HEPARIN SODIUM ROVI 5 000 IU/ML SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Heparin Sodium ROVI 5,000 IU/mL solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Heparin Sodium ROVI 5000 IU/mL solution for injection

Each mL contains 5,000 IU of heparin sodium.

Each vial contains 5 mL. One vial contains 25000 IU of heparin sodium.

Excipient(s) with known effect:

Each mL contains 10 mg of benzyl alcohol.

Each 5,000 IU/mL vial contains 14 mg sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

Colourless or slightly yellowish, clear solution, free of visible particles.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

– Prophylaxis of deep vein thrombosis and pulmonary embolism,

– Treatment of deep vein thrombosis and pulmonary embolism, unstable angina pectoris and acute peripheral arterial occlusion,

– Prophylaxis of mural thrombosis following myocardial infarction,

– Use in extracorporeal circulation and haemodialysis.

4.2 Posology and method of administration

Method of administration

By continuous intravenous infusion or by intermittent intravenous injection or by subcutaneous injection. The intravenous injection volume of heparin injection should not exceed 15 mL. As the effects of heparin are short-lived, administration by intravenous infusion or subcutaneous injection is preferable to intermittent intravenous injections.

Posology

Prophylaxis of deep vein thrombosis and pulmonary embolism

Adults:

2 hours pre-operatively:                   ­5,000 IU subcutaneously

followed by:                             ­5,000 IU 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.

Elderly:

Dosage reduction and monitoring of APTT may be advisable.

Paediatric population:

No dosage recommendations.

Treatment of deep vein thrombosis and pulmonary embolism Adults:

Elderly:

Dosage reduction may be advisable.

Children and small adults:

Treatment of unstable angina pectoris and acute peripheral arterial occlusion

Adults:

Loading dose:                           ­5,000 IU intravenously

Maintenance:

1,000–2,000 IU/hour by intravenous infusion, or 5,000–10,000 IU 4-hourly by

intravenous injection

Elderly:

Dosage reduction may be advisable.

Children and small adults:

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.

Prophylaxis of mural thrombosis following myocardial infarction

Adults:

12,500 IU 12-hourly subcutaneously for at least 10 days.

Elderly:

Dosage reduction may be advisable.

In extracorporeal circulation and haemodialysis:

Adults:

Cardiopulmonary bypass:

Initially 300 IU/kg intravenously, adjusted thereafter to maintain the activated clotting time (ACT) in the range 400–500 seconds.

Heparin resistance

Patients with altered heparin responsiveness or heparin resistance may require disproportionately higher doses of heparin to achieve the desired effect. Also refer to section 4.4, Special warnings and precautions for use.

4.3 Contraindications

Hypersensitivity to the active substance (s) or to any of the excipients listed in section 6.1.

This heparin formulation contains the preservative benzyl alcohol and so must not be given to children under 3 years old, premature babies or neonates. As benzyl alcohol may cross the placenta the use of this formulation must be avoided in pregnancy.

Current (or history of) immune-mediated heparin-induced thrombocytopenia.

An epidural anaesthesia during birth in pregnant women treated with heparin is contraindicated.

Regional 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.

Generalised or local haemorrhagic tendency.

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, preexisting 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 peri-dural 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 peri-dural or spinal catheter for anaesthesia, by the concomitant use of drugs affecting haemostasis such as non-steroidal anti-inflammatory drugs, 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 peri-dural 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 peri-dural 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 heparin induced thrombocytopenia and heparin induced thrombocytopenia with thrombosis.

This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

Heparin sodium ROVI contains benzyl alcohol (10mg/ml) as preservative.

Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in neonates (“gasping syndrome”). The minimum amount of benzyl alcohol at which toxicity may occur is not known. High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

4.5 Interaction with other medicinal products and other forms of interaction Heparin may prolong the one stage prothrombin time. Accordingly, when Heparin is given with dicoumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose of heparin should elapse before blood is drawn, if a valid prothrombin time is to be obtained.

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 antiinflammatory 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.

Nitrates: Reduced activity of heparin has been reported with simultaneous intravenous glyceryl trinitrate infusion.

4.6 Fertility, pregnancy and lactation

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 Sodium ROVI has no influence on the ability to drive and use machines.

4.8 Undesirable effects

The following adverse reactions have been observed and reported during treatment with Heparin sodium with the following frequencies: Very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10000 to < 1/1000); very rare (<1/10 000), not known (cannot be estimated from available data).

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.

Haemorrhage:

Haemorrhage is the chief complication that may result from heparin therapy. An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug. It should be appreciated that gastrointestinal or urinary tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific haemorrhage complications may be difficult to detect.

Adrenal haemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be discontinued in patients who develop signs and symptoms of acute adrenal haemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient's death.

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 at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Pharmacotherapeutic group: Antithrombotic agents, ATC code: B01AB01

Heparin 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

Absorption

Heparin is not absorbed from the gastrointestinal tract. Heparin is administered by injection.

Distribution

Heparin binds extensively to plasma proteins.

Elimination

Heparin and its metabolites are excreted in the urine.

The half-life of heparin depends on the dose administered, the route of administration and is subject to wide inter- and intra-individual variation.

5.3 Preclinical safety data

There are no pre-clinical data of relevance which are additional to those already included in other sections of the data sheet.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Benzyl alcohol

Sodium hydroxide (for pH adjustment)

Water for injections

6.2 Incompatibilities

Heparin sodium should not be mixed with other solutions for injection and/or infusion.

6.3 Shelf life

3 years.

Once the vial has been opened, administer the product immediately.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Type I glass vials, with bromobutyl stopper and aluminium capsule.

Heparin Sodium ROVI 5,000 IU/mL solution for injection: 5 mL vials in packs of 10 or 100 vials.

Not all pack sizes may be marketed

6.6 Special precautions for disposal

Only use if the solution is clear and colourless, and free of visible particles.

Any unused medicinal product or waste materials should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Laboratorios Farmacéuticos ROVI S.A,

Julián Camarillo, 35

28037 – Madrid

Spain

8 MARKETING AUTHORISATION NUMBER(S)

PL 15406/0017