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