ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1 1. NAME OF THE MEDICINAL PRODUCT

INFERGEN 9 micrograms solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION OF ACTIVE SUBSTANCE

INFERGEN contains as active substance interferon alfacon-1 (previously referred to as consensus interferon (CIFN)). It is provided as a solution containing 9 micrograms in 0.3 ml (30 micrograms/ml).

Interferon alfacon-1 is a protein of 166 amino acids. The amino acid sequence represents a consensus sequence (the most commonly appearing amino acids at each locus) of 14 naturally occurring human type-1 interferons. The DNA coding sequence was synthesised based on the derived consensus sequence and the molecule was cloned into an Escherichia coli expression system by means of recombinant DNA techniques.

3. PHARMACEUTICAL FORM

Solution for injection.

Infergen is a clear and colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of patients of 18 years and older with histologically proven chronic hepatitis and serum markers for hepatitis C virus (HCV) infection e.g. those who have elevated serum transaminase levels without decompensated liver disease. Consideration should be given to current official guidance on the appropriate use of interferons for the treatment of patients with chronic hepatitis C.

4.2 Posology and method of administration

The treatment with INFERGEN should be initiated under the supervision of a physician experienced in the treatment of the disease.

Posology

Adults: 9 micrograms three times a week, administered subcutaneously as a single injection. The total weekly dosage of interferon alfacon-1 should be equally divided over the week, preferably at least 48 hours should elapse between consecutive doses. The optimal duration of therapy with interferons is not yet fully established but a therapy of at least 12 months is currently advised.

In patients showing no improvement after 3-4 months treatment with 9 micrograms, discontinuation of therapy should be considered.

During the course of treatment with INFERGEN if adverse reactions develop, the dosage should be reduced or the therapy should be discontinued until the adverse reactions abate. Therapy should be resumed as soon as the adverse events become tolerable. INFERGEN dose reduction below 7.5 micrograms is not recommended. If persistent or recurrent intolerance develops following adequate dosage adjustment, or disease progresses, treatment should be discontinued. Children: The safety and efficacy of INFERGEN in children and adolescents of less than 18 years with chronic hepatitis C virus infection have not been studied.

4.3 Contra-indications

- patients with known hypersensitivity to the active substance or to any of the excipients; - patients with epilepsy or a history of severe psychiatric disorders such as severe depression, suicidal ideation or other severely compromised patients with central nervous system disorders (see also section 4.4); - severe pre-existing cardiac disease; - severe renal or hepatic dysfunction; - patients with decompensated liver disease; - chronic hepatitis in patients who are or have been treated recently with immunosuppressive therapy excluding short term corticosteroid withdrawal; - autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplant recipients - pre-existing thyroid disease unless adequately controlled with conventional treatment.

4.4 Special warnings and special precautions for use

- Interferon alfacon-1 should be used cautiously in patients with severe leukopenia or thrombocytopenia or who are receiving agents that are known to cause myelosuppression. Leukopenia, particularly granulocytopenia, may be severe in patients treated with alpha interferons, including interferon alfacon-1, and may necessitate dose reduction or temporary dose cessation. Thrombocytopenia is a common, but less severe, event often associated with alpha interferon therapy. Therapy should be withheld if the absolute neutrophil count (ANC) is < 500X106/L or if the platelet count is < 50X109/L. - Patients to be treated with interferon alfacon-1 should be informed that depressive disorders and suicidal ideation and other alterations of mental status, may be undesirable effects of interferon treatment and should report these symptoms to the prescribing physician immediately. Discontinuation of therapy should be considered. - Patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders who require interferon alfacon-1 therapy should be closely monitored. - Treatment with interferon alfacon-1 should be discontinued in patients with hepatitis who develop signs of liver decompensation. - Clinical manifestation of autoimmune disease during interferon therapy may occur frequently in patients predisposed to the development of autoimmune disease. - Serious acute hypersensitivity reactions have been reported in rare instances following treatment with alpha interferons. If hypersensitivity reactions occur (e.g., anaphylaxis, bronchoconstriction, pharyngeal edema, angioedema, urticaria), the drug should be discontinued immediately and appropriate medical treatment instituted. - Because of a risk of exacerbation of pre-existing psoriasis during interferon treatment, interferon alfacon-1 should be used in such patients only if the potential benefit outweighs the potential risk. - Ophthalmologic disorders have been reported in patients being treated with interferon alfacon-1. Any patient complaining of changes in visual acuity or visual fields or reporting other ophthalmologic symptoms during treatment should have an eye examination. A baseline ocular examination is recommended prior to treatment with interferon in patients with diabetes mellitus or hypertension. - Hypotension may occur during interferon therapy and may require supportive treatment. - Hypotension due to fluid depletion can occur and may require fluid replacement. - While fever may be associated with the flu-like syndrome, which occurs during therapy, other causes of fever should be ruled out. Flu-like symptoms can be controlled by bedtime administration of interferon alfacon-1 or symptomatically treated with analgesics like paracetamol. - Interferon alfacon-1 should be used cautiously in patients with coagulation disorders or debilitating medical conditions e.g. history of pulmonary disease such as chronic obstructive bronchitis, and diabetes mellitus prone to ketoacidosis. - Diabetes mellitus may be aggravated or may develop in patients with chronic hepatitis C infection treated with alpha interferons. Interferon alfacon-1 should be used with caution in patients with diabetes mellitus or a history of diabetes. - Pulmonary infiltrates, pneumonitis interstitial pneumonia and pneumonia have been observed rarely during interferon therapy in patients with chronic hepatitis C. Patients developing fever, cough, dyspnea, or other respiratory symptoms should have a chest X-ray taken. If necessary interferon therapy should be discontinued and corticosteroids may be indicated. - If patients treated for chronic hepatitis C with interferon alfacon-1 develop thyroid abnormalities, either hypothyroid or hyperthyroid, the abnormalities should be controlled by conventional therapy for thyroid dysfunction. Pre-existing abnormalities should also be controlled before initiation of interferon therapy. - If alanine aminotransferase flares during therapy, treatment may be continued unless signs and symptoms of liver failure are observed. - There are significant differences in specific activities among interferons. It should be realised that switching from one interferon to another may require adjustments of dosage and/or route of administration.

4.5 Interaction with other medicinal products and other forms of interaction

Interferon alfacon-1 may depress the level and activity of cytochrome P450 enzymes (based on animal data). Plasma levels of active substances, known to be metabolised by these enzymes, may increase when these are given together with INFERGEN. INFERGEN should be used cautiously in patients who are receiving agents known to be metabolized by this pathway. Patients taking drugs that are metabolized by this pathway should be monitored closely for changes in the therapeutic and/or toxic levels of concomitant drugs. Currently there are no data available from formal interaction studies with INFERGEN and other medicinal products.

4.6 Use during pregnancy and lactation

Use during pregnancy No studies have been conducted in pregnant women. Although in animal tests interferon alfacon-1, when administered during pregnancy, did not reveal teratogenic effects, - foetal harm such as growth retardation, cannot be excluded. In reproduction toxicity tests in animals, doses greatly in excess of the recommended clinical dose showed an abortifacient effect. In pregnancy, interferon alfacon-1 should be administered only if the benefit to the woman outweighs the potential risk to the foetus. Adequate contraceptive precautions should be advised if either partner is receiving interferon alfacon-1.

Use during lactation It is not known whether interferon alfacon-1 is excreted in human milk. A decision must be taken whether to suspend breast feeding or to discontinue administration, taking into account the importance of the medicinal product to the mother.

4.7 Effects on ability to drive and use machines

Patients who develop flu-like symptoms, dizziness, depressive symptoms, confusion, somnolence and fatigue should be cautioned to avoid driving or operating machinery.

4.8 Undesirable effects

Adverse experiences that were reported in the patients in the pivotal study, regardless of attribution to treatment, and in actual treatment are presented below, listed by body system and in decreasing order. The incidence of adverse events is expressed based on the number of patients experiencing each event at least once during treatment or post-treatment of the study. Most adverse events were mild-to-moderate in severity and abated with cessation of therapy. Flu-like symptoms (i.e. fever, fatigue, headache, myalgia) were the most frequently reported treatment-related adverse reactions. Most adverse events were short-lived and could be treated symptomatically.

Very Common (>1/10) Blood and the lymphatic system: neutropenia, thrombocytopenia, leukopenia Psychiatric: nervousness, depression, anxiety, emotional lability Nervous system: insomnia, dizziness, paresthesia, hypoesthesia. Respiratory, thoracic and mediastinal: upper respiratory tract infections/inflammation, coughing. Gastrointestinal: abdominal pain, nausea, diarrhoea, anorexia, dyspepsia, vomiting. Skin and subcutaneous tissue: alopecia, pruritis, rash. Musculoskeletal, connective tissue and bone: backpain. General and administration site: pain, injection site reactions, malaise. Flu-like symptoms: headache, fatigue, fever, myalgia, rigors, arthralgia, increased sweating.

Common (>1/100, <1/10) Blood and the lymphatic system: anemia Endocrine: hyperthyroidism, hypothyroidism Metabolism and nutrition: hypertriglyceridemia Psychiatric: decreased libido. Nervous system: confusion, somnolence. Eye: eye pain, retinal disorders. Cardiac: hypertension, hypotension Respiratory, thoracic and mediastinal: epistaxis, dyspnoea. Gastrointestinal: constipation, dry mouth. General and administration site: asthenia, edema, allergic reactions, weight changes. Special senses: taste alteration.

Uncommonly and rarely reported adverse events include herpes simplex, pneumonia, tachycardia, gingival bleeding, peripheral neuropathy, convulsions and hyperglycemia. Furthermore, depression may include suicidal ideation and attemped suicide, each of which have been reported rarely.

Cardiovascular adverse reactions, particularly arrhythmia appear to be correlated with pre-existing cardiovascular disease and prior therapy with cardiotoxic agents (see section 4.4 Special warnings and special precautions for use).

4.9 Overdose

The maximum tolerated dose of interferon alfacon-1 has not been determined in patients. One patient on study medication has been reported receiving ten times the prescribed dosage (150 micrograms) for 3 days. The patient experienced a mild increase in anorexia, chills, fever and myalgia. Increased laboratory values returned to the patient's baseline values within 30 days. Symptomatic treatment with frequent monitoring of vital signs and close observation of the patient is indicated in case of inaccidental overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Interferon alfacon-1 is a protein, an immunomodulator and immunoregulator with antiviral and antiproliferative effects (ATC code L 03AB09).

Interferons exert their biological effects by binding to specific membrane receptors on the cell surface. In binding assays interferon alfacon-1 displays a high affinity for the Interferon type-1 receptor. The binding is followed by a complex sequence of intracellular events that leads to the production of several interferon-stimulated gene products. These gene products (like 2'-5' oligoadenylate synthetase and ß–2 microglobulin) are responsible for the biological effects including antiviral, antiproliferative and immunomodulatory effects. Any or all of these effects may contribute to the therapeutic action of interferon. The antiviral, antiproliferative, natural killer cell activation and interferon stimulated gene– induction activities of interferon alfacon-1 compare favourably with naturally occurring type–1 interferons in in vitro assays.

Current clinical experience with INFERGEN showed that therapy with interferon alfacon-1 can produce normalisation of serum ALT, clearance of serum HCV-RNA and improvement of liver histology (although less extensively investigated) in a significant proportion of the patients. The effects of 9 micrograms interferon alfacon-1 in the treatment of chronic hepatitis-C virus (HCV) infection have been compared to 3 MU interferon a-2b in a randomised double-blind clinical trial involving 704 patients who were previously untreated with type-1 interferons. The overall response in patients treated three times a week with 9 micrograms interferon alfacon-1 for up to 6 months was similar to the comparator.

5.2 Pharmacokinetic properties

Due to low plasma levels, it was not possible to determine the pharmacokinetics of interferon alfacon- 1 in humans. Animal studies have shown that, following subcutaneous administration, interferon alfacon-1 was absorbed rapidly. Peak serum concentrations of interferon alfacon-1 were observed at 1 hour and 4 hours in hamsters and rhesus monkeys, respectively. Subcutaneous bioavailability was nearly 100% in both species. Clearance of interferon alfacon-1 was mainly mediated by the kidneys. The terminal elimination half-life was 1.3 hours in hamsters and 3.4 hours in rhesus monkeys.

5.3 Preclinical safety data

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity. For effects found in reproductive toxicology studies see section 4.6 Pregnancy and lactation.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

INFERGEN is formulated with 100 mM sodium chloride and 25 mM sodium phosphate at pH 7.0 ± 0.2 in water for injections.

6.2 Incompatibilities

INFERGEN must not be diluted before use.

6.3 Shelf-life

2 years.

6.4 Special precautions for storage

Store at 2° to 8°C (in a refrigerator). Do not freeze. Avoid vigorous shaking. Just prior to injection, INFERGEN may be allowed to reach room temperature. Vials should not be used after 24 hours at room temperature (15-25°C). 6.5 Nature and content of container

INFERGEN is supplied in colourless glass vials with rubber stoppers. INFERGEN is available in boxes of one, six or twelve single dose vials ready for use. Disposable syringes and needles for subcutaneous injections are included in each pack.

6.6 Instructions for use and handling, and disposal

- The solution for injection should be visually inspected prior to use and only clear solutions without particles should be used. - Any unused solution should be discarded as the product is for single use only.

7. MARKETING AUTHORISATION HOLDER

Yamanouchi Europe B.V. Elisabethhof 19 NL-2353 EW LEIDERDORP, The Netherlands

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

EU/1/98/087/001 (1 vial) EU/1/98/087/002 (6 vials) EU/1/98/087/003 (12 vials)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

1 February 1999.

10. DATE OF REVISION OF THE TEXT ANNEX III

LABELLING AND PACKAGE LEAFLET B. PACKAGE LEAFLET Please read this leaflet carefully before using INFERGEN injection as it contains important information. Do so even if you have read it before as the information may change from time to time.

INFERGEN 9 micrograms solution for injection (interferon alfacon-1). WHAT IS INFERGEN AND HOW DOES IT WORK? Composition INFERGEN contains interferon alfacon-1 as active substance. It is provided as an aqueous solution of: 9 micrograms interferon alfacon-1 in vials containing 0.3 ml. The inactive ingredients are sodium chloride, sodium phosphate and water for injections.

What does INFERGEN look like and how is it supplied? INFERGEN is a clear colourless solution for injection in a clear glass vial with a rubber stopper. It is for injection under the skin. INFERGEN is available in packs of one, six or twelve single dose vials ready for use. Disposable syringes with needles are also included in the pack.

How does INFERGEN work? The active substance interferon alfacon-1 is like other interferons, which are substances produced in the body to increase the resistance to viral infections, such as hepatitis C. The way it works is not fully known, but it is thought to have an antiviral effect and an effect on the immune system.

Who is Marketing Authorisation Holder for INFERGEN? Yamanouchi Europe B.V. Elisabethhof 19 NL-2353 EW LEIDERDORP The Netherlands

Who is manufacturing INFERGEN? Iberfar Indústria Farmacêutica S.A. R. Consiglieri Pedroso 123 Queluz de Baixo 2746-601 Barcarena Portugal

WHAT IS INFERGEN USED FOR?

INFERGEN is used in the treatment of chronic hepatitis C infections in patients 18 years of age or older.

WHAT YOU SHOULD KNOW BEFORE USING INFERGEN

When not to use INFERGEN? Do not use INFERGEN if you are allergic to the active substance or to the other ingredients. If you do have a serious allergic reaction after using INFERGEN, stop using it and tell your doctor or pharmacist. Do not use INFERGEN if you have uncontrolled liver disease, severe heart problems, severe renal or liver dysfunction or epilepsy. Do not use INFERGEN if you have a history of severe psychiatric disorders Do not use INFERGEN if you have been recently treated with medicines suppressing the immune system, if you suffer from severe immune, or autoimmune hepatitis or if you received a transplant. In addition, do not use INFERGEN if you have thyroid disease which is not controlled or cannot be controlled by medication. Precautions for the use of INFERGEN

If you get severely depressed or have suicidal thoughts while using INFERGEN, contact your doctor immediately There is no experience of the use of INFERGEN in patients under 18 years of age. The product is therefore not recommended for use in this age group. Autoimmune disease can occur as a side effect of INFERGEN treatment, especially if your family has a history of autoimmune diseases. If you have psoriasis, the disease may become worse during treatment. If you experience any change in your sight, tell your doctor immediately. Low blood pressure may be a side effect of the treatment. Although fever may be one of the most common adverse reactions of INFERGEN therapy, contact your doctor in persistent cases to rule out other possible causes of fever.

If you already have a history of cardiovascular disease, you may be predisposed to experience cardiovascular adverse events such as heart beat disturbances Your physician will closely monitor you. If liver decompensation occurs during therapy the treatment should be stopped. If you have blood clotting disorders or severe conditions like chronic lung disease or some forms of diabetes your physician will monitor your condition more closely. Diabetes mellitus may get more severe or may develop in patients with chronic hepatitis C infection treated with INFERGEN. If you have respiratory complications your physician will take an X-ray of your chest; if necessary he will stop treatment with Infergen and prescribe other medication. If you develop, or already experience problems with your thyroid gland, the physician will prescribe additional medication.

It should be realized that switching from one interferon to another may require adjustments of the dosage.

Interactions with other medicines As INFERGEN may interact with certain other medicines, tell your doctor if you are taking any of these other medicines so that this can be taken into account. Do not start taking any other medicines without the advice of your doctor or pharmacist.

Use during pregnancy and when you are breast-feeding The effect of INFERGEN upon the foetus is not known, so do not use INFERGEN if you are or think you may be pregnant. Adequate contraceptive measures should be taken if either partner is using INFERGEN. If you do become pregnant, inform your doctor immediately. It is not known if INFERGEN is excreted in breast milk. If you are breast-feeding, discuss with your doctor whether you should suspend breast-feeding or should discontinue the medicine.

Effects on the ability to drive or to operate machinery If flu-like symptoms, dizziness, depressive symptoms and muscle or joint pain develop, avoid driving or operating machinery.

GUIDELINES FOR THE USE OF INFERGEN

How to use INFERGEN? Treatment with INFERGEN will be started under the supervision of your doctor. It is to be injected under the skin three times a week, leaving preferably 48 hours between each injection. The duration of treatment is usually for at least12 months.

At the start, or during the course of treatment, you may be taught how to give yourself the injections. Please follow the advice of your doctor. To help you with the administration of INFERGEN under the skin, detailed instructions for self- injection are provided with this leaflet. Prior to use you should look at the contents of the vial and only use clear solutions without particles. What if you take too much INFERGEN? Administration of many times the dose of INFERGEN did not lead to life-threatening situations. However, in the case of accidental overdosage, consult your doctor immediately.

Have you missed an injection of INFERGEN? If an injection of INFERGEN is forgotten, it should be given as soon as possible, but after that wait for 48 hours before your next injection.

UNDESIRABLE EFFECTS

The majority of patients experience flu like symptoms such as fever, fatigue, headache and muscular pain. These usually become less with time but your doctor may prescribe a pain reliever, such as paracetamol, to reduce the symptoms. Using INFERGEN before bedtime may also help.

Furthermore the following symptoms may occur: inflammation or pain at the site of injection, depression, suicidal thoughts, nervousness, sleep disturbances, dizziness, anxiety, emotional instability, confusion, stiffness, decrease of appetite, nausea, vomiting, diarrhoea, abdominal pain and other sorts of pain, dry mouth, upper respiratory tract infections, cough, shortness of breath, increased sweating, taste alteration, feeling of weakness, sleepiness, numbness or tingling sensations, skin reactions like hairloss, itching or rash, bruising, pneumonia, weight changes, swelling, increased heartrate, dyspepsia, anemia, retinal disorder, convulsions, high and low bloodpressure, decreased libido, decreased perception of pain, constipation, gum bleeding, change in nervous function, changes in the function of the thyroid gland and changes in the fatty acids in the blood. Changes in the number of cells in your blood may occur. Therefore if you experience high fever or signs of acute infection, contact your physician.

If you have any of the undesirable effects mentioned above or if you notice any other undesirable effects, please tell your doctor.

HOW TO STORE INFERGEN

INFERGEN must be kept cool between 2°C and 8°C in a refrigerator (not in the freezing compartment). Do not shake the vial before use or dilute its contents.

Do not use INFERGEN after the expiry date printed on the package nor after it has been kept for more than 24 hours at room temperature.

Keep out of the reach of children. If you are injecting yourself, make sure to dispose of the used syringes properly. Ask your pharmacist for instructions.

This package leaflet was last updated on: SELF INJECTION PROCEDURE

The following instructions explain how to inject INFERGEN yourself. Please read the instructions carefully and follow them step by step. Your doctor or his/her assistant will instruct you in the technique of self-injection. Do not attempt to inject yourself unless you are sure you understand the procedure and requirements of self-injection.

Preparing for self-injection Collect the items you need before you begin, being a vial of INFERGEN, a syringe with two needles, alcohol and swaps. Wash your hands carefully..

Drawing up the required volume of solution into the syringe Remove the coloured cap from the vial, exposing the rubber stopper. Clean the vial top with alcohol. Remove the syringe from its wrapping. Do not touch the tip of the syringe. Take the long needle (green) out of its wrapping and place it firmly onto the tip of the syringe. Remove the needle guard without touching the needle.

Slowly insert the needle straight through the rubber stopper, into the vial. Turn the vial upside down and keep the needle tip in the solution. Take care not to shake the vial too much.

Hold the vial and syringe in one hand and slowly pull back the plunger of the syringe and withdraw the contents of the vial completely. Withdraw the needle from the vial.

Keep the syringe with the needle upwards. Replace the long needle with the short one (grey). Gently tap the syringe until any air bubbles rise to the top of the barrel of the syringe.

Carefully push in the plunger to eject ONLY THE AIR through the needle. Make sure that the syringe contains the required amount of solution (0.3 unless instructed otherwise).

Selection and cleaning of the injection site Choose an injection site. Use a different site each time. INFERGEN should be injected into subcutaneous tissue (under the skin). The best areas for injection are loose and soft, away from joints and vessels (preferably on your thighs or abdomen, except for the navel and waist). Changing the sites helps to prevent injection reactions. Keep a record of where and when you last gave yourself an injection. You may use a site again after waiting one week. If all areas become tender, talk to your doctor about choosing other sites.

Use an alcohol swab to clean the skin at the injection site. Let it air dry. Gently pinch the skin together around the site (to lift it up a bit).

Injecting the solution Inject under the skin as you were taught.

After the needle is in, let go of the skin. Pull plunger back slightly. If blood appears, do not inject INFERGEN, because the needle has entered a blood vessel. Withdraw the syringe and inject in a different place. Repeat this procedure at the second site, checking for blood before injecting.

If no blood appears, inject the solution by pushing the plunger slowly and steadily until the syringe is empty.

Hold a swab onto the injection site. Remove the needle from the skin.

Dispose of the syringe and needles in a proper way, as directed by your doctor, nurse or pharmacist. Use a needle container for the disposal of the needles. OTHER INFORMATION

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

Belgique/België Luxembourg Yamanouchi Pharma B.V. Yamanouchi Pharma B.V. Riverside Business Park Riverside Business Park Boulevard Internationale 55 B7 Boulevard Internationale 55 B7 B – 1070 Brussels B – 1070 Brussels +32.2.558.0737 +32.2.558.0737

Danmark Nederland Yamanouchi Pharma a/s Yamanouchi Pharma B.V. Naverland 4 Haagse Schouwweg 6 Postboks 1307 NL – 2332 KG Leiden DK – 2600 Glostrup +31.71.545.5854 +45.434.30355

Deutschland Österreich Yamanouchi Pharma GmbH Yamanouchi Pharma GmbH Im Breitspiel 19 Im Breitspiel 19 D – 69126 Heidelberg D – 69126 Heidelberg +49.6221.34340 +49.6221.34340

Ελλάδα Portugal P.N. Gerolymatos S.A. Yamanouchi Farma, Lda. Yamanouchi Pharma Lda Edifício Cinema 13 Asklipiou str. Rua José Fontana Nº. 1, 1º Andar GR – 145-68 Kryoneri Attika 2780-605 Paço de Arcos +30.1.8161107/907 +351.21.4401320

España Suomi Yamanouchi Pharma S.A. Algol Oy Centro Empresarial El Plantio PL 13 Calle Ochandiano 10 FIN – 02611 Espoo/Esbo E – 28023 Madrid +358.9.50.991 +34.91.3729.768

France Sverige Chiesi S.A. Yamanouchi Pharma AB 11, Avenue Dubonnet Ridspögatan 10, F – 92400 Courbevoie S – 21377 Malmö +33.1.4768.8899 +46.4030.6950 Ireland United Kingdom Yamanouchi Pharma Ltd. Yamanouchi Pharma Yamanouchi House Yamanouchi House Pyrford Road Pyrford Road West Byfleet West Byfleet UK - Surrey KT14 6RA Surrey KT14 6RA +44.1932.34.2291 +44.1932.34.2291

Italia Yamanouchi Pharma S.p.A. Via delle Industrie 2, I – 20061 Carugate (Milano) +39.02.921.1381