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ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT Betaferon® 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Interferon beta-1b 0.25 mg (8.0 million IU) per ml when reconstituted. The potency is determined using a cytopathic effect (CPE) bioassay using the WHO recombinant interferon beta reference standard. Betaferon® is formulated to contain 0.3 mg (9.6 million IU) of Interferon beta-1b per vial at a calculated overfill of 20 %. Interferon beta-1b is a purified, sterile, lyophilised protein that has 165 amino acids. It is produced by recombinant DNA techniques from a strain of Escherichia coli that bears a genetically engineered plasmid containing a modified human interferon betaser17-gene. Interferon beta-1b differs structurally from natural human interferon beta by the presence of serine instead of cysteine in position 17, lack of methionine in position 1 and absence of carbohydrate moieties.

3. PHARMACEUTICAL FORM

Sterile lyophilised white to off-white powder for solution for injection.

4. CLINICAL PARTICULARS 4.1 Therapeutic indications

Betaferon® is indicated for the reduction of frequency and degree of severity of clinical relapses, in ambulatory patients (i.e. patients who are able to walk unaided) with relapsing, remitting multiple sclerosis, characterised by at least two attacks of neurological dysfunction over the preceding two year period, followed by complete or incomplete recovery. Patients receiving Betaferon® showed a reduction in frequency (30%) and severity of clinical relapses, as well as the number of hospitalisations due to disease. Furthermore, there was a prolongation of the relapse-free interval. There is no evidence of an effect of Betaferon® on the duration of exacerbation’s, on symptoms in between exacerbation’s, or of the progression of the disease. There are also no data on the effect of Betaferon® on performance of daily activities or in the social field. Betaferon® has not yet been investigated in patients with progressive MS. There is no evidence of an effect on disability. The clinical studies show that not all patients respond to treatment with Betaferon®. Furthermore a deterioration in the bouts was observed in some of the patients despite the treatment. There are no clinical criteria that would allow prediction with regard to non-response or deterioration in the individual patient to be treated.

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4.2 Posology and method of administration

The treatment with Betaferon® should be initiated under the supervision of a physician experienced in the treatment of the disease. The recommended dose of Betaferon® is 0.25 mg (8.0 million IU), contained in 1 ml of the reconstituted solution (cf. 6.6 "Instructions for use/handling"), to be injected sub-cutaneously every other day. The optimal dose has not been fully clarified. At the present time, it is not known for how long the patient should be treated. Efficacy of treatment for longer than two years has not been sufficiently demonstrated. Full clinical assessment should be made at two years in all patients. A decision for longer-term treatment should be made on an individual basis by the treating physician. Exposure data for longer than three years are not available. Treatment is not recommended in patients with less than 2 exacerbation’s in the previous 2 years. If the patient fails to respond, for example: there is steady progression of disability for six months, or treatment with at least 3 courses of ACTH or corticosteroids during a one year period is required despite Betaferon® therapy, treatment with Betaferon® should be stopped. Efficacy and safety of Betaferon® were not investigated in children and adolescents of less than 18 years of age. Therefore, Betaferon® should not be administered to this age group.

4.3 Contra-indications

Betaferon® is contraindicated in the following conditions: Pregnancy (see Section 4.6). Patients with a history of hypersensitivity to natural or recombinant interferon-ß or human albumin. Patients with a history of severe depressive disorders and/or suicidal ideation. Patients with decompensated liver disease. Patients with epilepsy not adequately controlled by treatment. Serious hypersensitivity reactions (rare but severe acute reactions such as bronchospasm, anaphylaxis and urticaria) may occur. If reactions are severe, Betaferon® should be discontinued and appropriate medical intervention instituted.

4.4 Special warnings and special precautions for use

Patients to be treated with Betaferon® should be informed that depressive disorders and suicidal ideation may be a side effect of the treatment and should report these symptoms immediately to the prescribing physician. In rare cases these symptoms may result in a suicide attempt. Patients exhibiting depressive disorders and suicidal ideation should be monitored closely and cessation of therapy should be considered.

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Betaferon® should be administered with caution to patients with a history of seizures and of depressive disorders and to those receiving treatment with anti-epileptics (see Interactions Section). It should also be used with caution in patients with depressive disorders and to those who suffer from pre-existing cardiac disorders. Caution should be exercised when administering Betaferon® to patients with myelo-suppression; patients who develop neutropenia should be monitored closely for the development of fever or infection. Serious hypersensitivity reactions (rare but severe acute reactions such as bronchospasm, anaphylaxis and urticaria) may occur. If reactions are severe, Betaferon® should be discontinued and appropriate medical intervention instituted. Other moderate to severe adverse experiences may require modifications of the Betaferon® dosage regimen or even discontinuation of the agent. Differential WBC, SGOT and SGPT levels should be obtained prior to initiation of Betaferon® therapy and regularly during therapy. There are no data on patients with renal impairment. Renal function should be monitored carefully when such patients receive Betaferon® therapy. In the MS studies, 45 % of the patients developed serum interferon beta-1b neutralising activity on at least one occasion. One third had neutralising activity confirmed by at least two consecutive positive titres. This development of neutralising activity is associated with a reduction in clinical efficacy, becoming evident at 18-24 months. New adverse events have not been associated with the development of neutralising activity. However, the possibility of cross reactivity with endogenous interferon beta has not been investigated. There are sparse data in patients who have developed neutralising activity and have completed Betaferon® therapy.

4.5 Interaction with other medicinal products and other forms of interaction

No formal drug interaction studies have been carried out with Betaferon®. The effect of alternate-day administration of 0.25 mg (8.0 million IU) of Betaferon® on drug metabolism in MS patients is unknown. Corticosteroid or ACTH treatment of relapses for periods of up to 28 days has been well tolerated in patients receiving Betaferon®. Due to the lack of clinical experience in MS patients use of Betaferon® together with immunomodulators other than corticoids or ACTH is not recommended. Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. Caution should be exercised when Betaferon® is administered in combination with medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance, e.g. anti-epileptics. No interaction studies with anti-epileptics have been carried out. Influence on laboratory tests/findings

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At the recommended dose, leukopenia (lymphopenia, neutropenia), or elevated SGPT may be seen. Low calcium, high uric acid, or elevated SGOT have appeared to be associated with Betaferon® administration.

4.6 Use during pregnancy and lactation

It is not known whether Betaferon® can cause foetal harm when administered to a pregnant woman or can affect human reproductive capacity. Spontaneous abortions have been reported in subjects with MS in controlled clinical trials. Recombinant human interferon beta-1b in studies with rhesus monkeys has been proven embryotoxic, causing foetal death in the higher dose range. Therefore, Betaferon® is contraindicated during pregnancy and women of childbearing potential should take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking Betaferon®, she should be informed of the potential hazards and it should be recommended to discontinue therapy (for preclinical results refer to section 5.3). It is not known whether interferon beta-1b is excreted in human milk. Because of the potential for serious adverse reactions to Betaferon® in nursing infants a decision should be made whether nursing or Betaferon® should be discontinued.

4.7 Effects on ability to drive and use machines

This has not been investigated. Central nervous system-related adverse events associated with the use of Betaferon® might influence the ability to drive and use machines in susceptible patients.

4.8 Undesirable effects

Experience with Betaferon® in patients with MS is limited, consequently adverse events with low incidence may not yet have been observed. Injection site reactions occurred frequently after administration of Betaferon®. Inflamma-tion, pain, hypersensitivity, necrosis, and non-specific reactions were significantly associated with 0.25 mg (8.0 million IU) Betaferon® treatment. The incidence rate of injection site reactions usually decreased over time. Flu-like symptom complex (fever, chills, myalgia, malaise, or sweating) has been seen frequently. The incidence rate of the symptoms decreased over time. Serious hypersensitivity reactions (rare but severe acute reactions such as bronchospasm, anaphylaxis and urticaria) may occur. If reactions are severe, Betaferon® should be discontinued and appropriate medical intervention instituted. Menstrual disorders may occur in premenopausal females. Central nervous system (CNS) related adverse events including depression, anxiety, emotional liability, depersonalisation, convulsions, suicide attempts, and confusion have been observed.

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4.9 Overdose

Interferon beta-1b has been given without serious adverse events compromising vital functions to adult cancer patients at individual doses as high as 5.5 mg (176 million IU) i.v. three times a week.

5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Cytokines, ATC code LO3AA11

Interferons belong to the family of cytokines, which are naturally occurring proteins. Interferons have molecular weights ranging from 15,000 to 21,000 daltons. Three major classes of interferons have been identified: alpha, beta, and gamma. Interferon alpha, interferon beta, and interferon gamma have overlapping yet distinct biologic activities. The activities of interferon beta-1b are species-restricted and therefore, the most pertinent pharmacologic information on interferon beta-1b is derived from studies of human cells in culture or in human in vivo studies. Interferon beta-1b has been shown to possess both antiviral and immunoregulatory acti-vities. The mechanisms by which interferon beta-1b exerts its actions in multiple sclerosis (MS) are not clearly understood. However, it is known that the biologic response-modifying properties of interferon beta-1b are mediated through its interactions with specific cell receptors found on the surface of human cells. The binding of interferon beta-1b to these receptors induces the expression of a number of gene products that are believed to be the mediators of the biological actions of interferon beta-1b. A number of these products have been measured in the serum and cellular fractions of blood collected from patients treated with interferon beta-1b. Interferon beta-1b both decreases the binding affinity and enhances the internalisation and degradation of the interferon-γ receptor. Interferon beta-1b also enhances the suppressor activity of peripheral blood mononuclear cells. No separate investigations were performed regarding the influence of Betaferon® on the cardiovascular system, respiratory system and the function of endocrine organs.

5.2 Pharmacokinetic properties Betaferon® serum levels were followed in patients and volunteers by means of a not

completely specific bioassay. Maximum serum levels of about 40 IU/ml were found 1 - 8 hours after subcutaneous injection of 0.5 mg (16.0 million IU) interferon beta-1b. From various studies mean clearance rates and half-lives of disposition phases from serum were estimated to be at most 30 ml·min-1·kg-1 and 5 hours, respectively. Every other day Betaferon® injections do not lead to serum level increases and pharmacokinetics do not seem to change during therapy.

The absolute bioavailability of subcutaneously administered interferon beta-1b was

approximately 50 %.

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5.3 Preclinical safety data No acute toxicity studies have been carried out. As rodents do not react to human

interferon beta, repeated dose studies were carried out with rhesus monkeys. Transitory hyperthermia was observed, as well as a significant rise in lymphocytes and a significant decrease in thrombocytes and segmented neutrophils. No long-term studies have been conducted. Reproduction studies with rhesus monkeys revealed maternal and foetal toxicity, resulting in prenatal mortality. No malformations have been observed in the surviving animals. No investigations on fertility have been conducted. No influence on the monkey oestrous cycle has been observed. Experience with other interferons suggest a potential for impairment of male and female fertility.

In one single genotoxicity study (Ames test), no mutagenic effect has been observed.

Carcinogenicity studies have not been performed. An in vitro cell transformation test gave no indication of tumorigenic potential. Local tolerance studies after subcutaneous administration were negative. However, in clinical studies local reactions have been observed following use of Betaferon®.

6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Human albumin Ph. Eur Dextrose Ph. Eur 6.2 Incompatibilities None known. 6.3 Shelf life

− of the product as packaged for sale 18 months at 2-8 °C, starting from the date of sterile filtration of the formulated bulk solution.

− after reconstitution according to directions

up to 3 hours at 2 - 8 °C. 6.4 Special precautions for storage

Store at 2 - 8 °C before and after reconstitution. 6.5 Nature and content of container

3 ml clear glass vial with a 13 mm butyl rubber stopper and aluminium overseal. Each Betaferon® vial is provided with a separate diluent vial containing 2 ml sterile sodium chloride solution (0.54% w/v). The diluent is contained in a 3 ml vial with a 13 mm butyl rubber stopper and aluminium overseal. Each pack of Betaferon contains either 5 or 15 vials of interferon beta-1b and either 5 or 15 vials of 0.54% sodium chloride solution.

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

To reconstitute lyophilised interferon beta-1b for injection, use a sterile syringe and needle to inject 1.2 ml of the supplied diluent (sodium chloride solution, 0.54 % w/v) into the Betaferon® vial. Dissolve the powder completely without shaking. Inspect the reconstituted product visually before use. Discard the product before use if it contains particulate matter or is discoloured. The reconstituted solution contains 0.25 mg (8.0 million IU) of interferon beta-1b per ml. Store all medicinal products properly and keep them out of reach of children.

7. MARKETING AUTHORISATION HOLDER Schering Aktiengesellschaft D-13342 Berlin Telephone: (030) 468 - 0 8. NUMBER IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS 9. DATE OF FIRST AUTHORISATION 30.11.95 10. DATE OF REVISION OF TEXT

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ANNEX II HOLDERS OF THE MANUFACTURING AUTHORISATIONS RESPONSIBLE FOR

BATCH RELEASE AND IMPORTATION AND CONDITIONS OF THE MARKETING AUTHORISATION

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A. HOLDER OF THE MANUFACTURING AUTHORISATION Manufacturer of the medicinal product (dosage form): Dr. Karl Thomae GmbH (subsidiary of Boehringer Ingelheim) Birkendorfer Str 65, D-88397 Biberach an der Riss, Germany GMP certificate issued on 3 February 1995 by Regierungprasidium, Tubingen. Bender & Co GmbH (subsidiary of Boehringer Ingelheim) A-1121 Vienna, Dr. Boehringer-Gasse 5-11, Austria Manufacturing Authorisation issued on 30 January 1995 by the Bundesministerium fur Gesundheit and Konsumentenschutz, Wien. Manufacturer of the finished medicinal product, responsible for importation and batch release in the European Economic Area: Schering Aktiengesellschaft, D-13342 Berlin, Germany GMP certificate issued by Senatsverwaltung fur Gesundheit und Soziales, Berlin B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to non-renewable restricted medical prescription C. SPECIFIC OBLIGATIONS OF THE MARKETING AUTHORISATION HOLDER The company will submit safety update reports regularly according to legal requirements (Council Regulation 2309/93, Article 22). The company, after having been consulted (CPMP/357/95) will comply with the obligation to complete the identified programme of studies set out below. The results of those studies should be submitted within the defined timeframe to the EMEA after the marketing authorisation is granted, and shall form the basis of the annual re-assessment by the Agency of the marketing authorisation holder’s obligations and of the benefit/risk profile of the medicinal product BETAFERON. Clinical aspects: 1. The Company will submit a report of the study conducted in Europe (a) and in the USA/Canada (b) on the the secondary progressive form of multiple sclerosis:

a) Double -blind, placebo-controlled multicenter study to evaluate the safety and efficacy of 8 MIU Interferon beta-1b vs placebo. Final report should be submitted by 31 March 1999.

b) Double-blind, placebo controlled multicenter study to evaluate the safety and efficacy of two doses of Intereron beta-1b (8MIU per dose; 4.9 MIU/m2 body

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surface area). Final report should be submitted by 31 December 2000. 2. Further data on neutralising antibodies from the five years follow-up extension of studies TB 01/3103 and TB 01/3104 should be submitted by 31 December 1996 3. The Company must re-analyse retained plasma samples from all patients in the pivotal studies for neutralising activity using the new assay. The results should be analysed in relation to efficacy and safety and reported by 31 December 1996. 4. Pharmacokinetics studies: these investigations will be started by 1st January 1996, when a sensitive, validated assay for pharmacokinetic measurements is available. 5. Study on the persistence of effect in relapsing remitting form of Multiple Sclerosis:

The company should submit the detailed draft clinical protocol. Chemical, pharmaceutical and biological aspects: The following quality information should be addressed within the specified time frame.

a) PART IIB: • METHOD OF PREPARATION The bioburden limit in the Formulated Bulk before sterile filtration is too high. Unless justified, if the action limit can not be reduced to 10CFU/100ml. then a sterile filtration of the bulk solution of active ingredient should be implemented, or alternatively the final filtration should be through two filters. A report was presented. Additional information will be provided by 30 November 1996.

b) PART IIC:

• DOWN STREAM PROCESSING The drug substance in Betaferon is made using rDNA technology. However, it is unusual in that unlike ‘rDNA’ proteins it does not have a purity in the upper nineties percent region. The Company notes that the purification of the drug substance is difficult because of its hydrophobic nature and the ncessary use of high pH in one of the final steps. The Company should consider investigating the purification process with a view to defining the nature and reducing the level of impurities . A report was submitted. Additional information will be provided by 30 November 1996. • CHARACTERISATION/IMPURITIES The Company is asked to extend its answer to the question related to the apparent contradictions in the level of HMW species detected with two different methods. The Company states that the hand seen at pI 8.9 (15-35% of the IFN beta- lb protein) consists of HMW species (<3% as determined by non-reducing SDS-PAGE) but does not mention anything about the identity of the remaining protein apparently present in the IEF-band. The company should further characterize the identity of the band that contains the 15-35% at pl 8.9 on the IEF gel.

A report of the IFN-beta-1b protein documenting the progress of the characterisation was submitted. Additional information will be provided by 30 November 1996.

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c) PART IIE: • FINISHED PRODUCT SPECIFICATIONS With reference to additional testing required to be performed for the finished product specifications, the Company commented that further test methods are being investigated with a view to their possible inclusion in the finished product specifications. The Company should present information on the progress of such studies by 30 November 1996. The company should on an on-going basis monitor the bioassay results from batches of Betaferon produced at Chiron and at Boehringer Ingelheim to give reassurance that the batches from each site are comparable.

A report should be presented by 30 November 1996.

• The limit for the ELISA test for the content of interferon beta-1b in the dosage form should be reviewed after further experience with a view to tightening the limit. A report should be presented by 30 November 1996.

d) PART II F:

• STABILITY The Company is investigating the use of a RP-HPLC assay to separate HSA from IFN-β in the final product and to detect degradation of IFN-β. The Company should submit information on the progress of this assay by 30 November 1996.

• An assurance should be given that the IFN-β ELISA assay will be incorporated in the stability program of the final product. RP-HPLC should be incorporated in this program when available.

The Company should evaluate the IFN-β quantitative ELISA to determine if the assay is indicating stability. If so, the assay will be added to the stability program of the final product. The RP- HPLC assay will be incorporated into the final container stability program as soon as it is fully developed and validated.

• In due time, when sufficient additional stability data are available, the specification for moisture should be reconsidered and if possible tightened. A report should be presented by 30 November 1996.

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ANNEX III LABELLING AND PACKAGE LEAFLET

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A. LABELLING

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Betaferon® 0.25 mg (8 million IU)/ml Interferon beta-1b (pINN) Medicinal product subject to medical prescription. Keep out of reach of children I. 1 vial with powder for solution for injection contains Interferon beta-1b 0.25 mg (8

million IU)/ml after reconstitution* Human albumin Dextrose II. 1 diluent vial contains Sodium chloride 0.54% solution 2 ml For subcutaneous injection after reconstitution with 1.2 ml of Diluent for Betaferon® * Betaferon® is formulated to contain 0.3 mg (9.6 million IU) of Interferon beta-1b per vial at a calculated overfill of 20%. When reconstituted, each ml contains 0.25 mg (8 million IU) of Interferon beta-1b. Store at 2-8°C Single use See pack insert for instructions PL Product Licence Holder Schering AG D-13342 Berlin, Germany LOT EXP SCHERING 0.25 mg 5 vials with powder for solution for injection 5 diluent vials s. c.

Betaferon® Interferon beta-1b 1 vial with powder for solution for injection contains Interferon beta-1b 0.25 mg (8 million IU)/ml after reconstitution For subcutaneous injection. Store at 2-8°C Single use. LOT EXP SCHERING Diluent for Betaferon® Sodium chloride 0.54% solution 2 ml Store at 2-8°C Sterile. Single use. For dilution of the accompanying Betaferon® powder for solution for injection LOT EXP SCHERING

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B. PACKAGE LEAFLET

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B e t a f e r o n Important information, please read carefully. Betaferon contains the following substances (Composition) Active ingredients: 1 ml of the prepared solution for injection contains 0.25 mg (8 million IU) of Interferon beta-1b. Betaferon is formulated to contain 0.3 mg (9.6 million IU) of Interferon beta-1b per vial at a calculated overfill of 20 %. Inactive ingredients: Human albumin, dextrose. What presentations of Betaferon are available? Each pack of Betaferon contains either 5 or 15 vials of Interferon beta-1b and either 5 or 15 vials of 0.54 % sodium chloride solution. How does Betaferon work ? (Properties of the preparation) Multiple sclerosis (MS) is a disease of the central nervous system (CNS) (i. e. brain and spinal cord) and its exact cause is unknown. An abnormal response by the body's immune system is thought to play an important part in the process which damages the CNS. Interferon beta-1b has been shown to modify the immune system response. Interferons belong to the family of cytokines, which are naturally occurring proteins. Who is responsible for Betaferon? (Name and address of the holder of the marketing authorization, manufacturer) Schering AG D-13342 Berlin Germany For what purpose is Betaferon used? (Indications) Betaferon is indicated for use in ambulatory patients (patients who can walk) with relapsing-remitting multiple sclerosis (MS) characterized by at least two attacks of neurologic dysfunction over a two year period followed by complete or incomplete recovery. In this patient population Betaferon was shown to reduce the frequency and severity of clinical relapses, to reduce the number of MS related hospitalizations and to prolong the relapse-free time. There is no evidence of an effect of Betaferon on the length of attacks, symptoms in between attacks, or the progression of the disease. The effect of Betaferon on performance of daily activities or in the social field is not known. Betaferon has not yet been investigated in patients with progressive multiple sclerosis. There is no evidence of an effect on disability. Clinical studies show that not all patients respond to treatment with Betaferon. Despite treatment worsening of the symptoms during attacks has been observed in some patients. It is not possible to foresee which patients will not respond or whose symptoms will worsen despite treatment.

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When should Betaferon not be used? (Contraindications) You should not use Betaferon if you are pregnant or if you have a history of hypersensitivity to natural or recombinant interferon beta or human albumin. You should not use Betaferon if you are under 18 years of age, because it has not been investigated in this age group. You should also not use Betaferon if you have a history of severe depressive illness and/or suicidal thoughts, liver failure or inadequately treated epilepsy. If a serious hypersensitivity reaction occurs, treatment with Betaferon should be discontinued. What precautions must be observed during the use of Betaferon? Depression and suicidal thoughts have been reported by patients. In rare cases this may lead to suicidal attempts. If you experience such symptoms, contact your doctor promptly. If you have a history of seizures or of depression or if you suffer from pre-existing heart disorders, Betaferon should be administered with caution. Caution should also be exercised if you are taking anti-epileptic drugs. Betaferon should also be administered with caution, if you have a bone marrow disorder. If your white blood cell count decreases, your doctor should monitor you closely for the development of fever or infection. It is not known if Betaferon has a negative effect on human fertility but based on the experience with other interferons, a decrease in male or female fertility cannot be ruled out. There is no information on the use of Betaferon in patients with kidney problems. Therefore, if you have such problems, your kidney function should be monitored during treatment. During the treatment with Betaferon your body may produce substances which may reduce the effectiveness of the treatment. This is called neutralising activity and only occurs in some patients. However, it is not possible to foresee whether you belong to this group of patients with reduced efficacy or not. May Betaferon be used during pregnancy and lactation? Betaferon should not be used during pregnancy or if you are trying to become pregnant. If you wish to become pregnant, discuss the matter with your doctor first. While using Betaferon women of childbearing age should take appropriate contraceptive measures. If you do become pregnant you should stop your treatment and contact your doctor immediately. It is not known whether Interferon beta-1b is excreted in human milk. However, since serious adverse reactions to Interferon beta-1b in breast-fed infants are theoretically possible, you should discuss the matter with your doctor and make a decision whether breast-feeding or Betaferon should be stopped. What to be aware of if you are taking any other medicine (interactions) With the exception of corticoids or ACTH, Betaferon should not be used with substances modifying the immune system response.

Caution should be exercised when Interferon beta-1b is administered in combination with other drugs which need a certain liver enzyme system (known as cytochrome P450 system) for their metabolism. These drugs include some widely used antipyretics (drugs against fever and pain), oral contraceptives, and anti-epileptics.

How is Betaferon used?

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(Dosage and administration) The treatment with Betaferon should be initiated under the supervision of a physician experienced in the treatment of the disease. At the present time it is not known how long treatment with Betaferon should last. Effectiveness of this therapy for more than two years has not been established. The duration of treatment will be decided by your doctor. Treatment is not recommended if you have had fewer than two MS attacks in the previous two years. Before administration, the Betaferon solution for injection has to be prepared from a vial of Betaferon and 1.2 ml of liquid from a vial of diluent. 1.0 ml of the prepared Betaferon solution for injection is then injected subcutaneously (under the skin) every other day. This is equal to 0.25 mg (8 million IU). This will either be done by your doctor or his/her assistant or by yourself after you have been carefully and sufficiently instructed and trained. To assist you in subcutaneous self-administration of Betaferon, detailed instructions for self-injection are provided with this leaflet. These instructions also tell you how the Betaferon solution for injection is prepared. What to do if you miss an injection If you forget to administer your injection at the correct time you should give it as soon as you remember. Your next injection should be given 48 hours later. What effect could an overdose of Betaferon have? (Overdosage) Administration of many times the dose of Betaferon recommended for the treatment of MS did not lead to life-threatening situations. However, in the case of accidental overdosage, please consult the doctor who has prescribed Betaferon for you. Also if by mistake you administer your injection too frequently (e. g. one injection every 24 h instead of one injection every 48 h) you should consult you doctor. Are there any side effects during the use of Betaferon? Injection site reactions including inflammation, pain, hypersensitivity, skin cell-death (necrosis), and non-specific reactions occurs frequently. The occurrence of injection site reactions usually decreases over time. Flu-like symptoms (fever, chills, muscular pain, a general feeling of being unwell, or sweating) have been seen frequently. The occurrence of the symptoms decreased over time. Menstrual disorders may occur in premenopausal women. Central nervous system (CNS) related adverse events including depression, anxiety, emotional instability, loss of identity or reality (depersonalization), convulsions, suicide attempts, and confusion have been observed. Serious hypersensitivity reactions are rare. If a severe reaction occurs, consult your doctor immediately.

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The number of white blood cells can decrease and the activity of enzymes which are closely related to the function of the liver may increase. Therefore, a differential white blood count and determination of serum chemistry (SGOT, SGPT) should be obtained prior to treatment and repeated regularly during the therapy. If side effects are severe or if you notice any other side effects please inform your doctor. How should Betaferon be stored? Betaferon must be kept cold (2 - 8 °C). Store it in a refrigerator (but not in a freezer or the freezing compartment) before reconstitution (preparing the Betaferon solution for injection). If, after reconstitution, you do not inject Betaferon at once, you can store the reconstituted solution in a refrigerator (but not in a freezer or the freezing compartment) up to 3 hours. Please note the expiry date on the pack. Do not use after this date. Store all drugs properly and keep them out of the reach of children. Package insert was last updated on: Annex: SELF-INJECTION PROCEDURE The following instructions are intended to explain how to prepare Betaferon for administration and how to proceed in injecting Betaferon yourself. Please read the instructions carefully and follow them step by step. Your doctor or his/her assistant will instruct and assist you in learning the procedure and the technique of self-administration. Do not attempt self-administration until you are sure that you understand the requirements for preparing the injection solution and giving the injection to yourself. The instructions comprise the following main steps: I. Preparing for self-injection. II. Drawing up the diluent (sodium chloride solution) into the syringe. III. Injecting the required volume of diluent (1.2 ml) into the vial of Betaferon. IV. Drawing up the required volume of the solution for injection (1.0 ml) into the syringe. V. Choosing and preparing the injection site and injecting the Betaferon solution (1.0 ml)

subcutaneously (under the skin). I. Preparing for self-injection 1. Collect all your equipment before you begin the process. You will need: • vial of diluent for Betaferon (sodium chloride solution 0.54 %) • vial of Betaferon • 2-ml syringe • 21-gauge needle

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• 27-gauge needle • alcohol wipes • disposal unit (a container for used syringes and needles) 2. Wash your hands thoroughly with soap and water. 3. Remove the protective caps from both vials. 4. Use alcohol wipes to clean the tops of the vials - move in one direction and use one wipe per

vial. NOTE: Leave an alcohol wipe on top of each vial until you are ready to use it. II. Drawing up the diluent (sodium chloride solution) into the syringe. Only the vial of diluent (liquid) that comes inside your prescription package should be used to dissolve the white powder in the Betaferon vial. 1. Resting your hands on a stable surface, remove the syringe from its wrapping. Do not touch

the tip (nozzle) of the syringe. 2. Take the 21-gauge needle out of its wrapping and place it firmly onto the tip (nozzle) of the

syringe. Remove the needle guard from the needle. Do not touch the needle. 3. Pull back the plunger (on the syringe) to the 1.2 ml mark. NOTE: Read the label on the vials - find the diluent vial and throw away the alcohol wipe on top of it. 4. Holding the vial of diluent on a stable surface, slowly insert the needle straight through the

rubber stopper, into the top of the vial. NOTE: When inserting and removing needles from vials, be sure not to touch the needles or the rubber stoppers on the vials with your hands. If you do touch a stopper, clean it with a fresh alcohol wipe. If you touch a needle or the tip (nozzle) of the syringe, throw it away into the disposal unit and start with a new one. If the needle touches any surface, throw it away into the disposal unit and start with a new one. 5. Push in the plunger all the way to gently inject air into the vial (leave the needle in the vial

of diluent). 6. Turn the vial of diluent upside down. NOTE: Keep the needle tip in the liquid. 7. Resting your hands on a stable surface, hold the vial and syringe in one hand and slowly

pull back the plunger of the syringe to the 1.2 ml mark (to draw up that amount of liquid) with your other hand.

8. Keeping the vial upside down, gently tap the syringe until any air bubbles rise to the top of

the barrel of the syringe.

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9. Carefully push in the plunger to eject ONLY THE AIR through the needle. Make sure that

the syringe contains 1.2 ml of diluent. 10. Remove the needle with the syringe from the vial of diluent. III. Injecting the required volume of diluent (1.2 ml) into the vial of Betaferon NOTE: Find the Betaferon vial and throw away the alcohol wipe on top of it. 1. Holding the Betaferon vial on a stable surface, slowly insert the needle of the syringe

(containing 1.2 ml of liquid) all the way through the stopper of the vial. 2. Push the plunger down slowly, directing the needle toward the side of the vial to allow the

liquid to run down the inside wall (injecting diluent directly onto the powder will cause excess foaming).

3. Make sure that the needle does not come into contact with the powder or the resulting

solution. 4. After the diluent in the syringe has been completely injected into the Betaferon vial hold

the vial between your thumb, forefinger and middle finger with the needle and syringe resting against your hand.

5. Gently rotate your hand to completely dissolve the white powder of Betaferon. DO NOT

SHAKE! 6. Look closely at the solution (it should be clear). NOTE: If the mixture contains particles or is discoloured, throw it away and start again. IV. Drawing up the required volume of the solution for injection (1.0 ml) into the

syringe 1. Slightly incline the vial of Betaferon solution and keep the needle tip at the lowest point of

the vial. Note: Keep the needle tip in the liquid. 2. Pull back the plunger to withdraw 1.0 ml of liquid into the syringe. 3. Turn the vial upside down and hold the syringe with the needle pointing upward. 4. Tap the syringe gently until any air bubbles rise to the top of the barrel of the syringe. 5. Carefully push in the plunger to eject ONLY THE AIR through the needle. 6. Remove the syringe from the needle. Leave the needle in the vial. 7. Place the syringe (without needle) on a surface. Make sure that the tip (nozzle) of the

syringe does not touch the surface. 8. Find the 27-gauge needle, take it out of its wrapping and place it firmly onto the tip

(nozzle) of the syringe.

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9. Throw away unused portion of the solution remaining in the vial and the needle in it. NOTE: The injection should be administered immediately after mixing (if the injection is delayed, refrigerate the solution and inject it within 3 hours). Do not freeze. V. Choosing and preparing the injection site and injecting the Betaferon solution (1.0

ml) subcutaneously (under the skin) 1. Choose an injection site (see enclosed medication record card with an injection sites

diagram). You may want to hold the syringe like a pencil or dart. Use a different site each day you inject:

• Arms (upper back portion) • Abdomen (except around navel and waistline) • Buttocks • Thighs (front and sides except at groin and knee) NOTE: Do not use any areas in which you feel lumps, firm knots, depressions, pain, or discoloration; talk to your doctor or healthcare professional about anything you find. 2. Use an alcohol wipe to clean the skin at the injection site; let it air dry. 3. Throw away the wipe. 4. Find the syringe with the 27-gauge needle on it. Remove the needle guard from the needle.

Make sure not to touch the needle. 5. Gently pinch the skin together around the site (to lift it up a bit). 6. Resting your wrist on the skin near the site, stick the needle straight into the skin at a 90°

angle with a quick, firm motion. 7. Inject the drug by using a slow steady push (push the plunger all the way in until the

syringe is empty).

8. Hold a swab on the injection site. Remove the needle from the skin. 9. Gently massage the injection site with a dry cotton ball or gauze. 10. Throw away the syringe and the needle in the disposal unit.

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INJECTION SITE Picking an injection site Betaferon (Interferon beta-1b) therapy should be injected into subcutaneous (under the skin) tissue. The best areas for injection are loose and soft (flabby), away from joints and nerves. Each therapy day you can choose an injection site from the ones identified in the diagrams. It's a good idea to know where your injection will be given before you prepare your syringe. If there are any sites that are difficult for you to reach, you can ask your support person (or someone who has been trained to give injections) to help you. Rotating injection sites Changing sites each time helps prevent injection reactions: it gives the site time to "bounce back" from the last injection. Today's injection should not be given in the same areas as the last one. Keep a record of where and when you last gave yourself an injection. One way to do this is to note this information on the enclosed medication record card. You may use a site again after waiting 1 week. If all areas become tender, talk to your doctor about choosing other injection sites.

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For any information please contact the local representative of the marketing authorization holder. …Österreich Postfach 50 A- 1147 Wien Tel. (0222) 97037

United Kingdom The Brow GB-Burgess Hill, West Sussex, RH15 9NE Tel. 01444-232323

Belgique/België J.E. Mommaertslaan 14 B- 1831 Diegem Tel. 02-7204900

E

Deutschland D- 13342 Berlin Tel. 01 30-112322

Italia Via di Tor Cervara, 282 I- 00155 Roma Tel. 06-228901

Danmark Fjeldhammervej 8 DK- 2610 Rødovre Tel. 36 70 5555

Ireland 44 Darthmouth Square IRL- Dublin 6 Tel. 01-6688566

España C. Méndez Alvaro, 55 E- 28045 Madrid Tel. 902 246246

Nederland Postbus 116 NL- 1380 AC Weesp Tel. 0294-462424

France Rue de Toufflers F- 59390 Lys-Lez-Lannoy Tel. 20.81.37.00

Portugal Estrada Nacional 249, km 15 Apartado 16 P-2726 Mem Martins Codex Tel. 01-9268110

Suomi/Finland Eerikinkatu 24 SF-00100 Helsinki Tel. 09 685 0440

Sverige Box 23117 S-104 35 Stockholm Tel. 08-7297979

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