"The U.S. Food and Drug Administration today approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS).
MS is a chronic, inflammatory, autoimmune disease of the central nervous system"...
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The relationships between serum interferon beta-1a levels and measurable pharmacodynamic activities to the mechanism(s) by which REBIF exerts its effects in multiple sclerosis are unknown. No gender-related effects on pharmacodynamic parameters have been observed.
The pharmacokinetics of REBIF (interferon beta-1a) in people with multiple sclerosis have not been evaluated. In healthy subjects, a single subcutaneous (sc) injection of 60 mcg of REBIF (liquid formulation) resulted in a peak serum concentration (C max ) of 5.1 ± 1.7 IU/mL (mean ± SD), with a median time of peak serum concentration (T max ) of 16 hours. The serum elimination half-life (t ½) was 69 ± 37 hours, and the area under the serum concentration versus time curve (AUC) from zero to 96 hours was 294 ± 81 IU h/mL. Following every other day sc injections in healthy subjects, an increase in AUC of approximately 240% was observed, suggesting that accumulation of interferon beta-1a occurs after repeat administration. Total clearance is approximately 33-55 L/hour. There have been no observed gender-related effects on pharmacokinetic parameters. Pharmacokinetics of REBIF in pediatric and geriatric patients or patients with renal or hepatic insufficiency have not been established.
Two multicenter studies evaluated the safety and efficacy of REBIF in patients with relapsing-remitting multiple sclerosis.
Study 1 was a randomized, double-blind, placebo controlled study in patients with multiple sclerosis for at least one year, Kurtzke Expanded Disability Status Scale (EDSS) scores ranging from 0 to 5, and at least 2 acute exacerbations in the previous 2 years. Patients with secondary progressive multiple sclerosis were excluded from the study. Patients received subcutaneous injections of either placebo (n = 187), REBIF 22 mcg (n = 189), or REBIF 44 mcg (n = 184) administered three times per week for two years. Doses of study agents were progressively increased to their target doses during the first 4 to 8 weeks for each patient in the study [see DOSAGE AND ADMINISTRATION].
The primary efficacy endpoint was the number of clinical exacerbations. Numerous secondary efficacy endpoints were also evaluated and included exacerbation-related parameters, effects of treatment on progression of disability and magnetic resonance imaging (MRI)-related parameters. Progression of disability was defined as an increase in the EDSS score of at least one point sustained for at least 3 months. Neurological examinations were completed every 3 months, during suspected exacerbations, and coincident with MRI scans. All patients underwent proton density T2-weighted (PD/T2) MRI scans at baseline and every 6 months. A subset of 198 patients underwent PD/T2 and T1-weighted gadolinium-enhanced (Gd)-MRI scans monthly for the first 9 months. Of the 560 patients enrolled, 533 (95%) provided 2 years of data and 502 (90%) received 2 years of study agent.
Study results are shown in Table 5 and Figure 1. REBIF at doses of 22 mcg and 44 mcg administered three times per week significantly reduced the number of exacerbations per patient as compared to placebo. Differences between the 22 mcg and 44 mcg groups were not significant (p > 0.05).
The exact relationship between MRI findings and the 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 these studies has not been evaluated.
Table 5: Clinical and MRI Endpoints from Study 1
|Placebo||REBIF 22 mcg||REBIF 44 mcg|
|n = 187||n = 189||n = 184|
|Mean number of exacerbations per patient over 2 years1,2(Percent reduction)||2.56||1.82** (29%)||1.73*** (32%)|
|Percent (%) of patients exacerbation-free at 2 years3||15%||25%*||32%***|
|Median time to first exacerbation (months)1,4||4.5||7.6**||9 6***|
|MRI||n = 172||n = 171||n = 171|
|Median percent (%) change of MRI PD-T2 lesion area at 2 years5||11.0%||-1.2%***||-3.8%***|
|Median number of active lesions per patient per scan (PD/T2; 6 monthly)5||2.25||0.75***||0.5***|
|* p < 0.05 compared to placebo
** p < 0.001 compared to placebo
*** p < 0.0001 compared to placebo
1 Intent-to-treat analysis
2 Poisson regression model adjusted for center and time on study
3 Logistic regression adjusted for center. Patients lost to follow-up prior to an exacerbation were excluded from this analysis. (Analysis included 185, 183, and 184 patients for three times per week placebo, 22 mcg REBIF, and 44 mcg REBIF, respectively).
4 Cox proportional hazard model adjusted for center
5 ANOVA on ranks adjusted for center. Patients with missing scans were excluded from this analysis.
The time to onset of progression in disability sustained for three months was significantly longer in patients treated with REBIF than in placebo-treated patients. The Kaplan-Meier estimates of the proportions of patients with sustained disability are depicted in Figure 1.
Figure 1: Proportions of Patients with Sustained
The safety and efficacy of treatment with REBIF beyond 2 years have not been established.
Study 2 was a randomized, open-label, evaluator-blinded, active comparator study. Patients with relapsing-remitting multiple sclerosis with EDSS scores ranging from 0 to 5.5, and at least 2 exacerbations in the previous 2 years were eligible for inclusion. Patients with secondary progressive multiple sclerosis were excluded from the study. Patients were randomized to treatment with three times per week subcutaneous injections of REBIF 44 mcg (n=339) or once weekly intramuscular injections of 30 mcg AVONEX (n=338). Study duration was 48 weeks.
The primary efficacy endpoint was the proportion of patients who remained exacerbation-free at 24 weeks. The principal secondary endpoint was the mean number per patient per scan of combined unique active MRI lesions through 24 weeks, defined as any lesion that was T1 active or T2 active. Neurological examinations were performed every three months by a neurologist blinded to treatment assignment. Patient visits were conducted monthly, and mid-month telephone contacts were made to inquire about potential exacerbations. If an exacerbation was suspected, the patient was evaluated with a neurological examination. MRI scans were performed monthly and analyzed in a treatment-blinded manner.
Patients treated with REBIF 44 mcg three times per week were more likely to remain relapse-free at 24 and 48 weeks than were patients treated with AVONEX 30 mcg once per week (Table 6). This study does not support any conclusion regarding effects on the accumulation of physical disability.
Table 6: Clinical and MRI Results from Study 2
|REBIF 44 mcg||AVONEX 30 mcg||Absolute Difference||Risk of relapse on REBIF relative to AVONEX|
|Relapses Proportion of patients relapse-free at 24 weeks1||N=339 75%*||N=338 63%||12% (95% CI: 5%, 19%)||0.68 (95% CI: 0.54, 0.86)|
|Proportion of patients relapse-free at 48 weeks||62%**||52%||10% (95% CI: 2%, 17%)||0.81 (95% CI: 0.68, 0.96)|
|MRI (through 24 weeks) Median of the mean number of combined unique MRI lesions per patient per scan2 (25th, 75th percentiles)||N=325 0.17* (0.00, 0.67)||N=325 0.33 (0.00, 1.25)|
|* p < 0.001 (REBIF compared to AVONEX)
** p = 0.009 (REBIF compared to AVONEX)
1 Logistic regression model adjusted for treatment and center, intent to treat analysis
2 Nonparametric ANCOVA model adjusted for treatment and center, with baseline combined unique lesions as the single covariate
Last reviewed on RxList: 5/12/2014
This monograph has been modified to include the generic and brand name in many instances.
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