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.
DOSAGE AND ADMINISTRATION
The recommended dose of Extavia is 0.25 mg injected subcutaneously every other day.
Generally, patients should be started at 0.0625 mg (0.25 mL) subcutaneously every other day, and increased over a six week period to 0.25 mg (1 mL) every other day (see Table 1).
| Recommended Titration | Extavia Dose | Volume | |
| Weeks 1-2 | 25% | 0.0625 mg | 0.25 mL |
| Weeks 3-4 | 50% | 0.125 mg | 0.5 mL |
| Weeks 5-6 | 75% | 0.1875 mg | 0.75 mL |
| Week 7+ | 100% | 0.25 mg | 1 mL |
To reconstitute lyophilized Extavia for injection, attach the prefilled syringe containing the diluent (Sodium Chloride, 0.54% Solution) to the Extavia vial using the vial adapter. Slowly inject 1.2 mL of diluent into the Extavia vial. Gently swirl the vial to dissolve the drug 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. Visually inspect the reconstituted product before use; discard the product if it contains particulate matter or is discolored. 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. One mL of reconstituted Extavia solution contains 0.25 mg of Interferon beta-1b/mL.
Extavia is intended for use under the guidance and supervision of a physician. It is recommended that physicians or qualified medical personnel train patients in the proper technique for self-administering subcutaneous injections. Patients should be advised to rotate sites for subcutaneous injections (see Patient Counseling Information 17.6). Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms on treatment days. Extavia should be visually inspected for particulate matter and discoloration prior to administration.
Dosage Forms and Strengths
Extavia is supplied as a lyophilized powder containing 0.3 mg of Interferon beta-1b, 15 mg Albumin (Human), USP, and 15 mg Mannitol, USP. Drug is packaged in a clear glass, single-use vial (3 mL capacity). A pre-filled single-use syringe containing 1.2 mL of diluent (Sodium Chloride, 0.54% solution), two alcohol prep pads, and one vial adapter with attached 27 gauge needle are included for each vial of drug. Extavia and the diluent are for single-use only. Unused portions should be discarded. Store at room temperature.
CONTRAINDICATIONS
Extavia is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, Albumin (Human), USP, or any other component of the formulation.
WARNINGS AND PRECAUTIONS
Depression and Suicide
Extavia (Interferon beta-1b) should be used with caution in patients with depression, a condition that is common in people with multiple sclerosis. Depression and suicide have been reported to occur with increased frequency in patients receiving interferon compounds, including Interferon beta-1b. Patients treated with Extavia should be advised to report immediately any symptoms of depression and/or suicidal ideation to their prescribing physicians. If a patient develops depression, cessation of Extavia therapy should be considered.
In the four randomized controlled studies there were three suicides and eight suicide attempts among the 1532 patients in the Interferon beta-1b treated groups compared to one suicide and four suicide attempts among the 965 patients in the placebo groups.
Injection Site Necrosis
Injection site necrosis (ISN) has been reported in 4% of patients in controlled clinical trials [see Adverse Reactions (6.1)]. Typically, injection site necrosis occurs within the first four months of therapy, although post-marketing reports have been received of ISN occurring over one year after initiation of therapy. Necrosis may occur at a single or multiple injection sites. The necrotic lesions are typically three cm or less in diameter, but larger areas have been reported. Generally the necrosis has extended only to subcutaneous fat. However, there are also reports of necrosis extending to and including fascia overlying muscle. In some lesions where biopsy results are available, vasculitis has been reported. For some lesions debridement and, infrequently, skin grafting have been required.
As with any open lesion, it is important to avoid infection and, if it occurs, to treat the infection. Time to healing was varied depending on the severity of the necrosis at the time treatment was begun. In most cases healing was associated with scarring.
Some patients have experienced healing of necrotic skin lesions while Interferon beta-1b therapy continued; others have not. 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, Extavia should not be administered into the affected area until it is fully healed. If multiple lesions occur, therapy should be discontinued until healing occurs.
Patient understanding and use of aseptic self-injection techniques and procedures should be periodically reevaluated, particularly if injection site necrosis has occurred.
Injection Site Reactions
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 non-specific 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 the event during the first three months of treatment, compared to approximately 40% at the end of the studies.
Anaphylaxis
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)].
Flu-Like Symptom Complex
In controlled clinical trials, the rate of flu-like symptom complex was approximately 57%. The incidence decreased over time, with only 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)].
Leukopenia
In controlled clinical trials, leukopenia was reported in 18% of patients receiving Interferon beta-1b, 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 [see Warnings and Precautions (5.8)].
Hepatic enzymes elevations
In controlled clinical trials, elevations of SGPT to greater than five times baseline value were reported in 12% of patients receiving Interferon beta-1b, and increase of SGOT to greater than five times baseline value were reported in 4% of patients receiving Interferon beta-1b, leading to dose-reduction or discontinuation of treatment in some patients [see Adverse Reactions (6.1)]. Monitoring of liver function tests is recommended [see Warnings and Precautions (5.8)].
Laboratory Tests
In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts and blood chemistries, including liver function tests, 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. Thyroid function tests are recommended every six months in patients with a history of thyroid dysfunction or as clinically indicated. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.
Albumin (Human), USP
This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
ADVERSE REACTIONS
Clinical Studies Experience
In all studies, the most serious adverse reactions with Interferon beta-1b were depression, suicidal ideation and injection site necrosis (see Warnings and Precautions). The incidence of depression of any severity was approximately 30% in both Interferon beta-1b-treated patients and placebo-treated patients. Anaphylaxis and other allergic reactions have been reported in patients using Interferon beta-1b [see Warnings and Precautions (5.4)]. The most commonly reported adverse reactions were lymphopenia (lymphocytes<1500/mm3), injection site reaction, asthenia, flu-like symptom complex, headache, and pain. The most frequently reported adverse reactions resulting in clinical intervention (e.g., 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.
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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
The data described below reflect exposure to Interferon beta-1b in the four placebo controlled trials of 1407 patients with MS treated with 0.25 mg or 0.16 mg/m2, including 1261 exposed for greater than one year. The population encompassed an age range from 18 – 65 years. Sixty-four percent (64%) of the patients were female. The percentages of Caucasian, Black, Asian, and Hispanic patients were 94.8%, 3.5%, 0.1%, and 0.7%, respectively.
The safety profiles for Interferon beta-1b-treated patients with SPMS and RRMS were similar. Clinical experience with Interferon beta-1b in other populations (patients with cancer, HIV positive patients, etc.) provides additional data regarding adverse reactions; however, experience in non-MS populations may not be fully applicable to the MS population.
Table 2 enumerates adverse events and laboratory abnormalities that occurred among all patients treated with 0.25 mg or 0.16 mg/m2 Interferon beta-1b every other day for periods of up to three years in the four placebo controlled trials (Study 1-4) at an incidence that was at least 2.0% more than that observed in the placebo patients (System Organ Class, MedDRA v. 8.0).
| System Organ Class MedDRA v. 8.0 # Adverse Reaction | Placebo (n=965) | Interferon beta-1b (n=1407) |
| Blood and lymphatic system disorders | ||
| Lymphocytes count decreased (< 1500/mm3) x | 66% | 86% |
| Absolute neutrophil count decreased (< 1500/mm3) x | 5% | 13% |
| White blood cell count decreased (< 3000/mm3) x | 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)x | 4% | 12% |
| Aspartate aminotransferase increased(SGOT > 5 times baseline)x | 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 (various kinds ) 0 | 26% | 78% |
| Asthenia | 48% | 53% |
| Flu-like symptoms (complex)§ | 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% |
| # except for "injection site reaction (various kinds)o" and "flu-like symptom complex§" the most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions. x laboratory abnormality * pre-menopausal women ** men o "Injection site reaction (various kinds)" comprises all adverse events occurring at the injection site (except injection site necrosis), i.e., 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. § "Flu-like symptom complex" denotes flu syndrome and/or a combination of at least two AEs from fever, chills, myalgia, malaise, sweating. | ||
Laboratory Abnormalities
In the four clinical trials, 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. Monitoring of complete blood and differential white blood cell counts is recommended [see Warnings and Precautions (5.6, 5.8)].
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. Monitoring of liver function tests is recommended [see Warnings and Precautions (5.7, 5.8)].
Postmarketing Experience
The following adverse events have been observed during postmarketing experience with Interferon beta-1b and are classified within body system categories:
Blood and lymphatic system disorders: Anemia, Thrombocytopenia
Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction
Metabolism and nutrition disorders: Hypocalcemia, Hyperuricemia, Triglyceride increased, Anorexia, Weight decrease
Psychiatric disorders: Confusion, Depersonalization, Emotional lability
Nervous system disorders: Ataxia, Convulsion, Paresthesia, Psychotic symptoms
Cardiac disorders: Cardiomyopathy
Vascular disorders: Deep vein thrombosis, Pulmonary embolism
Respiratory, thoracic and mediastinal disorders: Bronchospasm, Pneumonia
Gastrointestinal disorders: Pancreatitis, Vomiting
Hepatobiliary disorders: Hepatitis, Gamma GT increased
Skin and subcutaneous tissue disorders: Pruritus, Skin discoloration, Urticaria
Renal and urinary disorders: Urinary tract infection, Urosepsis
General disorders and administration site conditions: Fatal capillary leak syndrome*.
*The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of this syndrome.
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 [see Clinical Studies (14)]. 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 [see Clinical Studies (14)], neutralizing activity was measured every 6 months and at end of study. At individual visits after start of therapy, activity was observed in 16.5% up to 25.2% of the Interferon beta-1b treated patients. Such neutralizing activity was measured at least once in 75 (29.9%) out of 251 Interferon beta-1b patients who provided samples during treatment phase; of these, 17 (22.7%) 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 rarely been reported with the use of Interferon beta-1b [see Warnings and Precautions (5.4)].
DRUG INTERACTIONS
No formal drug interaction studies have been conducted with Interferon beta-1b. In the placebo controlled studies in MS, corticosteroids or ACTH were administered for treatment of relapses for periods of up to 28 days in patients (N=664) receiving Interferon beta-1b.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C: There are no adequate and well-controlled studies of Interferon beta-1b in pregnant women; however, spontaneous abortions while on treatment were reported in four patients participating in the Interferon beta-1b RRMS clinical trial. Interferon beta-1b 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) 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 are (mg/m2) basis. A no-effect dose for embryo-fetal developmental toxicity in rhesus monkeys was not established.
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.
Pediatric Use
Safety and efficacy in pediatric patients have not been established.
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.
OVERDOSAGE
Safety of doses higher than 0.25 mg every other day has not been adequately evaluated. The maximum amount of Interferon beta-1b that can be safely administered has not been determined.
DESCRIPTION
Extavia® (Interferon beta-lb) is a purified, sterile, lyophilized protein product produced by recombinant DNA techniques. Interferon beta-1b is manufactured by bacterial fermentation of a strain of Escherichia coli that bears a genetically engineered plasmid containing the gene for human interferon betaser17. The native gene was obtained from human fibroblasts and altered in a way that substitutes serine for the cysteine residue found at position 17. Interferon beta-1b has 165 amino acids and an approximate molecular weight of 18,500 daltons. It does not include the carbohydrate side chains found in the natural material. Extavia contains the same active ingredients as other Interferon beta-1b products. For this reason, these products should not be given concomitantly.
The specific activity of Extavia is approximately 32 million international units (IU)/mg Interferon beta-lb. Each vial contains 0.3 mg of Interferon beta-lb. The unit measurement is derived by comparing the antiviral activity of the product to the World Health Organization (WHO) reference standard of recombinant human interferon beta. Mannitol, USP and Albumin (Human), USP (15 mg each/vial) are added as stabilizers.
Lyophilized Extavia is a sterile, white to off-white powder, for subcutaneous injection after reconstitution with the diluent supplied (Sodium Chloride, 0.54% Solution).
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of Interferon beta-1b in patients with multiple sclerosis is unknown.
Pharmacodynamics
Interferons (IFNs) are a family of naturally occurring proteins, produced by eukaryotic cells in response to viral infection and other biologic agents. Four major groups of interferons have been distinguished: alpha, beta, gamma and lambda. Interferons-alpha and -beta comprise the Type I interferons, interferon-gamma is the sole Type II interferon, and interferon-lambda is designated as Type III interferon. Type I interferons have considerably overlapping but also distinct biologic activities. The bioactivities of IFNs are mediated by their interactions with specific receptors found on the surfaces of human cells. Differences in bioactivites induced by IFNs likely reflect divergences in the signal transduction process induced by IFN-receptor binding.
Interferon beta-1b receptor binding induces the expression of proteins that are responsible for the pleiotropic bioactivities of Interferon beta-1b. A number of these proteins (including neopterin, β2-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 multiple sclerosis (MS).
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 IU/mL. Peak serum Interferon beta-1b concentrations occurred between one to eight hours, with a mean peak serum interferon concentration of 40 IU/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 2.0 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 2.0 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 8.0 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, β2- microglobulin, MxA protein, and the immunosuppressive cytokine, IL-10) increased significantly above baseline six-twelve 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 multiple sclerosis is unknown.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Interferon beta-1b has not been tested for its carcinogenic potential in animals.
Mutagenesis: Interferon beta-1b was not genotoxic in the in vitro Ames bacterial test or the in vitro chromosomal aberration assay in human peripheral blood lymphocytes. Interferon beta-1b treatment of mouse BALBc-3T3 cells did not result in increased transformation frequency in an in vitro model of tumor transformation.
Impairment of fertility: Administration of Interferon beta-1b (doses of up to 0.33 mg/kg) to normally cycling female rhesus monkeys had no apparent adverse effects on either menstrual cycle duration or associated hormonal profiles (progesterone and estradiol) when administered over three consecutive menstrual cycles. The highest dose tested is approximately 30 times the recommended human dose of 0.25 mg on a body surface area (mg/m2) basis. The potential for other effects on fertility or reproductive performance was not evaluated.
Clinical Studies
The clinical effects of Interferon beta-1b were studied in four randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis.
The effectiveness of Interferon beta-1b in relapsing-remitting MS (Study 1) was evaluated in a double blind, multiclinic, randomized, parallel, placebo controlled clinical investigation of two years’ duration. The study enrolled MS patients, aged 18 to 50, who were ambulatory (EDSS of ≤ 5.5), exhibited a relapsing-remitting clinical course, met Poser’s criteria1 for clinically definite and/or laboratory supported definite MS and had experienced at least two exacerbations over two years preceding the trial without exacerbation in the preceding month. 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.
| Efficacy Parameters | Treatment Groups | Statistical Comparisons p-value | |||||
| Primary End Points | Placebo N=123 | 0.05 mg N=125 | 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 | 0.90 | 0.005 | 0.113 | 0.0001 | |
| Proportion of exacerbation-free patients† | 16% | 18% | 25% | 0.609 | 0.288 | 0.094 | |
| Exacerbation frequency per patient | 0† 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†† | |||||||
| Median number of months to first on-study exacerbation | 5 | 6 | 9 | 0.299 | 0.097 | 0.010 | |
| Rate of moderate or severe exacerbations per year | 0.47 | 0.29 | 0.23 | 0.020 | 0.257 | 0.001 | |
| Mean number of moderate or severe exacerbation days per patient | 44.1 | 33.2 | 19.5 | 0.229 | 0.064 | 0.001 | |
| Mean change in EDSS score‡ at endpoint | 0.21 | 0.21 | -0.07 | 0.995 | 0.108 | 0.144 | |
| Mean change in Scripps score‡‡ at endpoint | -0.53 | -0.50 | 0.66 | 0.641 | 0.051 | 0.126 | |
| Median duration in days per exacerbation | 36 | 33 | 35.5 | ND | ND | ND | |
| % change in mean MRI lesion area at endpoint | 21.4% | 9.8% | -0.9% | 0.015 | 0.019 | 0.0001 | |
| ND Not done † 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. †† Sequelae and Functional Neurologic Status, both required by protocol, were not analyzed individually but are included as a function of the EDSS. ‡ EDSS scores range from 1-10, with higher scores reflecting greater disability ‡‡ Scripps neurologic rating scores range from 0-100, with smaller scores reflecting greater disability. | |||||||
Of the 372 RRMS patients randomized, 72 (19%) failed to complete two full years on their assigned treatments.
Over the two-year period, 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).
Distribution of Change in MRI Area
In an evaluation of frequent MRI scans (every six weeks) on 52 patients at one site, 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).
The exact relationship between MRI findings and clinical status of patients is unknown. Changes in lesion area often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in this study has not been evaluated.
Studies 2 and 3 were multicenter, randomized, double-blind, placebo controlled trials conducted to assess the effect of Interferon beta-1b in patients with 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 expanded disability status scale (EDSS) scores ranged from 3.0 to 6.5. 2 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/m2 of body surface area (n=314, mean assigned dose 0.30 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 lesser increases in T2 MRI lesion area and decreased number of active MRI lesions in patients in the Interferon beta-1b groups. The exact relationship between MRI findings and the clinical status of patients is unknown. Changes in MRI findings often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in these studies is not known.
In Study 4, 468 patients who had recently (within 60 days) experienced an isolated demyelinating event, and who had lesions typical of multiple sclerosis 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 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 on Study (Kaplan-Meier Methodology)
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.
Safety and efficacy of treatment with Interferon beta-1b beyond three years are not known.
REFERENCES
1. Poser CM, et al. Ann Neurol 1983; 13(3): 227-231.
2. Kurtzke JF. Neurology 1983; 33(11): 1444-1452.
HOW SUPPLIED/STORAGE AND HANDLING
The reconstituted product contains no preservative. Before reconstitution with diluent, store Extavia at room temperature 25°C (77°F). Excursions of 15° to 30°C (59° to 86°F) are permitted. After reconstitution, if not used immediately, the product should be refrigerated and used within three hours. Do not freeze.
Extavia is supplied as a lyophilized powder containing 0.3 mg of Interferon beta-1b, 15 mg Albumin (Human), USP, and 15 mg Mannitol, USP. Drug is packaged in a clear glass, single-use vial (3 mL capacity). A pre-filled single-use syringe containing 1.2 mL of diluent (Sodium Chloride, 0.54% solution), two alcohol prep pads, and one vial adapter with attached 27 gauge needle are included for each vial of drug. Extavia and the diluent are for single-use only. Unused portions should be discarded. Store at room temperature.
15 blister units, 0.3 mg/vial…………………….…….NDC 0078-0569-12
PATIENT COUNSELING INFORMATION
All patients should be instructed to carefully read the supplied Extavia Medication Guide. Patients should be cautioned not to change the dose or schedule of administration without medical consultation.
Depression
Advise patients that depression and suicidal ideation have been reported during the use of Interferon beta-1b. Advise patients of the symptoms of depression or suicidal ideation, and instruct patients to report them immediately to their physician [see Warnings and Precautions (5.1)].
Injection Site Reactions, Including Necrosis
Advise patients that injection site reactions occur in most patients treated with Interferon beta-1b, 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 (5.2, 5.3)].
Allergic Reactions and Anaphylaxis
Advise patients of the symptoms of allergic reactions and anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur [see Warnings and Precautions (5.4)].
Flu-like Symptoms
Patients should be informed that flu-like symptoms are common following initiation of therapy with Interferon beta-1b. In controlled clinical trials, antipyretics and analgesics were permitted for relief of these symptoms. In addition, gradual dose titration during initiation of Interferon beta-1b treatment may reduce flu-like symptoms [see Warnings and Precautions (5.5) and Dosage And Administration (2)].
Pregnancy
Advise patients that Extavia should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Special Population (8.1)].
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