AVONEX® (Interferon beta-1a)
`IM Injection
`
`DESCRIPTION
`
`AVONEX® (Interferon beta-1a) is a 166 amino acid glycoprotein with a predicted 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 AVONEX® is identical to that
`of natural human interferon beta.
`
`Using the World Health Organization (WHO) natural interferon beta standard, Second
`International Standard for Interferon, Human Fibroblast (Gb-23-902-531), AVONEX® has a
`specific activity of approximately 200 million international units (IU) of antiviral activity per
`mg of Interferon beta-1a determined specifically by an in v itro cytopathic effect bioassay
`using lung carcinoma cells (A549) and Encephalomyocarditis virus (ECM). AVONEX® 30
`mcg contains approximately 6 million IU of antiviral activity using this method. The activity
`against other standards is not known. Comparison of the activity of AVONEX® with other
`Interferon betas is not appropriate, because of differences in the reference standards and
`assays used to measure activity.
`
`30 mcg Lyophilized Powder Vial
`A vial of AVONEX® is formulated as a sterile, white to off-white lyophilized powder for
`intramuscular injection after reconstitution with supplied diluent (Sterile Water for Injection,
`USP). Each vial of reconstituted AVONEX® contains 30 mcg of Interferon beta-1a; 15 mg
`Albumin (Human), USP; 5.8 mg Sodium Chloride, USP; 5.7 mg Dibasic Sodium Phosphate,
`USP; and 1.2 mg Monobasic Sodium Phosphate, USP, in 1.0 mL at a pH of approximately
`7.3.
`
`30 mcg Prefilled Syringe
`A prefilled syringe of AVONEX® is formulated as a sterile liquid for intramuscular injection.
`Each 0.5 mL (30 mcg dose) of AVONEX® in a prefilled glass syringe contains 30 mcg of
`Interferon beta-1a, 0.79 mg Sodium Acetate Trihydrate, USP; 0.25 mg Glacial Acetic Acid,
`
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`USP; 15.8 mg Arginine Hydrochloride, USP; and 0.025 mg Polysorbate 20 in Water for
`Injection, USP at a pH of approximately 4.8.
`
`CLINICAL PHARMACOLOGY
`
`General
`
`Interferons are a family of naturally occurring proteins and glycoproteins that are produced
`by eukaryotic cells in response to viral infection and other biological inducers.
`Interferon
`beta, one member of this family, is produced by various cell types including fibroblasts and
`macrophages. Natural interferon beta and Interferon beta-1a are glycosylated, with each
`containing a single N-linked complex carbohydrate moiety. Glycosylation of other proteins is
`known to affect their stability, activity, aggregation, biodistribution, and half-life in blood.
`However, the effects of glycosylation of interferon beta on these properties have not been
`fully defined.
`
`Biologic Activities
`
`Interferons are cytokines that mediate antiviral, antiproliferative and immunomodulatory
`activities in response to viral infection and other biological inducers. Three major interferons
`have been distinguished: alpha, beta, and gamma.
`Interferons alpha and beta form the
`Type I class of interferons, and interferon gamma is a Type II interferon. These interferons
`have overlapping but clearly distinct biological activities.
`
`Interferon beta exerts its biological effects by binding to specific receptors on the surface of
`human cells. This binding initiates a complex cascade of intracellular events that leads to
`the expression of numerous interferon-induced gene products and markers. These include
`2-microglobulin, and neopterin. These products have
`2', 5'-oligoadenylate synthetase,
`been measured in the serum and cellular fractions of blood collected from patients treated
`with AVONEX®.
`
`The specific interferon-induced proteins and mechanisms by which AVONEX® exerts its
`effects in multiple sclerosis have not been fully defined. Clinical studies conducted in
`multiple sclerosis patients showed that interleukin 10 (IL-10) levels in cerebrospinal fluid
`were increased in patients treated with AVONEX® compared to placebo. Serum IL-10 levels
`were increased 48 hours after intramuscular (IM) injection of AVONEX® and remained
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`elevated for 1 week. However, no relationship has been established between absolute
`levels of IL-10 and clinical outcome in multiple sclerosis.
`
`Pharmacokinetics
`
`Pharmacokinetics of AVONEX® in multiple sclerosis patients have not been evaluated. The
`pharmacokinetic and pharmacodynamic profiles of AVONEX® in healthy subjects following
`doses of 30 mcg through 75 mcg have been investigated. Serum levels of AVONEX® as
`measured by antiviral activity are slightly above detectable limits following a 30 mcg IM
`dose, and increase with higher doses.
`
`After an IM dose, serum levels of AVONEX® typically peak between 3 and 15 hours and then
`decline at a rate consistent with a 10 hour elimination half-life. Serum levels of AVONEX®
`may be sustained after IM administration due to prolonged absorption from the IM site.
`Systemic exposure, as determined by AUC and Cmax values, is greater following IM than
`subcutaneous (SC) administration.
`
`Subcutaneous administration of AVONEX® should not be substituted for intramuscular
`administration. Subcutaneous and intramuscular administration have been observed to
`have non-equivalent pharmacokinetic and pharmacodynamic parameters following
`administration to healthy volunteers.
`
`Biological response markers (e.g., neopterin and 2-microglobulin) are induced by
`AVONEX® following parenteral doses of 15 mcg through 75 mcg in healthy subjects and
`treated patients. Biological response marker levels increase within 12 hours of dosing and
`remain elevated for at least 4 days. Peak biological response marker levels are typically
`observed 48 hours after dosing. The relationship of serum AVONEX® levels or levels of
`these induced biological response markers to the mechanisms by which AVONEX® exerts
`its effects in multiple sclerosis is unknown.
`
`Clinical Studies
`
`The clinical effects of AVONEX® in multiple sclerosis were studied in two randomized,
`multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis.1,2
`Safety and efficacy of treatment with AVONEX beyond 3 years is not known.
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`In Study 1, 301 patients received either 30 mcg of AVONEX® (n=158) or placebo (n=143) by
`IM injection once weekly. Patients were entered into the trial over a 2½ year period,
`received injections for up to 2 years, and continued to be followed until study completion.
`Two hundred eighty-two patients completed 1 year on study, and 172 patients completed 2
`years on study. There were 144 patients treated with AVONEX® for more than 1 year, 115
`patients for more than 18 months and 82 patients for 2 years.
`
`All patients had a definite diagnosis of multiple sclerosis of at least 1 year duration and had
`at least 2 exacerbations in the 3 years prior to study entry (or 1 per year if the duration of
`disease was less than 3 years). At entry, study participants were without exacerbation
`during the prior 2 months and had Kurtzke Expanded Disability Status Scale (EDSS3) scores
`ranging from 1.0 to 3.5. Patients with chronic progressive multiple sclerosis were excluded
`from this study.
`
`The primary outcome assessment was time to progression in disability, measured as an
`increase in the EDSS score of at least 1.0 point that was sustained for at least 6 months.
`An increase in EDSS score reflects accumulation of disability. This endpoint was used to
`ensure that progression reflected permanent increase in disability rather than a transient
`effect due to an exacerbation.
`
`Secondary outcomes included exacerbation frequency and results of magnetic resonance
`imaging (MRI) scans including gadolinium (Gd)-enhanced lesion number and volume and
`T2-weighted (proton density) lesion volume. Additional secondary endpoints included 2
`upper limb (tested in both arms) and 3 lower limb function tests.
`
`Twenty-three of the 301 patients (8%) discontinued treatment prematurely. Of these, 1
`patient treated with placebo (1%) and 6 patients treated with AVONEX® (4%) discontinued
`treatment due to adverse events. Thirteen of these 23 patients remained on study and were
`evaluated for clinical endpoints.
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`Figure 1
`Figure 1
`Onset of Sustained Disability Progression by Time on Study
`Onset of Sustained Disability Progression by Time on Study
`(Kaplan-Meier Methodology)
`(Kaplan-Meier Methodology)
`
`A VO
`
`N E X®
`
`P la cebo
`
`P = 0.02
`
`( 34.9 %
`
`)
`
`( 21.9 %
`
`)
`
`50
`
`40
`
`30
`
`20
`
`10
`10
`
`0
`
`PercentageofPatientsProgressing
`
`0
`
`26
`
`52
`Weeks
`Weeks
`
`78
`
`104
`
`N ote: D isa bilityprog ression representsa tlea sta 1.0pointincrea sein E D SS scoresusta inedfora t
`lea st6 m onth s.
`
`Time to onset of sustained progression in disability was significantly longer in patients
`treated with AVONEX® than in patients receiving placebo (p = 0.02). The Kaplan-Meier
`plots of these data are presented in Figure 1. The Kaplan-Meier estimate of the percentage
`of patients progressing by the end of 2 years was 34.9% for placebo-treated patients and
`21.9% for AVONEX®-treated patients, indicating a slowing of the disease process. This
`represents a 37% relative reduction in the risk of accumulating disability in the AVONEX®-
`treated group compared to the placebo-treated group.
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`Figure 2
`Figure 2
`Confirmed EDSS Change from Study Entry to End of Study
`Confirmed EDSS Change from Study Entry to End of Study
`50
`
`AVONEX® (N=150)
`N E X® (N =150)
`A VO
`P la cebo (N =136 )
`Placebo (N=136)
`
`P =0.006
`
`0
`
`# -1.0
`-1.0
`
`40
`
`30
`
`20
`
`10
`
`0
`
`PercentageofPatients
`
`0.5
`
`1.0
`
`-0.5
`1.5
`Better
`Worse
`Confirmed Change from Baseline EDSS
`Confirmed Change from Baseline EDSS
`
`$ 2.0
`2.0
`
`The distribution of confirmed EDSS change from study entry (baseline) to the end of the
`study is shown in Figure 2. There was a statistically significant difference between treatment
`groups in confirmed change for patients with at least 2 scheduled visits (136 placebo-treated
`and 150 AVONEX®-treated patients; p = 0.006; see Table 1).
`
`The rate and frequency of exacerbations were determined as secondary outcomes. For all
`patients included in the study, irrespective of time on study, the annual exacerbation rate
`was 0.67 per year in the AVONEX®-treated group and 0.82 per year in the placebo-treated
`group (p = 0.04).
`
`AVONEX® treatment significantly decreased the frequency of exacerbations in the subset of
`patients who were enrolled in the study for at least 2 years (87 placebo-treated patients and
`85 AVONEX®-treated patients; p = 0.03; see Table 1).
`
`Gd-enhanced and T2-weighted (proton density) MRI scans of the brain were obtained in
`most patients at baseline and at the end of 1 and 2 years of treatment. Gd-enhancing
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`lesions seen on brain MRI scans represent areas of breakdown of the blood brain barrier
`thought to be secondary to inflammation. Patients treated with AVONEX® demonstrated
`significantly lower Gd-enhanced lesion number after 1 and 2 years of treatment (p
`0.05;
`see Table 1). The volume of Gd-enhanced lesions was also analyzed, and showed similar
`treatment effects (p
`0.03). Percentage change in T2-weighted lesion volume from study
`entry to Year 1 was significantly lower in AVONEX®-treated than placebo-treated patients (p
`= 0.02). A significant difference in T2-weighted lesion volume change was not seen
`between study entry and Year 2.
`
`The exact relationship between MRI findings and the clinical status of patients is unknown.
`The prognostic significance of MRI findings in these studies has not been evaluated.
`
`Of the limb function tests, only 1 demonstrated a statistically significant difference between
`treatment groups (favoring AVONEX®). A summary of the effects of AVONEX® on the
`clinical and MRI endpoints of this study is presented in Table 1.
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`Table 1
`
`Clinical and MRI Endpoints in Study 1
`
`Endpoint
`
`Placebo
`
`AVONEX®
`
`P-Value
`
`--- See Figure 1 ---
`
`0.022
`
`34.9%
`
`21.9%
`
`0.50
`
`0.20
`
`0.0063
`
`26%
`30%
`11%
`14%
`18%
`
`26%
`
`0.82
`
`38%
`31%
`18%
`7%
`7%
`
`38%
`
`0.67
`
`0.033
`
`0.104
`
`0.045
`
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`
`PRIMARY ENDPOINT:
`
`Time to sustained progression
`in disability (N: 143, 158)1
`
`Percentage of patients progressing
`in disability at 2 years
`(Kaplan-Meier estimate)1
`
`SECONDARY ENDPOINTS:
`DISABILITY
`
`Mean confirmed change in EDSS
`from study entry to end of study
`(N: 136, 150)1
`
`EXACERBATIONS
`
`Number of exacerbations in subset
`completing 2 years (N: 87, 85)
`
`0123
`
`4
`
`Percentage of patients exacerbation-
`free in subset completing 2 years
`(N: 87, 85)
`
`Annual exacerbation rate
`(N: 143, 158)1
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`Table 1 (continued)
`
`Clinical and MRI Endpoints in Study 1
`
`Placebo
`
`AVONEX®
`
`P-Value
`
`2.3 (1.0)
`0-23
`
`3.2 (1.0)
`0-56
`
`1.6 (0)
`0-22
`
`1.6 (0)
`0-34
`
`1.0 (0)
`0-28
`
`0.8 (0)
`0-13
`
`-3.3%
`
`-13.1%
`
`-6.5%
`
`-13.2%
`
`0.023
`
`0.053
`
`0.023
`
`0.363
`
`Endpoint
`MRI
`
`Number of Gd-enhanced lesions:
`At study entry (N: 132, 141)
`Mean (Median)
`Range
`
`Year 1 (N: 123, 134)
`Mean (Median)
`Range
`
`Year 2 (N: 82, 83)
`Mean (Median)
`Range
`
`T2 lesion volume:
`Percentage change from study
`entry to Year 1 (N: 116, 123)
`Median
`
`Percentage change from study
`entry to Year 2 (N: 83, 81)
`Median
`
`N E X® pa tients, respectiv ely.
`N ote:(N :, ) denotesth enum berof ev a lua blepla cebo a ndA VO
`1P a tientda ta includedin th isa na lysisrepresentv a ria bleperiodsof tim eon study.
`2A na lyzedbyM a ntel-C ox(log ra nk) test.
`3A na lyzedbyM a nn-W h itneyra nk-sum test.
`4A na lyzedbyC och ra n-M a ntel-H a enszeltest.
`5A na lyzedbylikelih oodra tio test.
`
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`In Study 2, 383 patients who had recently experienced an isolated demyelinating event
`involving the optic nerve, spinal cord, or brainstem/cerebellum, and who had lesions typical
`of multiple sclerosis on brain MRI, received either 30 mcg AVONEX® (n = 193) or placebo (n
`= 190) by IM injection once weekly. All patients received intravenous steroid treatment for
`the initiating clinical exacerbation. Patients were enrolled into the study over a two-year
`period and followed for up to three years or until they developed a second clinical
`exacerbation in an anatomically distinct region of the central nervous system. Sixteen
`percent of subjects on AVONEX® and 14% of subjects on placebo withdrew from the study
`for a reason other than the development of a second exacerbation2.
`
`The primary outcome measure was time to development of a second exacerbation in an
`anatomically distinct region of the central nervous system. Secondary outcomes were brain
`MRI measures, including the cumulative increase in the number of new or enlarging T2
`lesions, T2 lesion volume compared to baseline at 18 months, and the number of Gd-
`enhancing lesions at 6 months.
`
`Time to development of a second exacerbation was significantly delayed in patients treated
`with AVONEX® compared to placebo (p = 0.002). The Kaplan-Meier estimates of the
`percentage of patients developing an exacerbation within 24 months were 38.6% in the
`placebo group and 21.1% in the AVONEX® group (Figure 3). The relative rate of developing
`a second exacerbation in the AVONEX® group was 0.56 of the rate in the placebo group
`(95% confidence interval 0.38 to 0.81). The brain MRI findings are described in Table 2.
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`Figure 3
`Onset of Second Exacerbation by Time on Study
`(Kaplan-Meier Methodology)
`
`A VO
`
`N E X
`
`P la cebo
`
`P = 0.002
`Ra teRa tio = 0.56
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Wi
`th a
`Sec
`Per
`on
`cen
`tag
`x
`ace
`f
`rba
`Pat
`tio
`ien
`n
`ts
`
`dE
`
`eo
`
`0
`
`3
`
`6
`
`9
`
`12 15 18 21 24 27 30 33 36
`Months
`
`Number of Subjects at
`AVONE grou 193
`Placebo
`190
`
`164
`146
`
`143
`131
`
`98
`
`73
`
`26
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`Table 2
`Brain MRI Data According to Treatment Group
`AVONEX®
`N = 119
`
`CHANGE IN T2 VOLUME @18
`MONTHS:
`
`Placebo
`N = 109
`
`Actual Change (mm3)1*
`Median (25th%, 75th%)
`
`Percentage Change1*
`Median (25th%, 75th%)
`
`NUMBER OF NEW OR ENLARGING
`T2 LESIONS @ 18 MONTHS1*:
`
`0
`1-3
`>4
`Mean (SD)
`
`NUMBER OF GD-ENHANCING
`LESIONS @ 6 MONTHS2*:
`
`0
`1
`>1
`Mean (SD)
`
`28 (-576, 397)
`
`313 (5, 1140)
`
`1 (-24, 29)
`
`N = 132
`N (%)
`
`62 (47)
`41 (31)
`29 (22)
`2.13 (3.19)
`
`N = 165
`N (%)
`
`115 (70)
`27 (16)
`23 (14)
`0.87 (2.28)
`
`16 (0, 53)
`
`N = 119
`N (%)
`
`22 (18)
`47 (40)
`50 (42)
`4.97 (7.71)
`
`N = 152
`N (%)
`
`93 (61)
`16 (11)
`43 (28)
`1.49 (3.14)
`
`1 P value <0.001
`2 P value <0.03
`* P value from a Mann-Whitney rank-sum test
`
`INDICATIONS AND USAGE
`
`AVONEX® (Interferon beta-1a) is indicated for the treatment of patients with relapsing forms
`of multiple sclerosis to slow the accumulation of physical disability and decrease the
`frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has
`been demonstrated include patients who have experienced a first clinical episode and have
`MRI features consistent with multiple sclerosis. Safety and efficacy in patients with chronic
`progressive multiple sclerosis have not been established.
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`CONTRAINDICATIONS
`AVONEX® is contraindicated in patients with a history of hypersensitivity to natural or
`recombinant interferon beta, or any other component of the formulation.
`
`The lyophilized vial formulation of AVONEX® is contraindicated in patients with a history of
`hypersensitivity to albumin (human).
`
`WARNINGS
`
`Depression and Suicide
`
`AVONEX® should be used with caution in patients with depression or other mood disorders,
`conditions that are common with multiple sclerosis. Depression and suicide have been
`reported to occur with increased frequency in patients receiving interferon compounds,
`including AVONEX . Patients treated with AVONEX® should be advised to report
`immediately any symptoms of depression and/or suicidal ideation to their prescribing
`physicians.
`If a patient develops depression or other severe psychiatric symptoms,
`cessation of AVONEX® therapy should be considered.
`In Study 2, AVONEX®-treated
`patients were more likely to experience depression than placebo-treated patients. An equal
`incidence of depression was seen in the placebo-treated and AVONEX -treated patients in
`Study 1. Additionally, there have been post-marketing reports of depression, suicidal
`ideation and/or development of new or worsening of pre-existing other psychiatric disorders,
`including psychosis. Some of these patients improved upon cessation of AVONEX dosing.
`
`Anaphylaxis
`
`Anaphylaxis has been reported as a rare complication of AVONEX use. Other allergic
`reactions have included dyspnea, orolingual edema, skin rash and urticaria (see ADVERSE
`REACTIONS).
`
`Decreased Peripheral Blood Counts
`
`Decreased peripheral blood counts in all cell lines, including rare pancytopenia and
`thrombocytopenia, have been reported from post-marketing experience (see ADVERSE
`REACTIONS). Some cases of thrombocytopenia have had nadirs below 10,000/ L. Some
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`cases reoccur with rechallenge (see ADVERSE REACTIONS). Patients should be
`monitored for signs of these disorders (see Precautions: Laboratory Tests).
`
`Hepatic Injury
`
`Severe hepatic injury, including cases of hepatic failure, has been reported rarely in patients
`taking AVONEX®. Asymptomatic elevation of hepatic transaminases has also been
`reported, and in some patients has recurred upon rechallenge with AVONEX®. In some
`cases, these events have occurred in the presence of other drugs that have been
`associated with hepatic injury. The potential risk of AVONEX® used in combination with
`known hepatotoxic drugs or other products (e.g. alcohol) should be considered prior to
`AVONEX® administration, or when adding new agents to the regimen of patients already on
`AVONEX®. Patients should be monitored for signs of hepatic injury (see Precautions:
`Laboratory Tests).
`
`Albumin (Human)
`
`The lyophilized vial of AVONEX® 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 been identified for albumin. The prefilled syringe
`of AVONEX® does not contain albumin.
`
`PRECAUTIONS
`
`Seizures
`
`Caution should be exercised when administering AVONEX® to patients with pre-existing
`seizure disorders.
`In the two placebo-controlled studies in multiple sclerosis, 4 patients
`receiving AVONEX® experienced seizures, while no seizures occurred in the placebo group.
`Three of these 4 patients had no prior history of seizure (see ADVERSE REACTIONS).
`It is
`not known whether these events were related to the effects of multiple sclerosis alone, to
`AVONEX®, or to a combination of both. The effect of AVONEX® administration on the medical
`management of patients with seizure disorder is unknown.
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`Cardiomyopathy and Congestive Heart Failure
`
`Patients with cardiac disease, such as angina, congestive heart failure, or arrhythmia,
`should be closely monitored for worsening of their clinical condition during initiation and
`continued treatment with AVONEX®. While AVONEX® does not have any known direct-
`acting cardiac toxicity, during the post-marketing period infrequent cases of congestive heart
`failure, cardiomyopathy, and cardiomyopathy with congestive heart failure have been
`reported in patients without known predisposition to these events, and without other known
`etiologies being established.
`In rare cases, these events have been temporally related to
`the administration of AVONEX®.
`In some of these instances recurrence upon rechallenge
`was observed.
`
`Autoimmune Disorders
`
`Autoimmune disorders of multiple target organs have been reported post-marketing
`including idiopathic thrombocytopenia, hyper- and hypothyroidism, and rare cases of
`autoimmune hepatitis have also been reported. Patients should be monitored for signs of
`these disorders (see Precautions: Laboratory Tests) and appropriate treatment implemented
`when observed.
`
`Information to Patients
`
`All patients should be instructed to read the AVONEX® 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 serious (see WARNINGS) and the most common
`adverse events associated with AVONEX® administration, including symptoms associated
`with flu syndrome (see ADVERSE REACTIONS). Symptoms of flu syndrome are most
`prominent at the initiation of therapy and decrease in frequency with continued treatment.
`Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms on
`treatment days.
`
`Patients should be cautioned to report depression or suicidal ideation (see WARNINGS).
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`Patients should be advised about the abortifacient potential of AVONEX® (see Precautions:
`If a woman becomes pregnant while taking AVONEX®,
`Pregnancy - Teratogenic Effects).
`she should be advised to consider enrolling in the AVONEX® Pregnancy Registry by calling
`1-800-456-2255.
`
`When a physician determines that AVONEX® can be used outside of the physician's office,
`persons who will be administering AVONEX® should receive instruction in reconstitution and
`injection, including the review of the injection procedures.
`If a patient is to self-administer,
`the physical ability of that patient to self-inject intramuscularly should be assessed. The first
`injection should be performed under the supervision of a qualified health care professional.
`A puncture-resistant container for disposal of needles and syringes should be used.
`Patients should be instructed in the technique and importance of proper syringe and needle
`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, complete blood and differential white blood cell counts, platelet counts, and blood
`chemistries, including liver function tests, are recommended during AVONEX® therapy (see
`WARNINGS: Decreased Peripheral Blood Counts and PRECAUTIONS: Cardiomyopathy
`and Congestive Heart Failure, and Autoimmune Disorders). During the placebo-controlled
`studies in multiple sclerosis, these tests were performed at least every 6 months. There
`were no significant differences between the placebo and AVONEX® groups in the incidence
`of liver enzyme elevation, leukopenia, or thrombocytopenia. However, these are known to
`be dose-related laboratory abnormalities associated with the use of interferons. Patients
`with myelosuppression may require more intensive monitoring of complete blood cell counts,
`with differential and platelet counts. Thyroid function should be monitored periodically.
`If
`patients have or develop symptoms of thyroid dysfunction (hypo- or hyperthyroidism),
`thyroid function tests should be performed according to standard medical practice.
`
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`Drug Interactions
`
`In the placebo-
`No formal drug interaction studies have been conducted with AVONEX .
`controlled studies in multiple sclerosis, corticosteroids or ACTH were administered for
`treatment of exacerbations in some patients concurrently receiving AVONEX®.
`In addition,
`some patients receiving AVONEX® were also treated with anti-depressant therapy and/or
`oral contraceptive therapy. No unexpected adverse events were associated with these
`concomitant therapies. However, the potential for hepatic injury should be considered when
`AVONEX® is used in combination with other products associated with hepatic injury, or
`when new agents are added to the regimen of patients already on AVONEX® (see
`WARNINGS: Hepatic Injury).
`
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`C a rcinog enesis: No carcinogenicity data for AVONEX® are available in animals or humans.
`
`M uta g enesis: AVONEX® was not mutagenic when tested in the Ames bacterial test and in
`an in v itro cytogenetic assay in human lymphocytes in the presence and absence of
`metabolic activation. These assays are designed to detect agents that interact directly with
`and cause damage to cellular DNA. AVONEX® is a glycosylated protein that does not
`directly bind to DNA.
`
`Im pa irm entof F ertility: No studies were conducted to evaluate the effects of AVONEX® on
`fertility in normal women or women with multiple sclerosis.
`It is not known whether
`AVONEX® can affect human reproductive capacity.
`
`Menstrual irregularities were observed in monkeys administered AVONEX® at a dose 100
`times the recommended weekly human dose (based upon a body surface area comparison).
`Anovulation and decreased serum progesterone levels were also noted transiently in some
`animals. These effects were reversible after discontinuation of drug.
`
`Treatment of monkeys with AVONEX® at 2 times the recommended weekly human dose
`(based upon a body surface area comparison) had no effects on cycle duration or ovulation.
`
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`In the placebo-
`The accuracy of extrapolating animal doses to human doses is not known.
`controlled studies in multiple sclerosis, 5% of patients receiving placebo and 6% of patients
`receiving AVONEX® experienced menstrual disorder.
`If menstrual irregularities occur in
`humans, it is not known how long they will persist following treatment.
`
`Pregnancy - Teratogenic Effects
`
`P reg na ncyC a teg oryC : The reproductive toxicity of AVONEX® has not been studied in
`In pregnant monkeys given AVONEX® at 100 times the recommended
`animals or humans.
`weekly human dose (based upon a body surface area comparison), no teratogenic or other
`adverse effects on fetal development were observed. Abortifacient activity was evident
`following 3 to 5 doses at this level. No abortifacient effects were observed in monkeys
`treated at 2 times the recommended weekly human dose (based upon a body surface area
`comparison). Although no teratogenic effects were seen in these studies, it is not known if
`teratogenic effects would be observed in humans. There are no adequate and well-
`controlled studies with interferons in pregnant women.
`If a woman becomes pregnant or
`plans to become pregnant while taking AVONEX®, she should be informed of the potential
`hazards to the fetus, and discontinuation of AVONEX® therapy should be considered.
`
`If a woman becomes pregnant while taking AVONEX®, consider enrolling her in the
`AVONEX® Pregnancy Registry by calling 1-800-456-2255.
`
`Nursing Mothers
`
`It is not known whether AVONEX® is excreted in human milk. Because of the potential of
`serious adverse reactions in nursing infants, a decision should be made to either
`discontinue nursing or to discontinue AVONEX®.
`
`Pediatric Use
`
`Safety and effectiveness of AVONEX® in pediatric patients below the age of 18 years have
`not been evaluated.
`
`Geriatric Use
`
`Clinical studies of AVONEX® did not include sufficient numbers of patients aged 65 and over
`to determine whether they respond differently than younger patients.
`
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`ADVERSE REACTIONS
`
`Depression, suicidal ideation, and new or worsening other psychiatric disorders have been
`observed to be increased in patients using interferon compounds including AVONEX® (see
`WARNINGS: Depression and Suicide). Anaphylaxis and other allergic reactions have been
`reported in patients using AVONEX® (see WARNINGS: Anaphylaxis). Decreased peripheral
`blood counts have been reported in patients using AVONEX® (see WARNINGS: Decreased
`Peripheral Blood Counts). Hepatic injury, including hepatic failure, hepatitis, and elevated
`serum hepatic enzyme levels, has been reported in post-marketing experience (see
`WARNINGS: Hepatic Injury). Seizures, cardiovascular adverse events, and autoimmune
`disorders also have been reported in association with the use of AVONEX® (see
`Precautions).
`
`The adverse reactions most commonly reported in patients associated with the use of
`AVONEX® were flu-like and other symptoms occurring within hours to days following an
`injection. Symptoms can include myalgia, fever, fatigue, headaches, chills, nausea, and
`vomiting. Some patients have experienced paresthesias, hypertonia and myasthenia.
`
`The most frequently reported adverse reactions resulting in clinical intervention (e.g.,
`discontinuation of AVONEX , or the need for concomitant medication to treat an adverse
`reaction symptom) were flu-like symptoms and depression.
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of AVONEX® cannot be directly compared to rates in clinical
`trials of other drugs and may not reflect the rates observed in practice.
`
`The data described below reflect exposure to AVONEX® in 351 patients, including 319
`patients exposed for 6 months, and 288 patients exposed for greater than one year in
`placebo-controlled trials. The mean age of patients receiving AVONEX® was 35 years, 74%
`were women and 89% were Caucasian. Patients received either 30 mcg AVONEX® or
`placebo.
`
`Table 3 enumerates adverse events and selected laboratory abnormalities that occurred at
`an incidence of at least 2% higher frequency in AVONEX®-treated subjects than was
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`observed in the placebo group. Reported adverse events have been classified using
`standard COSTART terms.
`
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`Table 3
`Adverse Events and Selected Laboratory Abnormalities in the Placebo-Controlled Studies
`
`Adverse Event
`Body as a Whole
`Headache
`Flu-like symptoms (otherwise unspecified)
`Pain
`Asthenia
`Fever
`Chills
`Abdominal pain
`Injection site pain
`Infection
`Injection site inflammation
`Chest pain
`Injection site reaction
`Toothache
`
`Nervous System
`Depression
`Dizziness
`
`Respiratory System
`Upper respiratory tract infection
`Sinusitis
`Bronchitis
`
`Digestive System
`Nausea
`
`Musculoskeletal System
`Myalgia
`Arthralgia
`
`Urogenital
`Urinary tract infection
`Urine constituents abnormal
`
`Skin and Appendages
`Alopecia
`
`Special Senses
`Eye disorder
`
`Hemic and Lymphatic System
`Injection site ecchymosis
`Anemia
`
`Cardiovascular System
`Migraine
`Vasodilation
`
`Placebo
`(N = 333)
`
`AVONEX®
`(N = 351)
`
`55%
`29%
`21%
`18%
`9%
`5%
`6%
`6%
`4%
`2%
`2%
`1%
`1%
`
`14%
`12%
`
`12%
`12%
`5%
`
`19%
`
`22%
`6%
`
`15%
`0%
`
`2%
`
`2%
`
`4%
`1%
`
`3%
`0%
`
`