Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 31 July 2018

Indication(s)

1 INDICATIONS AND USAGE EXTAVIA (interferon beta-1b) is indicated for the treatment of relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. EXTAVIA is an interferon beta indicated for the treatment of relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS EXTAVIA is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, Albumin (Human), or any other component of the formulation. History of hypersensitivity to natural or recombinant interferon beta, albumin or mannitol (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more details in other sections of labeling: •Hepatic Injury [see Warnings and Precautions (5.1)] •Anaphylaxis and Other Allergic Reactions [see Warnings and Precautions (5.2)] •Depression and Suicide [see Warnings and Precautions (5.3)] •Congestive Heart Failure [see Warnings and Precautions (5.4)] •Injection Site Necrosis and Reactions [see Warnings and Precautions (5.5)] •Leukopenia [see Warnings and Precautions (5.6)] •Thrombotic microangiopathy [see Warnings and Precautions (5.7)] •Flu-like Symptom Complex [see Warnings and Precautions (5.8)] •Seizures [see Warnings and Precautions (5.9)] •Drug Induced Lupus Erythematosus [see Warnings and Precautions (5.10)] In controlled clinical trials, the most common adverse reactions (at least 5% more frequent on interferon beta-1b than on placebo) were: injection site reaction, lymphopenia, flu-like symptoms, myalgia, leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions and over varying lengths of time, adverse reaction rates observed in the clinical trials of interferon beta-1b cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice. Among 1407 patients with MS treated with interferon beta-1b 0.25 mg every other day (including 1261 patients treated for greater than one year), the most commonly reported adverse reactions (at least 5% more frequent on interferon beta-1b than on placebo) were injection site reaction, lymphopenia, flu-like symptoms, myalgia leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia. The most frequently reported adverse reactions resulting in clinical intervention (for example, discontinuation of interferon beta-1b, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were depression, flu-like symptom complex, injection site reactions, leukopenia, increased liver enzymes, asthenia, hypertonia, and myasthenia. Table 2 enumerates adverse reactions and laboratory abnormalities that occurred among patients treated with 0.25 mg of interferon beta-1b every other day by subcutaneous injection in the pooled placebo-controlled trials (Study 1-4) at an incidence that was at least 2% more than that observed in the placebo-treated patients [see Clinical Studies (14)]. Table 2: Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled Studies 1, 2, 3, and 4 Adverse Reaction Placebo (N=965) Interferon beta-1b (N=1407) Blood and lymphatic system disorders Lymphocytes count decreased (<1500/mm3) 66% 86% Absolute neutrophil count decreased (<1500/mm3) 5% 13% White blood cell count decreased (<3000/mm3) 4% 13% Lymphadenopathy 3% 6% Nervous system disorders Headache 43% 50% Insomnia 16% 21% Incoordination 15% 17% Vascular disorders Hypertension 4% 6% Respiratory, thoracic and mediastinal disorders Dyspnea 3% 6% Gastrointestinal disorders Abdominal pain 11% 16% Hepatobiliary disorders Alanine aminotransferase increased (SGPT > 5 times baseline) 4% 12% Aspartate aminotransferase increased (SGOT > 5 times baseline) 1% 4% Skin and subcutaneous tissue disorders Rash 15% 21% Skin disorder 8% 10% Musculoskeletal and connective tissue disorders Hypertonia 33% 40% Myalgia 14% 23% Renal and urinary disorders Urinary urgency 8% 11% Reproductive system and breast disorders Metrorrhagia 7% 9% Impotence 6% 8% General disorders and administration site conditions Injection site reaction 1 26% 78% Asthenia 48% 53% Flu-like symptoms (complex) 2 37% 57% Pain 35% 42% Fever 19% 31% Chills 9% 21% Peripheral edema 10% 12% Chest pain 6% 9% Malaise 3% 6% Injection site necrosis 0% 4% 1 "Injection site reaction" comprises all adverse reactions occurring at the injection site (except injection site necrosis), that is, the following terms: injection site reaction, injection site hemorrhage, injection site hypersensitivity, injection site inflammation, injection site mass, injection site pain, injection site edema and injection site atrophy. 2 "Flu-like symptom (complex)" denotes flu syndrome and/or a combination of at least two adverse reactions from fever, chills, myalgia, malaise, sweating. In addition to the adverse reactions listed in Table 2, the following adverse reactions occurred more frequently on interferon beta-1b than on placebo, but with a difference smaller than 2%: alopecia, anxiety, arthralgia, constipation, diarrhea, dizziness, dyspepsia, dysmenorrhea, leg cramps, menorrhagia, myasthenia, nausea, nervousness, palpitations, peripheral vascular disorder, prostatic disorder, tachycardia, urinary frequency, vasodilatation, and weight increase. Laboratory Abnormalities In the four clinical trials (Studies 1, 2, 3, and 4), leukopenia was reported in 18% and 6% of patients in interferon beta-1b- and placebo-treated groups, respectively. No patients were withdrawn or dose reduced for neutropenia in Study 1. Three percent (3%) of patients in Studies 2 and 3 experienced leukopenia and were dose-reduced. Other abnormalities included increase of SGPT to greater than five times baseline value (12%), and increase of SGOT to greater than five times baseline value (4%). In Study 1, two patients were dose reduced for increased hepatic enzymes; one continued on treatment and one was ultimately withdrawn. In Studies 2 and 3, 1.5% of interferon beta-1b patients were dose-reduced or interrupted treatment for increased hepatic enzymes. In Study 4, 1.7% of patients were withdrawn from treatment due to increased hepatic enzymes, two of them after a dose reduction. In Studies 1-4, nine (0.6%) patients were withdrawn from treatment with interferon beta-1b for any laboratory abnormality, including four (0.3%) patients following dose reduction. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples were monitored for the development of antibodies to interferon beta-1b during Study 1. In patients receiving 0.25 mg every other day 56/124 (45%) were found to have serum neutralizing activity at one or more of the time points tested. In Study 4, neutralizing activity was measured every 6 months and at end of study. At individual visits after start of therapy, activity was observed in 17% up to 25% of the interferon beta-1b-treated patients. Such neutralizing activity was measured at least once in 75 (30%) out of 251 interferon beta-1b patients who provided samples during treatment phase; of these, 17 (23%) converted to negative status later in the study. Based on all the available evidence, the relationship between antibody formation and clinical safety or efficacy is not known. These data reflect the percentage of patients whose test results were considered positive for antibodies to interferon beta-1b using a biological neutralization assay that measures the ability of immune sera to inhibit the production of the interferon-inducible protein, MxA. Neutralization assays are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of neutralizing activity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to interferon beta-1b with the incidence of antibodies to other products may be misleading. Anaphylactic reactions have been reported with the use of interferon beta-1b [see Warnings and Precautions (5.2)]. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of interferon beta-1b. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Anemia, Thrombocytopenia Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction Metabolism and nutrition disorders: Triglyceride increased, Anorexia, Weight decrease, Weight increase Psychiatric disorders: Anxiety, Confusion, Emotional lability Nervous system disorders: Convulsion, Dizziness, Psychotic symptoms Cardiac disorders: Cardiomyopathy, Palpitations, Tachycardia Vascular disorders: Vasodilatation Respiratory, thoracic and mediastinal disorders: Bronchospasm Gastrointestinal disorders: Diarrhea, Nausea, Pancreatitis, Vomiting Hepatobiliary disorders: Hepatitis, Gamma GT increased Skin and subcutaneous tissue disorders: Alopecia, Pruritus, Skin discoloration, Urticaria Musculoskeletal and connective tissue disorders: Arthralgia; drug-induced lupus erythematosus Reproductive system and breast disorder: Menorrhagia General disorders and administration site conditions: Fatal capillary leak syndrome* *The administration of cytokines to patients with a preexisting monoclonal gammopathy has been associated with the development of this syndrome.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •For subcutaneous use only (2.1) •The recommended dose is 0.25 mg every other day. Generally, start at 0.0625 mg (0.25 mL) every other day, and increase over a six-week period to 0.25 mg (1 mL) every other day. (2.1) •Reconstitute lyophilized powder with supplied diluent; the removable diluent cap contains natural rubber latex (2.2) 2.1 Dosing Information The recommended starting dose is 0.0625 mg (0.25 mL) subcutaneously every other day, with dose increases over a six-week period to the recommended dose of 0.25 mg (1 mL) every other day (see Table 1). Table 1: Schedule for Dose Titration 1 Dosed every other day, subcutaneously EXTAVIA Dose1 Percentage of recommended dose Volume Weeks 1-2 0.0625 mg 25% 0.25 mL Weeks 3-4 0.125 mg 50% 0.5 mL Weeks 5-6 0.1875 mg 75% 0.75 mL Week 7 and thereafter 0.25 mg 100% 1 mL If a dose of EXTAVIA is missed, then it should be taken as soon as the patient remembers or is able to take it. The patient should not take EXTAVIA on two consecutive days. The next injection should be taken about 48 hours (two days) after that dose. If the patient accidentally takes more than their prescribed dose, or takes it on two consecutive days, they should be instructed to call their healthcare provider immediately. 2.2 Reconstitution of the Lyophilized Powder (a) Prior to reconstitution, verify that the vial containing lyophilized EXTAVIA is not cracked or damaged. Do not use cracked or damaged vials. (b) To reconstitute lyophilized EXTAVIA for injection, attach the pre-filled syringe containing the diluent (Sodium Chloride, 0.54% Solution) to the EXTAVIA vial using the vial adapter. The removable rubber cap of the diluent (Sodium Chloride, 0.54% Solution) pre-filled syringe contains natural rubber latex, which may cause allergic reactions and should not be handled by latex-sensitive individuals. (c) Slowly inject 1.2 mL of diluent into the EXTAVIA vial. (d) Gently swirl the vial to dissolve the lyophilized powder completely; do not shake. Foaming may occur during reconstitution or if the vial is swirled or shaken too vigorously. If foaming occurs, allow the vial to sit undisturbed until the foam settles. (e) 1 mL of reconstituted EXTAVIA solution contains 0.25 mg of interferon beta-1b. (f) After reconstitution, if not used immediately, refrigerate the reconstituted EXTAVIA solution at 35°F to 46°F (2°C to 8°C) and use within three hours. Do not freeze. 2.3 Important Administration Instructions (a) Perform the first EXTAVIA injection under the supervision of an appropriately qualified healthcare professional. If patients or caregivers are to administer EXTAVIA, train them in the proper subcutaneous injection technique and assess their ability to inject subcutaneously to ensure the proper administration of EXTAVIA. (b) Visually inspect the reconstituted EXTAVIA solution before use; discard if it contains particulate matter or is discolored. (c) Keeping the syringe and vial adapter in place, turn the assembly over so that the vial is on top. Withdraw the appropriate dose of EXTAVIA solution. Remove the vial from the vial adapter before injecting EXTAVIA. (d) Use safe disposal procedures for needles and syringes. (e) Do not re-use needles or syringes. (f) Advise patients and caregivers to rotate sites for subcutaneous injections to minimize the likelihood of severe injection site reactions, including necrosis or localized infection. 2.4 Premedication for Flu-like Symptoms Concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with EXTAVIA use [see Warnings and Precautions (5.8)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1) 8.1 Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women; however, spontaneous abortions while on treatment were reported in four patients participating in the interferon beta-1b RRMS clinical trial. EXTAVIA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When interferon beta-1b (doses ranging from 0.028 to 0.42 mg/kg/day) was administered to pregnant rhesus monkeys throughout the period of organogenesis (gestation days 20 to 70), a dose-related abortifacient effect was observed. The low-effect dose is approximately 3 times the recommended human dose of 0.25 mg on a body surface area (mg/m2) basis. A no-effect dose for embryo-fetal developmental toxicity in rhesus monkeys was not established. 8.3 Nursing Mothers It is not known whether interferon beta-1b is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from interferon beta-1b, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of drug to the mother. 8.4 Pediatric Use Safety and efficacy in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of interferon beta-1b did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether interferon beta-1b is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from interferon beta-1b, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of drug to the mother.

More information

Category Value
Authorisation number BLA125290
Orphan designation No
Product NDC 0078-0569
Date Last Revised 22-12-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 198360
Marketing authorisation holder Novartis Pharmaceuticals Corporation