RECIGEN

Human interferon beta (166 residues), glycosylated, MW=22.5kD.

It is produced by mammalian cells (Chinese Hamster Ovary cells) into which the human interferon beta gene has been introduced.

The amino acid sequence is identical to that of natural human interferon beta.

For treatment of relapsing/remitting multiple sclerosis, also for condyloma acuminatum

Interferon beta upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens.

This enhances the activation of

CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing.

I interferons also induce the synthesis of several key antiviral mediators including 2'-5' oligoadenylate synthetase (2'-5' A synthetase), beta-2 microglobulin and neopterin.

Interferon alpha/beta receptor 1 Agonist Interferon alpha/beta receptor 2 Agonist.

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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.

For subcutaneous injection only

The recommended dose is either 22 mcg or 44 mcg injected subcutaneously three times per week 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 Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms 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 or 44 mcg three times per week.

Patients prescribed a targeted dose of 22 mcg three times per week should use the prefilled syringes for 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 Dose Use 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 and after 22 mcg 22 mcg syringe or autoinjector Use full syringe or autoinjector Table 2: Titration Schedule for a 44 mcg Prescribed Dose Prefilled 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 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. 2.2 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 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 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.

is supplied as a sterile solution containing no preservative available in the following package presentations: Prefilled Syringes: REBIF (interferon beta -1a) Titration Pack, NDC 44087-8822-1.

• Six REBIF 8.8 mcg prefilled syringes and Six REBIF 22 mcg prefilled syringes REBIF (interferon beta -1a) 22 mcg Prefilled syringe.

• Twelve REBIF 22 mcg prefilled syringes, NDC 44087-0022.

• 3 REBIF (interferon beta -1a) 44 mcg Prefilled syringe.

• Twelve REBIF 44 mcg prefilled syringes, NDC 44087-0044-3 REBIF Rebidose Autoinjectors: REBIF Rebidose (interferon beta-1a) Titration Pack, NDC 44087-0188-1.

• Six REBIF Rebidose 8.8 mcg autoinjectors with lime-green injector buttons and Six REBIF Rebidose 22 mcg with yellow injector buttons.

Rebidose (interferon beta-1a) 22 mcg Autoinjector.

• Twelve REBIF Rebidose 22 mcg autoinjectors with yellow injector buttons, NDC 44087-3322-1 REBIF Rebidose (interferon beta-1a) 44 mcg Autoinjector.

• Twelve REBIF Rebidose 44 mcg autoinjectors with teal-green injector buttons, NDC 44087-3344-1 REBIF should be stored refrigerated between 36°F to 46°F (2°C to 8°C).

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.

Do not use beyond the expiration date printed on packages.

REBIF contains no preservatives.

Each prefilled syringe and REBIF

Rebidose autoinjector is intended for a single dose.

Unused portions should be discarded.

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

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.

Do not use beyond the expiration date printed on packages.

REBIF contains no preservatives.

Each prefilled syringe and REBIF

Rebidose autoinjector is intended for a single dose.

Unused portions should be discarded.

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.

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 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).

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of

REBIF did not include sufficient numbers of subjects aged 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.