Rebif
(interferon beta-1a)Dosage & Administration
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Rebif Prescribing Information
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.
Dosing Information
The recommended dose of REBIF is either 22 mcg or 44 mcg injected subcutaneously three times per week. REBIF should be administered, if possible, at the same time (preferably in the late afternoon or evening) on the same three days (e.g., Monday, Wednesday, and Friday) at least 48 hours apart each week.
Generally, patients should be started at 20% of the prescribed dose three times per week and increased over a 4-week period to the targeted dose, either 22 mcg three times per week (see Table 1) or 44 mcg three times per week (see Table 2). Patients prescribed a targeted dose of 22 mcg three times per week should use the prefilled syringes for titration.
A Titration Pack containing 6 doses of 8.8 mcg (0.2 mL) and 6 doses of 22 mcg (0.5 mL) is available for use during the titration period in both REBIF prefilled syringes and REBIF Rebidose autoinjectors.
| Week of Use | Dose | Syringe to Use | Amount of syringe |
|---|---|---|---|
| |||
| Week 1 Titration | 4.4 mcg | 8.8 mcg syringe | Use half of syringe |
| Week 2 Titration | 4.4 mcg | 8.8 mcg syringe | Use half of syringe |
| Week 3 Titration | 11 mcg | 22 mcg syringe | Use half of syringe |
| Week 4 Titration | 11 mcg | 22 mcg syringe | Use half of syringe |
| Week 5 and after | 22 mcg | 22 mcg syringe or autoinjector | Use full syringe or autoinjector |
| Week of Use | Dose | Syringe or Autoinjector to Use | Amount of syringe or autoinjector |
|---|---|---|---|
| |||
| Week 1 Titration | 8.8 mcg | 8.8 mcg syringe or autoinjector | Use full syringe or autoinjector |
| Week 2 Titration | 8.8 mcg | 8.8 mcg syringe or autoinjector | Use full syringe or autoinjector |
| Week 3 Titration | 22 mcg | 22 mcg syringe or autoinjector | Use full syringe or autoinjector |
| Week 4 Titration | 22 mcg | 22 mcg syringe or autoinjector | Use full syringe or autoinjector |
| Week 5 and after | 44 mcg | 44 mcg syringe or autoinjector | Use full syringe or autoinjector |
Decreased peripheral blood counts or elevated liver function tests may necessitate dose reduction or discontinuation of REBIF administration until toxicity is resolved [see Warnings and Precautions (5.2, 5.5) and Adverse Reactions (6)].
Important Administration Instructions
REBIF 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 using the prefilled syringe or injection device approved for use with REBIF. Injection depth of the REBIF Rebidose autoinjector is fixed at 8 mm; the healthcare provider should determine the injection technique.
The initial injection should be performed under the supervision of an appropriately qualified healthcare provider.
Appropriate instruction for self-injection or injection by another person should be provided to the patient or their caregiver, including careful review of the REBIF Medication Guide and the REBIF Rebidose autoinjector Instructions for Use that accompanies the product. Users should demonstrate competency in all aspects of the injection prior to independent use. If a patient is to self-administer REBIF, the physical and cognitive ability of that patient to self-administer and properly dispose of prefilled syringes or the REBIF Rebidose autoinjectors should be assessed. Patients with severe neurological deficits should not self-administer injections without assistance from a trained caregiver.
Advise patients and caregivers to:
- visually inspect REBIF for particulate matter and discoloration prior to administration
- use aseptic technique when administering REBIF
- rotate site of injection with each dose to minimize the likelihood of severe injection site reactions, including necrosis or localized infection [see Warnings and Precautions (5.4)]
- use a puncture-resistant container for safe disposal of used needles, prefilled syringes and REBIF Rebidose autoinjectors
- do not re-use needles, syringes or REBIF Rebidose autoinjectors
Premedication for Flu-like Symptoms
Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms associated with REBIF use on treatment days.
- Injection: 8.8 mcg per 0.2 mL in a graduated, single-dose REBIF prefilled syringe
- Injection: 22 mcg per 0.5 mL in a graduated, single-dose REBIF prefilled syringe
- Injection: 44 mcg per 0.5 mL in a graduated, single-dose REBIF prefilled syringe
- Injection: 8.8 mcg per 0.2 mL in a single-dose prefilled REBIF Rebidose autoinjector
- Injection: 22 mcg per 0.5 mL in a single-dose prefilled REBIF Rebidose autoinjector
- Injection: 44 mcg per 0.5 mL in a single-dose prefilled REBIF Rebidose autoinjector
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 [see Data].
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).
Lactation
Risk Summary
Limited published literature has described the presence of interferon beta-1a products in human milk at low levels. There are 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 Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
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 is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation.
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 [see Adverse Reactions (6.1)]. 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 [see Warnings and Precautions (5.9) and Dosage and Administration (2.1)].
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. 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 [see Dosage and Administration (2.1) and Warnings and Precautions (5.9)].
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 [see Dosage and Administration (2.1) and Warnings and Precautions (5.5)]. 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.