Rebif (Interferon Beta-1a)

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.

• For subcutaneous injection only (
  2.1 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.

  Table 1: Titration Schedule for a 22 mcg Prescribed DoseUse only prefilled syringes, not autoinjectors, to titrate to the 22 mcg Prescribed Dose

  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

  Table 2: Titration Schedule for a 44 mcg Prescribed DosePrefilled syringes or autoinjectors can be used to titrate to the 44 mcg Prescribed Dose

  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)].
  )
• The recommended dose is either 22 mcg or 44 mcg injected subcutaneously three times per week (
  2.1 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.

  Table 1: Titration Schedule for a 22 mcg Prescribed DoseUse only prefilled syringes, not autoinjectors, to titrate to the 22 mcg Prescribed Dose

  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

  Table 2: Titration Schedule for a 44 mcg Prescribed DosePrefilled syringes or autoinjectors can be used to titrate to the 44 mcg Prescribed Dose

  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)].
  )
• Titration: Generally, the starting dose should be 20% of the prescribed dose three times per week, and increased over a 4 week period to the targeted recommended dose of either 22 mcg or 44 mcg injected subcutaneously three times per week (
  2.1 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.

  Table 1: Titration Schedule for a 22 mcg Prescribed DoseUse only prefilled syringes, not autoinjectors, to titrate to the 22 mcg Prescribed Dose

  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

  Table 2: Titration Schedule for a 44 mcg Prescribed DosePrefilled syringes or autoinjectors can be used to titrate to the 44 mcg Prescribed Dose

  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)].
  )
• Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms (
  2.3 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: Epidemiological data do not suggest a clear relationship between interferon beta use and major congenital malformations, but interferon beta may cause fetal harm based on animal data (
  8.1 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).
  ).