250 microgram/ml powder and solvent for solution for injection

Transcription

1 פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר על ידו בספטמבר 2011 (interferon beta-1b) /ml powder and solvent for solution for injection Prescribing information 1 NAME OF THE MEDICINAL PRODUCT /ml powder and solvent for solution for injection 2 QUALITATIVE AND QUANTITATIVE COMPOSITION One vial with powder for solution for injection contains 300 microgram (9.6 million IU) recombinant Interferon beta-1b (including a calculated overfill of 20%). When reconstituted, 1 ml solution for injection contains (8.0 million IU) recombinant Interferon beta-1b*. * produced by genetic engineering from strain of Escherichia coli. 1 ml solution for injection contains 5.4 mg sodium chloride. For full list of excipients, see section PHARMACEUTICAL FORM Powder and solvent for solution for injection. Powder for solution for injection: white to off-white powder Solvent for solution for injection: clear, colorless liquid 4 CLINICAL PARTICULARS 4.1 Therapeutic indications is indicated for the treatment of: For use in relapsing-remitting and relapsing-progressive multiple sclerosis. It is designated for ambulatory patients who meet criteria for clinically definite and for laboratory supported definite MS, and who have experienced at least two exacerbations over the last two years. reduces the frequency of clinical exacerbations. In secondary progressive multiple sclerosis is indicated for slowing progression of disease and for the reduction of frequency of clinical relapses. Compared with placebo, patients receiving showed a statistically significant delay in time to progression of multiple sclerosis. The treatment effect occurred in patients with and without relapses and at all levels of disability investigated (patients with mild disease and those unable to walk were not studied). Patients receiving also showed a statistically significant delay in the time to become wheelchairbound when compared with placebo. See also Section 5.1 Pharmacodynamic properties. Secondary progressive multiple sclerosis patients receiving showed a reduction in EXT API SEP11 CL V1 1 REF Betaferon PI

2 frequency (30%) of clinical relapses. There is no evidence of an effect of on the duration of exacerbations. 4.2 Dosage and method of administration Method of administration: Subcutaneous injection Adults The treatment with should be initiated under the supervision of a physician experienced in the treatment of the disease. The recommended dose of is (8 million IU), contained in 1 ml of the reconstituted solution (see section 6.6 Instructions for use/handling), to be injected subcutaneously every other day. Generally, dose titration is recommended at the start of treatment. Patients should be started at 62.5 microgram (0.25 ml) subcutaneously every other day, and increased slowly to a dose of (1.0 ml) every other day (see Table A). The titration period may be adjusted according to individual tolerability. Table A: Schedule for dose titration* Treatment day Dose Volume 1, 3, microgram 0.25 ml 7, 9, microgram 0.5 ml 13, 15, microgram 0.75 ml ml * The titration period may be modified according to individual tolerability. Duration of treatment At the present time it is not known for how long the patient should be treated. Efficacy for a period of up to three years of treatment has been demonstrated in a controlled clinical trial. There are follow-up data under controlled clinical trial conditions for patients with relapsing-remitting MS for up to 5 years and for patients with secondary progressive MS for up to 3 years. Non-controlled follow-up data for patients with secondary progressive MS exist for up to 4.5 years. For relapsing-remitting MS, the available data for up to 5 years suggest sustained treatment efficacy of over the whole time period. For secondary progressive MS efficacy for a period of two years with limited data for a period of up to three years of treatment has been demonstrated under controlled clinical trial conditions. Children and adolescents Efficacy and safety of were not investigated systematically in children and adolescents of less than 18 years of age, therefore, should not be administered to this age group. 4.3 Contraindications is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon-ß, human albumin or to any excipients or to any of the excipients. Patients with current severe depression and/or suicidal ideation (see below) Patients with decompensated liver disease (see below). Initiation of treatment in pregnancy EXT API SEP11 CL V1 2 REF Betaferon PI

3 4.4 Special warnings and special precautions for use Nervous system Patients to be treated with should be informed that depressive and suicidal ideation may be a side effect of the treatment (see section 4.8 Undesirable effects) and should report these symptoms immediately to the prescribing physician. In rare cases these symptoms may result in a suicide attempt. Patients exhibiting depression and suicidal ideation should be monitored closely and cessation of therapy should be considered. In two controlled clinical trials involving 1657 patients with secondary progressive multiple sclerosis, there were no significant differences between treated patients and placebo treated patients with regard to depression and suicidal ideation. However, because it can not be excluded that treatment may be associated with depression and suicides in individual patients, should be used with caution in patients with previous or current depressive or suicidal ideation. Cessation of therapy should be considered if such events develop during therapy. This product contains human albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeld-Jacob disease (CJD) is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. should be administered with caution to patients with a history of seizures, to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with antiepileptics (see sections 4.5 and 4.8). Laboratory tests In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests (e.g. ASAT (SGOT), ALAT (SGPT) and γ-gt), are recommended prior to initiation and at regular intervals following introduction of therapy, and then periodically thereafter in the absence of clinical symptoms (see section 4.8 Undesirable effects). Thyroid function tests are recommended regularly in patients with a history of thyroid dysfunction or as clinically indicated. Patients with anemia, thrombocytopenia, leukopenia (alone or in any combination) may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. Patients who develop neutropenia should be monitored closely for the development of fever or infection. There have been reports of thrombocytopenia, with profound decreases in platelet count. Hepato-biliary Asymptomatic elevations of serum transaminases, in most cases mild and transient, occurred very commonly in patients treated with during clinical trials (see section 4.8 Undesirable effects). As for other beta interferons, cases of severe hepatic injury, including hepatic failure, have been reported. The most severe events often occurred in patients exposed to other drugs or substances known to be associated with hepatotoxicity or in the presence of comorbid medical conditions (e.g. metastasizing malignant disease, severe infection and sepsis, alcohol abuse). Patients should be monitored for signs of hepatic injury. The occurrence of elevations in serum transaminases should lead to close monitoring and investigation. Withdrawal of should be considered if the levels significantly increase or if they are associated with clinical symptoms such as jaundice. In the absence of clinical evidence for liver damage and after normalization of liver enzymes a reintroduction of therapy could be considered with appropriate follow-up of hepatic functions. Renal and urinary EXT API SEP11 CL V1 3 REF Betaferon PI

4 Caution should be used and close monitoring considered when administering interferon beta to patients with severe renal failure. Cardiac should be used with caution in patients with pre-existing significant cardiac disease, such as congestive heart failure, coronary artery disease or arrhythmias. While there is no evidence of a direct cardiotoxic potential for, these patients should be monitored for worsening of their cardiac condition. This applies particularly during initiation of treatment with, where flu-like symptoms, commonly associated with beta interferons, exert cardiac stress through fever, chills and tachycardia. This may aggravate cardiac symptoms in patients with pre-existing significant cardiac disease. During the postmarketing period very rare reports have been received of worsening of cardiac status in patients with pre-existing significant cardiac disease, temporally associated with the initiation of therapy. Cases of cardiomyopathy have been reported: if this occurs and a relationship to is suspected, treatment should be discontinued. Gastrointestinal Cases of pancreatitis were reported with use, often associated with hypertriglyceridaemia (see section 4.8 Undesirable effects). Immune system The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of systemic capillary leak syndrome with shock-like symptoms and fatal outcome. General and administration site conditions Serious hypersensitivity reactions (severe acute reactions such as bronchospasm, anaphylaxis and urticaria) may occur. If reactions are severe, should be discontinued and appropriate medical intervention instituted. Injection site necrosis (ISN) has been reported in patients using (see section 4.8 Undesirable effects). It can be extensive and may involve muscle fascia as well as fat and therefore can result in scar formation. Occasionally debridement and, less often, skin grafting are required and healing may take up to 6 months. If the patient experiences any break in the skin, which may be associated with swelling or drainage of fluid from the injection site, the patient should be advised to consult with their physician before continuing injections with. If the patient has multiple lesions should be discontinued until healing has occurred. Patients with single lesions may continue on provided the necrosis is not too extensive, as some patients have experienced healing of injection site necrosis whilst on. To minimize the risk of injection site necrosis patients should be advised to: use an aseptic injection technique rotate the injection sites with each dose The procedure for the self-administration by the patient should be reviewed periodically especially if injection site reactions have occurred. This medicinal product contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially 'sodium-free'. Immunogenicity EXT API SEP11 CL V1 4 REF Betaferon PI

5 As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples in controlled clinical trials were collected every 3 months for monitoring of development of antibodies to. In the different controlled clinical trials, between 23% and 41% of the patients developed serum interferon beta- 1b neutralising activity confirmed by at least two consecutive positive titres; of these patients, between 43% and 55% converted to a stable antibody negative status (based on two consecutive negative titres) during the subsequent observational period of the respective study. The development of neutralising activity is associated with a reduction in clinical efficacy only with regard to relapse activity. Some analyses suggest that this effect might be larger in patients with higher titre levels of neutralising activity. In the study of patients with a single clinical event suggestive of multiple sclerosis, neutralizing activity measured every 6 months was observed at least once in 32% (88) of the patients treated immediately with ; of these, 47% (41) returned to negative status over a 3-year period. Within this period, the development of neutralising activity was not associated with a reduction in clinical efficacy (with regard to time to clinically definite multiple sclerosis (CDMS), and time to confirmed EDSS progression). New adverse events have not been associated with the development of neutralising activity. It has been demonstrated in vitro that cross-reacts with natural interferon beta. However, this has not been investigated in vivo and its clinical significance is uncertain. There are sparse and inconclusive data on patients who have developed neutralising activity and have completed therapy. The decision to continue or discontinue treatment should be based on clinical disease activity rather than on neutralising activity status. 4.5 Interaction with other medicaments and other forms of interaction No formal drug interaction studies have been carried out with. The effect of 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. Use of was not studied with the co-administration of immunomodulators other than corticoids or ACTH. Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. Caution should be exercised when 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. Caution should be exercised with any co-medication which has an effect on the hematopoetic system. No interaction studies with anti-epileptics have been carried out. 4.6 Pregnancy and lactation Pregnancy It is not known whether can cause fetal 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 an increased rate of abortions with higher doses (for preclinical results see section 5.3 Preclinical safety data). Therefore, women of childbearing potential should take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking, she should be informed of the potential hazard and it should be recommended to discontinue therapy (for preclinical results refer to section 5.3 Preclinical safety data). In patients with a high relapse rate before treatment started, the risk of a severe relapse following discontinuation of EXT API SEP11 CL V1 5 REF Betaferon PI

6 in the event of pregnancy should be weighed against a possible increased risk of spontaneous abortion. Lactation It is not known whether interferon beta-1b is excreted in human milk. Because of the potential for serious adverse reactions to in nursing infants a decision should be made whether nursing or the drug 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 might influence the ability to drive and use machines in susceptible patients. 4.8 Undesirable effects a) At the beginning of treatment adverse reactions are common but in general they subside with further treatment. The most frequently observed adverse reactions are a flu-like symptom complex (fever, chills, arthralgia, malaise, sweating, headache, or myalgia), which is mainly due to the pharmacological effects of the medicinal product, and injection site reactions. Injection site reactions occurred frequently after administration of. Redness, swelling, discoloration, inflammation, pain, hypersensitivity, necrosis and non-specific reactions were significantly associated with (8 million IU) treatment. Generally, dose titration is recommended at the start of treatment in order to increase tolerability to (see section 4.2). Flu-like symptoms may also be reduced by administration of nonsteroidal anti-inflammatory medicinal products. The incidence of injection site reactions may be reduced by the use of an auto-injector. b) The following adverse event listing is based on reports from clinical trials (Table 1, adverse events and laboratory abnormalities) and from the post-marketing surveillance (Table 2, reporting rates based on spontaneous adverse drug reaction reports classified as very common 1/10, common 1/100 to <1/10, uncommon 1/1,000 to < 1/100, rare 1/10,000 to <1/1,000, very rare < 1/10,000) of use. Experience with in patients with multiple sclerosis (MS) is limited, consequently those adverse events which occur very rarely may not yet have been observed. Table 1 System Organ Class Adverse events and laboratory abnormalities with incidence rates 10% and the respective percentages under placebo; significantly associated side effects <10% Adverse Event and Laboratory Abnormalities Secondary Progressive (European Study) n=360 (n=358) Secondary Progressive (North American Study) n=317 (n=308) Relapsing- Remitting n=124 (n=123) Infections and infestations Infection 13% (11%) 11% (10%) 14% (13%) Abscess 4% (2 %) 4% (5%) 1 % (6 %) Blood and lymphatic system EXT API SEP11 CL V1 6 REF Betaferon PI

7 System Organ Class Adverse Event and Laboratory Abnormalities Lymphocyte count decreased (<1500/mm³) Absolute neutrophil count decreased (<1500/mm³) * White blood cell count decreased (<3000/mm³) * Secondary Progressive (European Study) n=360 (n=358) Secondary Progressive (North American Study) n=317 (n=308) Relapsing- Remitting n=124 (n=123) 53% (28%) 88% (68%) 82 % (67 %) 18% (5%) 4% (10%) 18 % (5 %) 13% (4%) 13% (4%) 16 % (4) % Lymphadenopathy 3% (1 %) 11% (5%) 14 % (11 %) Metabolism and nutrition Blood glucose decreased 27% (27%) 5% (3%) 15 % (13 %) (<55 mg/dl) Psychiatric Depression 24% (31%) 44% (41%) 25% (24%) Anxiety 6% (5 %) 10% (11%) 15 % (13 %) Nervous system Headache 47% (41 %) 55% (46%) 84 % (77 %) Dizziness 14% (14 %) 28% (26%) 35 % (28 %) Insomnia 12% (8 %) 26% (25%) 31 % (33 %) Migraine 4% (3 %) 5% (4%) 12 % (7 %) Paraesthesia 35% (39%) 40% (43%) 19% (21%) Eye Conjunctivitis 2% (3 %) 6% (6%) 12 % (10 %) Abnormal vision 11% (15%) 11% (11%) 7% (4%) Ear and labyrinth Ear pain <1% (1 %) 6% (8%) 16 % (15 %) Cardiac Palpitation * 2% (3 %) 5% (2%) 8 % (2 %) Vascular Vasodilatation 6% (4%) 13% (8%) 18% (17%) Hypertension 4% (2 %) 9% (8%) 7 % (2 %) Respiratory, thoracic and mediastinal Upper respiratory 3% (2%) infection Sinusitis 6 % (6%) 16% (18%) 36 % (26 %) Cough increased 5% (10%) 11% (15%) 31% (23%) Dyspnoea * 3% (2 %) 8% (6%) 8 % (2 %) Gastrointestinal Diarrhoea 7% (10 %) 21% (19%) 35 % (29 %) Constipation 12% (12 %) 22% (24%) 24 % (18 %) Nausea 13% (13%) 32% (30%) 48% (49%) Vomiting 4% (6 %) 10% (12%) 21 % (19 %) Abdominal pain 11% (6 %) 18% (16%) 32 % (24 %) EXT API SEP11 CL V1 7 REF Betaferon PI

8 System Organ Class Adverse Event and Laboratory Abnormalities Hepatobiliary Alanine aminotransferase increased (SGPT >5 times baseline) * Aspartate aminotransferase increased (SGOT Secondary Progressive (European Study) n=360 (n=358) Secondary Progressive (North American Study) n=317 (n=308) Relapsing- Remitting n=124 (n=123) 14% (5%) 4% (2%) 19 % (6 %) 4% (1%) 2% (1%) 4 % (0 %) >5 times baseline) * Skin and subcutaneous tissue Skin disorder 4% (4%) 19% (17%) 6% (8%) Rash 20% (12%) 26% (20%) 27% (32 %) Musculoskeletal and connective tissue Hypertonia 41% (31 %) 57% (57%) 26 % (24 %) Myalgia * 23% (9 %) 19% (29%) 44% (28 %) Myasthenia 39% (40 %) 57% (60%) 13% (10 %) Back pain 26% (24%) 31% (32%) 36% (37%) Pain in extremity 14% (12 %) 0 % (0 %) Renal and urinary Urinary retention 4% (6%) 15% (13%) Urinary protein positive 14% (11%) 5% (5%) 5 % (3 %) (>1+) Urinary frequency 6% (5%) 12% (11%) 3% (5%) Urinary incontinence 8% (15%) 20% (19%) 2% (1%) Urinary urgency 8% (7%) 21% (17%) 4% (2 %) Reproductive system and breast 89% (37%) 85% (37 %) Dysmenorrhoea <1% (<1%) 6% (5%) 18% (11 %) Menstrual disorder * 9% (13%) 10% (8%) 17% (8 %) Metrorrhagia 12% (6%) 10% (10%) 15% (8 %) Impotence 7% (4%) 10% (11%) 2% (1%) General and administration site conditions Injection site reaction 78% (20 %) (various kinds) * Injection site necrosis * 5% (0 %) 6% (0%) 5% (0 %) Flu-like symptoms & * 61% (40 %) 43% (33%) 52 % (48 %) Fever * 40% (13 %) 29% (24%) 59 % (41 %) Pain 31% (25 %) 59% (59%) 52 % (48 %) Chest pain 5% (4%) 15% (8%) 15% (15%) Peripheral oedema 7% (7%) 21% (18%) 7% (8%) Asthenia * 63% (58 %) 64% (58%) 49 % (35 %) Chills * 23% (7 %) 22% (12%) 46 % (19 %) Sweating * 6% (6%) 10% (10%) 23% (11 %) Malaise * 8% (5 %) 6% (2%) 15 % (3 %) EXT API SEP11 CL V1 8 REF Betaferon PI

9 System Organ Class Adverse Event and Laboratory Abnormalities Secondary Progressive (European Study) n=360 (n=358) Secondary Progressive (North American Study) n=317 (n=308) Relapsing- Remitting n=124 (n=123) Laboratory abnormality * Significantly associated with treatment for RRMS, p <0.05 Significantly associated with treatment for SPMS, p <0.05 Injection site reaction (various kinds) comprises all adverse events occurring at the injection site, i.e. the following terms: injection site haemorrhage, injection site hypersensitivity, injection site inflammation, injection site mass, injection site necrosis, injection site pain, injection site reaction, injection site oedema, and injection site atrophy & Flu-like symptom complex denotes flu syndrome and/or a combination of at least two adverse events from fever, chills, myalgia, malaise, sweating. The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions. Table 2 Reporting rates (very common 1/10, common 1/100 to <1/10, uncommon 1/1,000 to <1/100, rare 1/10,000 to <1/1,000, very rare <1/10,000) based on spontaneous adverse drug reaction reports System Organ Class Blood and lymphatic system Immune system Endocrine Metabolism and nutrition Psychiatric Nervous system Cardiac Very common 1/10 Common 1/100 to <1/10 Uncommon 1/1,000 to <1/100 Anemia, Thrombocytopenia, Leukopenia Depression (see also section 4.4) Rare 1/10,000 to <1/1,000 Lymphadenopathy Anaphylactic reactions Hyperthyroidism, Hypothyroidism, Thyroid disorder Blood triglycerides increased, Anorexia Confusion, Anxiety, Emotional lability, Suicide attempt (see also section 4.4) Convulsion Cardiomyopathy, Tachycardia, Palpitation EXT API SEP11 CL V1 9 REF Betaferon PI

10 System Organ Class Vascular Respiratory, thoracic and mediastinal Gastrointestinal Hepatobiliary Skin and subcutaneous tissue Musculoskeletal, connective tissue and bone Reproductive system and breast General and administration site conditions Very common 1/10 Flu-like symptoms*, Chills*, Fever *, Injection site reaction*, Injection site inflammation*, Injection site pain Investigations * frequencies based on clinical trials Common 1/100 to <1/10 Injection site necrosis* Uncommon 1/1,000 to <1/100 Hypertension Vomiting, Nausea Alanine aminotransferase increased, Aspartate aminotransferase increased Urticaria, Rash, Pruritus, Alopecia Myalgia, Hypertonia Rare 1/10,000 to <1/1,000 Bronchospasm, Dyspnoea Pancreatitis Blood bilirubin increased, Gamma-glutamyltransferase increased, Hepatitis Skin discolouration Menstrual disorder Chest pain, Malaise, Sweating Weight decrease The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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 Pharmacotherapeutic group: Cytokines, Interferons ATC Code: L03AB08 EXT API SEP11 CL V1 10 REF Betaferon PI

11 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 activities. 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 internalization 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 on the cardiovascular system, respiratory system and the function of endocrine organs. Clinical trial data for SP-MS and RR-MS: Patients with secondary progressive disease receiving showed a delay of up to 12 months in time to progression of disability including time to severely disabling stages, i.e. patients becoming wheelchair bound. This delay in disability occurred in patients with or without relapses and at all levels of disability investigated (expanded disability status scale [EDSS] 3-6.5). Both relapsing-remitting and secondary progressive multiple sclerosis patients receiving showed a reduction in frequency (30 %) and severity of clinical relapses, as well as a prolongation of the relapse-free interval. The number of hospitalizations and steroid usage due to disease were reduced. Furthermore, in both relapsing-remitting and secondary progressive multiple sclerosis demonstrated a significant beneficial effect on disease burden as measured by T2-weighted Magnetic Resonance Immaging (MRI) scans and on newly active lesions as measured by 6 weekly MRIs in relapsing-remitting MS and by monthly contrast medium (Gd-DTPA) enhanced T1 weighted MRIs (month 1-6 and 19-24) in secondary-progressive MS. An increase in MRI disease burden has been demonstrated to correlate with an increase in disability as measured by EDSS. 5.2 Pharmacokinetic properties serum levels were followed in patients and volunteers by means of a not completely specific bioassay. Following subcutaneous administration of the recommended dose of 0.25 mg of, serum concentrations of interferon beta-1b are low or not detectable. Pharmacokinetic information in patients with MS receiving the recommended dose of is therefore not available. Following subcutaneous injection of 0.5 mg of to healthy volunteers, maximum serum levels of about 40 IU/ml were found 1-8 hours after dosing. In this study, the absolute bioavailability of subcutaneously administered was estimated at approximately 50%. From various studies with intravenous administration of interferon beta-1b, mean clearance and disposition half-life from serum were estimated to be at most 30 ml/min/kg and 5 hours, respectively. Every other day injections do not lead to serum level increases and pharmacokinetics do not seem to change during therapy. Following every other day subcutaneous administration of 0.25 mg of in healthy volunteers, biologic response marker levels (neopterin, ß2-microglobulin and the immunosuppressive cytokine, IL- EXT API SEP11 CL V1 11 REF Betaferon PI

12 10) - increased significantly above baseline levels within 6 to 12 hours after the first dose. Biologic response marker levels peaked between 40 and 124 hours, and remained elevated above baseline throughout the seven day (168 hour) study period. The relationship between serum Interferon beta-1b levels or the levels of induced biologic response markers to the mechanism by which exerts its effects in MS is unknown. 5.3 Preclinical safety data No acute toxicity studies have been carried out. As rodents do not react to human interferon beta, risk assessment was based on repeated dose studies carried out with rhesus monkeys. Transitory hyperthermia was observed, as well as a significant transient rise in lymphocytes and a significant transient decrease in thrombocytes and segmented neutrophils. No long-term studies have been conducted. Reproduction studies with rhesus monkeys revealed maternal toxicity and an increased rate of abortions. No malformations have been observed in the surviving animals. No investigations on fertility have been conducted. No influence on the monkey estrous cycle has been observed. 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. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder for solution for injection: Human albumin Mannitol Solvent for solution for injection: Sodium chloride Water for injection 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products. 6.3 Shelf life of the product as packaged for sale 2 years, 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 Do not store above 25 C. Do not freeze. EXT API SEP11 CL V1 12 REF Betaferon PI

13 6.5 Nature and contents of container 3 ml clear glass vial (glass type I) with a 13 mm black chlorinated butyl rubber stopper and aluminum overseal. Each vial is provided with a separate pre-filled glass syringe (glass type I) of diluent containing 1.2 ml sterile sodium chloride solution (0.54% w/v). The tip cap is made of natural rubber. Pack sizes: For the 1.2-ml Vetter syringe: 15 vials with powder and 15 pre-filled syringes with solvent. 6.6 Instructions for use/handling Reconstitution/ Administration For the 1.2-ml Vetter syringe: To reconstitute lyophilized interferon beta-1b for injection, use a sterile syringe (here: the pre-filled diluent syringe) and a needle to inject 1.2 ml of the diluent (sodium chloride solution, 0.54 % w/v) into the vial. Dissolve the powder completely without shaking. After reconstitution, draw 1.0 ml from the vial into the syringe for the administration of s. For dose titration at the start of treatment draw the respective volume as given in section 4.2 Dosage and method of administration. Discard any unused solution for injection. Inspection prior to use Do not use cracked vials. Inspect the reconstituted product visually before use. Discard the product before use if it contains particulate matter or is discolored. The reconstituted solution contains 0.25 mg (8 million IU) of interferon beta-1b per ml. Use of an autoinjector The incidence of injection site reactions may be reduced by the use of autoinjectors. Manufacturer: Bayer Pharma AG, Germany For Novartis Pharma A.G., Basle, Switzerland Diluent, Solvent for solution for injection: Vetter Pharma-Fertigung GmbH & Co.K.G., Germany Registration holder: Novartis Pharma Services AG, 36 Shacham St., Petach-Tikva EXT API SEP11 CL V1 13 REF Betaferon PI