Revasc - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Revasc 15mg/0.5ml powder and solvent for solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 15 mg desirudin.

After reconstitution one vial contains 15 mg** desirudin* per 0.5 ml

Desirudin consists in a single chain polypeptide of 65 amino acid residues and 3 disulphide bridges.

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• * produced by recombinant DNA technology in yeast cells.

• * * corresponding to approximately 270,000 antit­hrombin units (ATU) or 18,000 ATU per mg of desirudin with reference to the WHO Second International Standard for alpha-thrombin.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

White powder and clear, colourless solvent for solution for injectio

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Prevention of deep venous thrombosis in patients undergoing elective hip or knee replacement surgery.

4.2 Posology and method of administration

Treatment with Revasc should be initiated under the guidance of a physician with experience in coagulation disorders. Instructions for the preparation of Revasc are provided in section 6.6.

Adult and elderly patien tsX^

The recommended dose is 15 mg twice daily. The first injection should be initiated 5 to 15 minutes before surgery but after induction of regional block anaesthesia, if used. Treatment with desirudin is then continued twice daily post-operatively for 9 days up to a maximum of 12 days or until the patient is fully ambulant, whichever occurs first. Currently, there is no clinical experience to support the use of desirudin beyond 12 days.

Administration is by subcutaneous injection, preferably at an abdominal site. Injections should be rotated between at least four different sites.

Children

There is no experience in children.

Patients with renal impairment

Desirudin is contraindicated in patients with severe renal impairment (creatinine clearance of less than 30ml/min corresponding to a serum creatinine > 2.5mg/dl or 221^mol/l; see section 4.3). In patients with mild or moderate renal impairment (creatinine clearance between 31 and 90 ml/min; see section 4.4) activated partial thromboplastin time (aPTT) should be monitored.

Patients with liver impairment

Desirudin is contraindicated in severe hepatic impairment (see section 4.3). In patients with mild to moderate liver impairment (see section 4.4) aPTT monitoring is recommended.

4.3 Contraindications

Desirudin is contraindicated in patients:

• – with hypersensitivity to the active substance or to any of the excipients – with active bleeding and/or irreversible coagulation disorders – with severe renal and hepatic impairment – during pregnancy (see section 4.6)

• – with severe uncontrolled hypertension and subacute bacterial endocarditis

4.4 Special warnings and precautions for use

Warnings

Anaphylaxis: Revasc may cause allergic reactions including anaphylaxis and shock (see section 4.8). Fatal anaphylactic reactions have been reported in patients re-exposed to hirudin product therapy in a second or subsequent treatment course. Although fatal reactions have not been reported with desirudin, alternative treatment options must be considered before the decision to re-expose a patient to Revasc. As these reactions are immune-mediated, patients with previous exposure to hirudin or hirudin analogue may be at an increased risk. Treatment initiation with Revasc should be undertaken only in a setting where medical assistance is readily available and where there is access to treatment for anaphylactic reactions. Patients should be informed that they have received Revasc.

Desirudin should not be administered by intramuscular injection owing to the risk of local haematoma.

Desirudin should be used with caution in conditions with increased risks of haemorrhage such as major surgery, biopsy or puncture of a non-compressible vessel within the last month; a history of haemorrhagic stroke, intracranial or intraocular bleeding including diabetic (haemorrhagic) retinopathy; a cerebral ischaemic attack within the last 6 months, a known haemostatic disorder (congenital or acquired, e.g. haemophilia, liver disease) or a history of gastrointestinal or pulmonary bleeding within the past 3 months.

Precautions

When desirudin is administered in patients with increased risk of bleeding complications, mild to moderate hepatic dysfunction and/or mild to moderate renal impairment, aPTT should be monitored and peak aPTT should not exceed twice the control value. If necessary, therapy with desirudin should be interrupted until aPTT returns to less than twice the control value at which time treatment with desirudin can be resumed at a reduced dose.

Desirudin should be used with care in patients receiving anticoagulants, and/or platelet inhibitors, and/or non-steroidal anti-inflammatory medicinal products. Monitoring for evidence of bleeding is advised (see section 4.5). The concomitant use of desirudin with thrombolytics and ticlopidine has not been investigated in this patient population.

The anticoagulant effect of desirudin is poorly reversible. aPTT levels can, however, be reduced by intravenous administration of DDAVP (desmopressin).

Laboratory Tests : Activated partial thromboplastin time (aPTT) should be monitored in patients with increased risk of bleeding and/or renal or hepatic impairment. Peak aPTT should not exceed twice the control value. If necessary, therapy with desirudin should be interrupted until aPTT falls to less than twice the control at which time treatment with desirudin can be resumed at a reduced dose (see also section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Any agent which may enhance the risk of haemorrhage should be discontinued prior to initiation of desirudin therapy. If co-administration cannot be avoided, close clinical and laboratory monitoring should be conducted (see section 4.4).

During prophylaxis, concomitant use of medicinal products containing heparins (unfractionated and low-molecular weight heparins) and dextrans is not recommended. The effects of desirudin and unfractionated heparins on prolongation of aPTT have been shown to be additive (see section 4.4).

As with other anticoagulants desirudin should be used with caution in conjunction with medicinal products which affect platelet function these medicinal products include: acetylsalicylic acid and NSAIDs, ticlopidine and clopidogrel, glycoprotein IIb/IIIa antagonists (abciximab, eptifibatide, tirofiban) and iloprost.

If a patient is switched from oral anticoagulants to desirudin therapy or from desirudin to oral anticoagulants, the anticoagulant activity should continue to be closely monitored with appropriate methods. That activity should be taken into account in the evaluation of the overall coagulation status of the patient during the switch (see section 4.2).

• 4.6 Pregnancy and lactation

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

In controlled clinical trials investigating desirudin 15 mg twice daily and a standard dose of unfractionated heparin, the nature of the hip surgery operation and the mode of action of the two drugs studied account for most of the adverse experiences reported. As with other anticoagulants, bleeding is the most common adverse reaction.

The following related adverse reactions were listed below by system organ class and within each frequency grouping, adverse reactions are presented in order of decreasing seriousness: common (> 1/100 to <1/10); uncommon (> 1/1,000 to <1/100); rare (> 1/10,000 to <1/1,000).

Investigations

Uncommon :      Increase in serum transaminases

4.9 Overdose

There is no antidote for desirudin. Overdosage of desirudin could lead to bleeding complications. In such cases desirudin should be discontinued. If necessary, plasma expanders and/or blood transfusion may be used.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anticoagulant, ATC code: B01AE01

Mechanism of action

Desirudin is a highly potent and selective inhibitor of free circulating and clot-bound thrombin. A mean peak aPTT prolongation of around 1.4 times baseline value is observed following a subcutaneous (SC) b.i.d. injection of 15mg desirudin. At therapeutic serum concentrations it has no effect on other enzymes of the haemostatic system such as factors IXa, Xa, kallikrein, plasmin, tPA, or activated protein C. In addition, it does not display any effect on other serine proteases, such as the digestive enzymes trypsin or chymotrypsin, or on complement activation by the classical or alternative pathways.

In two controlled double blind clinical trials, the overall rate of thromboembolic events in patients treated with desirudin 15mg s.c. b.i.d. (N=370) was half that in patients treated with a standard dose of unfractionated heparin (N=396) (p<0.0001); the rate of proximal deep venous thrombosis was only one fifth that observed with the heparin (p<0.0001). To date clinical data are available on hip surgery only.

Pharmacodynamic effects

The anticoagulant properties of desirudin are demonstrated by its ability to prolong the clotting time of human or rat plasma whether induced directly (thrombin time) or via the intrinsic (aPTT) or extrinsic (PT) pathways. Desirudin has no profibrinolytic activity.

5.2 Pharmacokinetic properties

Absorption

Mean absorption time of subcutaneous (SC) desirudin is 4.1, 4.5 and 5.4 h for dose levels of 0.1, 0.3 and 0.5 mg/kg, respectively (overall mean = 4.6 h). Absorption is complete based on mean area under the curve (AUC) values.

Following administration of single SC doses of 0.1–0.75 mg/kg, plasma concentrations of desirudin increased rapidly to maximum levels (Cmax) between 1 and 3 h. Both Cmax and AUC values are dose proportional.

^^^Distribution

Desirudin is distributed in the extracellular space with a distribution volume at steady state of 0.251/kg independently of the dose.

Metabolism and elimination

The disappearance of desirudin from plasma is rapid in the first phase with approximately 90% of an intravenous (IV) bolus dose disappearing from the circulation within 2 hours of the injection. A slower terminal elimination phase follows with a dose-independent mean terminal elimination halflife of 2 to 3 h. The mean residence times are 1.7–2 h and 6–7 h after IV and SC administration, respectively.

The total urinary excretion of unchanged desirudin amounts to 40–50 % of the administered dose. Metabolites lacking one or two C-terminal amino acids constitute a minor proportion of the material recovered from urine (<7%). In vitro and in vivo animal data indicate that desirudin is for the most part eliminated and metabolised by the kidney. Hepatic elimination of desirudin or the thrombin-desirudin complex does not appear to be significant.

5.3 Preclinical safety data

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life 3 years.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C when reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not store above 25°C.

Keep the vial and ampoule in the outer carton in order to protect from light.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container 15mg of powder in a vial (Type I glass) with stopper (butyl rubber) covered with a film (fluoropolymer) in the product side and 0.5ml of solvent in an ampoule (Type I glass).

Pack size of 1, 2 or 10.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

To prepare the reconstituted aqueous solution, 0.5ml of the accompanying mannitol solvent is added under aseptic conditions to the vial containing the powder for solution for injection. The active substance is rapidly redispersed by shaking gently producing a clear solution.

The reconstituted solution should be used as soon as possible (see section 6.3 above).

Any unused product or waste material should be disposed in accordance with local requirements.

Do not use reconstituted vials containing visible particles.

7. MARKETING AUTHORISATION HOLDER

Canyon Pharmaceuticals Limited 7th Floor

52–54 Gracechurch Street

London EC3V 0EH

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)EU/l/97/043/001EU/1/97/043/002EU/1/97/043/003

2 vials/2 ampoules of solvent

10 vials/10 ampoules of solvent

1 vial/1 ampoule of solvent