ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1

2 AVONEX 30µg (Interferon beta-1a) Flip-off presentation 1. NAME OF THE MEDICINAL PRODUCT AVONEX 30 µg powder and solvent for solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION AVONEX (Interferon beta-1a) contains a 30 µg (6 million IU) dose of Interferon beta-1a per vial. Using the World Health Organisation (WHO) natural interferon beta standard, Second International Standard for Interferon, Human Fibroblast (Gb ), 30 µg of AVONEX contains 6 million IU of antiviral activity. The activity against other standards is not known. 3. PHARMACEUTICAL FORM AVONEX (Interferon beta-1a) is a powder and solvent for solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications AVONEX (Interferon beta-1a) is indicated for the treatment of ambulatory patients with relapsing multiple sclerosis (MS) characterized by at least 2 recurrent attacks of neurologic dysfunction (relapses) over the preceding 3-year period without evidence of continuous progression between relapses. AVONEX slows the progression of disability and decreases the frequency of relapses. AVONEX is also indicated for the treatment of patients who have experienced a single demyelinating event with an active inflammatory process if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis (see section 5.1). AVONEX should be discontinued in patients who develop progressive multiple sclerosis. 4.2 Posology and method of administration The recommended dosage of AVONEX (Interferon beta-1a) for the treatment of relapsing MS is 30 µg injected (1 ml solution) IM once a week (see 6.6 Instructions for use and handling and disposal) and no additional benefit has been shown by administering a higher dose (60µg) once a week. Treatment should be initiated under supervision of a physician experienced in the treatment of the disease. There is no experience with AVONEX in patients aged 16 years or less. Therefore, AVONEX should not be used in children. The IM injection site should be varied each week (see 5.3 Preclinical safety data). Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with AVONEX administration. These symptoms are usually present during the first few months of treatment. 2

3 At the present time, it is not known for how long patients should be treated. Patients should be clinically evaluated after 2 years of treatment and longer-term treatment should be decided on an individual basis by the treating physician. Treatment should be discontinued if the patient develops chronic progressive multiple sclerosis. 4.3 Contraindications AVONEX (Interferon beta-1a) is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, human serum albumin or any other component of the formulation. AVONEX is contraindicated in pregnant patients (also see 4.6 Use during pregnancy and lactation), patients with severe depressive disorders and/or suicidal ideation and in epileptic patients with a history of seizures not adequately controlled by treatment. 4.4 Special warnings and special precautions for use Patients should be informed of the most common adverse events associated with interferon beta administration, including symptoms of the flu-like syndrome (see 4.8 Undesirable effects). These symptoms tend to be most prominent at the initiation of therapy and decrease in frequency and severity with continued treatment. AVONEX, as other interferons, should be used with caution in patients with depression or other mood disorders, conditions that are common with multiple sclerosis. Depression has been reported in association with AVONEX use and it may occur at any time during treatment. Patients treated with AVONEX should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting depression should be monitored closely during therapy with AVONEX and treated appropriately. Cessation of therapy should be considered. Caution should be exercised when administering AVONEX to patients with pre-existing seizure disorder. For patients without a pre-existing seizure disorder who develop seizures during therapy with AVONEX, an etiologic basis should be established and appropriate anti-convulsant therapy instituted prior to resuming AVONEX treatment. Caution should be used and close monitoring considered when administering AVONEX to patients with severe renal and hepatic failure and to patients with severe myelosuppression. Hepatic injury including elevated serum hepatic enzyme levels, hepatitis, autoimmune hepatitis and hepatic failure has been reported with Interferon beta in post-marketing. In some patients a recurrence of elevated serum levels of hepatic enzymes has occurred upon AVONEX rechallenge. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential of additive effects from multiple drugs or other hepatotoxic agents (e.g., alcohol) has not been determined. Patients should be monitored for signs of hepatic injury and caution exercised when interferons are used concomitantly with other drugs associated with hepatic injury. Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely monitored for worsening of their clinical condition during treatment with AVONEX. Symptoms of the flu-like syndrome associated with AVONEX therapy may prove stressful to patients with underlying cardiac conditions. Patients should be advised about the abortifacient potential of interferon beta (see 4.6 Use during pregnancy and lactation and 5.3 Preclinical safety data). Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete and differential white blood cell counts, platelet counts, and blood chemistry, including liver function tests, are recommended during AVONEX therapy. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. 3

4 Patients may develop antibodies to AVONEX. The antibodies of some of those patients reduce the activity of interferon beta-1a in vitro (neutralising antibodies). Neutralising antibodies are associated with a reduction in the in vivo biological effects of AVONEX and may potentially be associated with a reduction of clinical efficacy. It is estimated that the plateau for the incidence of neutralising antibody formation is reached after 12 months of treatment. Data from patients treated up to two years with AVONEX suggests that approximately 8% develop neutralising antibodies. The use of various assays to detect serum antibodies to interferons limits the ability to compare antigenicity among different products. 4.5 Interaction with other medicinal products and other forms of interaction No formal drug interaction studies have been conducted with AVONEX (Interferon beta-1a) in humans. The interaction of AVONEX with corticosteroids or ACTH has not been studied systematically. The clinical studies indicate that multiple sclerosis patients can receive AVONEX and corticosteroids or ACTH during relapses. Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. The effect of high-dose AVONEX administration on P450-dependent metabolism in monkeys was evaluated and no changes in liver metabolizing capabilities were observed. Caution should be exercised when AVONEX 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., antiepileptics and some classes of antidepressants. 4.6 Pregnancy and lactation Because of the potential hazards to the foetus, AVONEX (Interferon beta-1a) is contraindicated in pregnancy. There are no studies of Interferon beta-1a in pregnant women. At high doses, in rhesus monkeys, abortifacient effects were observed. It cannot be excluded that such effects will be observed in humans. Fertile women receiving AVONEX should take appropriate contraceptive measures. Patients planning for pregnancy and those becoming pregnant should be informed of the potential hazards and AVONEX should be discontinued. Nursing Mothers It is not known whether AVONEX is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made either to discontinue nursing or to discontinue AVONEX therapy. 4.7 Effects on ability to drive and use machines AVONEX has minor influence on the ability to drive and use machines (see 4.8 Undesirable effects ) 4.8 Undesirable effects The highest incidence of adverse reactions associated with AVONEX therapy is related to flu syndrome. The most commonly reported symptoms of the flu syndrome are myalgia, fever, chills, sweating, asthenia, headache and nausea. Symptoms of the flu syndrome tend to be most prominent at the initiation of therapy and decrease in frequency with continued treatment. Transient neurological symptoms that may mimic MS exacerbations may occur following injections. Transient episodes of hypertonia and/or severe muscular weakness that prevent voluntary movements 4

5 may occur at any time during treatment. These episodes are of limited duration, temporally related to the injections and may recur after subsequent injections. In some cases these symptoms are associated with flu-like symptoms. The frequencies of adverse reactions are expressed in patient-years, according to the following categories, Very common (>1/10 patient-years); Common (>1/100, <1/10 patient-years); Uncommon (>1/1, 000, <1/100 patient-years); Rare (>1/10, 000, <1/1,000 patient-years); Very rare (<1/10,000 patient-years); Patient time is the sum of individual units of time that the patient in the study has been exposed to AVONEX before experiencing the adverse reaction. For example, 100 person-years could be observed in 100 patients who were on treatment for one year or in 200 patients who were on treatment for half a year. EXPERIENCE FROM STUDIES (clinical trials and observational studies, with a period of follow-up ranging from 2 years to 6 years) Metabolism and nutrition disorders common anorexia Psychiatric disorders common Insomnia, depression(see section 4.4) Nervous system disorders very common common Vascular disorders common Respiratory disorders common rare Headache* hypoesthesia, muscle spasticity flushing rhinorrhoea dyspnoea, Gastrointestinal disorders common vomiting, diarrhoea, nausea* Skin and subcutaneous tissue disorders common uncommon rash, sweating increased, contusion alopecia 5

6 Musculoskeletal, connective tissue and bone disorders common muscle cramp, neck pain, myalgia*, arthralgia, pain in extremity, back pain muscle stiffness, musculoskeletal stiffness Reproductive system disorders Uncommon Uncommon metrorrhagia, menorrhagia General disorders and administration site conditions very common common uncommon Investigations common uncommon influenza-like illness, pyrexia*, chills*, sweating* injection site pain, injection site erythema, injection site bruising, asthenia*, pain, fatigue*, malaise, night sweats injection site burning lymphocyte count decreased, white blood cells count decreased, neutrophil count decreased, hematocrit decreased blood potassium increased, blood urea nitrogen increased platelet count decreased *The frequency of occurrence is higher at the beginning of treatment Other adverse reactions identified through spontaneous reporting, with unknown frequency are: Blood and lymphatic system disorders Endocrine disorders Psychiatric disorders Nervous system disorders Cardiac disorders pancytopenia,thrombocytopenia hypothyroidism,hyperthyroidism anxiety, suicide, psychosis,confusion, emotional lability neurological symptoms, syncope(1), hypertonia, dizziness, paraesthesia, seizures, migraine palpitations, tachycardia, arrythmia, cardiomyopathy, congestive heart failure (see section 4.4) 6

7 Vascular disorders Hepatobiliary disorders Skin and subcutaneous tissue disorders Musculoskeletal disorders General disorders and administration site conditions vasodilatation hepatitis, autoimmune hepatitis, hepatic failure (see section 4.4) pruritus, rash vesicular, urticaria, aggravation of psoriasis muscle weakness, arthritis, systemic lupus erythematosus injection site reaction, injection site inflammation, injection site cellulitis(2), injection site necrosis, chest pain Immune system disorders hypersensitivity, allergic reactions, anaphylactic reaction, anaphylactic shock Investigations weight decreased, weight increased, liver function tests abnormal Infections and infestations injection site abscess (2) (1) A syncope episode may occur after AVONEX injection, it is normally a single episode that usually appears at the beginning of the treatment and does not recur with subsequent injections. (2) Injection site reactions including pain, inflammation and very rare cases of abscess or cellulitis that may require surgical intervention have been reported. 4.9 Overdose No case of overdosage has been reported. However, in case of overdosage, patients should be hospitalised for observation and appropriate supportive treatment given. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Cytokines, ATC code L03 AB. Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons are cytokines that mediate antiviral, antiproliferative and immunomodulatory activities. Three major forms of interferons have been distinguished: alpha, beta and gamma. Interferons alpha and beta are classified as Type I interferons, and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinguishable biological activities. They can also differ with respect to their cellular sites of synthesis. Interferon beta is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and AVONEX (Interferon beta-1a) are glycosylated and have a single N-linked complex carbohydrate moiety. Glycosylation of other proteins is known to affect their stability, activity, biodistribution, and half-life in blood. However, the effects of interferon beta that are dependent on glycosylation are not fully defined. AVONEX exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include MHC Class I, Mx protein, 2 / 7

8 5 -oligoadenylate synthetase, β 2 -microglobulin, and neopterin. Some of these products have been measured in the serum and cellular fractions of blood collected from patients treated with AVONEX. After a single IM dose of AVONEX, serum levels of these products remain elevated for at least 4 days and up to 1 week. Whether the mechanism of action of AVONEX in multiple sclerosis is mediated by the same pathway as the biological effects described above is not known because the pathophysiology of multiple sclerosis is not well established. The effects of AVONEX in the treatment of multiple sclerosis were demonstrated in a single placebocontrolled study of 301 patients (AVONEX, n=158; placebo, n=143) with relapsing MS. Due to the design of the study, patients were followed for variable lengths of time. One hundred and fifty AVONEX-treated patients completed 1 year on study and 85 completed 2 years on study. In the study, the cumulative percentage of patients who developed disability progression (by Kaplan-Meier life table analysis) by the end of 2 years was 35% for placebo-treated patients and 22% for AVONEXtreated patients. Disability progression was measured as an increase in the Expanded Disability Status Scale (EDSS) of 1.0 point, sustained for at least 6 months. It was also shown that there was a one-third reduction in annual relapse rate. This latter clinical effect was observed after more than one year of treatment. A double-blind randomised dose comparison study of 802 relapsing MS patients (AVONEX 30 µg n=402, AVONEX 60 µg n=400) has shown no statistically significant differences or trends between the 30 µg and the 60 µg doses of AVONEX in clinical and general MRI parameters. The effects of AVONEX in the treatment of multiple sclerosis were also demonstrated in a randomised double blind study performed with 383 patients (AVONEX n= 193, placebo n=190) with a single demyelinating event associated with at least two compatible brain MRI lesions. A reduction of the risk of experiencing a second event was noted in the AVONEX treatment group. An effect on MRI parameters was also seen. The estimated risk of a second event was 50% in 3 years and 39% in 2 years in the placebo group and 35% (3 years) 21% (2 years) in the AVONEX group. In a post-hoc analysis, those patients with a baseline MRI with at least 1 Gd-enhancing lesion and 9 T2 lesions had a 2-year risk of suffering a second event of 56% in the placebo group and 21% in the AVONEX treatment group. However, the impact of early treatment with AVONEX is unknown even in this high-risk subgroup as the study was mainly designed to assess the time to the second event rather than the long term evolution of the disease. Furthermore, for the time-being there is no well established definition of a high risk patient although a more conservative approach is to accept at least 9 T2 hyperintense lesions on the initial scan and at least 1 new T2 or 1 new Gd-enhancing lesion on a follow-up scan taken at least 3 months after the initial scan. In any case treatment should only be considered for patients classified at high risk. 5.2 Pharmacokinetic properties The pharmacokinetic profile of AVONEX (Interferon beta-1a) has been investigated indirectly with an assay that measures interferon antiviral activity. This assay is limited in that it is sensitive for interferon but lacks specificity for interferon beta. Alternative assay techniques are not sufficiently sensitive. Following IM administration of AVONEX, serum antiviral activity levels peak between 5 and 15 hours post-dose and decline with a half-life of approximately 10 hours. With appropriate adjustment for the rate of absorption from the injection site, the calculated bioavailability is approximately 40%. The calculated bioavailability is greater without such adjustments. Intramuscular bioavailability is three-fold higher than subcutaneous bioavailability. Subcutaneous administration cannot be substituted for IM administration. 8

9 5.3 Preclinical safety data Carcinogenesis: No carcinogenicity data for Interferon beta-1a are available in animals or humans. Chronic Toxicity: No chronic toxicity data for Interferon beta-1a are available in animals. Local Tolerance: IM irritation has not been evaluated in animals following repeated administration to the same injection site. Mutagenesis: Limited but relevant mutagenesis tests have been carried out. The results have been negative. Impairment of Fertility: Fertility and developmental studies in rhesus monkeys have been carried out with a related form of interferon beta-1a. At very high doses, anovulatory and abortifacient effects in test animals were observed. Similar reproductive dose-related effects have also been observed with other forms of alpha and beta interferons. No teratogenic effects or effects on foetal development have been observed, but the available information on the effects of interferon beta-1a in the peri- and postnatal periods is limited. No information is available on the effects of interferon beta-1a on male fertility. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Human Serum Albumin, di- and monobasic Sodium Phosphate, Sodium Chloride. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage Do not store above 25 C. DO NOT FREEZE lyophilised or reconstituted product 6.5 Nature and contents of container AVONEX (Interferon beta-1a) is available as a package of four individual doses of AVONEX in a 3 ml clear glass vial with a 13 mm bromobutyl rubber stopper and aluminium seal. It is provided with a 1 ml pre-filled glass syringe of solvent for reconstitution and 2 needles. 6.6 Instructions for use and handling and disposal AVONEX should be administered after reconstitution. However, the reconstituted solution can be stored at 2-8 C for up to 6 hours, prior to injection. To reconstitute AVONEX for injection, the supplied pre-filled syringe of solvent is used. No other solvent should be used. The content of the syringe is injected into the vial of AVONEX using the green reconstitution needle. The contents in the vial are gently swirled until all materials are dissolved; DO NOT SHAKE. The reconstituted product is inspected and if it contains particulate matter or is 9

10 other than colourless to slightly yellow in colour, the vial should be discarded. After reconstitution, 1 ml is drawn from the vial (guidance mark on the pre-filled syringe) for the administration of 30 µg AVONEX. The needle for IM injection (blue) is provided. The formulation does not contain a preservative. Each vial of AVONEX contains a single dose only. The unused portion of any vial should be discarded. 7. MARKETING AUTHORISATION HOLDER BIOGEN IDEC LIMITED 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom 8. MARKETING AUTHORISATION NUMBERS EU/1/97/033/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION DATE OF REVISION OF THE TEXT 10

11 AVONEX 30µg (Interferon beta-1a) BIO-SET Presentation 1. NAME OF THE MEDICINAL PRODUCT AVONEX 30 µg powder and solvent for solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION AVONEX (Interferon beta-1a) contains a 30 µg (6 million IU) dose of Interferon beta-1a per vial. Using the World Health Organisation (WHO) natural interferon beta standard, Second International Standard for Interferon, Human Fibroblast (Gb ), 30 µg of AVONEX contains 6 million IU of antiviral activity. The activity against other standards is not known. 3. PHARMACEUTICAL FORM AVONEX (Interferon beta-1a) is a powder and solvent for solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications AVONEX (Interferon beta-1a) is indicated for the treatment of ambulatory patients with relapsing multiple sclerosis (MS) characterized by at least 2 recurrent attacks of neurologic dysfunction (relapses) over the preceding 3-year period without evidence of continuous progression between relapses. AVONEX slows the progression of disability and decreases the frequency of relapses. AVONEX is also indicated for the treatment of patients who have experienced a single demyelinating event with an active inflammatory process if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis (see section 5.1). AVONEX should be discontinued in patients who develop progressive multiple sclerosis. 4.2 Posology and method of administration The recommended dosage of AVONEX (Interferon beta-1a) for the treatment of relapsing MS is 30 µg injected (1 ml solution) IM once a week (see 6.6 Instructions for use and handling and disposal) and no additional benefit has been shown by administering a higher dose (60 µg) once a week. Treatment should be initiated under supervision of a physician experienced in the treatment of the disease. There is no experience with AVONEX in patients aged 16 years or less. Therefore, AVONEX should not be used in children. The IM injection site should be varied each week (see 5.3 Preclinical safety data). Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with AVONEX administration. These symptoms are usually present during the first few months of treatment. 11

12 At the present time, it is not known for how long patients should be treated. Patients should be clinically evaluated after 2 years of treatment and longer-term treatment should be decided on an individual basis by the treating physician. Treatment should be discontinued if the patient develops chronic progressive multiple sclerosis. 4.3 Contraindications AVONEX (Interferon beta-1a) is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, human serum albumin or any other component of the formulation. AVONEX is contraindicated in pregnant patients (also see 4.6 Use during pregnancy and lactation), patients with severe depressive disorders and/or suicidal ideation and in epileptic patients with a history of seizures not adequately controlled by treatment. 4.4 Special warnings and special precautions for use Patients should be informed of the most common adverse events associated with interferon beta administration, including symptoms of the flu-like syndrome (see 4.8 Undesirable effects). These symptoms tend to be most prominent at the initiation of therapy and decrease in frequency and severity with continued treatment. AVONEX, as other interferons, should be used with caution in patients with depression or other mood disorders, conditions that are common with multiple sclerosis. Depression has been reported in association with AVONEX use and it may occur at any time during treatment. Patients treated with AVONEX should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting depression should be monitored closely during therapy with AVONEX and treated appropriately. Cessation of therapy should be considered. Caution should be exercised when administering AVONEX to patients with pre-existing seizure disorder. For patients without a pre-existing seizure disorder who develop seizures during therapy with AVONEX, an etiologic basis should be established and appropriate anti-convulsant therapy instituted prior to resuming AVONEX treatment. Caution should be used and close monitoring considered when administering AVONEX to patients with severe renal and hepatic failure and to patients with severe myelosuppression. Hepatic injury including elevated serum hepatic enzyme levels, hepatitis, autoimmune hepatitis and hepatic failure has been reported with Interferon beta in post-marketing. In some patients a recurrence of elevated serum levels of hepatic enzymes has occurred upon AVONEX rechallenge. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential of additive effects from multiple drugs or other hepatotoxic agents (e.g., alcohol) has not been determined. Patients should be monitored for signs of hepatic injury and caution exercised when interferons are used concomitantly with other drugs associated with hepatic injury. Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely monitored for worsening of their clinical condition during treatment with AVONEX. Symptoms of the flu-like syndrome associated with AVONEX therapy may prove stressful to patients with underlying cardiac conditions. Patients should be advised about the abortifacient potential of interferon beta (see 4.6 Use during pregnancy and lactation and 5.3 Preclinical safety data). Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete and differential white blood cell counts, platelet counts, and blood chemistry, including liver function tests, are recommended during AVONEX therapy. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. 12

13 Patients may develop antibodies to AVONEX. The antibodies of some of those patients reduce the activity of interferon beta-1a in vitro (neutralising antibodies). Neutralising antibodies are associated with a reduction in the in vivo biological effects of AVONEX and may potentially be associated with a reduction of clinical efficacy. It is estimated that the plateau for the incidence of neutralising antibody formation is reached after 12 months of treatment. Data from patients treated up to two years with AVONEX suggests that approximately 8% develop neutralising antibodies. The use of various assays to detect serum antibodies to interferons limits the ability to compare antigenicity among different products. 4.5 Interaction with other medicinal products and other forms of interaction No formal drug interaction studies have been conducted with AVONEX (Interferon beta-1a) in humans. The interaction of AVONEX with corticosteroids or ACTH has not been studied systematically. The clinical studies indicate that multiple sclerosis patients can receive AVONEX and corticosteroids or ACTH during relapses. Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. The effect of high-dose AVONEX administration on P450-dependent metabolism in monkeys was evaluated and no changes in liver metabolizing capabilities were observed. Caution should be exercised when AVONEX 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., antiepileptics and some classes of antidepressants. 4.6 Pregnancy and lactation Because of the potential hazards to the foetus, AVONEX (Interferon beta-1a) is contraindicated in pregnancy. There are no studies of Interferon beta-1a in pregnant women. At high doses, in rhesus monkeys, abortifacient effects were observed. It cannot be excluded that such effects will be observed in humans. Fertile women receiving AVONEX should take appropriate contraceptive measures. Patients planning for pregnancy and those becoming pregnant should be informed of the potential hazards and AVONEX should be discontinued. Nursing Mothers It is not known whether AVONEX is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made either to discontinue nursing or to discontinue AVONEX therapy. 4.7 Effects on ability to drive and use machines AVONEX has minor influence on the ability to drive and use machines (see 4.8 Undesirable Effects ). 4.8 Undesirable effects The highest incidence of adverse reactions associated with AVONEX therapy is related to flu syndrome. The most commonly reported symptoms of the flu syndrome are myalgia, fever, chills, sweating, asthenia, headache and nausea. Symptoms of the flu syndrome tend to be most prominent at the initiation of therapy and decrease in frequency with continued treatment. Transient neurological symptoms that may mimic MS exacerbations may occur following injections. Transient episodes of hypertonia and/or severe muscular weakness that prevent voluntary movements 13

14 may occur at any time during treatment. These episodes are of limited duration, temporally related to the injections and may recur after subsequent injections. In some cases these symptoms are associated with flu-like symptoms. The frequencies of adverse reactions are expressed in patient-years, according to the following categories, Very common (>1/10 patient-years); Common (>1/100, <1/10 patient-years); Uncommon (>1/1, 000, <1/100 patient-years); Rare (>1/10, 000, <1/1,000 patient-years); Very rare (<1/10,000 patient-years); Patient time is the sum of individual units of time that the patient in the study has been exposed to AVONEX before experiencing the adverse reaction. For example, 100 person-years could be observed in 100 patients who were on treatment for one year or in 200 patients who were on treatment for half a year. EXPERIENCE FROM STUDIES (clinical trials and observational studies, with a period of follow-up ranging from 2 years to 6 years) Metabolism and nutrition disorders common anorexia Psychiatric disorders common Insomnia, depression(see section 4.4) Nervous system disorders very common common Vascular disorders common Respiratory disorders common rare Headache* hypoesthesia, muscle spasticity flushing rhinorrhoea dyspnoea, Gastrointestinal disorders common vomiting, diarrhoea, nausea* Skin and subcutaneous tissue disorders common uncommon rash, sweating increased, contusion alopecia 14

15 Musculoskeletal, connective tissue and bone disorders common muscle cramp, neck pain, myalgia*, arthralgia, pain in extremity, back pain muscle stiffness, musculoskeletal stiffness Reproductive system disorders Uncommon Uncommon metrorrhagia, menorrhagia General disorders and administration site conditions very common common influenza-like illness, pyrexia*, chills*, sweating* injection site pain, injection site erythema, injection site bruising, asthenia*, pain, fatigue*, malaise, night sweats injection site burning uncommon Investigations common uncommon lymphocyte count decreased, white blood cells count decreased, neutrophil count decreased, hematocrit decreased blood potassium increased, blood urea nitrogen increased platelet count decreased *The frequency of occurrence is higher at the beginning of treatment Other adverse reactions identified through spontaneous reporting, with unknown frequency are: Blood and lymphatic system disorders Endocrine disorders Psychiatric disorders Nervous system disorders Cardiac disorders pancytopenia, thrombocytopenia hypothyroidism, hyperthyroidism anxiety, suicide, psychosis,confusion, emotional lability neurological symptoms, syncope(1), hypertonia, dizziness, paraesthesia, seizures, migraine palpitations, tachycardia, arrythmia, cardiomyopathy, congestive heart failure (see section 4.4) 15

16 Vascular disorders Hepatobiliary disorders Skin and subcutaneous tissue disorders Musculoskeletal disorders General disorders and administration site conditions vasodilatation hepatitis, autoimmune hepatitis, hepatic failure (see section 4.4) pruritus, rash vesicular, urticaria, aggravation of psoriasis muscle weakness, arthritis, systemic lupus erythematosus injection site reaction, injection site inflammation, injection site cellulitis(2), injection site necrosis, chest pain Immune system disorders hypersensitivity, allergic reactions, anaphylactic reaction, anaphylactic shock Investigations weight decreased, weight increased, liver function tests abnormal Infections and infestations injection site abscess (2) (1) A syncope episode may occur after AVONEX injection, it is normally a single episode that usually appears at the beginning of the treatment and does not recur with subsequent injections. (2) Injection site reactions including pain, inflammation and very rare cases of abscess or cellulitis that may require surgical intervention have been reported. 4.9 Overdose No case of overdosage has been reported. However, in case of overdosage, patients should be hospitalised for observation and appropriate supportive treatment given. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Cytokines, ATC code L03 AB. Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons are cytokines that mediate antiviral, antiproliferative and immunomodulatory activities. Three major forms of interferons have been distinguished: alpha, beta and gamma. Interferons alpha and beta are classified as Type I interferons and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinguishable biological activities. They can also differ with respect to their cellular sites of synthesis. Interferon beta is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and AVONEX (Interferon beta-1a) are glycosylated and have a single N-linked complex carbohydrate moiety. Glycosylation of other proteins is known to affect their stability, activity, biodistribution, and half-life in blood. However, the effects of interferon beta that are dependent on glycosylation are not fully defined. AVONEX exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include MHC Class I, Mx protein, 2 / 16

17 5 -oligoadenylate synthetase, β 2 -microglobulin, and neopterin. Some of these products have been measured in the serum and cellular fractions of blood collected from patients treated with AVONEX. After a single IM dose of AVONEX, serum levels of these products remain elevated for at least 4 days and up to 1 week. Whether the mechanism of action of AVONEX in multiple sclerosis is mediated by the same pathway as the biological effects described above is not known because the pathophysiology of multiple sclerosis is not well established. The effects of AVONEX in the treatment of multiple sclerosis were demonstrated in a single placebocontrolled study of 301 patients (AVONEX, n=158; placebo, n=143) with relapsing MS. Due to the design of the study, patients were followed for variable lengths of time. One hundred and fifty AVONEX-treated patients completed 1 year on study and 85 completed 2 years on study. In the study, the cumulative percentage of patients who developed disability progression (by Kaplan-Meier life table analysis) by the end of 2 years was 35% for placebo-treated patients and 22% for AVONEXtreated patients. Disability progression was measured as an increase in the Expanded Disability Status Scale (EDSS) of 1.0 point, sustained for at least 6 months. It was also shown that there was a one-third reduction in annual relapse rate. This latter clinical effect was observed after more than one year of treatment. A double-blind randomised dose comparison study of 802 relapsing MS patients (AVONEX 30 µg n=402, AVONEX 60 µg n=400) has shown no statistically significant differences or trends between the 30 µg and the 60 µg doses of AVONEX in clinical and general MRI parameters. The effects of AVONEX in the treatment of multiple sclerosis were also demonstrated in a randomised double blind study performed with 383 patients (AVONEX n= 193, placebo n=190) with a single demyelinating event associated with at least two compatible brain MRI lesions. A reduction of the risk of experiencing a second event was noted in the AVONEX treatment group. An effect on MRI parameters was also seen. The estimated risk of a second event was 50% in 3 years and 39% in 2 years in the placebo group and 35% (3 years) 21% (2 years) in the AVONEX group. In a post-hoc analysis, those patients with a baseline MRI with at least 1 Gd-enhancing lesion and 9 T2 lesions had a 2-year risk of suffering a second event of 56% in the placebo group and 21% in the AVONEX treatment group. However, the impact of early treatment with AVONEX is unknown even in this high-risk subgroup as the study was mainly designed to assess the time to the second event rather than the long term evolution of the disease. Furthermore, for the time-being there is no well established definition of a high risk patient although a more conservative approach is to accept at least 9 T2 hyperintense lesions on the initial scan and at least 1 new T2 or 1 new Gd-enhancing lesion on a follow-up scan taken at least 3 months after the initial scan. In any case treatment should only be considered for patients classified at high risk. 5.2 Pharmacokinetic properties The pharmacokinetic profile of AVONEX (Interferon beta-1a) has been investigated indirectly with an assay that measures interferon antiviral activity. This assay is limited in that it is sensitive for interferon but lacks specificity for interferon beta. Alternative assay techniques are not sufficiently sensitive. Following IM administration of AVONEX, serum antiviral activity levels peak between 5 and 15 hours post-dose and decline with a half-life of approximately 10 hours. With appropriate adjustment for the rate of absorption from the injection site, the calculated bioavailability is approximately 40%. The calculated bioavailability is greater without such adjustments. Intramuscular bioavailability is three-fold higher than subcutaneous bioavailability. Subcutaneous administration cannot be substituted for IM administration. 17

18 5.3 Preclinical safety data Carcinogenesis: No carcinogenicity data for Interferon beta-1a are available in animals or humans. Chronic Toxicity: No chronic toxicity data for Interferon beta-1a are available in animals. Local Tolerance: IM irritation has not been evaluated in animals following repeated administration to the same injection site. Mutagenesis: Limited but relevant mutagenesis tests have been carried out. The results have been negative. Impairment of Fertility: Fertility and developmental studies in rhesus monkeys have been carried out with a related form of interferon beta-1a. At very high doses, anovulatory and abortifacient effects in test animals were observed. Similar reproductive dose-related effects have also been observed with other forms of alpha and beta interferons. No teratogenic effects or effects on foetal development have been observed, but the available information on the effects of interferon beta-1a in the peri- and postnatal periods is limited. No information is available on the effects of interferon beta-1a on male fertility. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Human Serum Albumin, di- and monobasic Sodium Phosphate, Sodium Chloride. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage Do not store above 25 C. DO NOT FREEZE lyophilised or reconstituted product 6.5 Nature and contents of container AVONEX (Interferon beta-1a) is available as a package of four individual doses of AVONEX in a 3 ml clear glass vial with BIO-SET device and a 13 mm bromobutyl rubber stopper. It is provided with a 1 ml pre-filled glass syringe of solvent for reconstitution and 1 needle. 6.6 Instructions for use and handling and disposal AVONEX should be administered after reconstitution. However, the reconstituted solution can be stored at 2-8 C for up to 6 hours, prior to injection. To reconstitute AVONEX for injection, the supplied pre-filled syringe of solvent is used. No other solvent should be used. The content of the syringe is injected into the vial of AVONEX by connecting the pre-filled syringe to the BIO-SET device. The contents in the vial are gently swirled until all materials are dissolved; DO NOT SHAKE. The reconstituted product is inspected and if it contains 18

19 particulate matter or is other than colourless to slightly yellow in colour, the vial should be discarded. After reconstitution, 1 ml is drawn from the vial (guidance mark on the pre-filled syringe) for the administration of 30 µg AVONEX. The needle for IM injection (blue) is provided. The formulation does not contain a preservative. Each vial of AVONEX contains a single dose only. The unused portion of any vial should be discarded. 7. MARKETING AUTHORISATION HOLDER BIOGEN IDEC LIMITED 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom 8. MARKETING AUTHORISATION NUMBERS EU/1/97/033/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION DATE OF REVISION OF THE TEXT 19

20 AVONEX 30mcg/0.5ml (Interferon beta-1a) Solution for Injection 1. NAME OF THE MEDICINAL PRODUCT AVONEX 30 micrograms/0.5 ml solution for injection. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 pre-filled syringe of 0.5 ml contains 30 micrograms (6 million IU) of Interferon beta-1a. Using the World Health Organisation (WHO) natural interferon beta standard, Second International Standard for Interferon, Human Fibroblast (Gb ), 30 µg of AVONEX contains 6 million IU of antiviral activity. The activity against other standards is not known. For excipients, see section PHARMACEUTICAL FORM Solution for injection. The solution for injection should be clear and colourless. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications AVONEX is indicated for the treatment of ambulatory patients with relapsing multiple sclerosis (MS) characterised by at least 2 recurrent attacks of neurologic dysfunction (relapses) over the preceding 3- year period without evidence of continuous progression between relapses. AVONEX slows the progression of disability and decreases the frequency of relapses. AVONEX is also indicated for the treatment of patients who have experienced a single demyelinating event with an active inflammatory process if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis (see section 5.1). AVONEX should be discontinued in patients who develop progressive multiple sclerosis. 4.2 Posology and method of administration The recommended dosage of AVONEX for the treatment of relapsing MS is 30 µg injected as intramuscular (IM) injection once a week (see 6.6 Instructions for use and handling, and disposal), and no additional benefit has been shown by administering a higher dose (60 µg) once a week. Treatment should be initiated under supervision of a physician experienced in the treatment of the disease. There is no experience with AVONEX in patients aged 16 years or less. Therefore, AVONEX should not be used in children and adolescents. The IM injection site should be varied each week (see 5.3 Preclinical safety data). 20

21 Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with AVONEX administration. These symptoms are usually present during the first few months of treatment. At the present time, it is not known for how long patients should be treated. Patients should be clinically evaluated after 2 years of treatment and longer-term treatment should be decided on an individual basis by the treating physician. Treatment should be discontinued if the patient develops chronic progressive multiple sclerosis. 4.3 Contraindications AVONEX is contraindicated in patients with hypersensitivity to natural or recombinant interferon beta, or to any of the excipients. AVONEX is contraindicated in pregnant patients (also see 4.6 Pregnancy and lactation). AVONEX is contraindicated in patients with severe depressive disorders and/or suicidal ideation. AVONEX is contraindicated in epileptic patients with a history of seizures not adequately controlled by treatment. 4.4 Special warnings and special precautions for use Patients should be informed of the most common adverse events associated with interferon beta administration, including symptoms of the flu-like syndrome (see 4.8 Undesirable effects). These symptoms tend to be most prominent at the initiation of therapy and decrease in frequency and severity with continued treatment. AVONEX, as other interferons, should be used with caution in patients with depression or other mood disorders, conditions that are common with multiple sclerosis. Depression has been reported in association with AVONEX use and it may occur at any time during treatment. Patients treated with AVONEX should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting depression should be monitored closely during therapy with AVONEX and treated appropriately. Cessation of therapy should be considered. Caution should be exercised when administering AVONEX to patients with pre-existing seizure disorder. For patients without a pre-existing seizure disorder who develop seizures during therapy with AVONEX, an etiologic basis should be established and appropriate anti-convulsant therapy instituted prior to resuming AVONEX treatment. Caution should be used and close monitoring considered when administering AVONEX to patients with severe renal and hepatic failure and to patients with severe myelosuppression. Hepatic injury including elevated serum hepatic enzyme levels, hepatitis, autoimmune hepatitis and hepatic failure has been reported with Interferon beta in post-marketing. In some patients a recurrence of elevated serum levels of hepatic enzymes has occurred upon AVONEX rechallenge. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential of additive effects from multiple drugs or other hepatotoxic agents (e.g., alcohol) has not been determined. Patients should be monitored for signs of hepatic injury and caution exercised when interferons are used concomitantly with other drugs associated with hepatic injury. Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely monitored for worsening of their clinical condition during treatment with AVONEX. Symptoms of the flu-like syndrome associated with AVONEX therapy may prove stressful to patients with underlying cardiac conditions. Patients should be advised about the abortifacient potential of interferon beta (see 4.6 Pregnancy and lactation and 5.3 Preclinical safety data). 21

22 Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests, are recommended during AVONEX therapy. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. Patients may develop antibodies to AVONEX. The antibodies of some of those patients reduce the activity of interferon beta-1a in vitro (neutralising antibodies). Neutralising antibodies are associated with a reduction in the in vivo biological effects of AVONEX and may potentially be associated with a reduction of clinical efficacy. It is estimated that the plateau for the incidence of neutralising antibody formation is reached after 12 months of treatment. Recent clinical studies with patients treated up to 3 years with AVONEX suggest that approximately 5% to 8% develop neutralising antibodies. The use of various assays to detect serum antibodies to interferons limits the ability to compare antigenicity among different products. The tip-cap of the pre-filled syringe contains dry natural rubber, which may cause allergic reactions. 4.5 Interaction with other medicinal products and other forms of interaction No formal drug interaction studies have been conducted with AVONEX in humans. The interaction of AVONEX with corticosteroids or ACTH has not been studied systematically. The clinical studies indicate that multiple sclerosis patients can receive AVONEX and corticosteroids or ACTH during relapses. Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. The effect of high-dose AVONEX administration on P450-dependent metabolism in monkeys was evaluated and no changes in liver metabolising capabilities were observed. Caution should be exercised when AVONEX 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., antiepileptics and some classes of antidepressants. 4.6 Pregnancy and lactation Because of the potential hazards to the foetus, AVONEX is contraindicated in pregnancy. There are no studies of Interferon beta-1a in pregnant women. At high doses, in rhesus monkeys, abortifacient effects were observed. It cannot be excluded that such effects will be observed in humans. Fertile women receiving AVONEX should take appropriate contraceptive measures. Patients planning for pregnancy and those becoming pregnant should be informed of the potential hazards and AVONEX should be discontinued. Breast-feeding Mothers: It is not known whether AVONEX is excreted in human milk. Because of the potential for serious adverse reactions in breast-feeding infants, a decision should be made either to discontinue breastfeeding or to discontinue AVONEX therapy. 4.7 Effects on ability to drive and use machines AVONEX has minor influence on the ability to drive and use machines (see 4.8 Undesirable effects) 4.8 Undesirable effects The highest incidence of adverse reactions associated with AVONEX therapy is related to flu syndrome. The most commonly reported symptoms of the flu syndrome are myalgia, fever, chills, 22

23 sweating, asthenia, headache and nausea. Symptoms of the flu syndrome tend to be most prominent at the initiation of therapy and decrease in frequency with continued treatment. Transient neurological symptoms that may mimic MS exacerbations may occur following injections. Transient episodes of hypertonia and/or severe muscular weakness that prevent voluntary movements may occur at any time during treatment. These episodes are of limited duration, temporally related to the injections and may recur after subsequent injections. In some cases these symptoms are associated with flu-like symptoms. The frequencies of adverse reactions are expressed in patient-years, according to the following categories, Very common (>1/10 patient-years); Common (>1/100, <1/10 patient-years); Uncommon (>1/1, 000, <1/100 patient-years); Rare (>1/10, 000, <1/1,000 patient-years); Very rare (<1/10,000 patient-years); Patient time is the sum of individual units of time that the patient in the study has been exposed to AVONEX before experiencing the adverse reaction. For example, 100 person-years could be observed in 100 patients who were on treatment for one year or in 200 patients who were on treatment for half a year. EXPERIENCE FROM STUDIES (clinical trials and observational studies, with a period of follow-up ranging from 2 years to 6 years) Metabolism and nutrition disorders common anorexia Psychiatric disorders common Insomnia,depression(see section 4.4) Nervous system disorders very common common Vascular disorders common Respiratory disorders common rare Headache* hypoesthesia, muscle spasticity flushing rhinorrhoea dyspnoea, Gastrointestinal disorders common vomiting, diarrhoea, nausea* 23

24 Skin and subcutaneous tissue disorders common uncommon rash, sweating increased, contusion alopecia Musculoskeletal, connective tissue and bone disorders common muscle cramp, neck pain, myalgia*, arthralgia, pain in extremity, back pain muscle stiffness, musculoskeletal stiffness Reproductive system disorders Uncommon Uncommon metrorrhagia, menorrhagia General disorders and administration site conditions very common common uncommon Investigations common uncommon influenza-like illness, pyrexia*, chills*, sweating* injection site pain, injection site erythema, injection site bruising, asthenia*, pain, fatigue*, malaise, night sweats injection site burning lymphocyte count decreased, white blood cells count decreased, neutrophil count decreased, hematocrit decreased blood potassium increased, blood urea nitrogen increased platelet count decreased *The frequency of occurrence is higher at the beginning of treatment Other adverse reactions identified through spontaneous reporting, with unknown frequency are: Blood and lymphatic system disorders Endocrine disorders Psychiatric disorders pancytopenia,thrombocytopenia hypothyroidism,hyperthyroidism anxiety, suicide, psychosis,confusion, emotional lability 24

25 Nervous system disorders Cardiac disorders Vascular disorders Hepatobiliary disorders Skin and subcutaneous tissue disorders Musculoskeletal disorders General disorders and administration site conditions neurological symptoms, syncope(1), hypertonia, dizziness, paraesthesia, seizures, migraine palpitations, tachycardia, arrythmia, cardiomyopathy, congestive heart failure (see section 4.4) vasodilatation hepatitis, autoimmune hepatitis, hepatic failure (see section 4.4) pruritus, rash vesicular, urticaria, aggravation of psoriasis muscle weakness, arthritis, systemic lupus erythematosus injection site reaction, injection site inflammation, injection site cellulitis(2), injection site necrosis, chest pain Immune system disorders hypersensitivity, allergic reactions, anaphylactic reaction, anaphylactic shock Investigations weight decreased, weight increased, liver function tests abnormal Infections and infestations injection site abscess (2) (1) A syncope episode may occur after AVONEX injection, it is normally a single episode that usually appears at the beginning of the treatment and does not recur with subsequent injections. (2) Injection site reactions including pain, inflammation and very rare cases of abscess or cellulitis that may require surgical intervention have been reported. 4.9 Overdose No case of overdosage has been reported. However, in case of overdosage, patients should be hospitalised for observation and appropriate supportive treatment given. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Cytokines, ATC code L03 AB. Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons are cytokines that mediate antiviral, antiproliferative, and immunomodulatory activities. Three major forms of interferons have been distinguished: alpha, beta, and gamma. Interferons alpha and beta are classified as Type I interferons, and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinguishable biological activities. They can also differ with respect to their cellular sites of synthesis. Interferon beta is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and AVONEX (Interferon beta-1 a) are glycosylated and have a single N-linked complex carbohydrate moiety. Glycosylation of other proteins is known to affect their stability, 25

26 activity, biodistribution, and half-life in blood. However, the effects of interferon beta that are dependent on glycosylation are not fully defined. AVONEX exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include MHC Class I, Mx protein, 2 / 5 -oligoadenylate synthetase, β 2 -microglobulin, and neopterin. Some of these products have been measured in the serum and cellular fractions of blood collected from patients treated with AVONEX. After a single IM dose of AVONEX, serum levels of these products remain elevated for at least 4 days and up to 1 week. Whether the mechanism of action of AVONEX in multiple sclerosis is mediated by the same pathway as the biological effects described above is not known because the pathophysiology of multiple sclerosis is not well established. The effects of lyophilised AVONEX in the treatment of multiple sclerosis were demonstrated in a placebo-controlled study of 301 patients (AVONEX, n=158; placebo, n=143) with relapsing MS. Due to the design of the study, patients were followed for variable lengths of time. One hundred fifty AVONEX-treated patients completed 1 year on study and 85 completed 2 years on study. In the study, the cumulative percentage of patients who developed disability progression (by Kaplan-Meier life table analysis) by the end of 2 years was 35% for placebo-treated patients and 22% for AVONEXtreated patients. Disability progression was measured as an increase in the Expanded Disability Status Scale (EDSS) of 1.0 point, sustained for at least 6 months. It was also shown that there was a one-third reduction in annual relapse rate. This latter clinical effect was observed after more than one year of treatment. A double blind randomized dose comparison study of 802 relapsing MS patients (AVONEX 30 µg n=402, AVONEX 60 µg n=400) has shown no statistically significant differences or trends between the 30 µg and the 60 µg doses of AVONEX in clinical and general MRI parameters. The effects of AVONEX in the treatment of multiple sclerosis were also demonstrated in a randomised double blind study performed with 383 patients (AVONEX n= 193, placebo n=190) with a single demyelinating event associated with at least two compatible brain MRI lesions. A reduction of the risk of experiencing a second event was noted in the AVONEX treatment group. An effect on MRI parameters was also seen. The estimated risk of a second event was 50% in 3 years and 39% in 2 years in the placebo group and 35% (3 years) 21% (2 years) in the AVONEX group. In a post-hoc analysis, those patients with a baseline MRI with at least 1 Gd-enhancing lesion and 9 T2 lesions had a 2-year risk of suffering a second event of 56% in the placebo group and 21% in the AVONEX treatment group. However, the impact of early treatment with AVONEX is unknown even in this high-risk subgroup as the study was mainly designed to assess the time to the second event rather than the long term evolution of the disease. Furthermore, for the time-being there is no well established definition of a high risk patient although a more conservative approach is to accept at least 9 T2 hyperintense lesions on the initial scan and at least 1 new T2 or 1 new Gd-enhancing lesion on a follow-up scan taken at least 3 months after the initial scan. In any case treatment should only be considered for patients classified at high risk. 5.2 Pharmacokinetic properties The pharmacokinetic profile of AVONEX has been investigated indirectly with an assay that measures interferon antiviral activity. This assay is limited in that it is sensitive for interferon but lacks specificity for interferon beta. Alternative assay techniques are not sufficiently sensitive. Following IM administration of AVONEX, serum antiviral activity levels peak between 5 and 15 hours post-dose and decline with a half-life of approximately 10 hours. With appropriate adjustment for the rate of absorption from the injection site, the calculated bioavailability is approximately 40%. The calculated bioavailability is greater without such adjustments. Intramuscular bioavailability is 26

27 three-fold higher than subcutaneous bioavailability. Subcutaneous administration cannot be substituted for IM administration. 5.3 Preclinical safety data Carcinogenesis: No carcinogenicity data for Interferon beta-1a are available in animals or humans. Chronic Toxicity: In a 26-week repeated toxicity study in rhesus monkey by IM route once per week, administered in combination with another immune modulating agent, an anti CD40 ligand monoclonal antibody, no immune response toward IFN beta-1 a and no signs of toxicity were demonstrated. Local Tolerance: IM irritation has not been evaluated in animals following repeated administration to the same injection site. Mutagenesis: Limited but relevant mutagenesis tests have been carried out. The results have been negative. Impairment of Fertility: Fertility and developmental studies in rhesus monkeys have been carried out with a related form of Interferon beta-1a. At very high doses, anovulatory and abortifacient effects in test animals were observed. Similar reproductive dose-related effects have also been observed with other forms of alpha and beta interferons. No teratogenic effects or effects on foetal development have been observed, but the available information on the effects of interferon beta-1a in the peri- and postnatal periods is limited. No information is available on the effects of Interferon beta-1a on male fertility. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium acetate, trihydrate, Acetic acid, Glacial, Arginine Hydrochloride, Polysorbate 20, Water for injections 6.2 Incompatibilities Not applicable. 6.3 Shelf life 18 months. 6.4 Special precautions for storage Store at 2-8 C in a refrigerator. DO NOT FREEZE. Store in the original package in order to protect from light (see 6.5 Nature and contents of container). 6.5 Nature and contents of container 1 ml pre-filled syringe made of glass (Type I) with tip cap (approximately 10% Dry Natural Rubber) and plunger stopper (Polypropylene) containing 0.5 ml of solution. Pack size: box of 4 pre-filled syringes of 0.5 ml. Each syringe is packed in a sealed plastic tray which also contains 1 injection needle for IM use. 27

28 6.6 Instructions for use and handling AVONEX is provided as ready to use solution for injection in a pre-filled syringe. Once removed from the refrigerator, AVONEX in a pre-filled syringe should be allowed to warm to room temperature (15-30 C) for about 30 minutes and used within 12 hours. Do not use external heat sources such as hot water to warm AVONEX 30 µg solution for injection. If the solution for injection contains particulate matter or if it is any colour other than clear colourless, the pre-filled syringe should not be used. The injection needle for IM injection is provided. The formulation does not contain a preservative. Each pre-filled syringe of AVONEX contains a single dose only. The unused portion of any pre-filled syringe should be discarded. 7. MARKETING AUTHORISATION HOLDER BIOGEN IDEC LIMITED 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom 8. MARKETING AUTHORISATION NUMBERS EU/1/97/033/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 24 June DATE OF REVISION OF THE TEXT 28

29 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OF THE MARKETING AUTHORISATION C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING AUTHORISATION HOLDER 29

30 A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers of the biological active substance Biogen Idec Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. Research Triangle Park-Biogen Idec Inc., 5000 Davis Drive, POB 14627, Research Triangle Park, North Carolina, 27709, USA. Name and address of the manufacturer responsible for batch release Biogen Idec B.V., Robijnlaan 8, 2132 WX Hoofddorp, The Netherlands. B. CONDITIONS OF THE MARKETING AUTHORISATION CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, 4.2). OTHER CONDITIONS The holder of this marketing authorisation must inform the European Commission about the marketing plans for the medicinal product authorised by this decision. C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING AUTHORISATION HOLDER The Marketing Authorisation Holder shall complete the following programme of studies within the specified time frame, the results of which shall form the basis of the annual reassessment of the benefit/risk profile. - Long-term follow-up of the patients entered study C (CHAMPS). A 5-year MRI report from this add-on study (CHAMPION) has been submitted in February 2004 and the final study report should be submitted in December

31 ANNEX III LABELLING AND PACKAGE LEAFLET 31

32 A. LABELLING 32

33 AVONEX 30µg (Interferon beta 1a) Flip-off presentation PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING 1. NAME OF THE MEDICINAL PRODUCT AVONEX 30µg Powder and solvent for solution for injection. Interferon beta-1a 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains 30µg (6 million IU) of Interferon beta-1a. 3. LIST OF EXCIPIENTS Human serum albumin, sodium chloride, di- and monobasic sodium phosphate. 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection - Packs of four doses presented as: medicinal product, pre-filled syringe of solvent for reconstitution, 2 needles: one for reconstitution (BD needle 21G, 1 1/2 ) and one for intramuscular administration (BD needle 23G, 1 1/4 ). 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intramuscular (IM) injection after reconstitution with solvent. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Not applicable. 8. EXPIRY DATE EXP {MM/YYYY} 33

34 9. SPECIAL STORAGE CONDITIONS Do not store above 25 C - DO NOT FREEZE. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Not applicable. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER BIOGEN IDEC LIMITED 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/1/97/033/ MANUFACTURER S BATCH NUMBER <Batch> 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 34

35 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 1. NAME OF THE MEDICINAL PRODUCT AVONEX, 30µg Powder and solvent for solution for injection Interferon beta-1a 2. NAME OF THE MARKETING AUTHORISATION HOLDER BIOGEN IDEC LIMITED 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER <Batch> 35

36 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Medicinal product (3 ml vial): 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION AVONEX, 30µg Powder for solution for injection IM 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER <Batch> 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 30µg Interferon beta-1a 36

37 Solvent for reconstitution: (1 ml prefilled syringe) 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Water for injection, 1 ml IM 2. METHOD OF ADMINISTRATION Not applicable 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER <Batch> 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1 ml 37

38 AVONEX 30µg (Interferon beta 1a) BIO-SET presentation PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING BIO-SET PRESENTATION 1. NAME OF THE MEDICINAL PRODUCT AVONEX, 30µg Powder and solvent for solution for injection. Interferon beta-1a 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains 30µg (6 million IU) of Interferon beta-1a. 3. LIST OF EXCIPIENTS Human serum albumin, sodium chloride, di- and monobasic sodium phosphate. 4. PHARMACEUTICAL FORM AND CONTENTS Packs of four doses presented as: vial with BIO-SET device containing medicinal product, pre-filled syringe of solvent for reconstitution, 1 needle for intramuscular (IM) administration (needle 23G, 1 ¼). 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intramuscular (IM) injection after reconstitution with solvent. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Not applicable. 38

39 8. EXPIRY DATE EXP {MM/YYYY}. 9. SPECIAL STORAGE CONDITIONS Do not store above 25 C. DO NOT FREEZE. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Not applicable. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER BIOGEN IDEC LIMITED 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/1/97/033/ MANUFACTURER S BATCH NUMBER <Batch> 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 39

40 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 1. NAME OF THE MEDICINAL PRODUCT AVONEX 30µg Powder and solvent for solution for injection Interferon beta-1a 2. NAME OF THE MARKETING AUTHORISATION HOLDER BIOGEN IDEC LIMITED 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER <Batch> 40

41 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Medicinal product (3 ml vial): 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION AVONEX 30µg Powder for solution for injection IM 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER <Batch> 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 30µg Interferon beta-1a 41

42 Solvent for reconstitution: (1 ml pre-filled syringe) 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Water for injection,1 ml IM 2. METHOD OF ADMINISTRATION Not applicable 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER <Batch> 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1 ml 42

43 AVONEX 30mcg/0.5ml (Interferon beta-1a) Solution for Injection PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING 1. NAME OF THE MEDICINAL PRODUCT AVONEX 30 micrograms/0.5 ml solution for injection. Interferon beta-1a 2. STATEMENT OF ACTIVE SUBSTANCE (S) Each pre-filled syringe of 0.5 ml contains 30 micrograms (6 million IU) of Interferon beta-1a. 3. LIST OF EXCIPIENTS Sodium acetate, Acetic acid Glacial, Arginine Hydrochloride, Polysorbate 20, Water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for injection. Box of 4 pre-filled syringes of 0.5 ml of solution. Each syringe is packed in a sealed plastic tray which also contains 1 injection needle for intramuscular (IM) use. 5. METHOD AND ROUTE (S) OF ADMINISTRATION For intramuscular (IM) use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING (S), IF NECESSARY 8. EXPIRY DATE EXP {MM/YYYY} 9. SPECIAL STORAGE CONDITIONS Store at 2-8 C in a refrigerator. DO NOT FREEZE. Store in the original package (sealed plastic tray) in order to protect from light. 43

44 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER BIOGEN IDEC LIMITED 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom 12. MARKETING AUTHORISATION NUMBER (S) EU/1/97/033/ MANUFACTURER S BATCH NUMBER Lot: {number}. 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 44

45 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 1. NAME OF THE MEDICINAL PRODUCT AVONEX 30 µg/0.5 ml solution for injection Interferon beta-1a 2. NAME OF THE MARKETING AUTHORISATION HOLDER BIOGEN IDEC LIMITED 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER Batch 45

46 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE (S) OF ADMINISTRATION AVONEX 30 µg/0.5 ml solution for injection IM use 2. METHOD OF ADMINISTRATION See Package leaflet 3. EXPIRY DATE EXP {MM/YYYY} 4. BATCH NUMBER Batch 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.5 ml 46

47 B. PACKAGE LEAFLET 47

48 PACKAGE LEAFLET AVONEX 30µg (Interferon beta 1a) Flip-off presentation Read all of this leaflet carefully before you start using this medicine - Keep this leaflet. You may need to read it again. - If you have further questions, please ask your doctor or your pharmacist. - This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours. In this leaflet: 1. What AVONEX is and what it is used for 2. Before you use AVONEX 3. How to use AVONEX 4. Possible side effects 5. Storing AVONEX 6. Further information - Name of the Medicinal Product: AVONEX 30µg Powder and solvent for solution for injection Interferon beta-1a Flip-off cap presentation - The active substance is Interferon beta-1a (30 microgram). - The other ingredients are: Human serum albumin, sodium chloride, dibasic sodium phosphate and monobasic sodium phosphate. - Marketing Authorisation Holder: BIOGEN IDEC LIMITED 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom - Manufacturer: BIOGEN IDEC BV Robijnlaan 8 NL-2132 WX Hoofddorp - The Netherlands 1. WHAT AVONEX IS AND WHAT IT IS USED FOR AVONEX is available as powder and solvent for solution for injection with a pack of four individual doses. An individual dose consists of lyophilised powder for injection (vial), a pre-filled syringe of solvent for reconstitution, and two needles (one green for reconstitution of the solution and one blue for intramuscular injection). Interferon beta-1a belongs to a group of substances, which help regulate your body s immune system. AVONEX (Interferon-beta-1a) is used to treat relapsing multiple sclerosis (MS). It has been shown to be useful in slowing the progression of the disease and reducing the frequency of clinical relapses. 48

49 2. BEFORE YOU USE AVONEX The medication should only be used under the strict supervision of a physician. Do not use AVONEX if you have one of the following conditions: - If you are hypersensitive (allergic) to interferon beta, human serum albumin or any of the other ingredients of the formulation, - If you are pregnant or intend to become pregnant, - If you are breast feeding, - If you have epileptic seizures that are not adequately controlled by treatment. Take special care with AVONEX: Each vial of AVONEX contains only one dose. Any product remaining in the vial after injection should be thrown away. If you have to visit the hospital or family doctor for any treatment or for a blood test, remember to tell the health professional/doctor that you are receiving AVONEX. AVONEX may affect the results of these tests. AVONEX is not recommended for use in patients under 16 years of age. Inform your doctor of any previous episode of depression. If you experience any symptom of depression, report immediately to your doctor. Inform your doctor of any history of epileptic seizures or heart disease so that he/she can closely monitor any worsening of these conditions. Inform your doctor immediately if you experience any of the following symptoms: jaundice, diffuse itching, nausea and vomiting and easy bruising of the skin. No formal drug interaction studies have been conducted with AVONEX in humans. The interaction of AVONEX with corticosteroids or ACTH has not been studied systematically. The clinical studies indicate that multiple sclerosis patients can receive AVONEX and corticosteroids or ACTH during relapses. Pregnancy AVONEX should not be administered if you are pregnant or if you plan to have a child. Ask your doctor or pharmacist for advice before taking any medicine. Breast-feeding AVONEX should not be used if you are breast-feeding. Prior to taking your medicine, please inform your doctor or pharmacist if you are breast-feeding. Driving and using machines: Certain reported undesirable effects on the central nervous system may influence the ability to drive and operate a machine. Taking other medicines: AVONEX (Interferon beta-1a) does not normally react with other medicines. Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines even those not prescribed. AVONEX should be given alone; do not mix with other liquids for injection. 49

50 3. HOW TO USE AVONEX - Posology: Always take AVONEX exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are unsure. The usual dose of AVONEX is 30µg (6 million IU) (1.0 ml of reconstituted solution in the vial) injected once a week. The product should be administered, if possible, at the same time on the same day each week. - Method and route of administration: AVONEX is to be injected into the muscle. The injection site should vary each week. - Instructions for reconstitution and injection: AVONEX is intended for use under the guidance and supervision of a doctor. Patients may self-inject if their doctor determines that it is appropriate, and after proper training in intramuscular injection technique has been given. The following instructions are provided for the person injecting AVONEX. Setting up Each individual dose package includes a vial of AVONEX, a pre-filled syringe of solvent, a needle for reconstitution (green) and a needle for injection (blue). It is a good idea to have alcohol swabs and sticking plasters ready. After washing your hands, find a clean surface to lay out the components. Remove the lid of the dose package carefully, using the holes for assistance. Reconstitution with solvent Remove the cap from the base of the pre-filled syringe by pulling. Be careful not to touch the connection port. Do not push on the plunger. Open the reconstitution needle (green) to expose the connection port. Keeping the protective wrapper over the needle, firmly twist the needle onto the syringe. Remove the cap of the AVONEX vial. Using an alcohol swab, wipe the top of the AVONEX vial. Remove the plastic needle cover by pulling. Do not twist. Push the needle through the rubber seal at the top of the AVONEX vial. Point the needle to the side of the vial and slowly inject the solvent (full contents of the syringe) into the vial. Keeping the needle and syringe attached to the vial, gently swirl the contents of the vial until all the powder has dissolved. Avoid shaking the vial vigorously, since this will produce a froth. Discard the vial if the solution appears cloudy or discoloured, or if you can see particles floating in it. Before drawing up the reconstituted liquid, push the plunger fully into the syringe to remove air. Then place the vial on the working surface at a slight angle. Keep the full needle length in the vial with the tip below the surface of the solution at all times. Slowly withdraw the liquid to the 1 ml mark on the side of the syringe. Withdraw the syringe and needle from the vial. Twist and remove the green needle from the syringe. Be careful not to touch the end of the syringe. Injection The injection site should be chosen and cleaned with a new alcohol swab before injecting. A second needle (blue) is supplied for the injection of AVONEX. It is a standard needle for intramuscular 50

51 injection. In the same process as before, twist the blue injection needle onto the syringe. To remove air, point the syringe upwards and gently tap to bring the bubbles to the top. Push the plunger carefully to remove the air without expelling more than a small drop of liquid. Insert the needle through the skin into the muscle. Inject slowly and remove the syringe. Then, if necessary, apply a sticking plaster to the site of injection, Disposing of the rubbish properly Put the needles, syringes, and vials into a sharps container. Waste paper and used swabs can be put in an ordinary rubbish bin. - Duration of treatment: The duration of the treatment will be determined by your physician. It is important to continue, and not alter, your medication unless your doctor advises you otherwise. - If you take more AVONEX than you should: No case of overdose has been reported. However, in case of overdose, call your doctor or pharmacist immediately for further advice. - If you forget to take AVONEX: If you miss the dose, continue to inject from the day of the next schedule dose. Do not take a double dose to make up for forgotten individual doses. 4. POSSIBLE SIDE EFFECTS Like all medicines, AVONEX can have side effects. The most common side effects are flu-like symptoms such as headache, fever, chills, muscular aches and pains, feelings of weakness and tiredness. These may be more common at the start of the treatment and decrease with continuing use. To help these symptoms, your doctor may advise you to take an antipyretic analgesic before a dose of AVONEX and then every six hours, for 24 hours after each injection. Always consult your doctor before taking anything with AVONEX. If he or she recommends an antipyretic analgesic, follow the advice carefully. Do not take more antipyretic analgesic than the recommended dose. Other less common side effects include palpitations, redness or pain at the injection site, loss of appetite and weight loss, weight gain, flushing, joint pain, nausea, vomiting, difficulty sleeping, diarrhoea, nervousness, hair loss, rash including itching and wheals, irregularities and/or changes in menstrual flow, fainting, hepatitis, numbness or tingling, shortness of breath, chest pain, rapid heart beat, muscle and joint pain, liver failure, aggravation of psoriasis and injection site reactions Serious allergic reactions are rare. If a severe reaction occurs, consult your doctor immediately. There is a possibility that you may experience transient neurological symptoms after injections including transient muscle weakness, increased muscle tensionand/or spasticity. These symptoms occur rarely, usually in the early stages of your therapy, and in some cases are associated with flu-like symptoms. A fainting episode may occur after AVONEX injection; it is normally a single episode that usually appears at the beginning of the treatment and does not recur with subsequent injections. The administration of interferons has been associated with certain autoimmune disorders, nervous system related side effects, heart disorders and changes of laboratory test results. Rare cases of heart failure, cardiomyopathy (disease of the heart muscle), arthritis, thyroid disorders (hypo- and hyperthyroidism), confusion, emotional instability and disordered thought processes, migraine, decrease in blood platelets and very rare cases of lupus erythematosus syndrome have been reported with AVONEX. 51

52 Tell your doctor, pharmacist or nurse immediately if you experience any of the above effects or notice anything else unusual while you are receiving treatment with AVONEX. 5. STORING AVONEX - Keep out of the reach and sight of children. - Do not store above 25 C. - Do not freeze or expose AVONEX to high temperature. - Store in the original package. The reconstituted solution (once in the syringe) can be stored at 2-8 C for up to 6 hours, prior to injection. The reconstituted solution should not be frozen or exposed to high temperature. The shelf life of AVONEX is 24 months. Do not use after the expiry date stated on the label. The first two numbers indicate the month after which the product can no longer be used, and the last four numbers indicate the year of expiry. DO NOT USE AVONEX if you notice: the vial seal is broken. the liquid obtained after reconstitution is coloured or you can see particles floating in it. 52

53 6. FURTHER INFORMATION For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Biogen Idec B.V. Robijnlaan 8 NL-2132 WX Hoofddorp Nederland Tél/Tel: +31 (0) Česká republika Richter Gedeon RT, zastoupení pro Českou republiku Na strži 63, PSC Praha 4 Tel.: Danmark Biogen Idec Denmark A/S Lyngbyvej 28 DK-2100 København Ø Danmark Tlf: Deutschland Biogen Idec GmbH Carl-Zeiss-Ring 6 D Ismaning Deutschland Tel: +49 (0) Eesti Gedeon Richter Ltd. Gyömrői út H-1103 Budapest Tel: Ελλάδα Genesis Pharma SA Φιλελλήνων 24 GR Χαλάνδρι Αθήνα Τηλ. +30 (210) España Biogen Idec Iberia SL Paseo de la Castellana, n 41- Planta Madrid España Tel: Luxembourg/ Luxemburg Biogen Idec B.V. Robijnlaan 8 NL-2132 WX Hoofddorp Nederland Tél: +31 (0) Magyarország Gedeon Richter Ltd. Gyömrői út H-1103 Budapest Tel: Malta Interpharma Co. Ltd. 7 Haven Lodge, St. George's Junction MT-STJ10 St Julians Tel: Nederland Biogen Idec B.V. Robijnlaan 8 NL-2132 WX Hoofddorp Nederland Tel: +31 (0) Norge Biogen Idec Denmark A/S Lyngbyvej 28 DK-2100 København Ø Danmark Tlf: Österreich Biogen Idec Austria G.m.b.H. Effingergasse 21 A-1160 Wien Osterreich Tel: +43 (0) Polska Gedeon Richter Ltd. S.A. Przedstawicielstwo w Polsce ul. Królowej Marysieńki 70 PL Warszawa Polska Tel.: + 48 (22)

54 France Biogen Idec France "Le Capitole" 55, avenue des Champs Pierreux F Nanterre France Tél: +33 (0) Ireland Biogen Idec Limited 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom Tel: +44 (0) ĺsland Icepharm PO Box 5080 IS-125 Reykjavik Island Tel: Italia Dompé Biotec S.p.A. Via San Martino, 12 IT Milano Italia Tel: +39 (0) Κύπρος Genesis Pharma Cyprus Ltd Κέννεντυ 8 - ιαµέρισµα 106 Λευκωσία 1087 Κύπρος Τηλ: Latvija Gedeon Richter Ltd. Budapest X., Gyömrői út H-1103 Vengrija Tel: Lietuva Gedeon Richter Ltd. Budapest X., Gyömrői út H-1103 Vengrija Tel: Portugal Biogen Idec Portugal, Sociedade Farmaceutica Unipessoal, Lda Avenida Duque d Avila, A Lisboa Portugal Tel : Slovenija SALUS, Ljubljana, d.d. Mašera Spasičeva ulica 10 SI-1000 Ljubljana Tel: Slovenská republika Gedeon Richter Ltd. Šoltésovej 12 SK Bratislava Tel: Suomi/Finland Biogen Idec Denmark A/S Lyngbyvej 28 DK-2100 København Ø Danmark Puh/Tel: Sverige Biogen Idec Denmark A/S Lyngbyvej 28 DK-2100 København Ø Danmark Tel: United Kingdom Biogen Idec Limited 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom Tel: +44 (0) This leaflet was last approved on: 54

55 PACKAGE LEAFLET AVONEX 30µg (Interferon beta-1a) BIO-SET Presentation Read all of this leaflet carefully before you start using this medicine - Keep this leaflet. You may need to read it again. - If you have further questions, please ask your doctor or your pharmacist. - This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours. In this leaflet: 1. What AVONEX is and what it is used for 2. Before you use AVONEX 3. How to use AVONEX 4. Possible side effects 5. Storing AVONEX 6. Further information - Name of the Medicinal Product: AVONEX 30µg Powder and solvent for solution for injection Interferon beta-1a BIO-SET presentation - The active substance is Interferon beta-1a (30 microgram). - The other ingredients are: Human serum albumin, sodium chloride, dibasic sodium phosphate and monobasic sodium phosphate. - Marketing Authorisation Holder: BIOGEN IDEC LIMITED 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom - Manufacturer: BIOGEN IDEC BV Robijnlaan 8 NL WX Hoofddorp - The Netherlands 1. WHAT AVONEX IS AND WHAT IT IS USED FOR AVONEX (Interferon beta-1a) is available as powder and solvent for solution for injection with a package of four individual doses of AVONEX. An individual dose is contained in a 3 ml clear glass vial with BIO-SET device and a 13 mm bromobutyl rubber stopper. It is provided with a 1 ml prefilled glass syringe of solvent for reconstitution and 1 needle. Interferon beta-1a belongs to a group of substances, which help regulate your body s immune system. 55

56 AVONEX (Interferon beta-1a) is used to treat relapsing multiple sclerosis (MS). It has been shown to be useful in slowing the progression of the disease and reducing the frequency of clinical relapses. 2. BEFORE YOU USE AVONEX The medication should only be used under the strict supervision of a physician. - Do not use AVONEX if you have one of the following conditions: - If you are hypersensitive (allergic) to interferon beta, human serum albumin or any of the other ingredients of the formulation, - If you are pregnant or intend to become pregnant, - If you are breast feeding, - If you have epileptic seizures that are not adequately controlled by treatment. - Take special care with AVONEX: Each vial of AVONEX contains only one dose. Any product remaining in the vial after injection should be thrown away. If you have to visit the hospital or family doctor for any treatment or for a blood test, remember to tell the health professional/doctor that you are receiving AVONEX. AVONEX may affect the results of these tests. AVONEX is not recommended for use in patients under 16 years of age. Inform your doctor of any previous episode of depression. If you experience any symptom of depression, report immediately to your doctor. Inform your doctor of any history of epileptic seizures or heart disease so that he/she can closely monitor any worsening of these conditions. Inform your doctor immediately if you experience any of the following symptoms: jaundice, diffuse itching, nausea and vomiting and easy bruising of the skin. No formal drug interaction studies have been conducted with AVONEX in humans. The interaction of AVONEX with corticosteroids or ACTH has not been studied systematically. The clinical studies indicate that multiple sclerosis patients can receive AVONEX and corticosteroids or ACTH during relapses. - Pregnancy AVONEX should not be administered if you are pregnant or if you plan to have a child. Ask your doctor or pharmacist for advice before taking any medicine. - Breast-feeding AVONEX should not be used if you are breast-feeding. Prior to taking your medicine, please inform your doctor or pharmacist if you are breast-feeding. - Driving and using machines: Certain reported undesirable effects on the central nervous system may influence the ability to drive and operate a machine. - Taking other medicines: AVONEX does not normally react with other medicines. 56

57 Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines even those not prescribed. AVONEX should be given alone; do not mix with other liquids for injection. 3. HOW TO USE AVONEX - Posology: Always take AVONEX exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are unsure. The usual dose of AVONEX is 30µg (6 million IU) (1.0 ml of reconstituted solution in the vial) injected once a week. The product should be administered, if possible, at the same time on the same day each week. - Method and route of administration: AVONEX is to be injected into the muscle. The injection site should vary each week. -Instructions for reconstitution and injection: AVONEX is intended for use under the guidance and supervision of a doctor. Patients may self-inject if their doctor determines that it is appropriate, and after proper training in intramuscular injection technique has been given. The following instructions are provided for the person injecting AVONEX. Setting up Each individual dose package includes a vial of AVONEX with BIO-SET device, a pre-filled syringe and a needle for injection. It is a good idea to have alcohol swabs and sticking plasters ready. After washing your hands, find a clean surface to lay out the components. Remove the lid of the dose package carefully, using the holes for assistance. Lay out the contents. Cap Contents of pack Connection port BIO-SET device Connection port of syringe Syringe cap Base of syringe Plunge Base Needle cover Needle Glass vial Connection port of needle 57

58 Reconstitution 1 Holding the base of the BIO-SET device, remove the cap by twisting, and then pulling. Do not touch the connection port. 2 Holding the base of the pre-filled syringe, remove the cap by pulling. Be careful not to touch the connection port. Do not push on the plunger 3 Place the BIO-SET on a flat surface. Align the connection port of the syringe with the BIO-SET device. Hold the base of the syringe and firmly screw it into the BIO-SET device with a clockwise turn. Click! 4 - Maintain the straight alignment of the syringe to the BIO-SET device, push the syringe firmly down into the BIO-SET device until the connector port is pushed completely down and until it clicks. Important: Do not proceed further until you have heard the click. 5 - Slowly push down the plunger, gradually injecting the full contents of the syringe into the vial. CAUTION: Rapid addition of the solvent may cause foaming, making it difficult to withdraw AVONEX. 6 - Keeping the syringe attached to the BIO-SET device, gently swirl the vial until all the powder has dissolved. Avoid shaking the vial vigorously, since this will produce a froth. Discard the vial if the solution appears cloudy or discoloured, or if you can see particles floating in it. 7 - Push the plunger fully into the syringe to remove air. 8 - Turn the syringe and vial upside down. Slowly pull the plunger back until all the liquid is in the syringe. 9 - Open the wrapping of the needle to expose the connection port. Keep the protective cover over the needle and set aside while processing step N

59 10 - Hold the base of the filled syringe and turn it anti-clockwise to remove it from the BIO-SET device. Do not touch the connection port Firmly twist the needle onto the filled syringe with a clockwise turn. Then lay the syringe aside, choose and clean the injection site with a new alcohol swab. 12- Pull the protective cover off the needle. Important: Do not twist the needle cover. Injection Turn the filled syringe and needle upside down. To remove air, gently tap the syringe to bring the bubbles to the top. Slowly push the plunger to remove the air without expelling more than a small drop of liquid. Insert the needle through the skin into the muscle. Inject slowly and remove the syringe. Then, if necessary, apply a sticking plaster to the site of injection. Disposing of the rubbish properly Put the needles, syringes, and vials into a sharps container. Waste paper and used swabs can be put in an ordinary rubbish bin. - Duration of treatment The duration of the treatment will be determined by your physician. It is important to continue, and not alter, your medication unless your doctor advises you otherwise. - If you take more AVONEX than you should: No case of overdose has been reported. However in case of overdose, call your doctor or pharmacist immediately for further advice. - If you forget to take AVONEX: If you miss the dose, continue to inject from the day of the next scheduled dose. Do not take a double dose to make up for forgotten individual doses. 4. POSSIBLE SIDE EFFECTS Like all medicines, AVONEX can have side effects. The most common side effects are flu-like symptoms such as headache, fever, chills, muscular aches and pains, feelings of weakness and tiredness. These may be more common at the start of the treatment and decrease with continuing use. To help these symptoms, your doctor may advise you to take an antipyretic analgesic before a dose of AVONEX and then every six hours, for 24 hours after each injection. Always consult your doctor before taking anything with AVONEX. If he or she recommends an antipyretic analgesic, follow the advice carefully. Do not take more antipyretic analgesic than the recommended dose. Other less common side effects include palpitations, redness or pain at the injection site, loss of appetite and weight loss, weight gain, flushing, joint pain, nausea, vomiting, difficulty sleeping, diarrhoea, nervousness, hair loss, rash including itching and wheals, irregularities and/or changes in 59

60 menstrual flow, fainting, hepatitis, numbness or tingling, shortness of breath, chest pain, rapid heart beat, muscle and joint pain, liver failure, aggravation of psoriasis and injection site reactions Serious allergic reactions are rare. If a severe reaction occurs, consult your doctor immediately. There is a possibility that you may experience transient neurological symptoms after injections including transient muscle weakness, increased muscle tension and/or spasticity. These symptoms occur rarely, usually in the early stages of your therapy, and in some cases are associated with flu-like symptoms. A fainting episode may occur after AVONEX injection; it is normally a single episode that usually appears at the beginning of the treatment and does not recur with subsequent injections. The administration of interferons has been associated with certain autoimmune disorders, nervous system related side effects, heart disorders and changes of laboratory test results. Rare cases of heart failure, cardiomyopathy (disease of the heart muscle), arthritis, thyroid disorders (hypo- and hyperthyroidism), confusion, emotional instability and disordered thought processes, migraine, decrease in blood platelets and very rare cases of lupus erythematosus syndrome have been reported with AVONEX. Tell your doctor, pharmacist or nurse immediately if you experience any of the above effects or notice anything else unusual while you are receiving treatment with AVONEX. 5. STORING AVONEX - Keep out of the reach and sight of children. - Do not store above 25 C. - Do not freeze or expose AVONEX to high temperature. - Store in the original package. The reconstituted solution (once in the syringe) can be stored at 2-8 C for up to 6 hours, prior to injection. The reconstituted solution should not be frozen or exposed to high temperature. The shelf life of AVONEX is 24 months. Do not use after the expiry date stated on the label. The first two numbers indicate the month after which the product can no longer be used, and the last four numbers indicate the year of expiry. DO NOT USE AVONEX if you notice the seal of the cap of the BIO-SET device is broken. the liquid obtained after reconstitution is coloured or you can see particles floating in it. 60

61 6. FURTHER INFORMATION For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder. België/Belgique/Belgien Biogen Idec B.V. Robijnlaan 8 NL-2132 WX Hoofddorp Nederland Tél/Tel: +31 (0) Česká republika Richter Gedeon RT, zastoupení pro Českou republiku Na strži 63, PSC Praha 4 Tel.: Danmark Biogen Idec Denmark A/S Lyngbyvej 28 DK-2100 København Ø Danmark Tlf: Deutschland Biogen Idec GmbH Carl-Zeiss-Ring 6 D Ismaning Deutschland Tel: +49 (0) Eesti Gedeon Richter Ltd. Gyömrői út H-1103 Budapest Tel: Ελλάδα Genesis Pharma SA Φιλελλήνων 24 GR Χαλάνδρι Αθήνα Τηλ. +30 (210) España Biogen Idec Iberia SL Paseo de la Castellana, n 41- Planta Madrid España Tel: Luxembourg/Luxemburg Biogen Idec B.V. Robijnlaan 8 NL-2132 WX Hoofddorp Nederland Tél: +31 (0) Magyarország Gedeon Richter Ltd. Gyömrői út H-1103 Budapest Tel: Malta Interpharma Co. Ltd. 7 Haven Lodge, St. George's Junction MT-STJ10 St Julians Tel: Nederland Biogen Idec B.V. Robijnlaan 8 NL-2132 WX Hoofddorp Nederland Tel: +31 (0) Norge Biogen Idec Denmark A/S Lyngbyvej 28 DK-2100 København Ø Danmark Tlf: Österreich Biogen Idec Austria G.m.b.H. Effingergasse 21 A-1160 Wien Osterreich Tel: +43 (0) Polska Gedeon Richter Ltd. S.A. Przedstawicielstwo w Polsce ul. Królowej Marysieńki 70 PL Warszawa Polska Tel.: + 48 (22)

62 France Biogen Idec France "Le Capitole" 55, avenue des Champs Pierreux F Nanterre France Tél: +33 (0) Ireland Biogen Idec Limited 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom Tel: +44 (0) ĺsland Icepharm PO Box 5080 IS-125 Reykjavik Island Tel: Italia Dompé Biotec S.p.A. Via San Martino, 12 IT Milano Italia Tel: +39 (0) Κύπρος Genesis Pharma Cyprus Ltd Κέννεντυ 8 - ιαµέρισµα 106 Λευκωσία 1087 Κύπρος Τηλ: Latvija Gedeon Richter Ltd. Budapest X., Gyömrői út H-1103 Vengrija Tel: Portugal Biogen Idec Portugal, Sociedade Farmaceutica Unipessoal, Lda Avenida Duque d Avila, A Lisboa Portugal Tel : Slovenija SALUS, Ljubljana, d.d. Mašera Spasičeva ulica 10 SI-1000 Ljubljana Tel: Slovenská republika Gedeon Richter Ltd. Šoltésovej 12 SK Bratislava Tel: Suomi/Finland Biogen Idec Denmark A/S Lyngbyvej 28 DK-2100 København Ø Danmark Puh/Tel: Sverige Biogen Idec Denmark A/S Lyngbyvej 28 DK-2100 København Ø Danmark Tel: United Kingdom Biogen Idec Limited 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom Tel: +44 (0) Lietuva Gedeon Richter Ltd. Budapest X., Gyömrői út H-1103 Vengrija Tel: This leaflet was last approved on: 62

63 PACKAGE LEAFLET AVONEX 30mcg/0.5ml (Interferon beta-1a) Solution for Injection Read all of this leaflet carefully before you start using this medicine - Keep this leaflet. You may need to read it again - If you have further questions, please ask your doctor or your pharmacist. - This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours. In this leaflet: 1. What AVONEX is and what it is used for 2. Before you use AVONEX 3. How to use AVONEX 4. Possible side effects 5. Storing AVONEX 6. Further information AVONEX 30 micrograms/0.5 ml solution for injection. Interferon beta-1a The active substance is Interferon beta-1a (30 micrograms). The other ingredients are: Sodium acetate, Trihydrate, Acetic acid glacial, Arginine Hydrochloride, Polysorbate 20, Water for injections. The tip-cap of the pre-filled syringe contains dry natural rubber. - Marketing Authorisation Holder: BIOGEN IDEC LIMITED 5 Roxborough Way Foundation Park Maidenhead Berkshire SL6 3UD United Kingdom - Manufacturer: BIOGEN IDEC BV Robijnlaan 8 NL-2132 WX Hoofddorp - The Netherlands 1. WHAT AVONEX IS AND WHAT IT IS USED FOR AVONEX is provided as a ready to use solution for injection. Each box of AVONEX contains 4 prefilled syringes of 0.5 ml of solution. Each syringe is packed in a sealed plastic tray which also contains 1 injection needle for intramuscular (IM) use. Interferon beta-1a belongs to a group of substances, which help regulate your body s immune system. AVONEX (Interferon-beta-1a) is used to treat relapsing multiple sclerosis (MS). It has been shown to be effective in slowing the progression of the disease and reducing the frequency of clinical relapses. 63

64 2. BEFORE YOU USE AVONEX The medicine should only be used under the strict supervision of a physician. You should tell your doctor if you have had a dry natural rubber sensitivity since the tip-cap of the AVONEX pre-filled syringe contains dry natural rubber, which may cause allergic reactions. Do not use AVONEX: - If you are hypersensitive (allergic) to interferon beta, or any other of the ingredients of the formulation; s. - If you are pregnant or intend to become pregnant, - If you suffer from severe depressive disorders and/or suicidal ideation - If you have epileptic seizures that are not adequately controlled by treatment. Take special care with AVONEX: If you have to visit the hospital or family doctor for any treatment or for a blood test, remember to tell the health professional/doctor that you are receiving AVONEX. AVONEX may affect the results of these tests. AVONEX is not recommended for use in patients under 16 years of age. Inform your doctor of any previous episode of depression. If you experience any symptom of depression, report immediately to your doctor. Inform your doctor of any history of epileptic seizures or heart disease so that he/she can monitor closely any worsening of these conditions. Inform your doctor immediately if you experience any of the following symptoms: jaundice, diffuse itching, nausea and vomiting and easy bruising of the skin. Pregnancy: AVONEX should not be administered if you are pregnant or if you plan to have a child. Ask your doctor or pharmacist for advice before taking any medicine. Breast-feeding: AVONEX should not be used if you are breast-feeding. Prior to taking any medicine, please inform your doctor or pharmacist if you are breast-feeding. Driving and using machines: Some reported undesirable effects on the central nervous system may influence the ability to drive and operate a machine. Taking other medicines: AVONEX does not normally react with other medicines. Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines even those not prescribed. No formal drug interaction studies have been conducted with AVONEX in humans. The interaction of AVONEX with corticosteroids or Adrenocorticotropic Hormone (ACTH) has not been studied systematically. The clinical studies indicate that multiple sclerosis patients can receive AVONEX and corticosteroids or ACTH during relapses. AVONEX should be given alone; do not mix with other liquids for injection. 64

65 3. HOW TO USE AVONEX - Posology: Always take AVONEX exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are unsure. The usual dose of AVONEX is the content of 1 pre-filled syringe, corresponding to 30 micrograms (6 million IU) Interferon beta-1a injected once a week. The product should be administered, if possible, at the same time on the same day each week. - Method and route of administration: AVONEX is intended for intramuscular (IM) injection. The injection site should vary each week. For single use only. Any unused solution should be discarded. - Instructions for injection: AVONEX is intended for use under the guidance and supervision of a doctor. Patients may self-inject if their doctor determines that it is appropriate, and after proper training in intramuscular (IM) injection technique has been given. The following instructions are provided for the person injecting AVONEX. Content of pack Each box includes 4 individual doses. An individual dose consists of 1 pre-filled syringe and 1 injection needle for intramuscular(im) administration. Setting up Allow the solution for injection to warm to room temperature before administration: remove 1 sealed plastic tray from the refrigerator. Be sure that the pre-filled syringe and the injection needle are in the sealed plastic tray before proceeding. Leave at room temperature (15-30 C) for approximately 30 minutes before injection and use the pre-filled syringe within 12 hours. This will make the injection more comfortable. DO NOT use external heat sources such as hot water to warm the solution for injection. Wash your hands and find a clean surface to lay out the items needed for administration. Prepare alcohol swabs and sticking plasters (not supplied). 65