solution prior to and following the reteplase injection.
Shelf Life
18 months
Special Precautions for Storage
Do not store above 25°C
Store in the original package
Nature and Contents of Container
5ml multidose neutral glass (Type 1, Ph Eur) vial. Carton containing 10 vials.
Instructions for Use/Handling
Each multidose vial should be restricted to use in a single patient.
MARKETING AUTHORISATION HOLDER
Artex Ltd
PO Box 249
15 Ruataniwha St
Waipukurau
New Zealand
DATE OF PREPARATION
July 2003