symptoms and laboratory findings consistent with tma occur and a relationship to extavia is suspected. ( 5.7 ) flu-like symptom complex: consider analgesics and/or antipyretics on injection days. ( 5.8 ) drug-induced lupus erythematosus: cases of drug-induced lupus erythematosus have been reported. discontinue extavia if patients develop new characteristic signs and symptoms. ( 5.10 ) 5.1 hepatic injury severe hepatic injury, including cases of hepatic failure, some of which have been due to autoimmune hepatitis, has been rarely reported in patients taking extavia. in some cases, these events have occurred in the presence of other drugs or comorbid medical conditions that have been associated with hepatic injury. consider the potential risk of extavia used in combination with known hepatotoxic drugs or other products (e.g., alcohol) prior to extavia administration, or when adding new agents to the regimen of patients already on extavia. monitor patients for signs and symptoms of hepatic injury. consider discontinuing extavia if serum transaminase levels significantly increase, or if they are associated with clinical symptoms, such as jaundice. asymptomatic elevation of serum transaminases is common in patients treated with extavia. in controlled clinical trials, elevations of serum glutamic-pyruvic transaminase (sgpt) to greater than five times baseline value were reported in 12% of patients receiving interferon beta-1b (compared to 4% on placebo), and increases of serum glutamic-oxaloacetic transaminase (sgot) to greater than five times baseline value were reported in 4% of patients receiving interferon beta-1b (compared to 1% on placebo), leading to dose-reduction or discontinuation of treatment in some patients [see adverse reactions (6.1)] . monitor liver function tests [see warnings and precautions (5.11)] . 5.2 anaphylaxis and other allergic reactions anaphylaxis has been reported as a rare complication of interferon beta-1b use. other allergic reactions have included dyspnea, bronchospasm, tongue edema, skin rash, and urticaria [see adverse reactions (6.1)] . discontinue extavia if anaphylaxis occurs. the removable rubber cap of the diluent (0.54% sodium chloride solution, usp) pre-filled syringe contains natural rubber latex, which may cause allergic reactions and should not be handled by latex-sensitive individuals. the safe use of extavia pre-filled syringe in latex-sensitive individuals has not been studied. 5.3 depression and suicide depression and suicide have been reported to occur with increased frequency in patients receiving interferon beta products, including interferon beta-1b. advise patients to report any symptom of depression and/or suicidal ideation to their healthcare provider. if a patient develops depression, discontinuation of extavia therapy should be considered. in randomized controlled clinical trials, there were three suicides and eight suicide attempts among the 1532 patients on interferon beta-1b compared to one suicide and four suicide attempts among 965 patients on placebo. 5.4 congestive heart failure monitor patients with preexisting congestive heart failure (chf) for worsening of their cardiac condition during initiation of and continued treatment with extavia. while beta interferons do not have any known direct-acting cardiac toxicity, cases of chf, cardiomyopathy, and cardiomyopathy with chf have been reported in patients without known predisposition to these events, and without other known etiologies being established. in some cases, these events have been temporally related to the administration of interferon beta-1b. recurrence upon rechallenge was observed in some patients. consider discontinuation of extavia if worsening of chf occurs with no other etiology. 5.5 injection site reactions including necrosis injection site reactions, including injection site necrosis, can occur with the use of interferon beta products, including extavia. injection site necrosis (isn) was reported in 4% of interferon beta-1b-treated patients in controlled clinical trials (compared to 0% on placebo) [see adverse reactions (6.1)] . typically, isn occurs within the first four months of therapy, although postmarketing reports have been received of isn occurring over one year after initiation of therapy. the necrotic lesions are typically 3 cm or less in diameter, but larger areas have been reported. generally the necrosis has extended only to subcutaneous fat, but has extended to the fascia overlying muscle. in some lesions where biopsy results are available, vasculitis has been reported. for some lesions, debridement, and/or skin grafting have been required. in most cases, healing was associated with scarring. in controlled clinical trials, injection site reactions occurred in 78% of patients receiving interferon beta-1b with injection site necrosis in 4%. injection site inflammation (42%), injection site pain (16%), injection site hypersensitivity (4%), injection site necrosis (4%), injection site mass (2%), injection site edema (2%), and nonspecific reactions were significantly associated with interferon beta-1b treatment. the incidence of injection site reactions tended to decrease over time. approximately 69% of patients experienced injection site reactions during the first three months of treatment, compared to approximately 40% at the end of the studies. injection site abscesses and cellulitis have been reported in the postmarketing setting with use of interferon beta products including extavia. some cases required treatment with hospitalization for surgical drainage and intravenous antibiotics. periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if injection site necrosis has occurred. patients should be advised of the importance of rotating injection sites with each dose. whether to discontinue therapy following a single site of necrosis is dependent on the extent of necrosis. for patients who continue therapy with extavia after injection site necrosis has occurred, avoid administration of extavia into the affected area until it is fully healed. if multiple lesions occur, change injection site or discontinue therapy until healing occurs. 5.6 leukopenia in controlled clinical trials, leukopenia was reported in 18% of patients receiving interferon beta-1b (compared to 6% on placebo), leading to a reduction of the dose of interferon beta-1b in some patients [see adverse reactions (6.1)] . monitoring of complete blood and differential white blood cell counts is recommended. patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. 5.7 thrombotic microangiopathy cases of thrombotic microangiopathy (tma), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products, including extavia. cases have been reported several weeks to years after starting interferon beta products. if clinical symptoms and laboratory findings consistent with tma occur and a relationship to extavia is suspected, discontinue treatment and manage as clinically indicated. 5.8 flu-like symptom complex in controlled clinical trials, the rate of flu-like symptom complex for patients on interferon beta-1b was 57% [see adverse reactions (6.1)] . the incidence decreased over time, with 10% of patients reporting flu-like symptom complex at the end of the studies. the median duration of flu-like symptom complex in study 1 was 7.5 days [see clinical studies (14)] . analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with extavia use. 5.9 seizures seizures have been temporally associated with the use of beta interferons in clinical trials and postmarketing safety surveillance. it is not known whether these events were related to a primary seizure disorder, the effects of ms alone, the use of beta interferons, other potential precipitants of seizures (e.g., fever), or to some combination of these. 5.10 drug-induced lupus erythematosus cases of drug-induced lupus erythematosus have been reported with some interferon beta products, including extavia. signs and symptoms of drug-induced lupus reported in extavia-treated patients have included rash, serositis, polyarthritis, nephritis, and raynaud’s phenomenon. cases have occurred with positive serologic testing (including positive anti-nuclear and/or anti-double-stranded dna antibody testing). if extavia-treated patients develop new signs and symptoms characteristic of this syndrome, extavia therapy should be stopped. 5.11 monitoring for laboratory abnormalities in addition to those laboratory tests normally required for monitoring patients with ms, complete blood and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests, are recommended at regular intervals (one, three, and six months) following introduction of extavia therapy, and then periodically thereafter in the absence of clinical symptoms.

avia 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 (0.54% sodium chloride solution, usp) to the extavia vial using the vial adapter. the removable rubber cap of the diluent (0.54% sodium chloride solution, usp) 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 [see warnings and precautions (5.5)] . 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)] .

adache, 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 (studies 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 a "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. b "flu-like symptom (complex)" denotes flu syndrome and/or a combination of at least two adverse reactions from fever, chills, myalgia, malaise, sweating. adverse reaction placebo (n = 965) interferon beta-1b (n = 1407) blood and lymphatic system disorders lymphocytes count decreased (< 1500/mm 3 ) 66% 86% absolute neutrophil count decreased (< 1500/mm 3 ) 5% 13% white blood cell count decreased (< 3000/mm 3 ) 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 a 26% 78% asthenia 48% 53% flu-like symptoms (complex) b 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% 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 to 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, hemolytic anemia 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.

en the use of interferon beta-1b during pregnancy and an increased risk of major birth defects. animal data 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 increase in the incidence of abortion was observed. the low-effect dose is approximately 3 times the recommended human dose of 0.25 mg on a body surface area (mg/m 2 ) basis. a no-effect dose for embryo-fetal developmental toxicity in rhesus monkeys was not established. 8.2 lactation risk summary there are no data on the presence of interferon beta-1b in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for extavia and any potential adverse effects on the breastfed child from extavia or from the underlying maternal condition. 8.4 pediatric use safety and effectiveness 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.

s. animal data 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 increase in the incidence of abortion was observed. the low-effect dose is approximately 3 times the recommended human dose of 0.25 mg on a body surface area (mg/m 2 ) basis. a no-effect dose for embryo-fetal developmental toxicity in rhesus monkeys was not established.

xpression of proteins that are responsible for the pleiotropic bioactivities of interferon beta-1b. a number of these proteins (including neopterin, β 2 -microglobulin, mxa protein, and il-10) have been measured in blood fractions from interferon beta-1b-treated patients and interferon beta-1b-treated healthy volunteers. immunomodulatory effects of interferon beta-1b include the enhancement of suppressor t-cell activity, reduction of pro-inflammatory cytokine production, down-regulation of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system. it is not known if these effects play an important role in the observed clinical activity of interferon beta-1b in ms. 12.3 pharmacokinetics because serum concentrations of interferon beta-1b are low or not detectable following subcutaneous administration of 0.25 mg or less of interferon beta-1b, pharmacokinetic information in patients with ms receiving the recommended dose of interferon beta-1b is not available. following single and multiple daily subcutaneous administrations of 0.5 mg interferon beta-1b to healthy volunteers (n = 12), serum interferon beta-1b concentrations were generally below 100 units/ml. peak serum interferon beta-1b concentrations occurred between 1 to 8 hours, with a mean peak serum interferon concentration of 40 units/ml. bioavailability, based on a total dose of 0.5 mg interferon beta-1b given as two subcutaneous injections at different sites, was approximately 50%. after intravenous administration of interferon beta-1b (0.006 mg to 2 mg), similar pharmacokinetic profiles were obtained from healthy volunteers (n = 12) and from patients with diseases other than ms (n = 142). in patients receiving single intravenous doses up to 2 mg, increases in serum concentrations were dose proportional. mean serum clearance values ranged from 9.4 ml/min•kg -1 to 28.9 ml/min•kg -1 and were independent of dose. mean terminal elimination half-life values ranged from 8 minutes to 4.3 hours, and mean steady-state volume of distribution values ranged from 0.25 l/kg to 2.88 l/kg. three-times-a-week intravenous dosing for two weeks resulted in no accumulation of interferon beta-1b in sera of patients. pharmacokinetic parameters after single and multiple intravenous doses of interferon beta-1b were comparable. following every-other-day subcutaneous administration of 0.25 mg interferon beta-1b in healthy volunteers, biologic response marker levels (neopterin, β 2 -microglobulin, mxa protein, and the immunosuppressive cytokine, il-10) increased significantly above baseline 6 to 12 hours after the first interferon beta-1b dose. biologic response marker levels peaked between 40 and 124 hours and remained elevated above baseline throughout the seven-day (168-hour) study. the relationship between serum interferon beta-1b levels or induced biologic response marker levels and the clinical effects of interferon beta-1b in ms is unknown. drug interaction studies no formal drug interaction studies have been conducted with interferon beta-1b.

n patients receiving single intravenous doses up to 2 mg, increases in serum concentrations were dose proportional. mean serum clearance values ranged from 9.4 ml/min•kg -1 to 28.9 ml/min•kg -1 and were independent of dose. mean terminal elimination half-life values ranged from 8 minutes to 4.3 hours, and mean steady-state volume of distribution values ranged from 0.25 l/kg to 2.88 l/kg. three-times-a-week intravenous dosing for two weeks resulted in no accumulation of interferon beta-1b in sera of patients. pharmacokinetic parameters after single and multiple intravenous doses of interferon beta-1b were comparable. following every-other-day subcutaneous administration of 0.25 mg interferon beta-1b in healthy volunteers, biologic response marker levels (neopterin, β 2 -microglobulin, mxa protein, and the immunosuppressive cytokine, il-10) increased significantly above baseline 6 to 12 hours after the first interferon beta-1b dose. biologic response marker levels peaked between 40 and 124 hours and remained elevated above baseline throughout the seven-day (168-hour) study. the relationship between serum interferon beta-1b levels or induced biologic response marker levels and the clinical effects of interferon beta-1b in ms is unknown. drug interaction studies no formal drug interaction studies have been conducted with interferon beta-1b.

fertility or reproductive performance was not evaluated.

performance was not evaluated.

ranges from 0 (normal neurologic exam) to 10 (death due to ms). patients who had received prior immunosuppressant therapy were excluded. an exacerbation was defined as the appearance of a new clinical sign/symptom or the clinical worsening of a previous sign/symptom (one that had been stable for at least 30 days) that persisted for a minimum of 24 hours. patients selected for study were randomized to treatment with either placebo (n = 123), 0.05 mg of interferon beta-1b (n = 125), or 0.25 mg of interferon beta-1b (n = 124), self-administered subcutaneously every other day. outcome based on the 372 randomized patients was evaluated after two years. patients who required more than three 28-day courses of corticosteroids were removed from the study. minor analgesics (acetaminophen, codeine), antidepressants, and oral baclofen were allowed ad libitum, but chronic nonsteroidal anti-inflammatory drug (nsaid) use was not allowed. the primary protocol-defined outcome measures were 1) frequency of exacerbations per patient and 2) proportion of exacerbation-free patients. a number of secondary clinical and magnetic resonance imaging (mri) measures were also employed. all patients underwent annual t2 mri imaging, and a subset of 52 patients at one site had mris performed every six weeks for assessment of new or expanding lesions. the study results are shown in table 3. table 3: two-year rrms study results of primary and secondary clinical outcomes (study 1) abbreviation: nd, not done. a 14 exacerbation-free patients (0 from placebo, six from 0.05 mg, and eight from 0.25 mg) dropped out of the study before completing six months of therapy. these patients are excluded from this analysis. b sequelae and functional neurologic status, both required by protocol, were not analyzed individually but are included as a function of the edss. c edss scores range from 1-10, with higher scores reflecting greater disability. d scripps neurologic rating scores range from 0-100, with smaller scores reflecting greater disability. efficacy parameters treatment groups statistical comparisons p-value primary endpoints placebo (n = 123) interferon beta-1b 0.05 mg (n = 125) interferon beta-1b 0.25 mg (n = 124) placebo vs 0.05 mg 0.05 mg vs 0.25 mg placebo vs 0.25 mg annual exacerbation rate 1.31 1.14 0.9 0.005 0.113 0.0001 proportion of exacerbation-free patients a 16% 18% 25% 0.609 0.288 0.094 exacerbation frequency per patient 0 a 1 2 3 4 > 5 20% 32% 20% 15% 15% 21% 22% 31% 28% 15% 7% 16% 29% 39% 17% 14% 9% 8% 0.151 0.077 0.001 secondary endpoints b median number of months to first on-study exacerbation 5 6 9 0.299 0.097 0.01 rate of moderate or severe exacerbations per year 0.47 0.29 0.23 0.02 0.257 0.001 mean number of moderate or severe exacerbation days per patient 44 33 20 0.229 0.064 0.001 mean change in edss score c at endpoint 0.21 0.21 -0.07 0.995 0.108 0.144 mean change in scripps score d at endpoint -0.53 -0.5 0.66 0.641 0.051 0.126 median duration in days per exacerbation 36 33 36 nd nd nd % change in mean mri lesion area at endpoint 21.4% 9.8% -0.9% 0.015 0.019 0.0001 of the 372 rrms patients randomized, 72 (19%) failed to complete two full years on their assigned treatments. over the two-year period in study 1, there were 25 ms-related hospitalizations in the 0.25 mg interferon beta-1b-treated group compared to 48 hospitalizations in the placebo group. in comparison, non-ms hospitalizations were evenly distributed among the groups, with 16 in the 0.25 mg interferon beta-1b group and 15 in the placebo group. the average number of days of ms-related steroid use was 41 days in the 0.25 mg interferon beta-1b group and 55 days in the placebo group (p = 0.004). mri data were also analyzed for patients in this study. a frequency distribution of the observed percent changes in mri area at the end of two years was obtained by grouping the percentages in successive intervals of equal width. figure 1 displays a histogram of the proportions of patients, which fell into each of these intervals. the median percent change in mri area for the 0.25 mg group was -1.1%, which was significantly smaller than the 16.5% observed for the placebo group (p = 0.0001). figure 1: distribution of change in mri area in patients with rrms in study 1 in an evaluation of frequent mri scans (every six weeks) on 52 patients at one site in study 1, the percent of scans with new or expanding lesions was 29% in the placebo group and 6% in the 0.25 mg treatment group (p = 0.006). patients with secondary progressive ms studies 2 and 3 were multicenter, randomized, double-blind, placebo-controlled trials conducted to assess the effect of interferon beta-1b in patients with secondary progressive ms (spms). study 2 was conducted in europe, and study 3 was conducted in north america. both studies enrolled patients with clinically definite or laboratory-supported ms in the secondary progressive phase, and who had evidence of disability progression (both study 2 and 3) or two relapses (study 2 only) within the previous two years. baseline kurtzke edss scores ranged from 3.0 to 6.5. patients in study 2 were randomized to receive interferon beta-1b 0.25 mg (n = 360) or placebo (n = 358). patients in study 3 were randomized to interferon beta-1b 0.25 mg (n = 317), interferon beta-1b 0.16 mg/m 2 of body surface area (n = 314, mean assigned dose 0.3 mg), or placebo (n = 308). test agents were administered subcutaneously, every other day for three years. the primary outcome measure was progression of disability, defined as a 1.0 point increase in the edss score, or a 0.5 point increase for patients with baseline edss ≥ 6.0. in study 2, time to progression in edss was longer in the interferon beta-1b treatment group (p = 0.005), with estimated annualized rates of progression of 16% and 19% in the interferon beta-1b and placebo groups, respectively. in study 3, the rates of progression did not differ significantly between treatment groups, with estimated annualized rates of progression of 12%, 14%, and 12% in the interferon beta-1b fixed dose, surface area-adjusted dose, and placebo groups, respectively. multiple analyses, including covariate and subset analyses based on sex, age, disease duration, clinical disease activity prior to study enrollment, mri measures at baseline, and early changes in mri following treatment were evaluated in order to interpret the discordant study results. no demographic or disease-related factors enabled identification of a patient subset where interferon beta-1b treatment was predictably associated with delayed progression of disability. in studies 2 and 3, like study 1, a statistically significant decrease in the incidence of relapses associated with interferon beta-1b treatment was demonstrated. in study 2, the mean annual relapse rates were 0.42 and 0.63 in the interferon beta-1b and placebo groups, respectively (p < 0.001). in study 3, the mean annual relapse rates were 0.16, 0.20, and 0.28, for the fixed dose, surface area-adjusted dose, and placebo groups, respectively (p < 0.02). mri endpoints in both study 2 and study 3 showed smaller increases in t2 mri lesion area and decreased number of active mri lesions in patients in the interferon beta-1b groups compared to the placebo group. patients with an isolated demyelinating event and typical ms lesions on brain mri in study 4, 468 patients who had recently (within 60 days) experienced an isolated demyelinating event, and who had lesions typical of ms on brain mri were randomized to receive either 0.25 mg interferon beta-1b (n = 292) or placebo (n = 176) subcutaneously every other day (ratio 5:3). the primary outcome measure was time to development of a second exacerbation with involvement of at least two distinct anatomical regions. secondary outcomes were brain mri measures, including the cumulative number of newly active lesions, and the absolute change in t2 lesion volume. patients were followed for up to two years or until they fulfilled the primary endpoint. eight percent of subjects on interferon beta-1b and 6% of subjects on placebo withdrew from the study for a reason other than the development of a second exacerbation. time to development of a second exacerbation was significantly delayed in patients treated with interferon beta-1b compared to patients treated with placebo (p < 0.0001). the kaplan-meier estimates of the percentage of patients developing an exacerbation within 24 months were 45% in the placebo group and 28% of the interferon beta-1b group (figure 2). the risk for developing a second exacerbation in the interferon beta-1b group was 53% of the risk in the placebo group (hazard ratio = 0.53; 95% confidence interval 0.39 to 0.73). figure 2: onset of second exacerbation by time in patients with isolated demyelinating event with typical ms lesions on brain mri in study 4* *kaplan-meier methodology in study 4, patients treated with interferon beta-1b demonstrated a lower number of newly active lesions during the course of the study. a significant difference between interferon beta-1b and placebo was not seen in the absolute change in t2 lesion volume during the course of the study. figure 1 figure 2

tely, refrigerate the reconstituted solution and use within three hours. do not freeze.

warnings and precautions (5.1)] . anaphylaxis and other allergic reactions advise patients of the symptoms of allergic reactions and anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur. inform latex-sensitive patients that the removable rubber cap of the diluent pre-filled syringe contains natural rubber latex [see warnings and precautions (5.2)] . depression and suicide advise patients that depression and suicidal ideation have been reported during the use of extavia. inform patients of the symptoms of depression or suicidal ideation, and instruct patients to report them immediately to their healthcare provider [see warnings and precautions (5.3)] . congestive heart failure advise patients that worsening of preexisting congestive heart failure have been reported in patients using extavia. advise patients of symptoms of worsening cardiac condition, and instruct patients to report them immediately to their healthcare provider [see warnings and precautions (5.4)] . injection site reactions including necrosis advise patients that injection site reactions occur in most patients treated with extavia, and that injection site necrosis may occur at one or multiple sites. instruct patients to promptly report any break in the skin, which may be associated with blue-black discoloration, swelling, or drainage of fluid from the injection site, prior to continuing their extavia therapy [see warnings and precautions (5.5)] . flu-like symptom complex inform patients that flu-like symptoms are common following initiation of therapy with extavia, and that 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), dosage and administration (2.4)] . seizures instruct patients to report seizures immediately to their healthcare provider [see warnings and precautions (5.9)] . drug-induced lupus erythematosus advise patients that drug-induced lupus erythematosus has been reported during the use of extavia. inform patients of the symptoms of rash, redness of the skin on the face, joint pain, fever, and weakness, and instruct patients to report them immediately to their healthcare provider [see warnings and precautions (5.10)] . pregnancy advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant [see use in specific populations (8.1)] . manufactured by: novartis pharmaceuticals corporation east hanover, new jersey 07936 u.s. license no. 1244 © novartis t2021-145