Extavia is indicated for the treatment of: • Patients with 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). • Patients with relapsing remitting multiple sclerosis and two or more relapses within the last two years. • Patients with secondary progressive multiple sclerosis with active disease, evidenced by relapses.

The treatment with Extavia should be initiated under the supervision of a physician experienced in the treatment of the disease. Posology Adults and adolescents from 12 17 years of age The recommended dose of Extavia is 250 microgram (8.0 million IU), contained in 1 ml of the reconstituted solution (see section 6.6), to be injected subcutaneously every other day. Generally, dose titration is recommended at the start of treatment. Patients should be started at 62.5 microgram (0.25 ml) subcutaneously every other day, and increased slowly to a dose of 250 microgram (1.0 ml) every other day (see Table A). The titration period may be adjusted, if any significant adverse reaction occurs. In order to obtain adequate efficacy, a dose of 250 microgram (1.0 ml) every other day should be reached. Table A Schedule for dose titration* Treatment day Dose Volume 1, 3, 5 62.5 microgram 0.25 ml 7, 9, 11 125 microgram 0.5 ml 13, 15, 17 187.5 microgram 0.75 ml = 19 250 microgram 1.0 ml * The titration period may be adjusted if any significant adverse reaction occurs. The optimal dose has not been fully clarified. At the present time, it is not known for how long the patient should be treated. There are follow-up data under controlled clinical conditions for patients with relapsing- remitting multiple sclerosis for up to 5 years and for patients with secondary progressive multiple sclerosis for up to 3 years. For relapsing-remitting multiple sclerosis, efficacy has been demonstrated for therapy for the first two years. The available data for the additional three years are consistent with sustained treatment efficacy of Extavia over the whole time period. In patients with a single clinical event suggestive of multiple sclerosis, efficacy has been demonstrated over a period of three years. Treatment is not recommended in patients with relapsing-remitting multiple sclerosis who have experienced less than 2 relapses in the previous 2 years or in patients with secondary-progressive multiple sclerosis who have had no active disease in the previous 2 years. If the patient fails to respond, for example a steady progression in Expanded Disability Status Scale (EDSS) for 6 months occurs or treatment with at least 3 courses of adrenocorticotropic hormone (ACTH) or corticosteroids during a one- year period is required despite Extavia therapy, treatment with Extavia should be stopped. Paediatric population No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. However, limited published data suggest that the safety profile in adolescents from 12 to 17 years of age receiving Extavia 8.0 million IU subcutaneously every other day is similar to that seen in adults. No data are available on the use of Extavia in children under 12 years of age and therefore Extavia should not be used in this population. Method of administration The reconstituted solution is to be injected subcutaneously every other day. For instructions on reconstitution of the medicinal product before administration, see section 6.6.

- Hypersensitivity to natural or recombinant interferon beta, human albumin or to any of the excipients listed in section 6.1. - Patients with current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). - Patients with decompensated liver disease (see sections 4.4, 4.5 and 4.8).

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Immune system disorders The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of systemic capillary leak syndrome with shock-like symptoms and fatal outcome. Gastrointestinal disorders Cases of pancreatitis were observed with Extavia use, often associated with hypertriglyceridaemia. Nervous system disorders Extavia should be administered with caution to patients with previous or current depressive disorders, in particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal ideation are known to occur with increased frequency in the multiple sclerosis population and in association with interferon use. Patients treated with Extavia 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 Extavia and treated appropriately. Cessation of therapy with Extavia should be considered (see also sections 4.3 and 4.8). Extavia should be administered with caution to patients with a history of seizures, to patients receiving treatment with anti-epileptics, and in particular to patients with epilepsy who are not adequately controlled with anti-epileptics (see sections 4.5 and 4.8). This medicinal product contains human albumin and hence carries a potential risk for transmission of viral diseases. A risk for transmission of Creutzfeld-Jacob disease (CJD) cannot be excluded. Laboratory tests Regular thyroid function tests are recommended in patients with a history of thyroid dysfunction or as clinically indicated. In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests (e.g. aspartate aminotransferase serum glutamic- oxaloacetic transaminase (SGOT), alanine aminotransferase serum glutamate pyruvate transaminase (SGPT) and gamma glutamyltransferase), are recommended prior to initiation and at regular intervals following introduction of Extavia therapy, and then periodically thereafter in the absence of clinical symptoms. Patients with anaemia, thrombocytopenia or leukopenia (alone or in any combination) may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. Patients who develop neutropenia should be monitored closely for the development of fever or infection. There have been reports of thrombocytopenia, with profound decreases in platelet count. Hepatobiliary disorders Asymptomatic elevations of serum transaminases, in most cases mild and transient, occurred very commonly in patients treated with Extavia during clinical trials. As for other beta interferons, cases of severe hepatic injury, including hepatic failure, have been reported in patients treated with Extavia. The most serious events often occurred in patients exposed to other medicinal products or substances known to be associated with hepatotoxicity or in the presence of co-morbid medical conditions (e.g. metastasising malignant disease, severe infection and sepsis, alcohol abuse). Patients should be monitored for signs of hepatic injury. The occurrence of elevations in serum transaminases should lead to close monitoring and investigation. Withdrawal of Extavia should be considered if the levels significantly increase or if they are associated with clinical symptoms such as jaundice. In the absence of clinical evidence for liver damage, and after normalisation of liver enzymes, a reintroduction of therapy could be considered with appropriate follow-up of hepatic functions. Thrombotic microangiopathy (TMA) and haemolytic anaemia (HA) Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta products. Early clinical features include thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. Additionally, cases of HA not associated with TMA, including immune HA, have been reported with interferon beta products. Life-threatening and fatal cases have been reported. Cases of TMA and/or HA have been reported at various time points during treatment and may occur several weeks to several years after starting treatment with interferon beta. If TMA and/or HA is diagnosed, and a relationship to Extavia is suspected, prompt treatment is required (in case of TMA considering plasma exchange) and immediate discontinuation of Extavia is recommended. Renal and urinary disorders Caution should be used and close monitoring considered when administering interferon beta to patients with severe renal failure. Nephrotic syndrome Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during treatment with interferon beta products. Events were reported at various time points during treatment and may occur after several years of treatment with interferon beta. Periodic monitoring of early signs or symptoms, e.g. oedema, proteinuria and impaired renal function, is recommended, especially in patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and discontinuation of treatment with Extavia should be considered. Cardiac disorders Extavia should also be used with caution in patients who suffer from pre-existing cardiac disorders. Patients with pre-existing significant cardiac disease, such as congestive heart failure, coronary artery disease or arrhythmia, should be monitored for worsening of their cardiac condition, particularly during initiation of treatment with Extavia. While Extavia does not have any known direct-acting cardiac toxicity, symptoms of the flu- like syndrome associated with beta interferons may prove stressful to patients with pre- existing significant cardiac disease. During the post-marketing period very rare reports have been received of temporary worsening of cardiac status at the start of Extavia therapy in patients with pre-existing significant cardiac disease.g Cases of cardiomyopathy have been reported. If this occurs and a relationship to Extavia is suspected, treatment should be discontinued. Hypersensitivity reactions Serious hypersensitivity reactions (severe acute reactions such as bronchospasm, anaphylaxis and urticaria) may occur. If reactions are severe, Extavia should be discontinued and appropriate medical intervention instituted. Injection site reactions Injection site reactions, including injection site infection and injection site necrosis have been reported in patients using Extavia (see section 4.8). Injection site necrosis can be extensive and may involve muscle fascia as well as fat and therefore can result in scar formation. Debridement and, less often, skin grafting are occasionally required and healing may take up to 6 months. If the patient experiences any break in the skin, which may be associated with swelling or drainage of fluid from the injection site, the patient should be advised to consult with his/her physician before continuing injections with Extavia. If the patient has multiple lesions Extavia should be discontinued until healing has occurred. Patients with single lesions may continue on Extavia provided the necrosis is not too extensive, as some patients have experienced healing of injection site necrosis whilst on Extavia. To minimise the risk of injection site infection and injection site necrosis, patients should be advised to: - use an aseptic injection technique, - rotate the injection sites with each dose. The incidence of injection site reactions may be reduced by the use of an auto-injector. In the pivotal study of patients with a single clinical event suggestive of multiple sclerosis an auto- injector was used in the majority of patients. Injection site reactions and necroses were observed less frequently in this study than in the other pivotal studies. The procedure for self-administration by the patient should be reviewed periodically, especially if injection site reactions have occurred. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In controlled clinical trials serum samples were collected every 3 months for monitoring of development of antibodies to Extavia. In the different controlled clinical trials, between 23% and 41% of the patients developed serum interferon beta-1b neutralising activity confirmed by at least two consecutive positive titres. Between 43% and 55% of these patients converted to a stable antibody negative status (based on two consecutive negative titres) during the subsequent observational period of the trial concerned. The development of neutralising activity is associated with a reduction in clinical efficacy only with regard to relapse activity. Some analyses suggest that this effect might be more pronounced in patients with higher titre levels of neutralising activity. In the study of patients with a single clinical event suggestive of multiple sclerosis, neutralising activity measured every 6 months was observed at least once in 32% (89) of the patients treated immediately with Extavia. 60% (53) of these patients returned to negative status based on the last available assessment within the 5-year period. Within this period, the development of neutralising activity was associated with a significant increase in newly active lesions and T2 lesion volume on magnetic resonance imaging. However, this did not seem to be associated with a reduction in clinical efficacy (with regard to time to clinically definite multiple sclerosis [CDMS], time to confirmed EDSS progression and relapse rate). New adverse events have not been associated with the development of neutralising activity. It has been demonstrated in vitro that Extavia cross-reacts with natural interferon beta. However, this has not been investigated in vivo and its clinical significance is uncertain. There are sparse and inconclusive data on patients who have developed neutralising activity and have completed Extavia therapy. The decision to continue or discontinue treatment should be based on clinical disease activity rather than on neutralising activity status. Excipients This medicinal product contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially ‘sodium-free’. Latex-sensitive individuals The removable tip cap of the Extavia pre-filled syringe contains a derivative of natural rubber latex. Although no natural rubber latex is detected in the cap, the safe use of Extavia pre-filled syringe in latex-sensitive individuals has not been studied and there is therefore a potential risk for hypersensitivity reactions which cannot be completely ruled out.

No

Pregnancy A large amount of data (more than 1000 pregnancy outcomes) from interferon beta registries, national registries and post-marketing experience indicates no increased risk of major congenital anomalies, after pre-conception exposure or exposure during the first trimester of pregnancy. However, the duration of exposure during the first trimester is uncertain, because data were collected when interferon beta use was contraindicated during pregnancy, and treatment was likely interrupted when the pregnancy was detected and/or confirmed. Experience with exposure during the second and third trimesters is very limited. Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. The risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be evaluated by means of the currently available data, but the data suggest no increased risk so far. If clinically needed, the use of Extavia may be considered during pregnancy. Breast-feeding Limited information available on the transfer of interferon beta-1b into breast milk, together with the chemical / physiological characteristics of interferon beta, suggests that levels of interferon beta-1b excreted in human milk are negligible. No harmful effects on the breast-fed newborn/infant are anticipated. Extavia can be used during breast-feeding. Fertility No investigations on fertility have been conducted (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. Adverse events related to the central nervous system associated with the use of Extavia might influence the ability to drive and use machines in susceptible patients.

Summary of the safety profile At the beginning of treatment adverse reactions are common but in general they subside with further treatment. The most frequently observed adverse reactions are a flu-like symptom complex (fever, chills, arthralgia, malaise, sweating, headache, or myalgia), which is mainly due to the pharmacological effects of the medicinal product, and injection site reactions. Injection site reactions occurred frequently after administration of Extavia. Redness, swelling, discolouration, inflammation, pain, hypersensitivity, infection, necrosis and non-specific reactions were significantly associated with 250 microgram (8.0 million IU) Extavia treatment. The most serious adverse reactions reported include thrombotic microangiopathy (TMA) and haemolytic anaemia (HA). Generally, dose titration is recommended at the start of treatment in order to increase tolerability to Extavia (see section 4.2). Flu-like symptoms may also be reduced by administration of non-steroidal anti-inflammatory medicinal products. The incidence of injection site reactions may be reduced by the use of an auto-injector. Tabulated list of adverse reactions The following adverse event listings are based on reports from clinical trials and from post- marketing surveillance (very common =1/10, common =1/100 to <1/10, uncommon =1/1000 to <1/100, rare =1/10000 to <1/1000, very rare <1/10000) of Extavia use. The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions. Table 1 Adverse drug reactions (ADRs) based on reports from clinical trials and identified during post-marketing surveillance (frequencies - where known - calculated based on pooled clinical trial data) System Organ Class Very common (=1/10) Common (=1/100 to <1/10) Uncommon (=1/1000 to <1/100) Rare (=1/10000 to <1/1000) Frequency not known Blood and lymphatic system disorders Lymphocyte count decreased (<1 500/mm3)e, White blood cell count decreased (<3 000/mm3)e, Absolute neutrophil count decreased (<1 500/mm3)e Lymphadenopathy, Anaemia Thrombocytopenia Thrombotic microangiopathy d including thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome b Haemolytic anaemia d Immune system disorders Anaphylactic reactions Capillary leak syndrome in pre-existing monoclonal gammopathy a Endocrine disorders Hypothyroidism Hyperthyroidism, Thyroid disorders Metabolism and nutrition disorders Weight increased, Weight decreased Blood triglycerides increased Anorexia a Psychiatric disorders Confusional state Suicide attempt (see also section 4.4), Emotional lability Depression, Anxiety Nervous system disorders Headache, Insomnia Convulsion Dizziness Cardiac disorders Tachycardia Cardiomyopathya Palpitation Vascular disorders Hypertension Vasodilatation Respiratory, thoracic and mediastinal disorders Dyspnoea Bronchospasma Pulmonary arterial hypertension c Gastrointestinal disorders Abdominal pain Pancreatitis Nausea, Vomiting, Diarrhoea Hepatobiliary disorders Alanine aminotransferase increased (ALAT >5 times baseline)e Aspartate aminotransferase increased (ASAT >5 times baseline)e, Blood bilirubin increased Gamma-glutamyl- transferase increased, Hepatitis Hepatic injury, Hepatic failurea Skin and subcutaneous tissue disorders Rash, Skin disorder Urticaria, Pruritus, Alopecia Skin discolouration Musculoskeletal and connective tissue disorders Myalgia, Hypertonia, Arthralgia Drug-induced lupus erythematosus Renal and urinary disorders Urinary urgency Nephrotic syndrome, Glomerulosclerosis (see section 4.4)a. , b Reproductive system and breast disorders Menorrhagia, Impotence, Metrorrhagia Menstrual disorder General disorders and administration site conditions Injection site reaction (various kindsf), Flu-like symptoms (complexg), Pain, Fever, Chills, Peripheral oedema, Asthenia Injection site necrosis, Chest pain, Malaise Sweating a ADRs derived only during post-marketing. b Class label for interferon beta products (see section 4.4). c Class label for interferon products, see below “Pulmonary arterial hypertension”. d Life-threatening and/or fatal cases have been reported. e Laboratory abnormality f ‘Injection site reaction (various kinds)’ comprises all adverse events occurring at the injection site (except injection site necrosis), e.g. the following terms: injection site atrophy, injection site oedema, injection site haemorrhage, injection site hypersensitivity, injection site infection, injection site inflammation, injection site mass, injection site pain and injection site reaction. g ‘Flu-like symptom complex’ denotes flu syndrome and/or a combination of at least two adverse events from fever, chills, myalgia, malaise, sweating. Pulmonary arterial hypertension Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. Events were reported at various time points including up to several years after starting treatment with interferon beta. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Interferon beta-1b has been given to adult cancer patients at individual doses as high as 5,500 microgram (176 million IU) intravenously three times a week without serious adverse events compromising vital functions.

Pharmacotherapeutic group: Immunostimulants, interferons, ATC code: L03AB08 Interferons belong to the family of cytokines, which are naturally occurring proteins. Interferons have molecular weights ranging from 15,000 to 21,000 Daltons. Three major classes of interferons have been identified: alpha, beta, and gamma. Interferon alpha, interferon beta, and interferon gamma have overlapping yet distinct biological activities. The activities of interferon beta-1b are species-restricted and therefore, the most pertinent pharmacological information on interferon beta-1b is derived from studies of human cells in culture or human in vivo studies. Mechanism of action Interferon beta-1b has been shown to possess both antiviral and immunoregulatory activity. The mechanisms by which interferon beta-1b exerts its actions in multiple sclerosis are not clearly understood. However, it is known that the biological response-modifying properties of interferon beta-1b are mediated through its

Extavia serum levels were followed in patients and volunteers by means of a bioassay that was not completely specific. Maximum serum levels of about 40 IU/ml were found 1-8 hours after subcutaneous injection of 500 microgram (16.0 million IU) interferon beta-1b. From various studies mean clearance rates and half-lives of disposition phases from serum were estimated to be at most 30 ml·min-1·kg-1 and 5 hours, respectively. Administration of Extavia injections every other day does not lead to serum level increase, and the pharmacokinetics do not seem to change during therapy. The absolute bioavailability of subcutaneously administered interferon beta-1b was approximately 50%.

No acute toxicity studies have been performed. As rodents do not react to human interferon beta, repeated dose studies were carried out with rhesus monkeys. Transitory hyperthermia was observed, as well as a significant rise in lymphocytes and a significant decrease in thrombocytes and segmented neutrophils. No long-term studies have been conducted. Reproduction studies with rhesus monkeys revealed maternal toxicity and an increased rate of abortion, resulting in prenatal mortality. No malformations have been observed in the surviving animals. No investigations on fertility have been conducted. No influence on the monkey oestrous cycle has been observed. Experience with other interferons suggest a potential for impairment of male and female fertility. In one single genotoxicity study (Ames test), no mutagenic effect has been observed. Carcinogenicity studies have not been performed. An in vitro cell transformation test gave no indication of tumorigenic potential.

Powder Human albumin Mannitol (E421) Solvent Sodium chloride Water for injection

This medicinal product must not be mixed with other medicinal products except for the supplied solvent mentioned in section 6.6.

2 years. After reconstitution immediate use is recommended. However, in-use stability has been demonstrated for 3 hours at 2°C - 8°C.

Do not store above 25°C. Do not freeze. For storage conditions after reconstitution of the medicinal product, see section 6.3.

Powder 3 ml vial (clear type I glass) with a butyl rubber stopper (type I) and aluminium overseal containing 300 microgram (9.6 million IU) of (recombinant interferon beta- 1b) powder. Solvent 2.25 ml graduated (with dose marks of: 0.25 ml, 0.5 ml, 0.75 ml, 1.0 ml) pre-filled syringe (type I glass) with 1.2 ml solvent. Pack sizes - Pack containing 5 vials with powder and 5 pre-filled syringes with solvent - Pack containing 14 vials with powder and 14 pre-filled syringes with solvent - Pack containing 15 vials with powder and 15 pre-filled syringes with solvent - Pack containing 14 vials with powder and 15 pre-filled syringes with solvent - 3-month multipack containing 42 (3x14) vials with powder and 42 (3x14) pre-filled syringes with solvent - 3-month multipack containing 45 (3x15) vials with powder and 45 (3x15) pre-filled syringes with solvent - 3-month multipack containing 42 (3x14) vials with powder and 45 (3x15) pre-filled syringes with solvent Not all pack sizes may be marketed.

The tip cap of the pre-filled syringe contains a derivative of natural rubber latex. Therefore, the tip cap may contain natural rubber latex, which should not be handled by persons sensitive to this substance. Reconstitution To reconstitute the powder, the pre-filled syringe with solvent should be used with a needle or a vial adapter to inject the 1.2 ml of the solvent (sodium chloride 5.4 mg/ml (0.54%) solution for injection) into the Extavia vial. The powder should dissolve completely without shaking. After reconstitution, 1.0 ml of the solution should be drawn from the vial into the syringe for the administration of 250 microgram Extavia. Inspection prior to use The reconstituted product should be inspected visually before use. The reconstituted product is colourless to light yellow and slightly opalescent to opalescent. The medicinal product should be discarded before use if it contains particulate matter or is discoloured. Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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