`Rebif(cid:210) (interferon beta-1a)
`
`DESCRIPTION
`
`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(cid:210)
`
` 44 mcg contains
`
`approximately 12 MIU of antiviral activity using this method.
`
`Rebif® (interferon beta-1a) is formulated as a sterile solution in a prefilled syringe intended for
`
`subcutaneous (sc) injection. Each 0.5 ml (0.5 cc) of Rebif® contains either 44 mcg or 22 mcg of
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`interferon beta-1a, 4 or 2 mg albumin (human) USP, 27.3 mg mannitol USP, 0.4 mg sodium
`
`acetate, Water for Injection USP.
`
`CLINICAL PHARMACOLOGY
`
`General
`
`Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in
`
`response to viral infection and other biological inducers. Interferons possess immunomodulatory,
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`antiviral and antiproliferative biological activities. They exert their biological effects by binding
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`to specific receptors on the surfa ce of cells. Three major groups of interferons have been
`
`distinguished: alpha, beta, and gamma. Interferons alpha and beta form the Type I interferons
`
`and interferon gamma is a Type II interferon. Type I interferons have considerably overlapping
`
`but also distinct biological activities. Interferon beta is produced naturally by various cell types
`
`including fibroblasts and macrophages. Binding of interferon beta to its receptors initiates a
`
`complex cascade of intracellular events that leads to the expression of numerous interferon-
`
`induced gene products and markers, including 2’, 5’-oligoadenylate synthetase, beta 2-
`
`microglobulin and neopterin, which may mediate some of the biological activities. The specific
`
`interferon-induced proteins and mechanisms by which interferon beta-1a exerts its effects in
`
`multiple sclerosis have not been fully defined.
`
`Pharmacokinetics
`
`The pharmacokinetics of Rebif® (interferon beta-1a) in people with multiple sclerosis have not
`
`been evaluated. In healthy volunteer subjects, a single subcutaneous (sc) injection of 60 mcg of
`
`Rebif® (liquid formulation), resulted in a peak serum concentration (Cmax) of 5.1 ± 1.7 IU/mL
`
`(mean ± SD), with a median time of peak serum concentration (Tmax) of 16 hours. The serum
`
`elimination half-life (t1/2) 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 volunteer 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/hours. 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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`Pharmacodynamics
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`Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are
`
`induced by interferon beta-1a following parenteral doses administered to healthy volunteer
`
`subjects and to patients with multiple sclerosis. Following a single sc administration of 60 mcg
`
`of Rebif® intracellular 2’,5’-OAS activity peaked between 12 to 24 hours and beta-2-
`
`microglobulin and neopterin serum concentrations showed a maximum at approximately 24 to 48
`
`hours. All three markers remained elevated for up to four days. Administration of Rebif 22 mcg
`
`three times per week (tiw) inhibited mitogen-induced release of pro-inflammatory cytokines
`
`(IFN-g, IL -1, IL-6, TNF-a
`
` and TNF-b ) by peripheral blood mononuclear cells that, on average,
`
`was near double that observed with Rebif® administered once per week (qw) at either 22 or 66
`
`mcg.
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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.
`
`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.(1) Patients with secondary
`
`progressive multiple sclerosis were excluded from the study. Patients received sc injections of
`
`either placebo (n = 187), Rebif® 22 mcg (n = 189), or Rebif® 44 mcg (n = 184) administered tiw
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`for two years. Doses of study agents were progressively increased to their target doses during
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`the first 4 to 8 weeks for each patient in the study (see DOSAGE AND ADMINISTRATION).
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`The primary efficacy endpoint was the number of clinical exacerbations. Numerous secondary
`
`efficacy endpoints were also evaluated and included exacerbation-related parameters, effects of
`
`treatment on progression of disability and magnetic resonance imaging (MRI)-related
`
`parameters. Progression of disability was defined as an increase in the EDSS score of at least 1
`
`point sustained for at least 3 months. Neurological examinations were completed every
`
`3 months, during suspected exacerbations, and coincident with MRI scans. All patients
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`underwent proton density T2-weighted (PD/T2) MRI scans at baseline and every 6 months. A
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`subset of 198 patients underwent PD/T2 and T1-weighted gadolinium-enhanced (Gd)-MRI scans
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`monthly for the first 9 months. Of the 560 patients enrolled, 533 (95%) provided 2 years of data
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`and 502 (90%) received 2 years of study agent.
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`Study results are shown in Table 1 and Figure 1. Rebif® at doses of 22 mcg and 44 mcg
`
`administered sc tiw significantly reduced the number of exacerbations per patient as compared to
`
`placebo. Differences between the 22 mcg and 44 mcg groups were not significant (p >0.05).
`
`The exact relationship between MRI findings and the clinical status of patients is unknown.
`
`Changes in lesion area often do not correlate with changes in disability progression. The
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`prognostic significance of the MRI findings in these studies has not been evaluated.
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`22 mcg tiw
`n = 189
`
`
`1.82**
`
`
`
`
`
`
`(29%)
`
`25%*
`
`
`7.6**
`
`n = 171
`-1.2***
`
`0.75***
`
`44 mcg tiw
`n = 184
`
`
`1.73***
`
`
`(32%)
`
`
`
`32%***
`
`
`9.6***
`
`n = 171
`-3.8***
`
`0.5***
`
`*** p<0.0001 compared to placebo
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`
`Table 1: Clinical and MRI Endpoints from Study 1
`
`Placebo
`
`n = 187
`
`Exacerbation-related
`
`
`2.56
` Mean number of exacerbations per patient
` over 2 years1,2
`
` (Percent reduction)
`
` Percent (%) of patients exacerbation-free at 2
` years3
`
`15%
`
`
`
`
` Median time to first exacerbation (months)1,4
`
`
`MRI
` Median percent (%) change of MRI PD-T2
` lesion area at 2 years 5
`
` Median number of active lesions per patient per
` scan (PD/T2; 6 monthly)5
`
`
`4.5
`
`n = 172
`11.0
`
`2.25
`
`
`
` *
`
` p<0.05 compared to placebo ** p<0.001 compared to placebo
`
`(1) Intent-to-treat analysis
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` (2) Poisson regression model adjusted for center and time on study
`
` (3) Logistic regression adjusted for center. Patients lost to follow-up prior to an exacerbation were
`
`excluded from this analysis (n = 185, 183, and 184 for the placebo, 22 mcg tiw, and 44 mcg tiw groups,
`
`respectively)
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`(4) Cox proportional hazard model adjusted for center
`
`(5) ANOVA on ranks adjusted for center. Patients with missing scans were excluded from this analysis
`
`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.
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`Figure 1: Proportions of Patients with Sustained Disability Progression
`
`Placebo
`
`Rebif 22 mcg
`
`37%
`
`29%
`26%
`
`Rebif 44 mcg
`
`44 mcg vs. placebo p=0.01
`
`22 mcg vs. placebo p=0.04
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`Proportionwith Progression
`
`0.0
`
`0.5
`
`1.0
`
`1.5
`
`2.0
`
`
`The safety and efficacy of treatment with Rebif® beyond 2 years have not been established.
`
`Years
`
`
`
`Study 2 was a randomized, open-label, evaluator-blinded, active comparator study.(2) 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 secondary
`
`progressive multiple sclerosis were excluded from the study. Patients were randomized to
`
`treatment with Rebif® 44 mcg tiw by sc injection (n=339) or Avonex® 30 mcg qw by
`
`intramuscular (im) injection (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
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`blinded to treatment assignment. Patient visits were conducted monthly, and mid-month
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`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 sc tiw were more likely to remain relapse-free at 24 and 48
`
`weeks than were patients treated with Avonex® 30 mcg im qw (Table 2). This study does not
`
`support any conclusion regarding effects on the accumulation of physical disability.
`
`Table 2: Clinical and MRI Results from Study 2
`
`
`
`Rebif®
`
`Avonex®
`
`
`
`N=339
`
`75%*
`
`
`
`62%**
`
`
`
`
`
`N=338
`
`63%
`
`
`52%
`
`
`
`
`Relapses
`
`Proportion of patients
`relapse-free at 24 weeks1
`
`
`Proportion of patients
`relapse-free at 48 weeks
`
`
`Absolute Difference Risk of relapse on
`Rebif® relative to
`Avonex®
`
`
`
`12%
`
`(95% CI: 5%, 19%)
`
`10%
`
`(95%CI: 2%, 17%)
`
`
`
`0.68
`
`(95% CI: 0.54, 0.86)
`
`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 scan2
`
`0.17*
`
`0.33
`
`
`
`
`
`(25th, 75th percentiles)
`
`(0.00, 0.67)
`
`(0.00, 1.29)
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`* p <0.001, and ** p = 0.009, Rebif® compared to Avonex®
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`(1) Logistic regression model adjusted for treatment and center, intent to treat analysis
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`(2) Nonparametric ANCOVA model adjusted for treatment, center, with baseline combined unique
`
`lesions as the single covariate.
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`The adverse reactions over 48 weeks were generally similar between the two treatment groups.
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`Exceptions included injection site disorders (83% of patients on Rebif® vs. 27% of patients on
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`Avonex®), hepatic function disorders (18% on Rebif® vs. 10% on Avonex®), and leukopenia
`
`(6% on Rebif® vs. <1% on Avonex®), which were observed with greater frequency in the
`
`Rebif® group compared to the Avonex® group.
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`INDICATIONS AND USAGE
`
`Rebif(cid:210) (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. Efficacy of Rebif® in chronic progressive multiple sclerosis has not been
`
`established.
`
`CONTRAINDICATIONS
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`Rebif® (interferon beta-1a) is contraindicated in patients with a history of hypersensitivity to
`
`natural or recombinant interferon, human albumin, or any other component of the formulation.
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`WARNINGS
`
`Depression
`
`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®. 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.
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`Hepatic Injury
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`A case of fulminant hepatic failure requiring liver transplantation in a patient who initiated
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`Rebif® therapy while taking another potentially hepato-toxic medication has been reported from
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`a non-U.S. postmarketing source. Symptomatic hepatic dysfunction, primarily presenting as
`
`jaundice, has been reported as a rare complication of Rebif use. Asymptomatic elevation of
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`hepatic transaminases (particularly SGPT) is common with interferon therapy (see ADVERSE
`
`REACTIONS). 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.
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`Dose reduction 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. Treatment with
`
`Rebif® should be stopped if jaundice or other clinical symptoms of liver dysfunction appear.
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`Anaphylaxis
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`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.
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`Albumin (Human)
`
`This product contains albumin, a derivative of human blood. Based on effective donor screening
`
`and product manufacturing processes, it carries an extremely remote risk for transmission of viral
`
`diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is
`
`considered extremely remote. No cases of transmission of viral diseases or CJD have ever been
`
`identified for albumin.
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`PRECAUTIONS
`
`General
`
`Caution should be exercised when administering Rebif® to patients with pre-existing seizure
`
`disorders. Seizures have been associated with the use of beta interferons. A relationship
`
`between occurrence of seizures and the use of Rebif® has not been established. Leukopenia and
`
`new or worsening thyroid abnormalities have developed in some patients treated with Rebif®
`
`(see ADVERSE REACTIONS). Regular monitoring for these conditions is recommended (see
`
`PRECAUTIONS: Laboratory Tests).
`
`Information for Patients
`
`All patients should be instructed to read the Rebif® Medication Guide supplied to them. Patients
`
`should be cautioned not to change the dosage or the schedule of administration without medical
`
`consultation.
`
`Patients should be informed of the most common and the most severe adverse reactions
`
`associated with the use of Rebif® (see WARNINGS and ADVERSE REACTIONS). Patients
`
`should be advised of the symptoms associated with these conditions, and to report them to their
`
`physician.
`
`Female patients should be cautioned about the abortifacient potential of Rebif® (see
`
`PRECAUTIONS: Pregnancy).
`
`Patients should be instructed in the use of aseptic technique when administering Rebif®.
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`Appropriate instruction for self-injection or injection by another person should be provided,
`
`including careful review of the Rebif® Medication Guide. If a patient is to self-administer
`
`Rebif®, the physical and cognitive ability of that patient to self-administer and properly dispose
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`of syringes should be assessed. The initial injection should be performed under the supervision
`
`of an appropriately qualified health care professional. Patients should be advised of the
`
`importance of rotating sites of injection with each dose, to minimize the likelihood of severe
`
`injection site reactions or necrosis. A puncture-resistant container for disposal of used needles
`
`and syringes should be supplied to the patient along with instructions for safe disposal of full
`
`containers. Patients should be instructed in the technique and importance of proper syringe
`
`disposal and be cautioned against reuse of these items.
`
`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. Thyroid function tests are recommended every 6 months in
`
`patients with a history of thyroid dysfunction or as clinically indicated. Patients with
`
`myelosuppression may require more intensive monitoring of complete blood cell counts, with
`
`differential and platelet counts.
`
`Drug Interactions
`
`No formal drug interaction studies have been cond ucted with Rebif®. Due to its potential to
`
`cause neutropenia and lymphopenia, proper monitoring of patients is required if Rebif® is given
`
`in combination with myelosuppressive agents.
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`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenesis: No carcinogenicity data for Rebif® are available in animals or humans.
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`Mutagenesis: Rebif® was not mutagenic when tested in the Ames bacterial test and in an in vitro
`
`cytogenetic assay in human lymphocytes in the presence and absence of metabolic activation.
`
`Impairment of Fertility: No studies have been conducted to evaluate the effects of Rebif® on
`
`fertility in humans. In studies in normally cycling female cynomolgus monkeys given daily sc
`
`injections of Rebif® 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. The validity of extrapolating doses used in animal studies to human doses is not
`
`established. In male monkeys, the same doses of Rebif® had no demonstrable adverse effects on
`
`sperm count, motility, morphology, or function.
`
`Pregnancy Category C
`
`Rebif® treatment has been associated with significant increases in embryolethal or abortifacient
`
`effects in cynomolgus monkeys administered doses approximately 2 times the cumulative
`
`weekly human dose (based on either body weight or surface area) either during the period of
`
`organogenesis (gestation day 21-89) or later in pregnancy. There were no fetal malformations or
`
`other evidence of teratogenesis noted in these studies. These effects are consistent with the
`
`abortifacient effects of other type I interferons. There are no adequate and well-controlled
`
`studies of Rebif® in pregnant women. However, in Studies 1 and 2, there were 2 spontaneous
`
`abortions observed and 5 fetuses carried to term among 7 women in the Rebif® groups. If a
`
`woman becomes pregnant or plans to become pregnant while taking Rebif®, she should be
`
`informed about the potential hazards to the fetus and discontinuation of Rebif® should be
`
`considered.
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`Nursing Mothers
`
`It is not known whether Rebif® is excreted in human milk. Because many drugs are excreted in
`
`human milk, caution should be exercised when Rebif® is administered to a nursing woman.
`
`Pediatric Use: The safety and effectiveness of Rebif® in pediatric patients have not been
`
`studied.
`
`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.
`
`ADVERSE REACTIONS
`
`The most frequently reported serious adverse reactions with Rebif® were psychiatric disorders
`
`including depression and suicidal ideation or attempt (see WARNINGS). The incidence of
`
`depression of any severity in the Rebif®-treated groups and placebo-treated group was
`
`approximately 25%. 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 symptom) were injection site disorders, influenza-like symptoms, depression
`
`and elevation of liver enzymes (see WARNINGS).
`
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`In Study 1, 6 patients randomized to Rebif® 44 mcg tiw (3%), and 2 patients who received
`
`Rebif® 22 mcg tiw (1%) developed injection site necrosis during two years of therapy. Rebif®
`
`was continued in 7 patients and interrupted briefly in one patient. There was one report of
`
`injection site necrosis in Study 2 during 48 weeks of Rebif treatment. All events resolved with
`
`conservative management; none required skin debridement or grafting.
`
`
`
`The rates of adverse reactions and association with Rebif® in patients with relapsing-remitting
`
`multiple sclerosis are drawn from the placebo-controlled study (n = 560) and the active
`
`comparator-controlled study (n = 339).
`
`
`
`The population encompassed an age range 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.
`
`
`
`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.
`
`
`
`Table 3 enumerates adverse events 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 .
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`Table 3. Adverse Reactions and Laboratory Abnormalities in Study 1
`
`Body System
` Preferred Term
`BODY AS A WHOLE
` Influenza-like symptoms
` Headache
` Fatigue
` Fever
` Rigors
` Chest Pain
` Malaise
`
`INJECTION SITE DISORDERS
` Injection Site Reaction
` Injection Site Necrosis
`
`CENTRAL & PERIPH NERVOUS SYSTEM DISORDERS
` Hypertonia
` Coordination Abnormal
` Convulsions
`
`ENDOCRINE DISORDERS
` Thyroid Disorder
`
`GASTROINTESTINAL SYSTEM DISORDERS
` Abdominal Pain
` Dry Mouth
`
`LIVER AND BILIARY SYSTEM DISORDERS
` SGPT Increased
` SGOT Increased
` Hepatic Function Abnormal
` Bilirubinaemia
`
`MUSCULO-SKELETAL SYSTEM DISORDERS
` Myalgia
` Back Pain
` Skeletal Pain
`
`HEMATOLOGIC DISORDERS
` Leukopenia
` Lymphadenopathy
` Thrombocytopenia
` Anemia
`
`PSYCHIATRIC DISORDERS
` Somnolence
`
`SKIN DISORDERS
` Rash Erythematous
` Rash Maculo-Papular
`
`URINARY SYSTEM DISORDERS
` Micturition Frequency
` Urinary Incontinence
`
`VISION DISORDERS
` Vision Abnormal
` Xerophthalmia
`
`Placebo tiw Rebif® 22 mcg tiw Rebif® 44 mcg tiw
`(n=187)
`(n=189)
`(n=184)
`
`
`
`51%
`56%
`59%
`63%
`65%
`70%
`36%
`33%
`41%
`16%
`25%
`28%
`5%
`6%
`13%
`5%
`6%
`8%
`1%
`4%
`5%
`
`
`
`
`
`
`39%
`89%
`92%
`0%
`1%
`3%
`
`
`
`
`
`
`5%
`7%
`6%
`2%
`5%
`4%
`2%
`5%
`4%
`
`
`
`
`
`
`3%
`4%
`6%
`
`
`
`
`
`
`17%
`22%
`20%
`1%
`1%
`5%
`
`
`
`
`
`
`4%
`20%
`27%
`4%
`10%
`17%
`2%
`4%
`9%
`1%
`3%
`2%
`
`
`
`
`
`
`20%
`25%
`25%
`20%
`23%
`25%
`10%
`15%
`10%
`
`
`
`
`
`
`14%
`28%
`36%
`8%
`11%
`12%
`2%
`2%
`8%
`3%
`3%
`5%
`
`
`
`
`
`
`1%
`4%
`5%
`
`
`
`
`
`
`3%
`7%
`5%
`2%
`5%
`4%
`
`
`
`
`
`
`4%
`2%
`7%
`2%
`4%
`2%
`
`
`
`
`
`
`7%
`7%
`13%
`0%
`3%
`1%
`
`
`
`15
`
`Petitioner TWi Pharms., Inc.
`EX1023, Page 15 of 19
`
`

`

`
`The adverse reactions were generally similar in Studies 1 and 2, taking into account the disparity
`
`in study durations.
`
`Immunogenicity
`
`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 45/184 (24%) of Rebif®-treated patients at the 44 mcg tiw dose at one or more times
`
`during the study. The clinical significance of the presence of NAb to Rebif® is unknown.
`
`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.
`
`Anaphylaxis and other allergic reactions have been observed with the use of Rebif® (see
`
`WARNINGS: Anaphylaxis).
`
`DRUG ABUSE AND DEPENDENCE
`
`There is no evidence that abuse or dependence occurs with Rebif® therapy. However, the risk of
`
`dependence has not been systematically evaluated.
`
`
`
`16
`
`Petitioner TWi Pharms., Inc.
`EX1023, Page 16 of 19
`
`

`

`
`OVERDOSAGE
`
`Safety of doses higher than 44 mcg sc tiw have not been adequately evaluated. The maximum
`
`amount of Rebif® that can be safely administered has not been determined.
`
`DOSAGE AND ADMINISTRATION
`
`The recommended dosage of Rebif® is 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 (see CLINICAL STUDIES). Generally, patients should be started at 8.8 mcg sc tiw
`
`and increased over a 4-week period to 44 mcg tiw (see Table 4). A Rebif® “Starter Pack”
`
`containing 22 mcg syringes, is available for use in titrating the dose during the first four weeks of
`
`treatment. Following the administration of each dose, any residual product remaining in the
`
`syringe should be discarded in a safe and proper manner.
`
`Table 4:
`
`
`Schedule for Patient Titration
`Rebif(cid:210)
`Dose
`
`Recommended
`Titration
`
`
`
`
`
`Volume
`
`Syringe
`Strength
`(per 0.5
`mL)
`
`Weeks 1-2
`
`20 %
`
`8.8 mcg
`
`0.2 mL
`
`22 mcg
`
`Weeks 3–4 50 %
`
`22 mcg
`
`0.5 mL
`
`22 mcg
`
`Weeks 5+
`
`100 %
`
`44 mcg
`
`0.5 mL
`
`44 mcg
`
`
`Leukopenia or elevated liver function tests may necessitate dose reductions of 20 – 50% until
`
`toxicity is resolved (see WARNINGS: Hepatic Injury and PRECAUTIONS: General).
`
`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-
`
`
`
`17
`
`Petitioner TWi Pharms., Inc.
`EX1023, Page 17 of 19
`
`

`

`
`administering subcutaneous injections using the pre-filled syringe. Patients should be advised to
`
`rotate sites for sc injections (see PRECAUTIONS: Information for Patients). Concurrent use of
`
`analgesics and/or antipyretics may help ameliorate flu-like symptoms on treatment days. Rebif®
`
`should be inspected visually for particulate matter and discoloration prior to administration.
`
`Stability and Storage
`
`Rebif® should be stored refrigerated between 2-8(cid:176) C (36-46(cid:176) F). DO NOT FREEZE. If a
`
`refrigerator is not available, Rebif® may be stored at or , below 25(cid:176) C/77(cid:176) F for up to 30 days
`
`and away from heat and light.
`
`Do not use beyond the expiration date printed on packages. Rebif® contains no preservatives.
`
`Each syringe is intended for single use. Unused portions should be discarded.
`
`HOW SUPPLIED
`
`Rebif® is supplied as a sterile, preservative-free solution packaged in graduated, ready to use 0.5
`
`mL pre-filled syringes with 27-gauge, 0.5 inch needle for subcutaneous injection. The following
`
`package presentations are available.
`
`
`
`Rebif® (interferon beta -1a) Starter Pack (for initial dose escalation)
`
`- Twelve Rebif® 22 mcg pre-filled syringes, NDC 44087-0022-3
`
`
`
`18
`
`Petitioner TWi Pharms., Inc.
`EX1023, Page 18 of 19
`
`

`

`
`
`Rebif® (interferon beta -1a) 44 mcg Prefilled syringe
`
`- One Rebif® 44 mcg pre-filled syringe, NDC 44087-0044-1
`
`- Three Rebif® 44 mcg pre-filled syringes, NDC 44087-0044-2
`
`- Twelve Rebif® 44 mcg pre-filled syringes, NDC 44087-0044-3
`
`RX only.
`
`
`
`References
`
`1.
`
`PRISMS Study Group. Randomized double-blind placebo-controlled study of interferon
`
`b- 1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498-1504.
`
`2. Data on file.
`
`
`
`
`
`Manufacturer: Serono, Inc. Rockland, MA 02370
`
`
`
`U.S. License # 1574
`
`
`
`Co-Marketed by:
`Serono, Inc.
`Rockland, MA 02370
`Pfizer Inc
`New York, NY 10017
`
`
`Revised: May 2003
`
`
`
`*Avonex® is a registered trademark of Biogen, Inc.
`
`
`
`SE0472-08
`
`
`
`19
`
`Petitioner TWi Pharms., Inc.
`EX1023, Page 19 of 19
`
`