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.
`Figure 1: Proportions of Patients with Sustained
`Disability Progression
`
`Proportion with Progression
`
`Years
`The safety and efficacy of treatment with Rebif® beyond
`2 years have not been established.
`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 blinded to treatment assignment. Patient
`visits were conducted monthly, and mid-month
`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®
`Absolute
`Risk of relapse on
`Rebif® relative
`Difference
`to Avonex®
`
`Relapses
`Proportion of patients
`relapse-free at 24
`weeks1
`Proportion of patients
`relapse-free at 48
`weeks
`MRI (through 24 weeks)
`Median of the mean
`number of combined
`unique MRI lesions per
`patient per scan2
`(25th, 75th percentiles)
`
`N=339
`
`N=338
`
`75%*
`
`63%
`
`12%
`(95%CI:5%,19%)
`
`0.68
`(95%CI: 0.54, 0.86)
`
`62%**
`
`52%
`
`10%
`(95%CI:2%,17%)
`
`0.81
`(95%CI: 0.68, 0.96)
`
`N=325
`
`N=325
`
`0.17*
`(0.00, 0.67)
`
`0.33
`(0.00, 1.25)
`
`* p <0.001, and **p=0.009, Rebif® compared to Avonex®
`(1) Logistic regression model adjusted for treatment and center, intent to treat analysis
`(2) Nonparametric ANCOVA model adjusted for treatment and center, with baseline
`combined unique lesions as the single covariate.
`The adverse reactions over 48 weeks were generally
`similar between the two treatment groups. Exceptions
`included injection site disorders (83% of patients
`on Rebif® vs. 28% of patients on 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.
`
`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. Efficacy of
`Rebif® in chronic progressive multiple sclerosis has not
`been established.
`
`Prescribing Information
`
`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® 8.8 mcg, 22 mcg and 44 mcg contain
`approximately 2.4 MIU, 6 MIU or 12 MIU, respectively,
`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 22 mcg or 44 mcg of interferon beta-1a, 2 or 4
`mg albumin (human) USP, 27.3 mg mannitol USP, 0.4
`mg sodium acetate, Water for Injection USP.
`Each 0.2 mL (0.2 cc) of Rebif® contains 8.8 mcg of
`interferon beta-1a, 0.8 mg albumin (human) USP, 10.9
`mg mannitol USP, 0.16 mg sodium acetate, and 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, antiviral and
`antiproliferative biological activities. They exert their
`biological effects by binding to specific receptors on
`the surface 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.
`Pharmacodynamics
`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.
`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
`for two years. Doses of study agents were progressively
`increased to their target doses during the first 4 to 8
`weeks for each patient in the study (see DOSAGE AND
`ADMINISTRATION).
`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 underwent
`proton density T2-weighted (PD/T2) MRI scans at
`baseline and every 6 months. A subset of 198 patients
`underwent PD/T2 and T1-weighted gadolinium-
`enhanced (Gd)-MRI scans monthly for the first 9
`months. Of the 560 patients enrolled, 533 (95%)
`provided 2 years of data and 502 (90%) received 2
`years of study agent.
`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 prognostic significance of the MRI
`findings in these studies has not been evaluated.
`Table 1: Clinical and MRI Endpoints from Study 1
`Placebo
`22 mcg tiw 44 mcg tiw
`n=187
`n=189
`n=184
`
`Exacerbation related
`Mean number of exacerbations
`per patient over 2 years1,2
`(Percent Reduction)
`Percent (%) of patients
`exacerbations-free at 2 years3
`Median time to first
`exacerbation (months)1,4
`MRI
`Median percent (%) change
`of MRI PD-T2 lesion area at
`2 years5
`Median number of active
`lesions per patient per scan
`(PD/T2; 6 monthly)5
`
`2.56
`
`1.82**
`
`1.73***
`
`15%
`
`4.5
`
`n=172
`11.0
`
`(29%)
`25%*
`
`7.6**
`
`n=171
`-1.2***
`
`(32%)
`32%***
`
`9.6***
`
`n=171
`-3.8***
`
`2.25
`
`0.75***
`
`0.5***
`
` ** p<0.001 compared to placebo
`* p<0.05 compared to placebo
`*** p<0.0001 compared to placebo
`(1) Intent-to-treat analysis
`(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)
`(4) Cox proportional hazard model adjusted for center
`(5) ANOVA on ranks adjusted center. Patients with missing scans were excluded
`for this analysis
`
`Page 1 of 3
`
`YEDA EXHIBIT NO. 2098
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`Rebif®, she should be informed about the potential
`hazards to the fetus and discontinuation of Rebif®
`should be considered.
`Nursing Mothers
`It is not known whether Rebif® is excreted in human
`milk. Because many drugs are excreted in human milk,
`is
`should be exercised when Rebif®
`caution
`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
`including
`with Rebif® were psychiatric disorders
`depression and suicidal ideation or attempt (see
`WARNINGS: Depression). 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).
`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.
`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.
`
`CONTRAINDICATIONS
`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.
`
`WARNINGS
`Depression and Suicide
`Rebif® (interferon beta-1a) should be used with caution
`in patients with depression, a condition that is common
`in people with multiple sclerosis. Depression, suicidal
`ideation, and suicide attempts have been reported to
`occur with increased frequency in patients receiving
`interferon compounds, including Rebif®. In addition,
`there have been postmarketing reports of suicide in
`patients treated with Rebif®. Patients should be advised
`to report immediately any symptoms of depression
`and/or suicidal ideation to the prescribing physician. If a
`patient develops depression, cessation of treatment
`with Rebif® should be considered.
`Hepatic Injury
`Severe liver injury, including some cases of hepatic
`failure requiring liver transplantation, has been reported
`rarely in patients taking Rebif®. Symptoms of liver
`dysfunction began from one to six months following
`the initiation of Rebif®. If jaundice or other symptoms of
`liver dysfunction appear, treatment with Rebif® should
`be discontinued immediately due to the potential for
`rapid progression to liver failure.
`Asymptomatic elevation of hepatic transaminases
`(particularly SGPT) is common with interferon therapy
`(see ADVERSE REACTIONS). 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
`(see PRECAUTIONS: Laboratory Tests
`normalized.
`and DOSAGE AND
`and Drug
`Interactions;
`ADMINISTRATION).
`Anaphylaxis
`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.
`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.
`
`PRECAUTIONS
`General
`Caution should be exercised when administering
`Rebif® to patients with pre-existing seizure disorders.
`Seizures have been associated with the use of
`including Rebif®. Leukopenia and
`beta
`interferons
`new or worsening
`thyroid abnormalities have
`developed in some patients treated with Rebif® (see
`ADVERSE REACTIONS). Regular monitoring for these
`(see PRECAUTIONS:
`conditions
`is recommended
`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®. 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 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
`interaction studies have been
`No
`formal drug
`conducted 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.
`Also, the potential for hepatic injury should be
` considered when Rebif® is used in combination with
`other products associated with hepatic injury, or when
`new agents are added to the regimen of patients
`already on Rebif® (see WARNINGS: Hepatic Injury).
`Immunization
`In a nonrandomized prospective clinical study, 86
`multiple sclerosis (MS) patients on Rebif® 44 mcg tiw for
`at least 6 months and 77 patients not receiving
`interferon
`received
`influenza
`vaccination.
`The
`proportion of patients achieving a positive antibody
`response (defined as a titer > 1:40 measured by a
`hemagglutination inhibition assay) was similar in the
`two groups (93% and 91% respectively). The exact
`relationship of antibody titers to vaccine efficacy was
`not studied and is not known in patients receiving
`Rebif®. Therefore, while patients receiving Rebif®
`may receive concomitant vaccination, the overall
`effectiveness of such vaccination is unknown.
`Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`Carcinogenesis: No carcinogenicity data for Rebif® are
`available in animals or humans.
`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
`
`Page 2 of 3
`
`YEDA EXHIBIT NO. 2098
`MYLAN PHARM. v YEDA
`IPR2015-00644
`
`

`
`HOW SUPPLIED
`Rebif® is supplied as a sterile, preservative-free solution
`packaged in graduated, ready to use in 0.2 mL or 0.5
`mL prefilled syringes with 29-gauge, 0.5 inch needle for
`subcutaneous
`injection. The
`following package
`presentations are available.
`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,
`NDC 44087-0022-3
`-Twelve Rebif® 22 mcg prefilled syringes,
`Rebif® (interferon beta -1a) 44 mcg Prefilled syringe,
`NDC 44087-0044-3
`-Twelve Rebif® 44 mcg prefilled syringes,
`RX only.
`
`References
`1. PRISMS Study Group. Randomized double-blind placebo-controlled
`study of interferon ß-1a in relapsing/remitting multiple sclerosis.
`Lancet 1998; 352: 1498-1504.
`2. Panitch H., Goodin DS, Francis G. et al. Randomized, comparative
`study of interferon ß-1a treatment regimens in MS. The EVIDENCE
`Trial. Neurology 2002; 59:1496-1506
`Manufacturer: EMD Serono, Inc. Rockland, MA 02370
`U.S. License #1773
`Co-Marketed by: EMD Serono, Inc., Rockland, MA
`02370
`Pfizer Inc, New York, NY 10017
`Revised: September 2009
`
`*Avonex® is a registered trademark of Biogen Idec Inc.
`
`N67Z0101G 09-20515
`
`45/ 184 (24%) of Rebif®-treated patients at the 22 mcg
`and 44 mcg tiw doses, respectively, 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.
`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
`Dosages of Rebif® shown to be safe and effective are 22
`mcg and 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 20% of the prescribed dose tiw
`and increased over a 4-week period to the targeted
`dose, either 22 mcg or 44 mcg tiw (see Table 4).
`Following the administration of each dose, any residual
`product remaining in the syringe should be discarded in
`a safe and proper manner.
`A Rebif® 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.
`
`Table 4: Schedule for Patient Titration
`Recommended
`Titration dose for
`Titration dose for
`Titration
`Rebif® 22 mcg
`Rebif® 44 mcg
`(% of final dose)
`20%
`50%
`100%
`
`4.4 mcg
`11 mcg
`22 mcg
`
`8.8 mcg
`22 mcg
`44 mcg
`
`Weeks 1–2
`Weeks 3–4
`Weeks 5+
`
`liver function tests may
`Leukopenia or elevated
`necessitate dose reduction or discontinuation of
`Rebif® administration until toxicity is resolved (see
`WARNINGS: Hepatic
`Injury,
`PRECAUTIONS:
`General and ADVERSE REACTIONS).
`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.
`Patients should be advised to rotate sites for sc
`(see PRECAUTIONS:
`Information for
`injections
`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°C
`(36-46°F). DO NOT FREEZE. If a refrigerator is not
`available, Rebif® may be stored at or below 25°C/77°F
`for up to 30 days and away from heat and light.
`Do not use beyond the expiration date printed on
`cartons. Rebif® contains no preservatives. Each syringe
`is intended for single use. Unused portions should be
`discarded.
`
`Table 3. Adverse Reactions and Laboratory
`Abnormalities in Study 1
`BODY SYSTEM
` Preferred Term
`
`Placebo tiw
`(n=187)
`
`Rebif®
`22 mcg tiw
`(n=189)
`
`Rebif®
`44 mcg tiw
`(n=184)
`
`56%
`65%
`33%
`25%
`6%
`6%
`4%
`
`4%
`
`22%
`1%
`
`20%
`10%
`4%
`3%
`
`25%
`23%
`15%
`
`28%
`11%
`2%
`3%
`
`4%
`
`7%
`5%
`
`2%
`4%
`
`59%
`70%
`41%
`28%
`13%
`8%
`5%
`
`92%
`3%
`
`6%
`4%
`4%
`
`6%
`
`20%
`5%
`
`27%
`17%
`9%
`2%
`
`25%
`25%
`10%
`
`36%
`12%
`8%
`5%
`
`5%
`
`5%
`4%
`
`7%
`2%
`
`51%
`63%
`36%
`16%
`5%
`5%
`1%
`
`14%
`8%
`2%
`3%
`
`1%
`
`3%
`2%
`
`4%
`2%
`
`BODY AS A WHOLE
` Influenza-like symptoms
` Headache
` Fatigue
` Fever
` Rigors
` Chest Pain
` Malaise
`INJECTION SITE DISORDERS
`89%
`39%
` Injection Site Reaction
`1%
`0%
` Injection Site Necrosis
`CENTRAL & PERIPH NERVOUS SYSTEM DISORDERS
` Hypertonia
`5%
`7%
` Coordination Abnormal
`2%
`5%
` Convulsions
`2%
`5%
`ENDOCRINE DISORDERS
`3%
` Thyroid Disorder
`GASTROINTESTINAL SYSTEM DISORDERS
` Abdominal Pain
`17%
` Dry Mouth
`1%
`LIVER AND BILIARY SYSTEM DISORDERS
` SGPT Increased
`4%
` SGOT Increased
`4%
` Hepatic Function Abnormal
`2%
` Bilirubinaemia
`1%
`MUSCULO-SKELETAL SYSTEM DISORDERS
` Myalgia
`20%
` Back Pain
`20%
` Skeletal Pain
`10%
`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
`7%
`7%
`13%
` Xerophthalmia
`0%
`3%
`1%
` The adverse reactions were generally similar in Studies
`1 and 2, taking into account the disparity in study
`durations.
`Postmarketing Experience
`In addition to adverse events reported from clinical
`trials, the following events have been reported during
`postmarketing use of Rebif®. Because these reactions
`were reported voluntarily from a population of
`uncertain size, the frequency or a causal relationship to
`Rebif cannot be reliably determined.
`
`Blood and Lymphatic System Disorders:
`Thrombotic thrombocytopenic purpura/hemolytic
`uremic syndrome (TTP/HUS).
`
`Eye Disorders: Retinal vascular disorders (e.g.
`retinopathy, cotton wool spots or obstruction of retinal
`artery or vein).
`Hepatobiliary Disorders: Rare cases of severe liver
`dysfunction, including hepatic failure requiring liver
`transplantation (see WARNINGS: Hepatic Injury).
`Nervous System: Seizures
`(see PRECAUTIONS:
`General). Transient neurological symptoms
`(i.e.,
`hypoesthesia, muscle spasm, paresthesia, difficulty
`walking, musculoskeletal stiffness) that mimic MS
`exacerbations of limited duration, temporally related
`to the injections and most prominent at the initiation
`of therapy. In some cases, these symptoms were
`associated with flu-like syndrome.
`Psychiatric Disorders: suicide (see WARNINGS:
`Depression and Suicide)
`Skin and Subcutaneous Tissue Disorders: Injection
`site abscesses, injection site infections, including
`cellulitis and necrosis requiring debridement, systemic
`antibiotic treatment and/or grafting; erythema
`multiforme, and Stevens-Johnson syndrome.
`Immunogenicity
`As with all therapeutic proteins, there is a potential for
`immunogenicity. In study 1, the presence of neutralizing
`(NAb) to Rebif® was determined by
`antibodies
`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
`
`Page 3 of 3
`
`YEDA EXHIBIT NO. 2098
`MYLAN PHARM. v YEDA
`IPR2015-00644