•
`
` __________________
`
`
`__________________ WARNINGS AND PRECAUTIONS
`
`
`• Depression and Suicide: Advise patients to immediately report any
`
`
`
`symptoms of depression and/or suicidal ideation; consider discontinuation
`
`
`
`
`of REBIF if depression occurs (5.1)
`
`• Hepatic injury: Monitor liver function tests; monitor patients for signs and
`
`
`
`
`
`
`
`
`symptoms of hepatic injury; consider discontinuing REBIF if hepatic injury
`
`
`occurs (5.2)
`
`• Anaphylaxis and Other Allergic Reactions: Discontinue REBIF if anaphylaxis
`
`
`
`
`
`occurs (5.3)
`
`
`
`
`Injection Site Reactions including Necrosis: Do not administer REBIF into
`
`
`
`affected area until fully healed; if multiple lesions occur, discontinue REBIF
`
`until healing of skin lesions (5.4)
`
`• Decreased Peripheral Blood Counts: Monitor complete blood counts (5.5)
`
`
`
`• Seizures: Monitor for seizures when administering REBIF to patients,
`
`
`
`
`
`
`
`
`particularly those with pre-existing seizure disorders (5.6)
`
`
`
`______________________ ADVERSE REACTIONS ______________________
`
`
`
`
`
`The most common adverse reactions in controlled clinical trials were injection
`
`
`site disorders, influenza-like symptoms, abdominal pain, depression, elevation
`
`
`of liver enzymes and hematologic abnormalities (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-
`
`283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`
`
`
`
`
` __________________
` __________________
`
`USE IN SPECIFIC POPULATIONS
`
`• Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`
`
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
`
`Revised: 04/2014
`
`
`
`
`
` 8
`
`
` 11
`
` 12
`
`
`
` 13
`
`
` 14
`
` 16
`
` 17
`
`
` Postmarketing Experience
` 6.3
`
`
`
` USE IN SPECIFIC POPULATIONS
`
`
` 8.1
` Pregnancy
`
` 8.3 Nursing Mothers
`
` 8.4
`
` Pediatric Use
`
` 8.5 Geriatric Use
`
` DESCRIPTION
`
`
` CLINICAL PHARMACOLOGY
`
` 12.1 Mechanism of Action
`
`
` 12.2 Pharmacodynamics
`
`
` 12.3 Pharmacokinetics
`
` NONCLINICAL TOXICOLOGY
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of
`
` Fertility
` CLINICAL STUDIES
`
`
`
` HOW SUPPLIED/STORAGE AND HANDLING
`
` PATIENT COUNSELING INFORMATION
`
` *Sections or subsections omitted from the full prescribing
`
` information are not listed
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
`
`REBIF safely and effectively. See full prescribing information for REBIF.
`
`
`
`
`
`REBIF (interferon beta-1a), for subcutaneous injection
`Initial U.S. Approval: 1996
`
`
` ____________________
`
`____________________INDICATIONS AND USAGE
`
`
`
`
`
`
`REBIF is an interferon beta indicated for the treatment of patients with
`
`relapsing forms of multiple sclerosis to decrease the frequency of clinical
`
`
`exacerbations and delay the accumulation of physical disability (1)
`
`
`
`_________________ DOSAGE AND ADMINISTRATION _________________
`
`• For subcutaneous injection only (2.1)
`
`
`
`
`• The recommended dose
`
`
`
`
`
`is either 22 mcg or 44 mcg
`
`
`
`subcutaneously three times per week (2.1)
`
`• 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)
`
`• Analgesics and/or antipyretics on treatment days may help ameliorate flu-
`
`
`
`like symptoms (2.3)
`
` ________________
` ________________
`
`DOSAGE FORMS AND STRENGTHS
`
`•
`
`
`
`
`
`
`Injection: 8.8 mcg in 0.2 mL, and 22 mcg or 44 mcg in 0.5 mL in single-dose
`
`
`
`prefilled syringe (3)
`
`
`
`Injection: 8.8 mcg in 0.2 mL, and 22 mcg or 44 mcg in 0.5 mL in single-
`
`
`
`dose autoinjector (3)
`
`
` _____________________
` _____________________
`CONTRAINDICATIONS
`
`• History of hypersensitivity to natural or recombinant interferon beta,
`
`
`
`
`
`
`
`human albumin, or any other component of the formulation (4)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
` INDICATIONS AND USAGE
` DOSAGE AND ADMINISTRATION
`
` 2.1 Dosing Information
`
`
`
`
` Important Administration Instructions
`
`2.2
`
` Premedication for Flu-like Symptoms
`
`2.3
` DOSAGE FORMS AND STRENGTHS
`
`
` CONTRAINDICATIONS
`
` WARNINGS AND PRECAUTIONS
`
`
` 5.1 Depression and Suicide
`
` 5.2 Hepatic Injury
`
`
`
` 5.3
` Anaphylaxis and Other Allergic Reactions
`
`
`5.4
` Injection Site Reactions including Necrosis
`
`
` 5.5 Decreased Peripheral Blood Counts
`
`
` 5.6
`
` Seizures
`
`
`5.7
` Laboratory Tests
` ADVERSE REACTIONS
`
`
` Clinical Trial Experience
`
`6.1
`
` 6.2
`
` Immunogenicity
`
`
`
`
`
`
`
`
` 1
`
` 2
`
`
`
`
` 3
`
` 4
`
` 5
`
`
`
` 6
`
`
`
`
`
`
`
`Reference ID: 3442196
`
`
`
`
`injected
`
`
`
`
`
`
`•
`
`Page 1 of 29
`
`Coalition Exhibit 1069
`Coalition v. Biogen
`IPR2015-01993
`
`

`
`FULL PRESCRIBING INFORMATION
`
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
`
` REBIF (interferon beta-1a) is indicated for the treatment of patients with relapsing forms of
`
`
`
`
` multiple sclerosis to decrease the frequency of clinical exacerbations and delay the
` accumulation of physical disability.
`
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`
`
`
`
` 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 Dose*
`
`
`
` Week of Use
`
`
`
` Dose
`
`
`
` Syringe to Use
`
`
`
` Week 1 Titration
`
`
`
` 4.4 mcg
`
`
`
` Week 2 Titration
`
`
`
` 4.4 mcg
`
`
`
` Week 3 Titration
`
`
`
` 11 mcg
`
`
`
` Week 4 Titration
`
`
`
` 11 mcg
`
`
`
` 8.8 mcg syringe
`
`
`
`
`
` 8.8 mcg syringe
`
`
`
`
`
` 22 mcg syringe
`
`
`
` 22 mcg syringe
`
`
`
` Amount of syringe
`
`
`
` Use half of syringe
`
`
`
` Use half of syringe
`
`
`
` Use half of syringe
`
`
`
` Use half of syringe
`
`
`
` Week 5 and after
`
`
`
`
`
` 22 mcg
`
`
`
` 22 mcg syringe or autoinjector
`
`
`
` Use full syringe or autoinjector
`
`
`
`
`
`
`
`
`
`
`
`
`
` *Use only prefilled syringes, not autoinjectors, to titrate to the 22 mcg Prescribed Dose
`
`
`
`
`
`
`
`Reference ID: 3442196
`
`
`
`Page 2 of 29
`
`

`
`Table 2: Titration Schedule for a 44 mcg Prescribed Dose**
`
`
`
`
` Week of Use
`
`
`
` Dose
`
`
`
` Week 1 Titration
`
`
`
` 8.8 mcg
`
`
`
` Week 2 Titration
`
`
`
` 8.8 mcg
`
`
`
` Week 3 Titration
`
`
`
` 22 mcg
`
`
`
`
`
` Syringe or Autoinjector to Use
`
`
`
`
`
`
`
` 8.8 mcg syringe or autoinjector
`
`
`
`
`
` 8.8 mcg syringe or autoinjector
`
`
`
`
`
` 22 mcg syringe or autoinjector
`
`
`
` Week 4 Titration
`
`
`
` 22 mcg
`
`
`
` 22 mcg syringe or autoinjector
`
`
`
` Week 5 and after
`
`
`
` 44 mcg
`
`
`
` 44 mcg syringe or autoinjector
`
`
`
` Amount of syringe or autoinjector
`
`
`
` Use full syringe or autoinjector
`
`
`
`
`
` Use full syringe or autoinjector
`
`
`
`
`
` Use full syringe or autoinjector
`
`
`
`
`
` Use full syringe or autoinjector
`
`
`
`
`
` Use full syringe or autoinjector
`
`
`
`
`
` **Prefilled syringes or autoinjectors can be used to titrate to the 44 mcg Prescribed Dose
`
`
`
`
`
`
`
`
`
`
`
`
` 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)].
`
`
`
`
`
`
` 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
`
`
`
`
`
` health care provider should determine the injection technique.
`
`
`
`
`
`
`
`
`
` The initial injection should be performed under the supervision of an appropriately qualified
`
` health care 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 or necrosis [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
`
`
`
`
`
`
`
`Reference ID: 3442196
`
`
`
`Page 3 of 29
`
`

`
`
`
` 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.
`
`
`
`
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
` 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.
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
` 5.1 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.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3442196
`
`
`
`Page 4 of 29
`
`

`
`
`
` 5.2 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 (5.7); and
`
`
`
`
`Dosage and Administration (2.1)].
`
`
`
`
`
`
`
`
` 5.3 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.
`
`
`
`
`
`
`
`
` 5.4
`
`
`
` Injection Site Reactions including Necrosis
`
`
`
`
` 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. All events resolved with conservative management.
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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).
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`Reference ID: 3442196
`
`
`
`Page 5 of 29
`
`

`
`
`
` 5.5 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 (5.7)].
`
`
`
`
`
`
` 5.6
`
`
`
` 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.
`
`
`
`
`
`
` 5.7
`
`
`
` 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.
`
`
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
`
`
`
`
` The following adverse reactions are discussed in more detail in the Warnings and Precautions
` section of the label:
`
`
` • Depression and Suicide [see Warnings and Precautions (5.1)]
`
` • Hepatic Injury [see Warnings and Precautions (5.2)]
`
`
`
`
` • Anaphylaxis and Other Allergic Reactions [see Warnings and Precautions (5.3 )]
`
`
`
` Injection Site Reactions including Necrosis [see Warnings and Precautions (5.4)]
`
`
`•
` • Decreased Peripheral Blood Counts [see Warnings and Precautions (5.5 )]
`
`
`
`
` Seizures [see Warnings and Precautions (5.6)]
`
`
`•
` Laboratory Tests [see Warnings and Precautions (5.7)]
`
`
`•
`
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`Reference ID: 3442196
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`Page 6 of 29
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` 6.1
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` Clinical Trial Experience
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`
`
` 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.
`
`
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`
`
` 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) [see Clinical Studies
`
`
`
`
`
`
`
` (14)]. Ages ranged from 18 to 55 years. Nearly three-fourths of the patients were female, and
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` more than 90% were Caucasian, largely reflecting the general demographics of the population of
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` patients with multiple sclerosis.
`
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`
` 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 [see Warnings and Precautions (5)].
`
`
`
`
`
`
`
` 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 4 enumerates adverse reactions and
`
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`
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` laboratory abnormalities that occurred at an incidence that was at least 2% more in either
`
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` REBIF-treated group than was observed in the placebo group.
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` Table 4. Adverse Reactions and Laboratory Abnormalities in Study 1
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` Body System
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`
`
` Preferred Term
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`
` BODY AS A WHOLE
`
`
`
`
`
` Influenza-like symptoms
`
` Placebo tiw
`
`
` (n=187)
`
`%
`
`
`
`
`
`
`
` 51
`
`
`
` 63
`
`
`
`
` (n=189)
`
` REBIF 22 mcg tiw REBIF 44 mcg tiw
`
` (n=184)
`
`
`
`
`
` %
`
`
`
`
`
` 56
`
`
`
` 65
`
`
`
` %
`
`
`
`
`
` 59
`
`
`
` 70
`
`
`
`
`
` Headache
`
`
`
`
`
` Fatigue
`
`
`
`
`
` Fever
`
`
`
`
`
` Rigors
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`
`
`
`
` Chest pain
`
`
`
`
`
` Malaise
`
`Reference ID: 3442196
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`
`
` 33
`
`
`
` 25
`
`
`
` 6
`
`
`
` 6
`
`
`
` 4
`
`
`
` 41
`
`
`
` 28
`
`
`
` 13
`
`
`
` 8
`
`
`
` 5
`
`
`
` 36
`
`
`
` 16
`
`
`
` 5
`
`
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` 5
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`
`
` 1
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`Page 7 of 29
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`

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` Body System
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`
`
`
`
` Preferred Term
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`
`
` INJECTION SITE DISORDERS
`
`
`
`
`
`
`
` Injection Site Reaction
`
`
`
`
`
` Injection Site Necrosis
`
`
`
` NERVOUS SYSTEM DISORDERS
`
`
`
`
`
`
`
` Hypertonia
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`
`
`
`
`
`
`
`
` Coordination Abnormal
`
`
`
` Convulsions
`
`
`
` Somnolence
`
`
`
` ENDOCRINE DISORDERS
`
`
`
` Thyroid Disorder
`
` Placebo tiw
`
`
` (n=187)
`
`%
`
`
`
`
`
`
`
` 39
`
`
`
` 0
`
`
`
` 5
`
`
`
` 2
`
`
`
` 2
`
`
`
` 1
`
`
`
`
`
` 3
`
`
`
`
` (n=189)
`
` REBIF 22 mcg tiw REBIF 44 mcg tiw
`
` (n=184)
`
`
`
`
`
` %
`
`
`
`
`
` 89
`
`
`
` 1
`
`
`
` 7
`
`
`
` 5
`
`
`
` 5
`
`
`
` 4
`
`
`
`
`
` 4
`
`
`
` %
`
`
`
`
`
` 92
`
`
`
` 3
`
`
`
` 6
`
`
`
` 4
`
`
`
` 4
`
`
`
` 5
`
`
`
`
`
` 6
`
`
`
`
`
` GASTROINTESTINAL SYSTEM DISORDERS
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`
`
`
`
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`
` Abdominal Pain
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`
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` Dry Mouth
`
`
`
` LIVER AND BILIARY SYSTEM DISORDERS
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`
`
`
`
` SGPT Increased
`
`
`
`
`
` SGOT Increased
`
`
`
`
`
` Bilirubinemia
`
`
`
` MUSCULO-SKELETAL SYSTEM DISORDERS
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`
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`
`
` Myalgia
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`
`
`
`
` Back Pain
`
`
`
`
`
` Skeletal Pain
`
`Reference ID: 3442196
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` 22
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`
`
` 1
`
`
`
`
`
` 20
`
`
`
` 10
`
`
`
` 3
`
`
`
`
`
` 25
`
`
`
` 23
`
`
`
` 15
`
`
`
`
`
` 20
`
`
`
` 5
`
`
`
`
`
` 27
`
`
`
` 17
`
`
`
` 2
`
`
`
`
`
` 25
`
`
`
` 25
`
`
`
` 10
`
`
`
`
`
` 17
`
`
`
` 1
`
`
`
`
`
` 4
`
`
`
` 4
`
`
`
` 1
`
`
`
`
`
` 20
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`
`
` 20
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`
`
` 10
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`Page 8 of 29
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`

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` Body System
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`
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`
`
` Preferred Term
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`
`
` HEMATOLOGIC DISORDERS
`
`
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`
`
` Leukopenia
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`
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` Lymphadenopathy
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` Thrombocytopenia
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` Anemia
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` SKIN DISORDERS
`
` Rash Erythematous
`
` Placebo tiw
`
`
` (n=187)
`
`%
`
`
`
`
`
`
`
` 14
`
`
`
` 8
`
`
`
` 2
`
`
`
` 3
`
`
`
`
`
` 3
`
`
`
`
` (n=189)
`
` REBIF 22 mcg tiw REBIF 44 mcg tiw
`
` (n=184)
`
`
`
`
`
` %
`
`
`
`
`
` 28
`
`
`
` 11
`
`
`
` 2
`
`
`
` 3
`
`
`
`
`
` 7
`
`
`
` %
`
`
`
`
`
` 36
`
`
`
` 12
`
`
`
` 8
`
`
`
` 5
`
`
`
`
`
` 5
`
`
`
`
`
`
`
`
`
` Rash Maculo-Papular
`
`
`
` URINARY SYSTEM DISORDERS
`
`
`
`
`
`
`
` Micturition Frequency
`
`
`
`
`
` Urinary Incontinence
`
`
`
` VISION DISORDERS
`
`
`
`
`
` Vision Abnormal
`
`
`
` Xerophthalmia
`
`
`
`
`
`
`
` 2
`
`
`
`
`
` 4
`
`
`
` 2
`
`
`
`
`
` 7
`
`
`
` 0
`
`
`
` 5
`
`
`
`
`
` 2
`
`
`
` 4
`
`
`
`
`
` 7
`
`
`
` 3
`
`
`
` 4
`
`
`
`
`
` 7
`
`
`
` 2
`
`
`
`
`
` 13
`
`
`
` 1
`
`
`
`
`Adverse reactions in Study 2, a 1-year active-controlled (vs. interferon beta-1a, 30 mcg once
`
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`
`weekly intramuscular injection, n=338) study including 339 patients with MS treated with REBIF
`
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`were generally similar to those in Study 1, taking into account the disparity in study durations.
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` 6.2
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`
`
` Immunogenicity
`
` Anaphylaxis and other allergic reactions have been observed with the use of REBIF [see
`
`
`
`
`
` Warnings and Precautions (5.3)]. As with all therapeutic proteins, there is a potential for
`
`
` immunogenicity. In Study 1, the presence of neutralizing antibodies (NAb) to REBIF was
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` 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
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` REBIF-treated patients at the 22 mcg and 44 mcg three times per week doses, respectively, at
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` one or more times during the study. The data reflect the percentage of patients whose test
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` results were considered positive for antibodies to REBIF using an antiviral cytopathic effect
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`Reference ID: 3442196
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`Page 9 of 29
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`assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the
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`observed incidence of NAb positivity in an assay may be influenced by several factors including
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`sample handling, timing of sample collection, concomitant medications and underlying disease.
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`For these reasons, comparison of the incidence of antibodies to REBIF with the incidence of
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`antibodies to other products may be misleading.
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` 6.3
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`
`
` Postmarketing Experience
`
` The following adverse reactions have been identified during post-approval use of REBIF.
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` 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
`
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`
`
` Blood and Lymphatic System Disorders: Thrombotic thrombocytopenic purpura/hemolytic
`
`uremic syndrome (TTP/HUS)
`
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` Eye Disorders: Retinal vascular disorders (i.e. retinopathy, cotton wool spots or obstruction of
` retinal artery or vein)
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` Skin and Subcutaneous Tissue Disorders: Erythema multiforme, Stevens-Johnson syndrome
`
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`
` 8 USE IN SPECIFIC POPULATIONS
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` 8.1
`
`Pregnancy
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` Pregnancy Category C
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` There are no adequate and well-controlled studies in pregnant women. REBIF should be used
` during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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`
` 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
`
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`
`
` development were observed; however, the possibility of adverse effects cannot be ruled out
`
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` because of the small number of animals tested (six per dose group at each developmental
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`
`
` period).
`
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`
` 8.3 Nursing Mothers
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`
`
` It is not known whether REBIF is excreted in human milk. Because many drugs are excreted in
`
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` human milk, caution should be exercised when REBIF is administered to a nursing woman.
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`Reference ID: 3442196
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`Page 10 of 29
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` 8.4 Pediatric Use
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` Safety and effectiveness in pediatric patients have not been established.
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` 8.5 Geriatric Use
`
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`
` 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.
`
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`
`
` 11 DESCRIPTION
`
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`
`
` REBIF (interferon beta-1a) is a purified 166 amino acid glycoprotein with a molecular weight of
` approximately 22,500 daltons. It is produced by recombinant DNA technology using genetically
`
`
`
` engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been
` introduced. The amino acid sequence of REBIF is identical to that of natural fibroblast derived
`
`
`
`
`
`
`human interferon beta. Natural interferon beta and interferon beta-1a (REBIF) are glycosylated
`
`with each containing a single N-linked complex carbohydrate moiety.
`
`
`
`
`
`Using a reference standard calibrated against the World Health Organization natural interferon
`
`beta standard (Second International Standard for Interferon, Human Fibroblast GB 23 902 531),
`
`
`
`
`
`REBIF has a specific activity of approximately 270 million international units (MIU) of antiviral
`
`
`
`
`
`activity per mg of interferon beta-1a determined specifically by an in vitro cytopathic effect
`
`
`
`
`bioassay using WISH cells and Vesicular Stomatitis virus. REBIF 8.8 mcg, 22 mcg and 44 mcg
`
`
`
`
`
`
`
`
`contains approximately 2.4 million international units, 6 million international units or 12 million
`
`
`
`
`
`
`international units, respectively, of antiviral activity using this method.
`
`
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`
`
`REBIF (interferon beta-1a) is formulated as a sterile solution in a prefilled syringe or REBIF
`
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`Rebidose autoinjector intended for subcutaneous (sc) injection. Each 0.5 mL (0.5 cc) of REBIF
`
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`
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`contains either 22 mcg or 44 mcg of interferon beta-1a, 2 mg or 4 mg albumin (human), 27.3 mg
`
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`
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`mannitol, 0.4 mg sodium acetate, and water for injection. Each 0.2 mL (0.2 cc) of REBIF contains
`
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`
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`8.8 mcg of interferon beta-1a, 0.8 mg albumin (human), 10.9 mg mannitol, 0.16 mg sodium
`
`
`acetate, and water for injection.
`
`
`
` 12 CLINICAL PHARMACOLOGY
`
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`
`
`
` 12.1 Mechanism of Action
`
`
`
`
`
` The mechanism(s) by which REBIF (interferon beta-1a) exerts its therapeutic effects in patients
` with multiple sclerosis is unknown.
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`Reference ID: 3442196
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`Page 11 of 29
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` 12.2 Pharmacodynamics
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`
`
` The relationships between serum interferon beta-1a levels and measurable pharmacodynamic
` activities to the mechanism(s) by which REBIF exerts its effects in multiple sclerosis are
`
`
`
`
`
`
` unknown. No gender-related effects on pharmacodynamic parameters have been observed.
`
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`
`
` 12.3 Pharmacokinetics
`
`
`
`
`
`
`
`
` The pharmacokinetics of REBIF (interferon beta-1a) in people with multiple sclerosis have not
` been evaluated. In healthy subjects, a single subcutaneous (sc) injection of 60 mcg of
`
`
`
`
`
`
`
`
` REBIF (liquid formulation) resulted in a peak serum concentration (C max ) of 5.1 ± 1.7 IU/mL
`
`
`
`(mean ± SD), with a median time of peak serum concentration (T max ) of 16 hours. The serum
`
`
`
`
`
`elimination half-life (t 1/2) was 69 ± 37 hours, and the area under the serum concentration versus
`
`
`
`
`time curve (AUC) from zero to 96 hours was 294 ± 81 IU h/mL. Following every other day sc
`
`
`
`
`
`
`
`
`
`injections in healthy subjects, an increase in AUC of approximately 240% was observed,
`
`
`
`
`
`suggesting that accumulation of interferon beta-1a occurs after repeat administration. Total
`
`clearance is approximately 33-55 L/hour. There have been no observed gender-related effects
`
`
`
`
`
`
`on pharmacokinetic parameters. Pharmacokinetics of REBIF in pediatric and geriatric patients or
`
`
`
`
`
`patients with renal or hepatic insufficiency have not been established.
`
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`
`
`
`
` 13 NONCLINICAL TOXICOLOGY
`
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` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
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`
`
` Carcinogenesis: REBIF has not been tested for carcinogenic potential in animals.
`
`
`
`
`
` Mutagenesis: Interferon beta was negative in an in vitro bacterial reverse mutation (Ames) assay
`
`
`
`
`and an in vitro cytogenetic assay in human lymphocytes in the presence and absence of
`
`
`
`
`
`
`metabolic activation.
`
`Impairment of Fertility: In studies in normally cycling female cynomolgus monkeys given daily
`
`
`
`
`
`
`
`
`subcutaneous injections of interferon beta for six months at doses of up to 9 times the
`
`
`
`
`recommended weekly human dose (based on body surface area), no effects were observed on
`
`
`
`
`
`either menstrual cycling or serum estradiol levels. In male monkeys, the same doses of
`
`
`
`
`
`interferon beta had no demonstrable adverse effects on sperm count, motility, morphology, or
`
`function.
`
`Reference ID: 3442196
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`Page 12 of 29
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`

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` 14 CLINICAL STUDIES
`
`
`
`
`
`
`
`
`
` 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 secondary
`
`
`
`
`
`
` progressive 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)
`
`
`
`
`
`
`
`
`