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Product Summary

1.    Trade Name of the Medicinal Product

HEPARIN MUCOUS INJECTION BP

2.    Qualitative and Quantitative Composition

Each ml contains Heparin Sodium 1,000 IU.

3.    Pharmaceutical Form

Solution for Injection.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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.

4.2    Posology and method of administration

For the treatment or prevention of thrombo-embolic disorders:

For intravenous or subcutaneous injection.

Treatment Dosage:

Intravenous administration

5,000 - 10,000 IU every 4 hours or 500 IU/kg bodyweight daily as a continuous infusion in sodium chloride injection or dextrose injection. Doses should be individually adjusted according to coagulation tests.

Subcutaneous administration

The initial dose is 250 IU/kg bodyweight. Further doses should be given every 12 hours and individually adjusted according to coagulation tests.

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time, whole blood clotting time or activated partial thromboplastin time 1.5 to 2 times that of control on blood withdrawn 4 - 6 hours after the first injection or commencement of infusion and at similar intervals until the patient is stabilised.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    IU should be given 2 hours pre-operatively and then every 8 - 12 hours postoperatively for 10 - 14 days or until the patient is ambulant, whichever is the longer.

Following myocardial infarction:

5.000    IU should be given twice daily for 10 days or until the patient is mobile.

Other patients:

5.000    IU 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 alterations are unnecessary for prophylaxis in the elderly.

Pregnancy

This heparin formulation contains the preservative benzyl alcohol. As benzyl alcohol may cross the placenta the use of this formulation should be avoided in pregnancy. 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:

It is recommended that plasma heparin levels be maintained below 0.4 IU/ml as determined by specific anti-Xa assay. A suggested dosage is 5,000 IU every 12 hours in early pregnancy increasing to 10,000 IU 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 IU.

Maintenance: 1,000 - 2,000 IU per hour, adjusted to maintain clotting time > 40 minutes.

4.3 Contraindications

Known hypersensitivity to constituents.

Current or history of 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 (Mucous) Injection contains 10 mg/ml of the preservative benzyl alcohol. This formulation must not be given to premature babies or neonates (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.

4.4 Special warnings and precautions for use

Heparin should be used with caution in patients with hypersensitivity to low molecular weight heparin.

Care should be taken when heparin is administered to patients with increased risk of bleeding complications, hypertension, renal or hepatic insufficiency.

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, 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 hyperkalaemia 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 monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days.

Drugs affecting platelet function or the coagulation system should in general 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 antiinflammatory 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 delayed until the surgical procedure is completed.

Should a physician decide to administer anti-coagulation in the context of peridural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised 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.

Heparin should not be administered by intramuscular injection due to the risk of haematoma.

Due to increased bleeding risk, care should be taken when giving concomitant intramuscular injections, lumbar puncture and similar procedures.

As 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.

Heparin (Mucous) Injection contains the preservative benzyl alcohol 10mg/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.

Heparin (Mucous) Injection contains esters of parahydroxybenzoates as a preservative system. These may cause allergic reactions (possibly delayed), and exceptionally, bronchospasm.

4.5 Interaction with other medicinal products and other forms of interaction

The anticoagulant effect of heparin may be enhanced by concomitant medication with other drugs affecting platelet function or the coagulation system, e.g. platelet aggregation inhibitors, thrombolytic agents, salicylates, non-steroidal anti-inflammatory drugs, vitamin K antagonists, dextrans, activated protein C. Where such combination cannot be avoided, careful clinical and biological monitoring is required.

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.

Because of the known haemorrhagic effect, heparin should be used with caution in pregnant women and only if the benefits outweigh the risks according to the physician’s judgement. Precaution is particularly required because of uteroplacental haemorrhage, especially at the time of delivery. If epidural anaesthesia is envisaged, heparin treatment should be suspended, whenever possible.

Heparin (Mucous) Injection 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 newborns (especially in preterm babies) is contraindicated (see Section 4.3).

As benzyl alcohol may cross the placenta, 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 excreted in breast milk.

4.7 Effects on ability to drive and use machines

Heparin has no or negligible influence on the ability to drive or use machines.

4.8 Undesirable effects

Very common Common Uncommon Rare

Very rare

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). Reversible after drug withdrawal.

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. If this occurs treatment must be withdrawn

immediately.

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

4.9 Overdose

Bleeding is the main sign of overdose with heparin. As heparin is eliminated quickly, a discontinuation of treatment is sufficient in case of minor haemorrhages. In case of severe haemorrhages heparin may be neutralised with protamine sulphate injected slowly intravenously. One mg of protamine sulphate neutralises approximately 100 IU of heparin. Nevertheless, the required protamine sulphate dose varies according to the time of heparin administration and the dose administered.

It is important to avoid overdosage of protamine sulphate because protamine itself has anticoagulant properties. A single dose of protamine sulphate should never exceed 50 mg.

Intravenous injection of protamine may cause a sudden fall in blood pressure, bradycardia, dyspnoea and transitory flushing, but these may be avoided or diminished by slow and careful administration.

Pharmacological Properties

5.1. Pharmacodynamic Properties

Heparin is a naturally occurring anticoagulant which prevents the coagulation of blood in-vivo and in-vitro. It potentiates the inhibition of several activated coagulation factors, including thrombin and factor X.

5.2. Pharmacokinetic Properties

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.

5.3. Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Pharmaceutical Particulars

6.1. List of Excipients

Benzyl alcohol, Methylparahydroxybenzoate Propylparahydroxybenzoate, Sodium citrate dihydrate, Sodium chloride and Water for Injections.

6.2.    Incompatibilities

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

6.3.    Shelf Life

3 years.

6.4.    Special Precautions    for Storage

Store below 25°C.

5 x 5 ml vials 10 x 5 ml vials 50 x 5 ml vials

6.6. Instruction for Use/Handling

From a microbiological point of view, once opened, the product may be stored for a maximum of 14 days below 25°C. Other in use storage times and conditions are the responsibility of the user.

7    MARKETING AUTHORISATION HOLDER

LEO Laboratories Limited

Horizon

Honey Lane

Hurley

Maidenhead

Berkshire

SL6 6RJ

UK

8.    MARKETING AUTHORISATION NUMBER(S)

PL 0043/0041R.

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03 December 1975 / 25^th January 1996

10 DATE OF REVISION OF THE TEXT

02/12/2013