4 Annex I Summary of Product Characteristics

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

4 1. NAME OF THE MEDICINAL PRODUCT

Revasc 15 mg powder and solvent for solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of Revasc powder and solvent for solution for injection contains 15 mg desirudin (INN) 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 α-thrombin. Desirudin is a recombinant DNA product derived from yeast cells.

Desirudin is a single chain polypeptide consisting of 65 amino acid residues and 3 disulphide bridges.

Vials of desirudin are supplied with solvent ampoules containing pyrogen-free Mannitol Ph. Eur. in Water for injections Ph. Eur.

3. PHARMACEUTICAL FORM

Powder for injection to be reconstituted prior to subcutaneous injection with 0.5 ml mannitol solvent for solution (3%) which is supplied with the product.

4. CLINICAL PARTICULARS

4.1 THERAPEUTIC INDICATIONS

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

4.2 POSOLOGY AND METHOD OF ADMINISTRATION

Adult and elderly patients

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 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 clinical experience with desirudin in children.

Patients with renal impairment

5 Desirudin is contraindicated in patients with severe renal impairment (creatinine clearance of less than 30 ml/min corresponding to a serum creatinine > 2.5 mg/dl or 221 μmol/l). In patients with moderate renal impairment (creatinine clearance between 31 and 60 ml/min; see Precautions) activated partial thromboplastin time (aPTT) should be monitored.

Patients with liver impairment

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

4.3 Contra-indications

Desirudin is contraindicated in patients with known hypersensitivity to natural or recombinant hirudins, in patients with active bleeding and/or irreversible coagulation disorders, in severe renal and hepatic impairment and during pregnancy (see Pregnancy and lactation). Desirudin is also contraindicated in patients with severe uncontrolled hypertension and subacute bacterial endocarditis.

4.4 Special warnings and special precautions for use

Warnings

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

Desirudin, like other anticoagulants, 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. antithrombin III, protein C or protein S deficiencies, liver disease) or a history of gastrointestinal or pulmonary bleeding within the past 3 months.

Precautions aPTT should be monitored in patients with increased risk of bleeding complications, hepatic dysfunction and/or moderate renal impairment and in combined therapy with oral anticoagulants. In these patients peak aPTT should not exceed 85 seconds or twice the upper limit of the normal aPTT range. If necessary, therapy with desirudin should be interrupted until aPTT falls within this therapeutic range 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 drugs. Monitoring for evidence of bleeding is advised (see Interactions). The concomitant use of desirudin with thrombolytics and ticlopidine has not been investigated in this patient population.

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

4.5 Interaction with other medicinal products and other forms of interaction

6 During prophylaxis, concomitant medication with 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.

Desirudin prolongs prothrombin time (PT). When desirudin is given with oral anticoagulants, a period of at least 24 hours should elapse after the last dose of desirudin before blood is drawn to obtain a valid PT. Whilst desirudin and an oral anticoagulant are being administered concurrently, aPTT and PT should be monitored until the oral anticoagulant has entered its therapeutic range as measured by INR. Desirudin should then be discontinued.

As with other anticoagulants desirudin should be used with caution in conjunction with drugs which affect platelet function such as acetylsalicylic acid and other non-steroidal anti- inflammatory drugs.

4.6 Use during pregnancy and lactation

Desirudin is contraindicated during pregnancy; i.e. pregnancy must be excluded and a pregnancy test performed in women of childbearing age. Birth defects in animal experiments, characterized by spina bifida in rabbits and omphalocele in rats, were seen at doses comparable to or above the human therapeutic dose range and were causally related to the administration of desirudin. It is not known whether desirudin is excreted in human milk. However, lactating mothers should be advised to avoid breast feeding or alternative drugs used.

4.7 Effects on ability to drive and use machines

Unknown.

4.8 Undesirable effects

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 in controlled clinical trials investigating desirudin 15 mg twice daily and a standard dose of unfractionated heparin. As with other anticoagulants, bleeding is the most common adverse experience. All adverse experiences irrespective of trial drug relationship and reported with an incidence of more than 1.0 % are by decreasing order of frequency the following:

Bleeding episodes, nausea, wound secretion, fever, injection site mass, haematomas, anaemia, hypotension, urinary retention, deep thrombophlebitis, hypokalaemia, insomnia, vomiting, hyperpyrexia, constipation, oedema in legs, urinary tract infection, cystitis, dizziness, haematuria, joint dislocation, pain in legs, pain, dyspnoea, impaired wound healing, hypertension and oliguria.

Other adverse experiences reported with a frequency equal or below 1% included: epistaxis, abdominal and chest pain, confusion, haematemesis, increases in serum transaminases, rash and urticaria.

Allergic reactions have been reported in the same proportion (1.6 %) of patients treated with desirudin (N=2,367) or with unfractionated heparin (N=1,134) in clinical trials, regardless of causality. Very rarely anti-hirudin antibodies have been detected upon reexposure to desirudin.

7 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 PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anticoagulant, ATC code: B01 AX.

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 15 mg 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 15 mg 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 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 0.25 l/kg independently of the dose.

Metabolism and elimination 8

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 half-life 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 constitutes 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.

Total clearance of desirudin has been found to be in the same range following either SC or IV administration (ca 1.95-2.20 ml/min/kg) and was dose-independent. The total and renal clearances of desirudin are slightly reduced in elderly subjects compared to young volunteers. This decrease can be considered unlikely to be of clinical significance, thus allowing no dose reduction.

5.3 Preclinical safety data

General toxicology studies with a variety of laboratory animal species have not displayed any evidence of target organ or systemic toxicity. Doses were limited by the pharmacological activity of desirudin, which was characterised by bleeding at the sites of injection and in some organs resulting from the inhibition of blood clotting activity. A low grade vasculitis and fibrinoid necrosis were only observed in the dog. These effects were associated with a low and inconsistent presence of antibodies specific to desirudin in the dog and as such they have been attributed to a dog specific immunological reaction. No such antibodies were found in rabbits or baboons. Reproductive toxicology studies showed desirudin to be teratogenic with changes comprising spina bifida in rabbits and omphaloceles in rats. No mutagenic potential was demonstrated.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

One vial contains, in addition to desirudin, magnesium chloride Ph. Eur. and sodium hydroxide for injections Ph. Eur. One solvent ampoule contains mannitol Ph. Eur. dissolved in water for injections Ph . Eur. No preservatives are included.

6.2 Incompatibilities

Desirudin should not be mixed/injected with other agents/solvents.

6.3 Shelf-life

The shelf life of the packaged product is 2 years when stored under the recommended conditions.

6.4 Special precautions for storage

9 Do not store above 25 °C. Keep the container in the outer carton in order to protect from light.

6.5 Nature and content of container

Dry substance

Colourless glass vial 2 ml, glass type I, according to Ph. Eur., with stoppers made from butyl rubber covered with a fluoropolymer film on the product side.

Solvent

Colourless glass ampoule 1 ml, hydrolytic glass type I, according to Ph. Eur.

6.6 Instructions for use and handling, and disposal (if appropriate)

To prepare the reconstituted aqueous solution, 0.5 ml of the accompanying mannitol ampoule is added under aseptic conditions to the vial containing the dry substance. The drug is rapidly redispersed by shaking gently. The reconstituted solution should be used as soon as possible. It is, however, stable for 24 hours if stored at 2 °C – 8 °C (in a refrigerator); after this period, the reconstituted solution should be discarded.

Do not use reconstituted vials containing visible particles.

7. MARKETING AUTHORISATION HOLDER

Aventis Pharma S.A. 20 avenue Raymond Aron 92165 Antony Cedex France

8. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

EU/1/97/043/001 2 vials/2 ampoules of solvent EU/1/97/043/002 10 vials/10 ampoules of solvent

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

9 July 1997

10. DATE OF REVISION OF THE TEXT

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

12 Revasc is provided in packages containing 2 vials and 2 ampoules and in packages containing 10 vials and 10 ampoules

VIAL LABEL AMPOULE LABEL

Revasc Mannitol Ph. Eur. 3 % w/v EXP 000000 15 mg EXP 000000 Sterile aqueous solvent 0.5 ml Desirudin INN Batch 000000 Batch 000000 For SC injection only

CARTON FOR 2 VIALS AND 2 AMPOULES

Front Panel Revasc 15 mg powder and solvent for solution for injection Desirudin INN 18,000 ATU/mg corresponding to approximately 270,000 ATU per vial For subcutaneous injection only Powder and solvent for solution for injection 2 vials 15 mg 2 ampoules of solvent 0.5 ml

Back Panel Revasc 15 mg powder and solvent for solution for injection Each vial contains 15 mg desirudin INN Also contains: magnesium chloride, sodium hydroxide Each ampoule of solvent contains mannitol, Water for injections Ph. Eur. in 0.5 ml

Reconstitute immediately before use with ampoule of 0.5 ml solvent provided. The reconstituted solution is stable for 24 hours if stored at 2 °C – 8 °C (in a refrigerator): after this period the solution should be discarded

For subcutaneous use only Medicinal product subject to medical prescription

Marketing authorization holder:

Aventis Pharma S.A. 20 avenue Raymond Aron 92165 Antony Cedex France

Right Side Flap Do not store above 25 °C. Keep the container in the outer carton in order to protect from light.

Keep out of reach and sight of children Use only as directed by a doctor See enclosed leaflet

13 Revasc 15 mg 2 vials 15 mg 2 ampoules of solvent 0.5 ml

Top Flap Revasc 15 mg 2 vials 15 mg EXP 000000 2 ampoules of solvent 0.5 ml Batch 000000

EU/1/97/043/001

CARTON FOR 10 VIALS AND 10 AMPOULES

Front Panel Revasc 15 mg powder and solvent for solution for injection Desirudin INN 18,000 ATU/mg corresponding to approximately 270,000 ATU per vial For subcutaneous injection only

Powder and solvent for solution for injection 10 vials 15 mg 10 ampoules of solvent 0.5 ml

For subcutaneous use only Medicinal product subject to medical prescription

Marketing authorization holder:

Aventis Pharma S.A. 20 avenue Raymond Aron 92165 Antony Cedex France

Right Side Flap Do not store above 25 °C. Keep the container in the outer carton in order to protect from light.

Keep out of reach and sight of children Use only as directed by a doctor 14 See enclosed leaflet

Revasc 15 mg 10 vials 15 mg 10 ampoules of solvent 0.5 ml

Top Flap Revasc 15 mg 10 vials 15 mg EXP 000000 10 ampoules of solvent 0.5 ml Batch 000000

EU/1/97/043/002

B. PACKAGE LEAFLET

16 Read this leaflet carefully because it contains important information about this medicine. If you have further questions or special concerns, ask your doctor, nurse, or pharmacist.

1. WHAT IS THE NAME OF YOUR MEDICINE?

The name of this medicine is Revasc powder and solvent for solution for injection. Its common name is desirudin. Desirudin is a recombinant DNA product derived from yeast cells.

2. WHAT IS IN THE REVASC PACK?

Revasc consists of a vial and an ampoule. The vial contains 17.7 mg of powder with 15 mg desirudin and two inactive substances, magnesium chloride and sodium hydroxide. The ampoule contains a solution of mannitol in water, in which the powder is dissolved for injection under the skin.

Pack sizes: 2 vials and 2 ampoules in one package. 10 vials and 10 ampoules in one package.

3. HOW IS REVASC SUPPLIED?

Powder and solvent for solution for injection. One vial contains 15 mg desirudin.

4. HOW DOES REVASC WORK?

Desirudin belongs to a group of medicines called anticoagulants, which prevent blood clots from forming in the blood vessels.

5. WHO IS RESPONSIBLE FOR MARKETING REVASC?

Name of Marketing Authorisation Holder:

Aventis Pharma S.A. 20 avenue Raymond Aron 92165 Antony Cedex France

Manufacturer responsible for batch release:

Novartis Pharma S.A. Site industriel de Huningue 26 rue de la Chapelle 68330 Huningue France

17 6. WHAT IS REVASC USED FOR?

Revasc is used to prevent blood clotting after surgery, for example, harmful blood clots can form in the blood vessels of the legs. It is often given for several days after operations such as hip replacement, because blood clots are most likely to form when you are resting in bed.

7. INFORMATION NECESSARY BEFORE USING REVASC

The risks of taking a medicine must always be weighed against its beneficial effects. The following points should be considered in the case of Revasc.

You should not be given Revasc (contra-indications)

• if you have ever had any unusual or allergic reaction to natural or synthetic hirudin, including desirudin;

• if you are bleeding a lot or have any serious bleeding disorder (e.g. haemophilia);

• if you have serious kidney or liver disease;

• a heart infection;

• uncontrolled high blood pressure;

• if you are pregnant.

Before you take Revasc it is important for your doctor to know if you have other medical problems (Special Precautions for Use)

Make sure you tell your doctor if you are likely to have an increased risk of bleeding, which may be the case if you have, or have had:

• Known bleeding disorders or a family history of;

• stomach ulcers or any other bleeding disease of the gut;

• history of a stroke, or bleeding within the brain or eye;

• recent operation (including dental surgery), especially or biopsy or pricking of a blood vessel within the last month;

• a brief shortage of blood supply to a part of the brain within the last six months;

• history of bleeding in the gut or lung within the past 3 months.

Your risk of bleeding may also be increased:

• if you have recently given birth, fallen, or suffered a blow to the body or head;

• if you are already taking medicines, especially blood-thinners (see below).

If any of the above apply to you, the doctor or nurse will monitor your blood for clotting activity and may change your dose or dosing schedule accordingly.

Medicines or substances that may affect the action of Revasc (Interactions)

Before treatment with Revasc is started, tell your doctor about any other medicines that you are taking. It may be necessary to change the dose, to take other precautions, or in some cases to stop taking one of the medicines. This applies to both prescription and non-prescription medicines, especially:

• medicines used to prevent blood-clotting (warfarin, heparin and dicoumarol);

• medicines which affect the function of platelets (particles in the blood involved in blood-clotting), e.g. aspirin and other non-steroidal anti-inflammatory agents; • all medicines given by intramuscular injection.

Pregnancy and breast-feeding

You should not be given Revasc if you are pregnant. Revasc can cause serious harm to your baby. It is also advisable not to breast-feed during treatment. It is therefore important to tell your doctor if you are pregnant or planning to become pregnant, or if you are breast-feeding. If you are of a child bearing age, a pregnancy test may be done by your doctor to rule out pregnancy.

Children and elderly patients

There is no experience with Revasc in children. Experience in elderly patients is substantial, since more than half of patients treated in clinical trials were over 65 years.

8. HOW TO USE REVASC?

You will be given Revasc as an injection under the skin.

For the Health professional: Administration is by subcutaneous injection, preferably at an abdominal site. Injections should be rotated between at least four different sites. The first injection should be initiated 5 to 15 minutes before surgery but after induction of regional block anaesthaesia, if used. Treatment with desirudin is then continued twice daily post-operatively for 9 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 Revasc beyond 12 days. If a longer duration of prophylaxis is indicated, a switch to an oral anticoagulant should be considered.

Usual dosage

The usual dosage is 15 mg injected twice a day for 9 days to a maximum of 12 days. You will be given the first injection within 5 to 15 minutes before the operation. If you need treatment for longer than 12 days, the doctor may switch you to another similar medicine.

19 If you have a kidney or liver disease, the doctor or nurse will monitor your blood for clotting activity and may change your dose or dosing schedule accordingly.

If a dose is missed

If a dose of this medicine is missed, it should be given to you as soon as possible. If it is almost time for the next dose you will skip the missed dose and go back to the normal dosage schedule. The dose should not be doubled.

In case of overdose

Overdose with Revasc may lead to bleeding. If this occurs, Revasc will be stopped and treatment given for the bleeding.

9. ARE THERE ANY UNWANTED OR TROUBLESOME EFFECTS OF REVASC?

Revasc may have unwanted effects in addition to its good effects; some of these unwanted reactions may be similar to the effects of surgery. The most likely side effect is bleeding.

Tell the doctor or nurse as soon as possible if any of the following side effects occur, some of which may be confused with side effects of surgery:

More common

Bleeding from the wound or from other areas.

Less common

Oozing of fluid from the wound; collection of blood at sites such as the wound or at the injection site (haematoma); unusual tiredness or weakness (anaemia); fever; nausea; dizziness (low blood pressure); slower healing of the wound; nosebleed; bruising, pain on urination.

Rare

Swelling of lower legs; chest pain; vomiting (with or without blood); blood in the urine; sleeplessness; dizziness; cramps or pain in the legs; rash; allergic reactions.

If you notice any other effects not mentioned in this leaflet, check with your doctor, nurse or pharmacist.

10. REFERENCE TO THE EXPIRY DATE INDICATED ON THE LABEL WITH FURTHER INFORMATION

Expiry date (shelf life)

Revasc should not be used after the expiry date shown on the pack.

How to store Revasc (Special Precautions for Storage)

This product should be stored away from direct light and not above 25 °C. Keep it out of the reach and sight of children.

The solution of Revasc which is prepared for injection is stable only for 24 hours if stored at 2 °C – 8 °C (in the refrigerator). Therefore, it should be used as soon as possible.

SOLUTIONS FOR INJECTION CONTAINING VISIBLE PARTICLES SHOULD NOT BE USED.

11. DATE ON WHICH THE PACKAGE LEAFLET WAS LAST REVISED

12. OTHER INFORMATION

For any information about this medicinal product, please contact your local representative of Aventis Pharma S.A.

België / Belgique / Belgien Luxembourg / Luxemburg Aventis Pharma Aventis Pharma Boulevard de la Plaine, 9 Boulevard de la Plaine, 9 B-1050 Bruxelles B-1050 Bruxelles Tél/Tel: (32) (2) 529 4611 Tél : (32) ( 2) 529 4611

Danmark Nederland Rhône-Poulenc Rorer A/S Rhône-Poulenc Rorer BV Slotsmarken 13 Bijenvlucht 30 DK-2970 Hørsholm NL- 3871 JJ Hoevelaken Tlf: (45) 45 16 70 00 Tel: (31) (033) 2533911

Deutschland Österreich Aventis Pharma Deutschland GmbH Aventis Pharma GmbH Postfach 1109 Altmannsdorfer Straße 104 D-65796 Bad Soden A-1121 Wien Tel: (49) (0) 69 305 22044 Tel: (43) (1) 801 01-0

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Ireland United Kingdom Aventis Pharma Ltd. Aventis Pharma Ltd, Lake Drive, 3004 Citywest, 50 Kings Hill Avenue, Naas Road, West Malling, IRL-Dublin 24 Kent - ME 194 AH - UK Tel: (353) (1) 4035600 Tel: (44) (0) 8705 239 604

Italia Aventis Pharma Via Rossini 1/A I-20020 Lainate MI Tel : (39) 02 93 76 66 44 22