Rebif

— THERAPEUTIC CATEGORIES —
  • Multiple sclerosis
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Rebif Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Interferon beta-1a 8.8mcg/0.2mL, 22mcg/0.5mL, 44mcg/0.5mL; soln for SC inj; contains albumin (human); preservative-free.

    Pharmacological Class

    Immunomodulator.

    How Supplied

    Prefilled syringe (22mcg, 44mcg)—1, 12; Rebidose autoinjector (22mcg, 44mcg)—12; Titration Pack: Prefilled syringes or Rebidose autoinjectors (6×8.8mcg + 6×22mcg)—1

    How Supplied

    Prefilled Syringes

    Rebif Titration Pack: 

    • Six Rebif 8.8 mcg prefilled syringes + Six Rebif 22 mcg prefilled syringes

    Rebif 22 mcg Prefilled syringe:

    • Twelve Rebif 22 mcg prefilled syringes

    Rebif 44 mcg Prefilled syringe:

    • Twelve Rebif 44 mcg prefilled syringes

     

    Rebif Rebidose Autoinjectors

    Rebif Rebidose Titration Pack:

    • Six REBIF Rebidose 8.8 mcg autoinjectors with lime-green injector buttons + Six Rebif Rebidose 22 mcg with yellow injector buttons

    Rebif Rebidose 22 mcg Autoinjector:

    • Twelve Rebif Rebidose 22 mcg autoinjectors with yellow injector buttons

    Rebif Rebidose 44 mcg Autoinjector

    • Twelve Rebif Rebidose 44 mcg autoinjectors with teal-green injector buttons

     

    Storage

    Rebif should be stored refrigerated between 36° F to 46° F (2° C to 8° C). 

    Do not freeze.

    If needed, Rebif may be stored between 36° F to 77° F (2° C to 25° C) for up to 30 days and away from heat and light, but refrigeration is preferred.

    Manufacturer

    EMD Serono, Inc.

    Generic Availability

    NO

    Mechanism of Action

    Interferons possess immunomodulatory, antiviral and antiproliferative biological activities. They exert their biological effects by binding to specific receptors on the surface of cells.

    Rebif Indications

    Indications

    Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

    Rebif Dosage and Administration

    Adult

    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.

    Children

    Not established.

    Administration

    The initial injection should be performed under the supervision of an appropriately qualified healthcare provider. 

    Rotate site of injection with each dose to minimize the likelihood of severe injection site reactions, including necrosis or localized infection.

    Do not re-use needles, syringes or Rebif Rebidose autoinjectors.

    Rebif Contraindications

    Not Applicable

    Rebif Boxed Warnings

    Not Applicable

    Rebif Warnings/Precautions

    Warnings/Precautions

    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.

    Warnings/Precautions

    Depression and Suicide 

    • Rebif should be used with caution in patients with depression, a condition that is common in people with multiple sclerosis.
    • Depression, suicidal ideation, and suicide attempts have been reported to occur with increased frequency in patients receiving interferon compounds, including Rebif. In addition, there have been postmarketing reports of suicide in patients treated with Rebif.
    • Patients should be advised to report immediately any symptoms of depression and/or suicidal ideation to the prescribing physician. If a patient develops depression, cessation of treatment with Rebif should be considered. 

    Hepatic Injury 

    • Severe liver injury, including some cases of hepatic failure requiring liver transplantation, has been reported rarely in patients taking Rebif.
    • Symptoms of liver dysfunction began from one to six months following the initiation of Rebif.
    • If jaundice or other symptoms of liver dysfunction appear, treatment with Rebif should be discontinued immediately due to the potential for rapid progression to liver failure.
    • Asymptomatic elevation of hepatic transaminases (particularly SGPT) is common with interferon therapy.
    • Rebif should be initiated with caution in patients with active liver disease, alcohol abuse, increased serum SGPT (>2.5 times ULN), or a history of significant liver disease. Also, the potential risk of Rebif used in combination with known hepatotoxic products should be considered prior to Rebif administration, or when adding new agents to the regimen of patients already on Rebif. Reduction of Rebif dose should be considered if SGPT rises above 5 times the upper limit of normal. The dose may be gradually re-escalated when enzyme levels have normalized.

    Anaphylaxis and Other Allergic Reactions 

    • Anaphylaxis has been reported as a rare complication of Rebif use.
    • Other allergic reactions have included skin rash and urticaria, and have ranged from mild to severe without a clear relationship to dose or duration of exposure.
    • Several allergic reactions, some severe, have occurred after prolonged use. Discontinue Rebif if anaphylaxis occurs. 

    Injection Site Reactions Including Necrosis

    • Injection site reactions, including injection site necrosis, can occur with the use of interferon beta products, including Rebif.
    • In controlled clinical trials, injection site reactions occurred more frequently in Rebif-treated patients (92% in the 44 mcg group and 89% in the 22 mcg group) than in placebo-treated patients (39%) and at a higher frequency in Rebif treated patients (83%) than in Avonex-treated patients (28%).
    • Injection site necrosis also occurred more frequently in Rebif-treated patients (3% in the 44 mcg group and 1% in the 22 mcg group) than in placebo-treated patients (0) during the two years of therapy.
    • Injection site reactions including injection site pain, erythema, edema, cellulitis, abscess, and necrosis have been reported in the postmarketing setting. Some occurred more than 2 years after initiation of Rebif. Necrosis occurred at single and at multiple injection sites.

    Decreased Peripheral Blood Counts 

    • Decreased peripheral blood counts in all cell lines, including pancytopenia, have been reported in Rebif-treated patients.
    • In controlled clinical trials, leukopenia occurred at a higher frequency in Rebif-treated patients (36% in 44 mcg group and 28% in 22 mcg group) than in placebo-treated patients (14%) and at a higher frequency in Rebif-treated patients (6%) compared to the Avonex-treated patients (<1%).
    • Thrombocytopenia and anemia occurred more frequently in 44 mcg Rebif-treated patients (8% and 5%, respectively) than in placebo-treated patients (2% and 3%, respectively). Patients should be monitored for symptoms or signs of decreased blood counts. Monitoring of complete blood and differential white blood cell counts is also recommended.

    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 Rebif. Cases have been reported several weeks to years after starting interferon beta products.
    • Discontinue Rebif if clinical symptoms and laboratory findings consistent with TMA occur, and manage as clinically indicated.

    Pulmonary Arterial Hypertension

    • Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products, including Rebif.
    • Assess for PAH if unexplained symptoms develop.
    • Discontinue treatment and manage as clinically indicated if a diagnosis of PAH is confirmed.

    Seizures 

    • Caution should be exercised when administering Rebif to patients with pre-existing seizure disorders.
    • Seizures have been temporally associated with the use of beta interferons, including Rebif, in clinical trials and in postmarketing reports.

    Laboratory Tests 

    • In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, blood cell counts and liver function tests are recommended at regular intervals (1, 3, and 6 months) following introduction of Rebif therapy and then periodically thereafter in the absence of clinical symptoms.
    • Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.
    • New or worsening thyroid abnormalities have developed in some patients treated with Rebif. Thyroid function tests are recommended every 6 months in patients with a history of thyroid dysfunction or as clinically indicated.

    Pregnancy Considerations

    Data from a large population-based cohort study, as well as other published studies over several decades, have not identified a drug-associated risk of major birth defects with the use of interferon beta during early pregnancy. Findings regarding a potential risk for low birth weight or miscarriage with the use of interferon beta in pregnancy have been inconsistent (see full labeling). It is unclear whether, as a class of products, administration of interferon beta therapies to pregnant animals at doses greater than those used clinically results in an increased rate of abortion. The potential for Rebif to have adverse effects on embryo-fetal development has not been fully assessed in animals (see full labeling).

    Nursing Mother Considerations

    Limited published literature has described the presence of interferon beta-1a products in human milk at low levels. There is no data on the effects of interferon beta-1a on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Rebif and any potential adverse effects on the breastfed child from Rebif or from the underlying maternal condition.

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established.

    Geriatric Considerations

    Clinical studies of Rebif did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

    Rebif Pharmacokinetics

    See Literature

    Rebif Interactions

    Interactions

    Risk of hepatic injury with concomitant hepatotoxic drugs or alcohol.

    Rebif Adverse Reactions

    Adverse Reactions

    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).

    Rebif Clinical Trials

    Clinical Trials

    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:

    Exacerbation-related:

    • 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)

    MRI:

    • 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:

    Relapses:

    • 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)

    Rebif Note

    Not Applicable

    Rebif Patient Counseling

    Patient Counseling

    Depression and Suicide 

    • Advise patients that depression, suicidal ideation, and suicide have been reported during the use of Rebif.
    • Inform patients of the symptoms of depression and suicidal ideation and instruct patients to immediately report any of these symptoms to their healthcare provider.

    Hepatic Injury 

    • Advise patients that severe liver injury, including hepatic failure, has been reported with the use of Rebif.
    • Educate patients about the symptoms of hepatic injury and instruct patients to report them immediately to their healthcare provider.

    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.

    Injection Site Reactions Including Necrosis 

    • Advise patients that injection site reactions occur in most patients treated with Rebif and that injection site necrosis may occur.
    • 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 Rebif therapy.
    • To minimize the likelihood of injection site reactions, inform patients of the importance of rotating injection sites with each dose and the use of aseptic injection technique.
    • Advise patients not to re-use needles or syringes and instruct patients on safe disposal procedures.

    Decreased Peripheral Blood Counts 

    • Advise patients that they may develop a lowering of their peripheral blood counts, including their white blood counts, red blood counts, and platelets, and that their blood counts will be checked during therapy with Rebif.
    • Inform patients that they may be more likely to get infections, anemia, or be at risk for bleeding, and that they should contact their healthcare provider if they develop symptoms of these adverse reactions. 

    Seizures 

    • Instruct patients to report seizures immediately to their healthcare provider. 

    Flu-like Symptoms 

    • Inform patients that flu-like symptoms are common following initiation of therapy with Rebif.
    • Advise patients that concurrent use of analgesics and/or antipyretics may help reduce flu-like symptoms on treatment days. 

    Pregnancy 

    • Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant.

    Cost Savings Program

    The Rebif patient support program is available here.

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