Indications for: REBIF
Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
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 chronic progressive forms of 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.
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.
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 following results are for placebo vs Rebif 22 mcg and Rebif 44 mcg, respectively:
- Mean number of exacerbations per patient over 2yrs: 2.56 vs 1.82 (P <.001; percent reduction of 29%) and 1.73 (P <.0001; percent reduction of 32%)
- Percent (%) of patients exacerbation-free at 2yrs: 15% vs 25% (P <.05) and 32% (P <.0001)
- Median time to first exacerbation (months): 4.5 vs 7.6 (P <.001) and 9.6 (P <.0001)
- Median percent (%) change of MRI PD-T2 lesion area at 2yrs: 11% vs -1.2% (P <.0001) and -3.8% (P <.0001)
- Median number of active lesions per patient per scan (PD/T2; 6 monthly): 2.25 vs 0.75 (P <.0001) and 0.5 (P <.0001)
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.
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 chronic progressive forms of 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.
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. The following results are for Rebif 44 mcg vs Avonex 30 mcg, respectively:
- Proportion of patients relapse-free at 24 weeks: 75% (P <.001) vs 63%; absolute difference: 12% (95% CI, 5%-19%); risk of relapse on Rebif relative to Avonex: 0.68 (95% CI, 0.54-0.86)
- Proportion of patients relapse-free at 48 weeks: 62% (P =.009) vs 52%; absolute difference: 10% (95% CI, 2%-17%); risk of relapse on Rebif relative to Avonex: 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 scan (25th, 75th percentiles): 0.17 (P <.001)(0.00, 0.67) vs 0.33 (0.00, 1.25)
Pre-medicate with analgesics and/or antipyretics on treatment days to ameliorate flu-like symptoms. Give by SC inj at least 48hrs apart, preferably in the PM. Rotate inj sites. Initially 4.4mcg 3 times per week for 2 weeks, titrate to target 22mcg 3 times per week by Week 5; or, initially 8.8mcg 3 times per week for 2 weeks, titrate to target 44mcg 3 times per week by Week 5. See full labeling. May need dose reduction if SGPT >5×ULN or leukopenia occurs.
Depression; consider discontinuing if occurs. Suicidal ideation. Discontinue immediately if jaundice or other signs of liver dysfunction occur. Active or history of liver disease. Increased serum SGPT >2.5×ULN. Alcohol abuse. Seizure disorders. Risk of thrombotic microangiopathy; discontinue if occurs. Risk for pulmonary arterial hypertension (PAH); evaluate and discontinue if PAH is confirmed. History of thyroid dysfunction; do thyroid tests every 6 months. Monitor blood counts and liver function at 1, 3, and 6 months after initiation, then periodically thereafter. If myelosuppression, monitor CBCs with differential and platelets more intensively. Elderly. Pregnancy. Nursing mothers.
Risk of hepatic injury with concomitant hepatotoxic drugs or alcohol.
Inj site reactions (necrosis, cellulitis, abscess, inflammation, pain), flu-like symptoms, abdominal pain, depression, elevated liver enzymes, hematologic abnormalities; rare: hepatic failure, anaphylaxis (discontinue if occurs).
Generic Drug Availability:
Prefilled syringe (22mcg, 44mcg)—1, 12; Rebidose autoinjector (22mcg, 44mcg)—12; Titration Pack: Prefilled syringes or Rebidose autoinjectors (6×8.8mcg + 6×22mcg)—1