- For the treatment of thrombo-embolic disorders such as deep vein thrombosis, acute arterial embolism or thrombosis, thrombophlebitis, pulmonary embolism and fat embolism;
- For prophylaxis against deep vein thrombosis and thrombo-embolic events in susceptible patients;
- For the prevention of clotting in the extracorporeal circuit during haemodialysis

For the treatment or prevention of thrombo-embolic disorders:
For intravenous or subcutaneous injection
Treatment dosage: Intravenous administration
5,000 – 10,000 i.u. every four hours or 500 i.u./kg bodyweight as continuous infusion in Sodium Chloride Injection or Dextrose Injection. However, the dose should be monitored with coagulation tests performed just before each administration and varied according to individual response.
Subcutaneous administration:
Initial dose is 250 i.u./kg bodyweight and further dose should be given every 12 hours and the dose should be monitored with coagulation tests and individually adjusted.
Dosage adjustment:
It is recommended that dosages be adjusted to maintain a thrombin clotting time, whole blood clotting time or activated partial thromboplastin time 1.5 to 2 times that of control on blood withdrawn 4 - 6 hours after the first injection or commencement of infusion and at similar intervals until the patient is stabilised.

Prophylactic dosage:
Administration is by subcutaneous injection.
Patients undergoing major elective surgery:
5,000 i.u. should be given 2 hours pre-operatively and every 8-12 hours post- operatively for 10-14 days or until the patient is mobile, whichever is the longer.
Following myocardial infarction:
5,000 i.u. should be given twice daily for 10 days or until the patient is ambulant.
Other patients:
5,000 i.u. should be given every 8-12 hours.
These standard prophylactic regimens do not require routine control.
Dosage in children
Treatment dosage:
Standard treatment dosages should be given initially. Subsequent dosages and/or dosage intervals should be individually adjusted according to changes in thrombin clotting time, whole blood clotting time and/or activated partial thromboplastin time.
Dosage in the elderly
Treatment dosage:
Lower treatment dosages may be required. However, standard treatment dosages should be given initially and then subsequent dosages and/or dosage intervals should be individually adjusted according to changes in thrombin clotting time, whole blood clotting time and/or activated partial thromboplastin time.

 

Prophylactic dosage:
Dosage adjustments are unlikely for prophylaxis in the elderly.
Pregnancy:
This heparin formulation contains the preservative benzyl alcohol. The use of this formulation should be avoided in pregnancy as benzyl alcohol may cross the placenta. If use is considered essential, the dosage recommendations given in this section should be followed.

Treatment dosage:
Standard treatment dosages should be given initially by continuous intravenous infusion, or every 12 hours by subcutaneous injection. Intermittent intravenous injections are not advised. Subsequent dosages and/or dosage intervals should be individually adjusted according to changes in thrombin clotting time, whole blood clotting time and/or activated partial thromboplastin time.
Prophylactic dosage:
A plasma heparin level is recommend to be maintained below 0.4 i.u./ml as determined by specific anti-Xa assay. A recommended dosage is 5,000 i.u. every 12 hours in early pregnancy increasing to 10,000 i.u. every 12 hours in the last trimester. The dosage should be reduced during labour and the standard prophylactic dosage is suitable in the puerperium.
For the prevention of clotting during haemodialysis:
An initial bolus dose should be given, followed by a continuous intravenous infusion.
Adults:
Initially: 1,000 - 5,000 i.u.
Maintenance: 1,000 - 2,000 i.u. per hour, adjusted to maintain clotting time > 40 minutes.
 

Contraindicated in patients known to have hypersensitivity to heparin and its constituents. Heparin-induced thrombocytopenia. Generalised or local haemorrhagic tendency, including uncontrolled severe hypertension, severe liver insufficiency, active peptic ulcer, acute or subacute septic endocarditis, intracranial haemorrhage or injuries and operations on the central nervous system, eyes and ears, and in women with abortus imminens. Heparin without preservatives should be used in premature infants (see Section 4.6). An epidural anaesthesia during birth in pregnant women treated with heparin is contraindicated (see Section 4.6). In patients receiving heparin for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contra-indicated because the use of heparin may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis.

Heparin should be used with caution in patients with hypersensitivity to low molecular weight heparin, patients with increased risk of bleeding complications, hypertension, and renal or hepatic insufficiency.
Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium or taking potassium sparing drugs. The risk of hyperkalaemia seems to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly afterward particularly if treatment is continued more than 7 days.
Generally, drugs affecting platelet function or the coagulation system should not be given concomitantly with heparin (see Section 4.5).
In patients undergoing peridural or spinal anaesthesia or spinal puncture, the prophylactic use of heparin may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis. The risk is increased by the use of a peridural or spinal catheter for anaesthesia, by the concomitant use of drugs affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors or anticoagulants, and by traumatic or repeated puncture.
In decision making on the interval between the last administration of heparin at prophylactic doses and the placement or removal of a peridural or spinal catheter, the product characteristics and the patient profile should be taken into account. Subsequent dose should not take place before at least four hours have elapsed. Re- administration should be deferred until the surgical procedure is completed.
Should a physician decide to administer anti-coagulation in the context of peridural or spinal anaesthesia, extreme caution and frequent monitoring must be applied to detect any signs and symptoms of neurologic impairment, such as back pain, sensory and motor deficits and bowel or bladder dysfunction. Patients should be instructed to inform immediately a nurse or a clinician if they experience any of these.
The intramuscular route cannot be recommended because of high incidence of haematoma.
Care should be taken when giving concomitant intramuscular injections, lumbarAs there is a risk of antibody-mediated heparin-induced thrombocytopenia, 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.
Heparin induced thrombocytopenia and heparin induced thrombocytopenia with thrombosis can occur up to several weeks after discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.
The formulation contains preservative, benzyl alcohol 10 mg/ml. This product should be administered with caution to infants and children up to 3 years old, as there is a risk that benzyl alcohol may cause toxic reactions and allergic reactions (anaphylactoid) in this age group.

Drugs (such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, thrombolytic agents, vitamin K antagonists and activated protein C) that interfere with platelet-aggregation reactions may induce bleeding and should be used with caution in patients receiving heparin.
Combined use with ACE inhibitors or angiotensin II antagonists may increase the risk of hyperkalaemia.
Use of glyceryl trinitrate infusion may reduce the anticoagulant effect of heparin.

Heparin should be used with caution in pregnant women and only if the benefits outweigh the risks according to the physician's judgement due to the known haemorrhagic effect. Precaution is particularly required because of uteroplacental haemorrhage, especially at the time of delivery. If epidural anaesthesia is envisaged, whenever possible, heparin treatment should be suspended.
The formulation contains 10 mg/ml of the preservative benzyl alcohol. Cases of “Gasping Syndrome” have occurred in premature infants when large amounts of benzyl alcohol have been administered (99-404 mg/kg/day). Therefore the use of this formulation in premature is contraindicated (see Section 4.3).
Benzyl alcohol may cross the placenta; hence the use of this formulation should be avoided during pregnancy.

The use of heparin in women with abortus imminens is contraindicated (see Section 4.3).
Heparin does not cross the placental barrier and is not secreted into breast milk.

Negligible or no influence on the ability to drive or use machines.

Very common >1/10
Common >1/100 and <1/10 Uncommon >1/1,000 and <1/100 Rare >1/10,000 and <1/1,000
Very rare <1/10,000
The most frequently reported undesirable effects are bleeding events, reversible increase in liver enzymes, reversible thrombocytopenia and various skin reactions. Isolated reports of generalised allergic reactions, skin necrosis and priapism have been reported.
• Blood and lymphatic system disorders
Heparin can cause thrombocytopenia either through a direct effect or through an immune effect producing a platelet-aggregating antibody (see Section 4.4). The effect is reversible after withdrawal of administration.

Common: Thrombocytopenia type I
Rare: Thrombocytopenia type II, probably of an immunoallergic nature (see section 4.4)
In some cases thrombocytopenia type II has been accompanied by venous or arterial thrombi.
• Immune system disorders
Rare: Allergic reactions of all types and severities, with various manifestations Very rare: Anaphylactoid reactions and anaphylactic shock

• Metabolism and nutrition disorders
Rare: Hypoaldosteronism. Heparin products can cause hypoaldosteronism, which may result in an increase in plasma potassium. Rarely, clinically significant hyperkalaemia may occur particularly in patients with chronic renal failure and diabetes mellitus (see Section 4.4).
• Vascular disorders Common: Haemorrhage
Haemorrhages may affect any organ, particularly in connection with high doses. In some cases haemorrhage has resulted in death or permanent disability.
Very rare cases of epidural and spinal haematoma have been reported in patients receiving heparin for prophylaxis undergoing spinal or epidural anaesthesia or spinal puncture (see Section 4.4).
• Hepatobiliary disorders
Common: Raised transaminases, gamma-GT, LDH and lipase levels. They are reversible after drug withdrawal.
• Skin and subcutaneous tissue disorder
Uncommon: Rash (various types of rash such as erythematous and maculopapular), urticaria, pruritus.
Rare: Skin necrosis. Treatment must be withdraw immediately upon occurance.
One case of erythema multiforme was also reported.
• Musculoskeletal and connective tissue disorders
Uncommon: Osteoporosis has been reported in connection with long-term heparin treatment.
• Reproductive system and breast disorders Very rare: Priapism

• General disorders and administration site conditions
Common: Injection site reactions; local irritation may occur when injected subcutaneously
To reports any side effect(s):
 The National Pharmacovigilance Centre (NPC):
 Fax: +966-11-205-7662
 Call NPC at +966-11-2038222, Ext 2317-2356-2340
 SFDA Call Center: 19999
 E-mail: npc.drug@sfda.gov.sa
 Website: https://ade.sfda.gov.sa/

Bleeding may be a complication of therapy.
Slight epistaxis, occasional red cells in the urine, and bruising are signs of overdosage. Withdrawing the drug can usually treat slight haemorrhage due to overdosage. Severe bleeding may be reduced by the administration of protamine sulphate.
The effect of heparin can be reversed immediately by intravenous administration of 1% protamine sulphate solution. The injection should be given very slowly (over one to three minutes). The quantity of protamine required for neutralization falls rapidly with the lapse of time after the administration of heparin. If given within 15 minutes of the heparin injection 10 mg of protamine will neutralize 1,000 i.u. of heparin.
It is important to avoid over dosage of protamine sulphate because protamine itself has anticoagulant properties.
The dosage should not exceed the equivalent of 50 mg protamine sulphate. Intravenous injection of protamine may cause a sudden fall in blood pressure, bradycardia, dyspnoea, and transitory flushing, but these may avoided or diminished by slow administration.

Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with anti-thrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin.

The increase in clotting time provided by heparin becomes apparent immediately after administration and lasts for four to six hours after intravenous injection and for about eight hours after subcutaneous injection.

Not applicable

Sodium Chloride, Benzyl Alcohol, Water for Injection

Heparin has been reported to be incompatible in aqueous solution with certain substances, e.g. some antibiotics, hydrocortisone, phenothiazines, narcotic analgesics and some antihistamines.

The shelf life is 3 years. The expiry date is printed on the label and box. The expiry date is marked with the letters EXP.

Do not store above 30oC.
If withdrawal of injection solution from the container is performed under aseptic conditions, a vial can be stored over up to 14 days after the first use. The date of first withdrawal must be noted on the label.
Not to be used if solution is not clear.

The 5ml sterile, clear solution is packed in ISO Glass Vial Clear 6R (USP Type 1) with grey rubber plug and flip off by plastic aluminium seal.

Not applicable