INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo HEPARIN SODIUM-FRESENIUS 1 000 i.u./mL
HEPARIN SODIUM-FRESENIUS 5 000 i.u./mL
HEPARIN SODIUM-FRESENIUS 12 500 i.u./mL
HEPARIN SODIUM-FRESENIUS 25 000 i.u./mL

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

HEPARIN SODIUM-FRESENIUS 1 000 i.u./mL
HEPARIN SODIUM-FRESENIUS 5 000 i.u./mL
HEPARIN SODIUM-FRESENIUS 12 500 i.u./mL
HEPARIN SODIUM-FRESENIUS 25 000 i.u./mL
(Injection)

COMPOSITION:
1 mL ampoule and 5 mL vial containing 1 000 i.u./mL
Heparin Mucosal
1 mL ampoule and 5 mL vial containing 5 000 i.u./mL Heparin Mucosal
1 mL ampoule containing 12 500 i.u./mL Heparin Mucosal
5 mL vial containing 25 000 i.u./mL Heparin Mucosal
Preservative: Chlorocresol 0,1% m/v

PHARMACOLOGICAL CLASSIFICATION:
A 8.2 Anticoagulants.

PHARMACOLOGICAL ACTION:
Heparin inhibits the clotting of blood both in vitro, and in vivo. Whole-blood clotting time, thrombin time and one-stage prothrombin time are prolonged, and thromboplastin generation is abnormal. Clotting time is proportional to the concentration of the medicine in the blood. However, with therapeutic doses bleeding time is usually unaffected and a patient can carry on normal activities, such as shaving, without danger of bleeding. The anticoagulant action of the heparin requires the presence of a plasma alpha-globulin, referred to as "heparin cofactor", a substance that appears to be identical with normal plasma antithrombin (antithrombin III). Heparin does not block prothrombin synthesis in the liver as do the oral anticoagulants but it does inhibit factors involved in the conversion of prothrombin to thrombin. This action is probably exerted by the facilitation of the formation of complexes of the heparin cofactor (antithrombin) with each of the four activated proteases of the coagulation cascade (activated factors IX, X, XI and XII). A similar heparin-stimulated reaction also occurs between antithrombin and thrombin. The detailed mechanism of this phenomenon may involve a heparin-induced conformational change of the inhibitor. It requires 30 to 40 times more heparin to inhibit the action of formed thrombin than it does to prevent thrombin formation.
Therefore the prevention of thrombin formation is probably its primary effect. Heparin is not effective after oral or sublingual administration but it is well absorbed after intramuscular or subcutaneous injection. In the blood it is evenly distributed between white cells and plasma. Heparin disappears exponentially from the circulation at a rate dependent upon the dose. The half-lives of 100, 200 and 400 units/kg, injected intravenously, are 56, 96 and 152 minutes respectively. Heparin is metabolized by the liver and a partially degraded, weakly active form of heparin (uroheparin) is excreted in the urine; after very large intravenous doses, up to 50% of nonmetabolized heparin may appear in the urine. The exact mechanism of renal elimination is unknown.

INDICATIONS:
Heparin is used as an anticoagulant in vascular surgery and occasionally in blood transfusions, but its chief use is in the treatment of arterial and venous thrombosis. It may also be used prophylactically after surgery to prevent thrombo-embolic complications.

CONTRA-INDICATIONS:
Known hypersensitivity to heparin, especially when severe heparin-induced thrombocytopenia has occurred in recent months.
Haemorrhagic blood disorders - especially thrombocytopenia and haemophilia.
Haemorrhage, active or suspected - especially cerebrovascular, gastrointestinal, except in disseminated intravascular coagulation.
Conditions where haemorrhage is a particular risk;
Aneurysm, cerebral or aortic
Hypertension severe or uncontrolled
Threatened abortion
Recent childbirth
Subacute bacterial endocarditis
Pericarditis
Vasculitis, severe
Active cavitating tuberculosis
Visceral carcinoma if there is a possibility of intracranial metastasis
Peptic ulceration
During or after eye, brain or spinal chord surgery or trauma
Prior to lumbar puncture or regional anaesthetic block
Surgical or traumatic wounds resulting in large open surfaces
Severe renal function impairment
Severe hepatic function impairment

WARNINGS:
Rarely retroperitoneal haemorrhage can occur even if the clotting time is not prolonged.

DOSAGE AND DIRECTIONS FOR USE:
The usual practice is to give an initial intravenous injection of 12 500 units of heparin, followed by doses of 10 000 units every 4 hours to keep the clotting time, tested not less than 3 hours after the last injection, at about 3 times the pretreatment figure. The dose for this purpose usually ranges from 6 000 to 12 000 units. For continuous infusion 10 000 to 20 000 units of heparin is added to 1 litre of Dextrose injection or Sodium chloride injection and started at about 20 drops per minute.
A suggested initial dose for children is 50 units per kg body mass by intravenous infusion in Dextrose injection 5% increased to 100 units per kg every 4 hours to keep the clotting time at 20 to 30 minutes. If blood transfusions are required during anticoagulant therapy, 3 units of heparin per mL may be added to the transfused blood in addition to the dose already being administered. Bleeding from the site of operation is unlikely if heparin is started after the fourth post-operative day.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
Heparin can give rise to haemorrhage as a consequence of its action. It can also cause thrombocytopenia, either through a direct effect or through an immune effect producing a platelet-aggregating antibody. Consequent platelet aggregation and thrombosis may therefore exacerbate the condition being treated.
Hypersensitivity reactions may occur, as may local irritant effects, and skin necrosis. Alopecia and osteoporosis resulting in spontaneous fractures have occurred after prolonged use of heparin.
Special precautions:
Since heparin has caused thrombocytopenia with severe thrombo-embolic complications, platelet counts should be monitored in patients receiving heparin for more than a few days.
A test dose has been recommended for patients with a history of allergy.
Heparin should be used with care in conjunction with anticoagulants or agents, such as aspirin and dipyridamole, which affect platelet function. Other medicines which affect the coagulation process and which may therefore increase the risk of haemorrhage include dextran injections, thrombolytic enzymes such as streptokinase, high doses of penicillins and some cephalosporins, some contrast media, asparaginase, and epoprostenol. Estimations of oral anticoagulant control may be modified by heparin’s action on prothrombin.
Dosage of heparin may need to be reduced in old people; elderly women appear to be especially susceptible to haemorrhage after heparin administration.
Pregnancy - although heparin does not cross the placenta and is not likely to adversely affect the fetus or neonate, there is a risk of maternal bleeding.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
The chief side-effect of heparin is haemorrhage. Careful laboratory control is necessary. Bleeding may be encountered from an unsuspected lesion, such as a peptic ulcer. The haemorrhagic complications recorded include haematuria, haemarthrosis, wound haematoma and gastrointestinal bleeding. The haemorrhage may produce a haematoma in the surgical wound, but this is rarely serious if infection is prevented and larger accumulations of blood are aspirated. Mild effects of heparin overdosage usually respond to simple withdrawal of the medicine. In the event of major haemorrhage, the use of the specific heparin antagonist, Protamine sulphate, is imperative.

IDENTIFICATION:
A clear colourless or straw-coloured liquid in amber glass ampoules or vials, free from turbidity and from matter which deposits on standing.

PRESENTATION:
1 mL amber glass ampoules packed in containers of 10.
5 mL amber glass vials packed in containers of 10.

STORAGE INSTRUCTIONS:
Store below 25°C. Do not freeze.
Keep out of reach of children.

REGISTRATION NUMBER:
Heparin Sodium-Fresenius 1 000 i.u./mL (1 mL ampoule, 5 mL vial) J/8.2/405
Heparin Sodium-Fresenius 5 000 i.u./mL (1 mL ampoule, 5 mL vial) J/8.2/406
Heparin Sodium-Fresenius 25 000 i.u./mL (5 mL vial) J/8.2/407
Heparin Sodium-Fresenius 12 500 i.u./mL (1 mL ampoule) J/8.2/408

NAME AND BUSINESS ADDRESS OF APPLICANT:
BODENE (PTY) LTD trading as Intramed, 6 Gibaud Road’
Port Elizabeth, 6001, South Africa

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
August 1984

        12-142/07-02(574)
        Pro-Print

Updated on this site: March 2005
Source: State Hospital Pharmacy

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