Rebif Drug Information
Generic name: INTERFERON BETA-1A
Interferon beta [EPC]
Uses of Rebif
is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Rebif is an interferon beta indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Dosage & Administration of Rebif
| Week 1 Titration | 4.4 mcg |
|---|---|
| Week 2 Titration | 4.4 mcg |
| Week 3 Titration | 11 mcg |
| Week 4 Titration | 11 mcg |
| Week 5 and after | 22 mcg |
Side Effects of Rebif
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of REBIF cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. A total of 712 patients with relapsing-remitting multiple sclerosis (RRMS) in two controlled clinical trials took REBIF (22 mcg or 44 mcg given three times per week). Ages ranged from 18 to 55 years. Nearly three-fourths of the patients were female, and more than 90% were Caucasian, largely reflecting the general demographics of the population of patients with multiple sclerosis.
The most commonly reported adverse reactions were injection site disorders, influenza-like symptoms (headache, fatigue, fever, rigors, chest pain, back pain, myalgia), abdominal pain, depression, elevation of liver enzymes and hematologic abnormalities. The most frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of REBIF, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction were injection site disorders, influenza-like symptoms, depression, and elevation of liver enzymes . Study 1 was a 2-year placebo-controlled study in RRMS patients treated with REBIF 22 mcg (n=189), 44 mcg (n=184), or placebo (n=187). Table 3 enumerates adverse reactions and laboratory abnormalities that occurred at an incidence that was at least 2% more in either REBIF-treated group than was observed in the placebo group. Table 3. Adverse Reactions and Laboratory Abnormalities in Study 1 Body System Placebo tiw (n=187) REBIF 22 mcg tiw (n=189) REBIF 44 mcg tiw (n=184) Preferred Term % % % BODY AS A WHOLE Influenza-like symptoms 51 56 59 Headache 63 65 70 Fatigue 36 33 41 Fever 16 25 28 Rigors 5 6 13 Chest pain 5 6 8 Malaise 1 4 5 INJECTION SITE DISORDERS Injection Site Reaction 39 89 92 Injection Site Necrosis 0 1 3 NERVOUS SYSTEM DISORDERS Hypertonia 5 7 6 Coordination Abnormal 2 5 4 Convulsions 2 5 4 Somnolence 1 4 5 ENDOCRINE DISORDERS Thyroid Disorder 3 4 6 GASTROINTESTINAL SYSTEM DISORDERS Abdominal Pain 17 22 20 Dry Mouth 1 1 5 LIVER AND BILIARY SYSTEM DISORDERS SGPT Increased 4 20 27 SGOT Increased 4 10 17 Bilirubinemia 1 3 2 MUSCULO-SKELETAL SYSTEM DISORDERS Myalgia 20 25 25 Back Pain 20 23 25 Skeletal Pain 10 15 10 HEMATOLOGIC DISORDERS Leukopenia 14 28 36 Lymphadenopathy 8 11 12 Thrombocytopenia 2 2 8 Anemia 3 3 5 SKIN DISORDERS Rash Erythematous 3 7 5 Rash Maculo-Papular 2 5 4 Hyperhidrosis 2 4 4 URINARY SYSTEM DISORDERS Micturition Frequency 4 2 7 Urinary Incontinence 2 4 2 VISION DISORDERS Vision Abnormal 7 7 13 Xerophthalmia 0 3 1 Adverse reactions in Study 2, a 1-year active-controlled (vs. interferon beta-1a, 30 mcg once weekly intramuscular injection, n=338) study including 339 patients with MS treated with REBIF were generally similar to those in Study 1, taking into account the disparity in study durations.
Immunogenicity Anaphylaxis and other allergic reactions have been observed with the use
of REBIF . As with all therapeutic proteins, there is a potential for immunogenicity. In Study 1, the presence of neutralizing antibodies (NAb) to REBIF was determined by collecting and analyzing serum pre-study and at 6 month time intervals during the 2 years of the clinical trial. Serum NAb were detected in 59/189 (31%) and 45/184 (24%) of REBIF-treated patients at the 22 mcg and 44 mcg three times per week doses, respectively, at one or more times during the study.
The data reflect the percentage of patients whose test results were considered positive for antibodies to REBIF using an antiviral cytopathic effect assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of NAb positivity 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 REBIF with the incidence of antibodies to other products may be misleading.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of REBIF. 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. Autoimmune Disorders: Drug-induced lupus erythematosus, autoimmune hepatitis Eye Disorders: Retinal vascular disorders (i.e. retinopathy, cotton wool spots or obstruction of retinal artery or vein) Respiratory, Thoracic and mediastinal disorders: Pulmonary Arterial Hypertension Skin and Subcutaneous Tissue Disorders: Erythema multiforme, Stevens-Johnson syndrome Blood and Lymphatic System Disorders: Hemolytic anemia
Warnings & Cautions for Rebif
Depression and Suicide
REBIF (interferon beta-1a) 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 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.
Some cases of injection site necrosis required treatment with intravenous antibiotics and surgical intervention (debridement and skin grafting). Some cases of injection site abscesses and cellulitis required treatment with hospitalization for surgical drainage and intravenous antibiotics. Patient understanding and use of aseptic self-injection techniques and procedures should be periodically evaluated, particularly if injection site necrosis has occurred. Patients should be advised of the importance of rotating sites of injection with each dose and not reusing syringes.
Patients should be advised against injecting an area which is inflamed, edematous, erythematous, ecchymotic, or has any other signs of infection. These signs should be reported to a healthcare professional immediately. If multiple lesions occur, change injection site or discontinue therapy until healing occurs.
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). In a pooled analysis of 7 placebo controlled trials with REBIF doses of 22 mcg or 44 mcg, the rate of pancytopenia (in subjects with normal baseline values who developed laboratory values less than the lower limit of normal for all 3 hematology parameters simultaneously) was higher in the total REBIF group (5.5 per 1000 subject-year) than in the placebo group (1.2 per 1000 subject-year). 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. PAH has occurred in patients treated with interferon beta products in the absence of other contributory factors. Many of the reported cases required hospitalization, including one case with interferon beta in which the patient underwent a lung transplant. PAH has developed at various time points after initiating therapy with interferon beta products and may occur several years after starting treatment.
Patients who develop unexplained symptoms (e.g., dyspnea, new or increasing fatigue) should be assessed for PAH. If alternative etiologies have been ruled out and a diagnosis of PAH is confirmed, discontinue treatment and manage as clinically indicated.
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 Safety for Rebif
Pregnancy Risk Summary 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 Data ). 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 embryofetal development has not been fully assessed in animals.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Human data The majority of observational studies reporting on pregnancies exposed to interferon beta products did not identify an association between the use of interferon beta products during early pregnancy and an increased risk of major birth defects.
In a population-based cohort study conducted in Finland and Sweden, data were collected from 1996—2014 in Finland and from 2005—2014 in Sweden on 2,831 pregnancy outcomes from women with MS. 797 pregnancies were in women exposed to interferon beta only. No evidence was found of an increased risk of major birth defects among women with MS exposed to interferon beta products compared to women with MS that were unexposed to any non-steroid therapy for MS (n=1,647) within the study. No increased risks were observed for miscarriages and ectopic pregnancies, though there were limitations in obtaining complete data capture for these outcomes, making the interpretation of the findings more difficult.
Two small cohort studies that examined pregnancies exposed to interferon beta products (without differentiating between subtypes of interferon beta products) suggested that a decrease in mean birth weight may be associated with interferon beta exposure during pregnancy, but this finding was not confirmed in larger observational studies. Two small studies observed an increased prevalence of miscarriage, although the finding was only statistically significant in one study. Most studies enrolled patients later in pregnancy, which made it difficult to ascertain the true percentage of miscarriages.
In one small cohort study, a significantly increased risk of preterm birth following interferon beta exposure during pregnancy was observed. Animal data In a study in pregnant cynomolgus monkeys, interferon beta was administered daily (intramuscular doses approximately 1, 2, and 7 times the maximum recommended cumulative weekly human dose, based on body surface area) either throughout the period of organogenesis or later in pregnancy (gestation day 90 to term). No adverse effects on embryofetal development were observed; however, the possibility of adverse effects cannot be ruled out because of the small number of animals tested (six per dose group at each developmental period).
Pediatric Use of Rebif
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Contraindications for Rebif
is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation. History of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation
Clinical Studies of Rebif
MRI n = 172 n = 171 n = 171 Median percent
(%) change of MRI PD-T2 lesion area at 2 years ANOVA on ranks adjusted for center. Patients with missing scans were excluded from this analysis. 11.0% -1.2% -3.8% Median number of active lesions per patient per scan (PD/T2; 6 monthly) 2.25 0.75
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 Disability Progression 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. 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 5). This study does not support any conclusion regarding effects on the accumulation of physical disability.
Table 5: Clinical and MRI Results from Study 2 REBIF 44 mcg AVONEX 30 mcg Absolute Difference Risk of relapse on REBIF relative to AVONEX Relapses N=339 N=338 Proportion of patients relapse-free at 24 weeks Logistic regression model adjusted for treatment and center, intent to treat analysis 75% p <0.001 (REBIF compared to AVONEX) 63% 12% (95% CI: 5%, 19%) 0.68 (95% CI: 0.54, 0.86) Proportion of patients relapse-free at 48 weeks 62% p = 0.009 (REBIF compared to AVONEX) 52% 10% (95% CI: 2%, 17%) 0.81 (95% CI: 0.68, 0.96) MRI (through 24 weeks) N=325 N=325 Median of the mean number of combined unique MRI lesions per patient per scan Nonparametric ANCOVA model adjusted for treatment and center, with baseline combined unique lesions as the single covariate (25 th, 75 th percentiles) 0.17 0.33 Figure 1
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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