103725.5$lp).fina16.
`mter eron eta- l a
`RebIt-
`
`DESCRIPTION
`
`RebifI (interferon beta- 1 a) is a purfied 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 RebifI is identical to that of natural fibroblast derived
`
`human interferon beta. Natual interferon beta and interferon beta-l a (RebifI 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),
`RebifI has a specific activity of approximately 270 million international unts (Mil) 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. RebifI 8. 8 mcg, 22 mcg and 44 mcg
`
`contains approximately 2.4 Mil, 6 Mil or 12 Mil, respectively, of antiviral activity using this
`
`method.
`
`RebifI (interferon beta- 1a) is formulated as a sterile solution in a pre filled syringe intended for
`
`subcutaneous (sc) injection. Each 0. 5 ml (0.5 cc) of RebifI contain either 22 mcg or 44 mcg of
`
`interferon beta-
`
`, 2 mg or 4 mg albumin (human) USP , 27. 3 mg mannitol USP, 0.4 mg sodium
`
`acetate, Water for Injection USP. Each 0.2 m1 (0. 2 cc) of RebifI contains 8. 8 mcg of interferon
`
`beta-
`
`, 0. 8 mg albumin (human) USP, 10.9 mg mannitol USP , 0. 16 mg sodium acetate, and
`
`Water for Injection USP.
`
`RebifQ9
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`. 23
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`eLlNi AtWbMACOLOGY
`
`General
`
`Interferons are a family of natually occurng 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 gama. 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 natually by varous 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' -0ligoadeny1ate synthetase, beta 2-
`
`micro globulin and neopterin, which may mediate some of the biological activities. The specific
`
`interferon-induced proteins and mechanisms by which interferon beta- l a exerts its effects in
`
`multiple sclerosis have not been fully defined.
`
`Pharmacokinetics
`
`The pharacokinetics ofRebifI (interferon beta- l a) in people with multiple sclerosis have not
`
`been evaluated. In healthy volunteer subjects, a single subcutaneous (sc) injection of 60 mcg of
`
`RebifI (liquid formulation), resulted in a peak serum concentration (Cmax) of 5. 1 :! 1.7 il/mL
`(mean:! SD), with a median time of peak seru concentration (Tmax) of 16 hours. The serum
`was 69:! 37 hours, and the area under the seru concentration versus
`
`elimination half- life
`
`(t1l)
`
`time curve (AUC) from zero to 96 hours was 294:! 81 il'h/mL. Following every other day sc
`
`injections in healthy volunteer subjects, an increase in AUC of approximately 240% was
`
`Rebif(!
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`. 46
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`lQ3795.5062.I final 6.
`OlJservea, sugges!mg t a accumu a IOn 0 mterleron eta.. a occurs a er repeat a mlstratIOn.
`
`05
`
`Total clearance is approximately 33-55 L/hour. There have been no observed gender-related
`
`effects on pharmacokinetic parameters. Pharmacokinetics of RebifI in pediatric and geriatric
`
`patients or patients with renal or hepatic insuffciency have not been established.
`
`Pharmacodynamics
`
`Biological response markers (e.
`
`, 2' 5' -OAS activity, neopterin and beta 2-microglobulin) are
`
`induced by interferon beta- l a following parenteral doses administered to healthy volunteer
`
`subjects and to patients with multiple sclerosis. Following a single sc administration of60mcg
`
`of RebifI intracellular 2' , 5' -OAS activity peaked between 12 to 24 hours and beta-
`micro globulin and neopterin seru concentrations showed a maximum at approximately 24 to 48
`
`hours. All three markers remained elevated for up to four days. Administration of Rebif22 mcg
`
`three times per week (tiw) inhbited mitogen-induced release of pro-inflammatory cytokines
`
`(IF-y, IL- , IL- , TNF-a and TN- ) by peripheral blood mononuclear cells that, on average
`
`was near double that observed with RebifCI administered once per week (qw) at either 22 or 66
`
`mcg.
`
`The relationships between seru interferon beta- l a levels and measurable pharmacodynamic
`
`activities to the mechanism(s) by which Rebi
`
`exerts its effects in multiple sclerosis are
`
`unkown. No gender-related effects on pharmacodynamic parameters have been observed.
`
`CLINICAL STUDIES
`
`Two multicenter studies evaluated the safety and efficacy of RebifCI in patients with re1apsing-
`
`remitting multiple sclerosis.
`
`Rebif(I
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`. 67
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`W379..5Q62PI fina16.
`::tuay 1 was a ran omIze , ou e- m , pace 0 contro e stu y m patIents WIt 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) Patiems \vith secondary
`
`progressive multiple sclerosis were excluded from the study. Patients received sc injections of
`
`either placebo (n = 187), RebifI 22 mcg (n = 189), or Rebi
`
`44 mcg (n = 184) administered tiw
`
`for two years. Doses of study agents were progressively increased to their target doses durng
`
`the first 4 to 8 weeks for each patient in the study (see DOSAGE AND ADMINISTRATION).
`
`The primar efficacy endpoint was the number of clinical exacerbations. Numerous secondary
`
`effcacy endpoints were also evaluated and included exacerbation-related parameters, effects of
`
`treatment on progression of disability and magnetic resonance imaging (MRI-rdated
`
`parameters. Progression of disability was defined as an increase in the EDSS score of at least
`
`point sustained for at least 3 months. Neurological examinations were completed every
`
`3 months, durng suspected exacerbations, and coincident with MRI scans. All patients
`
`underwent proton density T2-weighted (PD/T2) MRI scans at baseline and every 6 months.
`
`subset of 198 patients underwent PD/T2 and Tl-weighted gadolinium-enhanced (Gd)-MR scans
`
`monthly for the first 9 months. Of the 560 patients emolled, 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. Rebi
`
`at doses of 22 mcg and 44 mcg
`
`administered sc tiw signficantly reduced the number of exacerbations per patient as compared
`
`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 unkown.
`
`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.
`
`RebifCI
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`. 90
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`ibpOf2P
`
`Ci.
`mica an
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`d MRI
`
`n lDomts rom
`E d
`
`S d
`
`Exacerbation-related
`
`Mean number of exacerbations per patient
`over 2 years
`(Percent reduction)
`
`Placebo
`
`22 mcg tiw
`
`44 mcg tiw
`
`n = 187
`
`n = 189
`
`n = 184
`
`82**
`
`(29%)
`
`1.73***
`
`(32%)
`
`Percent (%) of patients exacerbation-free at 2
`years
`
`15%
`
`25%*
`
`32%***
`
`Median time to first exacerbation (months)I
`
`6**
`
`6***
`
`Median percent (%) change of MR PD-
`
`lesion area at 2 years
`
`Median number of active lesions per patient per
`6 monthly)5
`
`(pDIT2;
`
`scan
`
`n = 172
`
`11.0
`
`n = 171
`
`1.2***
`
`n = 171
`
`8***
`
`75***
`
`5***
`
`* p':0. 05 compared to placebo ** p':O. OOI compared to placebo
`
`*** p':O. OOOI 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
`
`100
`
`(5) ANOV A on ranks adjusted for center. Patients with missing scans were excluded from this analysis
`
`101
`
`The time to onset of progression in disability sustained for three months was significantly longer
`
`102
`
`103
`
`in patients treated with RebifI than in placebo-treated patients. The Kaplan-Meier estimates of
`the proportions of patients with sustained disability are depicted in Figue
`
`Rebif(I
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`. . . .
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`?)
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`'104
`
`..D3795.50.!2PUina16.
`proportions 0 atlents Wit ustamed Disability Progression
`lfgure 1:
`
`0S.
`
`0.4
`
`5 0.
`
`37%
`
`29%
`
`26%
`
`44 mcg vs. placebo p=O.
`
`22 mcg vs. placebo p=O.
`
`105
`
`106
`
`107
`
`108
`
`109
`
`110
`
`111
`
`112
`
`113
`
`114
`
`115
`
`116
`
`117
`
`118
`
`The safety and effcacy of treatment with RebifI beyond 2 years have not been established.
`
`Years
`
`Study 2 was a randomized, open-label, evaluator-blinded, active comparator study
`
`Patients
`
`with relapsing-remitting multiple sclerosis with EDSS scores ranging from 0 to 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
`iI 30 mcg qw by
`
`treatment with RebifI 44 mcg tiw by sc injection (n=339) or Avonex
`
`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 Tl active
`
`or T2 active. Neurological examinations were performed every three months by a neurologist
`
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`120
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`121
`
`122
`
`123
`
`124
`
`125
`
`bCfRd
`
`nt assignent. 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 maner.
`
`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 (Table2). This study does not
`
`support any conclusion regarding effects on the accumulation of physical disability.
`
`126
`
`Table 2: Clinical and MRI Results from Study 2
`
`Rebif
`
`Avonex(!
`
`Absolute Difference Risk of relapse on
`Rebif
`relative to
`A vonex
`
`Relapses
`
`N=339
`
`N=338
`
`Proportion of patients
`relapse-free at 24 weeks
`
`rroportion of patients
`relapse-free at 48 weeks
`
`75%*
`
`63%
`
`12%
`
`(95% CI: 5% 19%)
`
`(95% CI: 0.
`
`, 0. 86)
`
`62%**
`
`52%
`
`10%
`
`(95%CI: 2%, 17%)
`
`(95%CI: 0.
`
`, 0.96)
`
`MR (through 24 weeks)
`
`N=325
`
`N=325
`
`Median of the mean number
`of combined unique MRI
`lesions per patient per
`scan (25 , 75 percentiles)
`
`17*
`
`(0.
`
`, 0.67)
`
`(0.
`
`, 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 ANCOV A model adjusted for treatment and center, with baseline combined unique
`
`lesions as the single covariate.
`
`RebifCI
`
`127
`
`128
`
`129
`
`130
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`131
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`132
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`133
`
`134
`
`135
`
`.J795.5062Pl final 6.
`1 ne aoverse reactiOnS over wee s were genera y Slml ar etween t e two treatment groups.
`
`05
`
`Exceptions included injection site disorders (83% of patients on Rebi
`
`vs. 28% of patients on
`
`Avonex\R), hepatic function disorders (18% on Rebif vs. 10% on AvolJcx(R), and kukopci:ia
`
`(6% on Rebi
`
`vs. 0:1 % on Avonex(I), which were observed with greater frequency in the
`
`Rebif(I group compared to the A vonex(I group.
`
`136
`
`INDICATIONS AND USAGE
`
`137
`
`138
`
`139
`
`140
`
`RebifI (interferon beta- 1 a) 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. Effcacy of Rebif(I in chronic progressive multiple sclerosis has not been
`
`established.
`
`141
`
`CONTRAINDICATIONS
`
`142
`
`143
`
`RebifI (interferon beta- l a) is contraindicated in patients with a history of hypersensitivity to
`
`natural or recombinant interferon, human albumin, or any other component of the formulation.
`
`144 WARNINGS
`
`145 Depression
`
`RebifI (interferon beta- l a) 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(I. 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 RebifI should be considered.
`
`146
`
`147
`
`148
`
`149
`
`150
`
`151
`
`152
`
`RebiW
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`, 153
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`Q3795.5Q62PI final 6.
`epa lC InIUry
`
`154
`
`155
`
`156
`
`157
`
`158
`
`159
`
`160
`
`161
`
`162
`
`163
`
`164
`
`165
`
`166
`
`167
`
`Severe liver injury, including some cases of hepatic failure requiring liver transplantation , has
`
`been reported rarely in patients taking RebifI. Symptoms ofliver dysfuction began from one
`
`to six months following the initiation of RebifI. If jaundice or other symptoms ofliver
`
`dysfunction appear, treatment with RebifI should be discontinued immediately due to the
`
`potential for rapid progression to liver failure.
`
`Asymptomatic elevation of hepatic transaminases (paricularly SGPT) is common with interferon
`
`therapy (see ADVERSE REACTIONS). RebifI should be initiated with caution in patients
`
`with active liver disease, alcohol abuse, increased seru SGPT (:: 2.5 times ULN), or a history
`
`of significant liver disease. Also, the potential risk of RebifI used in combination with known
`
`hepatotoxic products should be considered prior to RebifI administration, or when adding new
`
`agents to the regimen of patients already on RebifI. Reduction ofRebifI 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 PRECAUTIONS: Laboratory Tests
`
`and Drug Interactions; and DOSAGE AND ADMINISTRATION)
`
`168 Anaphvlaxis
`
`Anaphylaxis has been reported as a rare complication of RebifCI use. Other allergic reactions
`
`have included skin rash and uricara, and have ranged from mild to severe without a clear
`
`relationship to dose or duration of exposure. Several allergic reactions, some severe, have
`
`occured after prolonged use.
`
`169
`
`170
`
`171
`
`172
`
`173
`
`174
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`175
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`176
`
`177
`
`178
`
`179
`
`W1i2
`
`.f.I vi!l
`
`L.o.1- \
`
`This product contains albumin, a derivative of human blood. Based on effective donor screening
`
`and product manufactung processes, it cares an extremely remote risk for transmission of viral
`
`diseases. A theoretical risk for transmission ofCreutzfeldt-Jakob disease (CJD) also is
`
`considered extremely remote. No cases of transmission of viral diseases or CJD have ever been
`
`180
`
`identified for albumin.
`
`181
`
`PRECAUTIONS
`
`182
`
`General
`
`183
`
`184
`
`185
`
`186
`
`187
`
`188
`
`Caution should be exercised when administering RebifI to patients with pre-existing seizure
`
`disorders. Seizures have been associated with the use of beta interferons. A relationship
`
`between occurence of seizures and the use of RebifI has not been established. Leukopenia and
`
`new or worsening thyroid abnormalities have developed in some patients treated with RebifCI
`
`(see
`
`ADVERSE REACTIONS).
`
`PRECAUTIONS: Laboratory
`
`Regular monitoring for these conditions is recommended (see
`
`Tests).
`
`189
`
`Information for Patients
`
`190
`
`191
`
`192
`
`193
`
`194
`
`195
`
`All patients should be instrcted to read the RebifCI 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 ofRebifCI (see
`
`WARNINGS and ADVERSE REACTIONS).
`
`Patients
`
`should be advised of the symptoms associated with these conditions, and to report them to their
`
`196
`
`physician.
`
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`, 197
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`. W3795.S062PlfinaI6.
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`l'emale patients snou e cautIone a out tea ortl1aClent potentia
`
`0$
`
`./
`
`e 11\! see
`
`198
`
`PRECAUTIONS: Pregnancy).
`
`199
`
`200
`
`201
`
`202
`
`203
`
`204
`
`205
`
`206
`
`207
`
`208
`
`209
`
`Patients should be instrcted in the use of aseptic technique when administering RebifCI.
`
`Appropriate instruction for self-injection or injection by another P7fson should be provided
`
`including careful review of the RebifCI Medication Guide. If a patient is to self-administer
`
`RebifC, the physical and cogntive ability ofthat patient to self-administer and properly dispose
`
`of syrnges 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 punctue-resistant container for disposal of used needles
`
`and syrges should be supplied to the patient along with instrctions for safe disposal of full
`
`containers. Patients should be instructed in the technique and importance of proper syrnge
`
`disposal and be cautioned against reuse of these items.
`
`210
`
`Laboratory Tests
`
`211
`
`212
`
`213
`
`214
`
`215
`
`216
`
`217
`
`In addition to those laboratory tests normally required for monitoring patients with multiple
`
`sclerosis, blood cell counts and liver fuction tests are recommended at regular intervals (1 , 3
`
`and 6 months) following introduction of RebifI therapy and then periodically thereafter in the
`
`absence of clinical symptoms. Thyroid fuction tests are recommended every 6 months in
`
`patients with a history of thyroid dysfuction or as clinically indicated. Patients with
`
`myelosuppression may require more intensive monitoring of complete blood cell counts, with
`
`differential and platelet counts.
`
`Rebif(I
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`:218
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`103795.5Q62PI final 6.
`urug lDteraCtlOnS
`
`219
`
`220
`
`221
`
`222
`
`223
`
`224
`
`No formal drug interaction studies have been conducted with RebifI. Due to its potential to
`cause neutropenia and lymphopenia, proper monitoring of patients is required if RebifY is given
`
`in combination with myelosuppressive agents.
`
`Also, the potential for hepatic injur should be considered when RebifY is used in combination
`with other products associated with hepatic injur, or when new agents are added to the regimen
`WARINGS: Hepatic injury).
`
`of patients already on RebifY (see
`
`225
`
`Immunization
`
`226
`
`227
`
`228
`
`229
`
`230
`
`231
`
`232
`
`In a nOllandomized prospective clinical study, 86 multiple sclerosis (MS) patients on Rebi
`
`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 RebifCI. Therefore, while patients receiving RebifCI may
`receive concomitant vaccination, the overall effectiveness of such vaccination is unkown.
`
`233
`
`Carcinogenesis, Mutagenesis, Impairment of Fertilty
`
`234
`
`Carcinogenesis:
`
`No carcinogenicity data for RebifCI are available in animals or humans.
`
`235
`
`236
`
`237
`
`238
`
`239
`
`240
`
`241
`
`Mutagenesis:
`
`Rebi
`
`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 ofRebifI on
`
`fertilityin humans. In studies in normally cycling female cynomolgus monkeys given daily sc
`
`injections ofRebifCI 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
`
`Rebif(I
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`10379."s0(i2Plfnal 6.05
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`estaDllsnea. II male monkeys, the same doses of Rebl
`
`sperm count, motility, morphology, or fuction.
`
`'242
`
`243
`
`244
`
`Pregnancy Category C
`
`had no demonstrable adverse effects on
`
`245
`
`246
`
`247
`
`248
`
`249
`
`250
`
`251
`
`252
`
`253
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`254
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`Rebif(I treatment has been associated with significant increases in embryo lethal or abortifacient
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`effects in cynomolgus monkeys administered doses approximately 2 times the cumulative
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`weekly human dose (based on either body weight or surface area) either during the period of
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`organogenesis (gestation day 21-89) or later in pregnancy. There were no fetal malformations or
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`other evidence of teratogenesis noted in these studies. These effects are consistent with the
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`abortifacient effects of other type I interferons. There are no adequate and well-controlled
`
`studies ofRebi
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`in pregnant women. However, in Studies 1 and 2, there were 2 spontaneous
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`abortions observed and 5 fetuses carred to term among 7 women in the Rebi
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`groups. If a
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`woman becomes pregnant or plans to become pregnant while takng RebifI, she should be
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`informed about the potential hazards to the fetus, and discontinuation ofRebi
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`should be
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`considered.
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`256
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`Nursing Mothers
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`257
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`258
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`259
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`261
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`262
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`263
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`It is not known whether RebifI is excreted in human milk. Because many drugs are excreted in
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`human milk, caution should be exercised when Rebif(I is administered to a nursing woman.
`
`The safety and effectiveness ofRebifI in pediatrc patients have not been
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`Pediatric Use:
`
`studied.
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`Geriatric Use:
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`Clinical studies of RebifI did not include suffcient numbers of subjects aged
`
`and over to determine whether they respond differently than younger subjects. In general, dose
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`selection for an elderly patient should be cautious, usually starting at the low end of the dosing
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`Rebif(I
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`---
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`264
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`265
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`i03795,5062l? fin 16. QS
`range, renecung tne greater equency 0 ecrease epatIc, rena or car laC ctIon, and of
`
`concomitant disease or other drg therapy.
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`266
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`ADVERSE REACTIONS
`
`The most frequently reported serious adverse reactions with Rebif( were psychiatric disorders
`
`including depression and suicidal ideation or attempt (see WARINGS). The incidence of
`
`depression of any severity in the Rebif(I-treated groups and placebo-treated group was
`
`approximately 25%. In post-marketing experience, RebifI administration has been rarely
`
`associated with severe liver dysfuction, including hepatic failure requiring liver transplantation
`
`(see WARINGS: Hepatic Injury).
`
`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 ofliver enzymes and hematologic abnormalities.
`
`The most frequently reported adverse reactions resulting in clinical intervention (e.
`
`discontinuation ofRebif(I, 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 ofliver enzymes (see WARNINGS).
`
`In Study 1 , 6 patients randomized to Rebif(I 44 mcg tiw (3%), and 2 patients who received
`
`Rebif(I 22 mcg tiw (1 %) developed injection site necrosis during two years of therapy. Rebif(I
`
`was continued in 7 patients and interrpted 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.
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`267
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`268
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`269
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`270
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`271
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`272
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`273
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`274
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`275
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`276
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`277
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`278
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`280
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`282
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`283
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`Rebif(I
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`J.795.5062PI f\Ual 6. 05
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`The rates or aaverse reactIOns an aSSociatIOn Wit e I
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`'288
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`1D .
`'8 II patIents Wit re apsIlg-remlttmg
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`289 multiple sclerosis are drawn from the placebo-controlled study (n = 560) and the active
`
`290
`
`291
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`292
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`293
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`294
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`295
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`296
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`297
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`298
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`299
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`300
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`301
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`302
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`303
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`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 trals are conducted under widely varying conditions, adverse reaction rates
`
`observed in the clinical trals of RebifCI canot be directly compared to rates in the clinical trials
`
`of other drgs 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 RebifCI-treated group than was observed in the placebo group.
`
`Table 3. Adverse Reactions and Laboratory Abnormalities in Study
`
`Body System
`Preferred Term
`ODY AS A WHOLE
`Influenza-like symptoms
`Headache
`Fatigue
`Fever
`Rigors
`Chest Pain
`Malaise
`
`INJECTION SITE DISORDERS
`Injection Site Reaction
`Injection Site Necrosis
`
`CENTRAL & PERlH NERVOUS SYSTEM DISORDERS
`Hypertonia
`Coordination Abnonnal
`Convulsions
`
`Rebif(S
`
`51%
`63%
`36%
`16%
`
`56%
`65%
`33%
`25%
`
`59%
`70%
`41%
`28%
`13%
`
`39%
`
`89%
`
`92%
`
`Mylan Pharms. Inc. Exhibit 1045 Page 15
`
`

`
`.;)
`
`22%
`
`20%
`10%
`
`25%
`23%
`15%
`
`28%
`11%
`
`17%
`
`1%)
`
`20%
`20%
`10%
`
`14%
`
`20%
`
`27%
`17%
`
`25%
`25%
`10%
`
`36%
`12%
`
`m&ctIJil
`
`Thyroid Disorder
`
`ASTROINTESTINAL SYSTEM DISORDERS
`Abdominal Pain
`Dry Mouth
`
`LIVER AND BILIAY SYSTEM DISORDERS
`SOPT Increased
`SOOT Increased
`Hepatic Function Abnormal
`Bilirubinaemia
`
`USCULO-SKELETAL SYSTEM DISORDERS
`Myalgia
`Back Pain
`Skeletal Pain
`
`EMATOLOGIC DISORDERS
`Leukopenia
`Lymhadenopathy
`Thrombocytopenia
`Anemia
`
`SYCHIATRIC DISORDERS
`Somnolence
`
`SKI DISORDERS
`Rah Eryhematous
`Rash Maculo-Papular
`
`Micturition Frequency
`
`Urinary Incontinence
`
`IS ION DISORDERS
`Vision Abnormal
`Xero hthalmia
`The adverse reactions were generally similar in Studies 1 and 2, taking into account the disparity
`
`13%
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`in study durations.
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`304
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`305
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`306
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`Immunogenicity
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`307
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`308
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`309
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`310
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`311
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`312
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`As with all therapeutic proteins , there is a potential for immunogenicity. In study
`
`the presence
`
`of neutralizing antibodies (NAb) to Rebif(I was determined by collecting and analyzing serum
`pre-study and at 6 month time intervals during the 2 years of the clinical trial. Seru NAb were
`
`detected in 59/189 (31 %) and 45/184 (24%) of RebiftI-treated patients at the 22 mcg and 44 mcg
`
`tiw doses, respectively, at one or more times durng the study. The clinical significance of the
`
`presence of NAb to Rebif(I is unkown.
`
`RebifCI
`
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`

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`..
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`313
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`314
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`315
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`316
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`317
`
`W795.5062PI fJW16 7 ,.05
`Ine aata renec me percen age 0 pa Ien s w ose test resu ts were conSI ere posItIve lor
`
`antibodies to Rebif(I 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, comparson of
`
`318
`
`. the incidence of antibodies to Rebif(I with the incidence of antibodies to other products may be
`
`319
`
`misleading.
`
`320
`
`321
`
`Anaphylaxis and other allergic reactions have been observed with the use of Rebif( (see
`
`WARINGS: Anaphylaxis).
`
`322
`
`DRUG ABUSE AND DEPENDENCE
`
`323
`
`324
`
`There is no evidence that abuse or dependence occurs with RebifI therapy. However, the risk of
`
`dependence has not been systematically evaluated.
`
`325
`
`OVERDOSAGE
`
`326
`
`327
`
`Safety of doses higher than 44 mcg sc tiw has not been adequately evaluated. The maximum
`
`amount of RebifI that can be safely administered has not been determined.
`
`328 DOSAGE AND ADMINISTRATION
`
`329
`
`330
`
`331
`
`Dosages of RebifI shown to be safe and effective are 22 mcg and 44 mcg injected
`
`subcutaneously three times per week. RebifI should be administered, if possible, at the same
`
`time (preferably in the late afternoon or evening) on the same three days (e.
`
`, Monday,
`
`332 Wednesday, and Friday) at least 48 hours apart each week (see CLINICAL STUDIES).
`
`333
`
`334
`
`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
`
`RebifCI
`
`Mylan Pharms. Inc. Exhibit 1045 Page 17
`
`

`
`, .
`
`103795, 506ZPI flla16. Q5
`
`aammlstratton 01 eac ose, any reSI ua pro uct remallmg m t e synnge s ou be dIscarded in
`
`335
`
`336.
`
`a safe and proper maner.
`
`337
`
`338
`
`339
`340
`341
`
`342
`343
`
`344
`
`345
`
`346
`
`347
`
`348
`
`349
`
`350
`
`351
`
`352
`
`A RebifI Titration Pack containing 6 doses of 8. 8 mcg (0.2 mL) and 6 doses of22 mcg (0. 5 mL)
`
`is available for use durng the titration period.
`
`Table 4:
`
`Schedule for Patient Titration
`
`Recommended
`Titration
`
`(% of final dose)
`
`Titration
`dose for
`RebifCI
`22mcg
`
`Titration
`dose for
`RebifCI
`44 mcg
`
`Weeks 1-
`
`Weeks 3-4
`
`20%
`
`50%
`
`4.4 mcg
`
`8mcg
`
`11 mcg
`
`22 mcg
`
`Weeks 5+
`
`100%
`
`22 mcg
`
`44 mcg
`
`Leukopenia or elevated liver fiction tests may necessitate dose reduction or discontinuation of
`RebifI administration until toxicity is resolved (see WARINGS: Hepatic Injury,
`
`PRECAUTIONS: General and ADVERSE REACTIONS).
`
`RebifI 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 pre-filled syrnge. 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.
`
`RebifI should be inspected visually for pariculate matter and discoloration prior
`
`administration.
`
`Rebif
`
`Mylan Pharms. Inc. Exhibit 1045 Page 18
`
`

`
`\D3795. OQl?I final
`'353 MabI ny ana IS orage
`
`354
`
`Rebi
`
`should be stored refrgerated between 2- C (36-
`
`F). DO NOT FREEZE. If a
`
`355
`
`356
`
`357
`
`358
`
`refrgerator is not available, RebifI 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 packages. RebifI contains no preservatives.
`
`Each syrnge is intended for single use. Unused portions should be discarded.
`
`359
`
`HOW SUPPLIED
`
`360
`
`361
`
`362
`
`363
`
`364
`
`365
`
`366
`
`367
`
`368
`
`369
`
`370
`
`RebifI is supplied as a sterile, preservative-free solution packaged in graduated, ready to use in
`
`0.2 mL or 0. 5 mL pre-filled syrnges with 27-gauge, 0. 5 inch needle for subcutaneous injection.
`
`The following package presentations are available.
`
`nterferon beta - 1 a) Titration Pack. NDC 44087-8822-
`
`- Six Rebi
`
`8 mcg pre-filled syrnges and Six Rebi
`
`22 mcg pre-filled syringe
`
`nterferon beta -1a) 22 mC2 Pre-filled svrin2e
`
`- One Rebi
`
`22 mcg pre-filled syrnge, NDC 44087-0022-
`
`- Twelve Rebi
`
`22 mcg pre-filled syrnges, NDC 44087-0022-
`
`Rebi
`
`(inter
`
`beta -1a) 44 mC2 Pre-filled svrin2e
`
`- One RebifI 44 mcg pre-filled syrnge, NDC 44087-0044-
`
`- Twelve Rebi
`
`44 mcg pre-filled syrnges, NDC 44087-0044-
`
`371
`
`RX only.
`
`RebifCI
`
`Mylan Pharms. Inc. Exhibit 1045 Page 19
`
`

`
`372' 103795.
`
`5062PI final 6.
`
`373
`
`References
`
`374
`
`375
`
`376
`
`377
`
`378
`
`379
`
`380
`381
`382
`383
`384
`385
`
`386
`
`387
`
`388
`
`389
`
`390
`
`PRISMS Study Group. Randomized double-blind placebo-controlled study of interferon
`
`la in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498- 1504.
`
`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 100