Confirmed Change from Baseline EDSS
`
`AVONEX™
`30 meg through 75 meg have been investigated. Serum
`Figure 2
`co.
`levels of Interferon beta-1a as measured by antiviral activi-
`Confirmed EDSS Change From Study Entryto End of Stuch—
`INTERFERONBETA-1a
`ty are slightly above detectablelimits following a 30 mcg
`[MOE Neri!
`intramuscular(IM) dose, and increase with higher doses.
`DESCRIPTION
`1 Plueetuse\ ftelai
`Table 1 compares general pharmacokinetic parameters
`AVONEX™(\nterferon beta-ta) is produced by
`for AVONEX™following administration of a 60 mcg dose
`recombinant DNA technology. Interferon beta-1a is
`by IM and subcutaneous (SC) routes to healthy volunteers.
`a 166 amino acid glycoprotein with a predicted
`After an IM dose, serum levels of Interferon beta-1a typi-
`molecular weight of approximately 22,500 daltons.
`cally peak between 3 and 15 hours and then decline at a
`It
`is produced by mammalian ceils (Chinese
`rate consistent with a 10 hour elimination haif-life. Serum
`Hamster Ovary cells) into which the humaninterfer-
`levels of Interferon beta-ta may be sustained after IM
`on beta gene has been introduced. The amino acid
`administration due to prolonged absorption from the IM
`sequence of AVONEX™is identical to that of natur-
`a\ humaninterferon beta.
`site. Systemic exposure, as determined by AUC and
`Cmax values, is greater following IM than SC administration.
`Using the World Health Organization (WHO) nat-
`Biological
`response markers (e.g., neopterin and
`ural interferon beta standard, SecondInternational
`B2-microglobulin) are induced by Interferon beta-1a follow-
`Standard for Interferon, Human Fibroblast (Gb-23-
`ing parenteral doses of 15 meg through 75 mcgin healthy
`902-531), AVONEX™ has a specific activity of
`subjects and treated patients. Biological response marker
`approximately 200 million international units (IU) of
`IN patients receiving placebo (p = 0.02). The Kaplan-
`levels increase within 12 hours of dosing and remain ele-
`antiviral activity per mg; 30 mcg of AVONEX™con-
`Meier plots of these data are presented in Figure 1. The
`vated forat least 4 days. Peak biological response marker
`tains 6 million |U of antiviral activity. The activity
`Kaplan-Meier estimate of the percentage of patient
`levels are typically observed 48 hours after dosing. The
`against other standards is not known.
`Progressing by the end of 2 years was 34.9% for place”
`relationship of serum Interferon beta-1a leveis or levels of
`AVONEX"™is formulated as a sterile, white to off-
`bo-treated patients and 21.9% for AVONEX'™-treated
`these induced biological response markers to the mecha-
`white lyophilized powderfor intramuscular injection
`Patients, indicating a slowing of the disease process-
`nisms by which AVONEX™exerts its effects in multiple
`after reconstitution with supplied diluent or Sterile
`This represents a 37% reduction in the risk of accumu-
`sclerosis is unknown.
`Water for Injection, USP, preservative-free.
`lating disability in the AVONEX'’-treated group com-
`Each 1.0 mL (1.0 cc} of reconstituted AVONEX™
`Pared to the placebo-treated group.
`Clinicat Studies: Effects in Multiple Sclerosis
`contains 30 mcg of Interferon beta-1a, 15 mg
`Thedistribution of confirmed EDSS change from study
`The Clinical effects of AYONEX™(Interferon beta-1a) in
`Albumin Human, USP, 5.8 mg Sodium Chloride,
`multiple sclerosis were studied in a randomized, multicen-
`entry (baseline) to the end of the study is shown in
`USP, 5.7 mg Dibasic Sodium Phosphate, USP and
`Figure 2. There wasastatistically significant difference
`ter, double-blind, placebo-controlled study in patients with
`1.2 mg Monobasic Sodium Phosphate, USP at a
`between treatment groups in confirmed change for
`relapsing (stable or progressive) multiple sclerosis’. In this
`pH of approximately 7.3.
`Patients with at least two scheduled visits (136 placebo-
`study, 301 patients received either 6 million IU (30 mcg) of
`treated and 150 AVONEX™-treated patients: p = 0.006;
`AVONEX™ (n= 158) or placebo (n= 143) by IM injection
`once weekly. Patients were entered into the trial over a
`see Table 2). Confirmed EDSS change was calculated
`CLINICAL PHARMACOLOGY
`as the difference between the EDSS scoreat study entry
`2’/: year period, received injections for up to 2 years, and
`and one of the scores determinedat the last two sched-
`General
`continued to be followed until study completion. Two
`uled visits.
`If the EDSS score at either of the last two
`hundred eighty-two patients compieted 1 year on study.
`interferons are a family of naturally occurring pro-
`scheduled visits showed improvement (reduction in
`and 172 patients completed 2 years on study. There were
`teins and glycoproteins that are produced by
`score), the higher score was used. Otherwise, the lower
`eukaryotic cells in responseto viral infection and
`144 patients treated with AVONEX™for more than 1 year,
`115 patients for more than 18 months and 82 patients for
`other biological
`inducers.
`Interferon beta, one
`2 years.
`memberof this family, is produced by various cell
`All patients had a definite diagnosis of multiple sclerosis
`types including fibroblasts and macrophages.
`Table 2
`Natural
`interferon beta and Interferon beta-1a
`of at least 1 year duration and had at least two exacerba-
`Major Clinical Endpoints
`tions in the 3 years prior to study entry (or one per year if
`are glycosylated, with each containing a single
`
`Endpoint AVONEX™=P-Value Placebo
`
`the duration of disease was less than 3 years). At entry,
`N-linked complex carbohydrate moiety. Glyco-
`sylation of other proteins is known to affect their
`study participants were without exacerbation during the
`stability, activity, biodistribution and half-life in
`prior 2 months and had Kurtzke Expanded Disability
`Status Scale (EDSS’) scores ranging from 1.0 to 3.5.
`blood. However, the effects of glycosylation of
`Patients with chronic progressive multiple sclerosis were
`interferon beta on these properties have not been
`excluded from this study.
`fully defined.
`The primary outcome assessment was time to progres-
`Biologic Activities
`sion in disability, measured as an increase in the EDSS of
`interferons are cytokines that mediate antiviral,
`at least 1.0 point that was sustained for at least 6 months.
`An increase in EDSS score reflects accumulation of dis-
`antiproliferative and immunomodulatory activities in
`response to viral
`infection and other biological
`ability. This endpoint was used to assure that progression
`inducers. Three major interferons have been distin-
`reflected permanent increase in disability rather than a
`transient effect due to an exacerbation.
`guished: alpha, beta and gamma.interferons alpha
`and beta form the Type | class of interferons, and
`Secondary outcomes included exacerbation frequency
`interferon gammais a Type II interferon. These
`and results of magnetic resonance imaging (MRI) scans
`interferons have overlapping but clearly distinct
`including gadolinium (Gd)-enhanced lesion number and
`biological activities.
`volume and T2-weighted (proton density) lesion volume.
`Interferon beta exerts its biological effects by
`Additional secondary endpoints included two upper limb
`binding to specific receptors on the surface of
`(tested in both arms) and three lowerlimb functiontests.
`human cells. This binding initiates a complex cas-
`Twenty-three of the 301 patients (8%) discontinued
`cade of
`intracellular events that
`leads to the
`treatment prematurely. Of these, one patient treated with
`expression of numerous interferon-induced gene
`placebo (1%) and six patients treated with AVONEX™
`products and markers. These include 2’, 5’-oligoa-
`(4%) discontinued treatment due to adverse events.
`denylate synthetase, 8B.-microglobulin and neo-
`Thirteen of these 23 patients remained on study and were
`pterin. These products have been measured in the
`evaluated for clinical endpoints.
`serum and cellular fractions of blood collected from
`Time to onset of sustained progression in disability was
`patients treated with AVONEX™(Interferon beta-
`significantly longer in patients treated with AVONEX™than
`ta}.
`The specific interferon-induced proteins and
`mechanisms by which AVONEX™exertsits effects
`in multiple scierosis have not beenfully defined.
`Pharmacokinetics
`Pharmacokinetics of AVONEX™in multiple scle-
`rosis patients have not been evaluated. The phar-
`macokinetic and pharmacodynamic profiles of
`AVONEX™in healthy subjects following doses of
`
`¥oE= == &==£
`
`Figure|
`Onset of Sustained Disability Progression by Time on Study
`(Kaplan-Meier Methodology)
`
`TT AVONEX ©
`
`
`P=O02
`
`Placebo
`
`
`
`(24.9%
`
`Table 1
`Mean Single Dose Pharmacokinetic
`Parameters Following 60 mcg Administration
`Elimination
`Route of
`AUC
`Cinax
`Tmax (Range)
`Half-life
`
`Administration
`((U*h/mLi
`duymiy
`(h}
`{hy
`(M
`1352
`43
`9.8 (3-15)
`10.0
`
`SC 8.6 478 30 7.8 (3-18)
`
`
`
`
`C2E Pd
`
`Note: Disability progression represents at least a 1.0 point increase
`in EDSS score sustainedfor at least 6 months.
`
`
`
`=
`
`Better
`
`—>
`
`io
`
`Worse
`
`:
`
`PRIMARY ENDPOINT:
`Time to sustained progression
`in disability (N: 143. 158)
`Percentage of patients progressing
`In disability at 2 years
`(Kaplan-Meier estimate)
`
`~See Figure 1-
`
`0.02
`
`34.9%
`
`21.9%
`
`SECONDARY ENDPOINTS:
`ABILITY
`Mean confirmed change in EDSS
`from study entry to end of study
`{N: 136, 150)
`ATH
`Numberof exacerbations in subset
`completing 2 years (N: 87, 85)
`1
`2
`3
`24
`Percentageof patients exacerbation-
`free in subset completing 2 years
`(N: 87, 85)
`Annual exacerbation rate
`(N: 143, 158)
`
`0.50
`
`26%
`30%
`1%
`14%
`18%
`
`26%
`0.82
`
`0.20
`
`0.006
`
`38%
`31%
`18%
`7%
`7%
`
`38%
`0.67
`
`0.03
`
`0.04
`
`2.3: (4.0)
`0-23
`
`3.2 4.0)
`0-56
`
`1.6 (0)
`0-22
`
`1.6 (0)
`0-34
`
`1.0 (0)
`0-28
`
`0.8 (0)
`0-13
`
`0.02
`
`0.05
`
`MAI
`Number of Gd-enhancedlesions:
`At study entry (N: 132. 147)
`Mean (Median)
`Range
`Year # (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
`
`
`-13.2%6.5% 0.36
`Note. (N: .) denotes the numberof evaiuable placebo and
`AVONEX™(interferon beta-1a) patients, respectively.
`‘Patient data included in this analysis represent variable penodsoftime
`on Study.
`“Analyzed by Mantel-Cox (logrank) test.
`‘Analyzed by Mann-Whitney rank-sum test.
`“Analyzed by Cochran-Mante!-Haenszeitest.
`‘Analyzedby likelihood ratio test.
`
`-3.3%
`
`“13.1%
`
`0.02
`
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`EX1021, Page 1 of 4
`
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`
`

`

`
`
`Score was used. Nineteen patients had one score higher
`and one score lowerthan baseline: the higher score was
`used. The last two scheduled visits Occurred at varying
`time points amongpatients.
`,
`The rate and frequency of exacerbations were deter-
`mined as secondary outcomes. Foralt 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).
`
`Biogen,Inc.
`
`BIOGEN®
`
`MN
`
`AVONEX™
`INTERFERONBETA-1la
`
`Biogen, Inc.
`
`BIOGEN®
`
`163000-1
`
`AVONEX™
`INTERFERONBETA-1la
`
`AVONEX™(Interferon beta-1a) treatment significantly
`decreased the frequency of exacerbations in the subset
`of patients who wereenrolled in the study for at least 2
`years (87 placebo-treated patients and 85 AVONEX™-
`treated patients; p = 0.03; see Table 2).
`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 lesions seen on brain MRI scans repre-
`sent areas of breakdown of the blood brain barrier
`thought to be secondary to inflammation. Patients treat-
`ed with AVONEX™ demonstrated significantly lower
`Gd-enhanced lesion numberafter 1 and 2 years of treat-
`
`ment (p<0.05; see Table 2). The volume of Gd-
`enhanced lesions wasalso analyzed, and showed simi-
`lar treatment effects (p <0.03). Percentage change in
`T2-weighted lesion volume from study entry to year 1
`wassignificantly lower
`in AVONEX™-treated than
`placebo-treated patients (p= 0.02). A significant differ-
`ence in T2-weighted lesion volume change was not
`seen between study entry and year2.
`The exact relationship between MRI findings and the
`clinical status of patients is unknown. Changesin lesion
`area often do not correlate with changesin disability
`progression. The prognostic significance of the MRI
`findings in this study has not been evaluated.
`Of the limb function tests, only one demonstrated a
`Statistically significant difference between treatment
`groups (favoring AVONEX™).
`A summary of the effects of AVONEX™on the primary
`and major secondary endpoints of this study is present-
`ed in Table 2.
`Safety and efficacy of treatment with AVONEX™
`beyond 2 years are not known.
`
`INDICATIONS AND USAGE
`AVONEX™(interferon beta-1a) is indicated for the
`treatment of relapsing forms of multiple sclerosis to
`slow the accumulation of physical disability and de-
`crease the frequencyofclinical exacerbations. Safety
`and efficacy in patients with chronic progressive multi-
`ple scierosis have not been evaluated.
`
`CONTRAINDICATIONS
`AVONEX™(interferon beta-1a) is contraindicated in
`patients with a history of hypersensitivity to natural or
`recombinant interferon beta, human albumin, or any
`other componentof the formulation.
`WARNINGS
`AVONEX™(Interferon beta-1a) should be used with
`caution in patients with depression. Depression and sui-
`cide have been reported to occurin patients receiving
`other interferon compounds. Depression and suicidal
`ideation are known to occur at an increased frequency
`in the multiple sclerosis population. A relationship
`between occurrence of depression and/or suicidal
`ideation and the use of AVONEX™hasnot been estab-
`lished. An equal incidence of depression was seen in
`the placebo-treated and AVONEX™-treated patients in
`the placebo-controlied multiple
`sclerosis
`study.
`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, cessation of AVONEX™
`therapy should be considered.
`
`PRECAUTIONS
`
`General
`Caution should be exercised when administering
`AVONEX™(interferon beta-1a) to patients with pre-
`existing seizure disorder.
`in the placebo-controlled
`study, four patients receiving AVONEX™ experienced
`seizures, while no seizures occurred in the placebo
`group. Three of these four patients had no prior history
`of seizure.
`It
`is not known whether these events were
`related to the effects of multiple sclerosis alone, to
`AVONEX™, or to a combination of both.
`For patients
`with no prior history of seizure who develop seizures
`during therapy with AVONEX™, an etiologic basis
`should be established and appropriate anti-convulsant
`therapy instituted prior to considering resumption of
`AVONEX™treatment. The effect of AYONEX™adminis-
`tration on the medical managementof patients with
`seizure disorder is unknown.
`Patients with cardiac disease, such as angina, con-
`gestive heart failure or arrhythmia, should be closely
`monitored for worsening oftheir clinical condition during
`initiation of therapy with AVONEX™. AVONEX™ does
`not have any knowndirect-acting cardiac toxicity; how-
`ever, symptomsof flu syndrome seen with AVONEX™
`therapy may prove stressful to patients with severe car-
`diac conditions.
`
`information to Patients
`Patients should be informed of the most common
`adverse events associated with AVONEX™ administra-
`tion, including symptoms associated with flu syndrome
`(see Adverse Reactions section and precautionsin
`
`Patient Information). Symptomsof fiu syndrome are
`most prominent at the initiation of therapy and
`decrease in frequency with continued treatment.
`In
`the placebo-controlled study, patients were instruct-
`ed to take 650 mg acetaminophen immediately prior
`to injection and for an additional 24 hours after each
`injection to modulate acute symptoms associated
`with AVONEX™administration.
`Patients should be cautioned to report depression
`or suicidalideation (see Warnings).
`Patients should be advised aboutthe abortifacient
`potential of
`interferon beta (see Pregnancy -
`Teratogenic Effects).
`Whena 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 (see Dosage
`and Administration). if a patient is to self-administer,
`the physicai ability of that patient to seff-inject intra-
`muscularly should be assessed. Thefirst injection
`should be performed under the supervision of a
`qualified health care professional. A puncture-resis-
`tant 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 normaily
`required for monitoring patients with multiple sclero-
`sis, complete blood and differential white blood cell
`counts, platelet counts, and blood chemistries,
`including liver function tests, are recommended dur-
`ing AVONEX™(Interferon beta-1a) therapy. During
`the placebo-controlled study, these tests were per-
`formed at least every 6 months. There were no sig-
`nificant differences between the placebo and
`AVONEX™groupsin the incidence ofliver enzyme
`elevation, leukopenia or thrombocytopenia. How-
`ever, these are known to be dose-related laboratory
`abnormalities associated with the use ofinterferons.
`Patients with myelosuppression may require more
`intensive monitoring of complete blood cell counts,
`with differential and platelet counts.
`
`DrugInteractions
`No forma! drug interaction studies have been con-
`ducted with AVONEX™.in the placebo-controlled
`study, corticosteroids or ACTH were administered
`for treatment of exacerbations in some patients con-
`Currently receiving AVONEX™.
`In addition, some
`patients receiving AVONEX™werealso treated with
`anti-depressant therapy and/or oral contraceptive
`therapy. No unexpected adverse events were asso-
`ciated with these concomitanttherapies.
`Other interferons have been noted to reduce
`cytochrome P-450 oxidase-mediated drug metabo-
`lism. Formal hepatic drug metabolism studies with
`AVONEX™in humans have not been conducted.
`Hepatic microsomesisolated from AVONEX™-treat-
`ed rhesus monkeys showed no influence of
`AVONEX™on hepatic P-450 enzyme metabolism
`activity.
`.
`As with all interferon products, proper monitoring
`of patients is required if AVONEX™is given in com-
`bination with myelosuppressive agents.
`
`Carcinogenesis, Mutagenesis and
`ImpairmentofFertility
`Carcinogenesis: No carcinogenicity data for
`Interferon beta-1a are available in animals or
`humans.
`
`Mutagenesis: Interferon beta-1a was not muta-
`genic when tested in the Ames bacterial test and in
`an in vitro cytogenetic assay in human lymphocytes
`in the presence and absence of metabolic activa-
`tion. These assays are designed to detect agents
`that interact directly with and cause damageto cel-
`lular DNA. Interferon beta-1a is a glycosylated pro-
`tein that does notdirectly bind to DNA.
`Impairmentof Fertility: No studies were conducted
`to evaluate the effects of interferon beta onfertility in
`normal women or women with multiple sclerosis.
`It
`is not known whether Interferon beta-1a can affect
`human reproductive capacity.
`
`MNME
`
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`
`
`Menstrualirregularities were observedin monkeys
`administered interferon beta 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 interferon beta at 2
`times the recommended weekly human dose (based
`upon a body surface area comparison) had no
`effects on cycle duration or ovulation.
`The accuracy of extrapolating animai doses to
`human dosesis not known. In the placebo-con-
`troiled study, 6% of patients receiving placebo and
`5% of patients receiving AVONEX™ experienced
`menstrual disorder.
`If menstrualirregularities occur
`in humans,it is not known how long they will persist
`following treatment.
`
`Pregnancy~ Teratogenic Effects
`Pregnancy Category C: The reproductive toxicity
`of AVONEX™has not been studied in animals or
`humans. in pregnant monkeys given interferon beta
`at 100 times the recommended weekly human dose
`(based upon a body surface area comparison), no
`teratogenic or other adverse effects on fetal devel-
`opment were observed. Abortifacient activity was
`evidentfollowing 3 to 5 dosesatthis level. No abor-
`tifacient 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 knownif teratogenic effects would
`be observed in humans. There are no adequate and
`well-controlled studies with interferons in pregnant
`women. If a woman becomes Pregnantor plans to
`become pregnant while taking AVONEX™, she
`should be informed of the potential hazards to the
`fetus, and it should be recommended that the
`woman discontinue therapy.
`
`Nursing Mothers
`It
`is not known whether Interferon beta-1a is
`excreted in human milk. Because of the potential of
`serious adverse reactions in nursing infants, a deci-
`sion should be madetoeither discontinue nursing or
`to discontinue AVONEX™,
`
`Pediatric Use
`Safety and effectiveness in pediatric patients
`below the age of 18 years have not been estab-
`lished.
`
`ADVERSE REACTIONS
`The safety data describing the use of AVONEX™
`(Interferon beta-1a) in multiple sclerosis patients are
`based on the placebo-controlled trial in which 158
`patients randomized to AVONEX™were treated for
`up to 2 years (see Clinical Studies).
`The five most common adverse events associated
`{at p < 0.075) with AVONEX™treatment were flu-like
`symptoms (otherwise unspecified), muscle ache,
`fever, chills and asthenia. The incidence of all five
`adverse events diminished with continued treat-
`ment.
`One patient in the placebo group attempted sui-
`cide; no AVONEX™-treated patient attempted sui-
`cide. The incidence of depression was equal in the
`two treatment groups. However, since depression
`and suicide have been reported with other interferon
`products, AVONEX™should be used with caution in
`Patients with depression (see Warnings).
`In the placebo-controlled study, four patients
`receiving AVONEX™experienced seizures, while no
`seizures occurred in the placebo group. Three of
`these four patients had no prior history of seizure.It
`is not known whether these events were related to
`the effects of multiple sclerosis alone, to AVONEX™,
`or to a combination of both (see Precautions).
`Table 3 enumerates adverse events and selected
`laboratory abnormalities that occurred at an inci-
`dence of 2% or more among the 158 multiple scle-
`rosis patients treated with 30 meg of AVONEX™
`once weekly by IM injection. Reported adverse
`events have been classified using standard
`COSTARTterms. Terms so general as to be uninfor-
`mative and those events that were equalin inci-
`dence or more common in the placebo-treated
`patients have been excluded.
`
`AVONEX"™(interferon beta-1a) has also been evaluat-
`ed in 290 patients with illnesses other than muitiple
`sclerosis. The majority of these Patients were enrolled in
`Studies to evaluate AVONEX™treatment of chronic viral
`hepatitis B and C,
`in which the doses studied ranged
`from 15 meg to 75 mcg, given SC, 3 times a week, for
`up to 6 months. The incidence of common adverse
`events in these studies was generally seen at a frequen-
`cy similar to that seen in the placebo-controlled multiple
`sclerosis study. In these non-multiple sclerosis studies,
`inflammationat the site of the SC injection was seen in
`52% of treated patients.
`In contrast,
`injection site
`inflammation was seen in 3% of multiple sclerosis
`patients receiving AVONEX™, 30 mcg byIM injection.
`Subcutaneousinjections were also associated with the
`following local reactions: injection site necrosis, injection
`site atrophy, injection site edema and injection site hem-
`orrhage. None of the above was observedin the multi-
`ple sclerosis patients participating in the placebo-
`controlled study.
`Other events observed during premarket evaluation of
`AVONEX™, administered either SC or IM in all patient
`populations studied, are listed in the Paragraphthatfol-
`lows. Because most of the events were observedin
`Open and uncontrolled studies, the role of AVONEX™in
`their causation cannot be reliably determined. Body as
`a Whole:abscess, ascites, cellulitis, facial edema,her-
`nia, injection site fibrosis, injection site hypersensitivity,
`lipoma, neoplasm, photosensitivity reaction, sepsis,
`sinus headache, toothache; Cardiovascular System:
`arrhythmia,arteritis, heart arrest, hemorrhage, hypoten-
`sion, palpitation, Pericarditis, peripheral
`ischemia,
`peripheral vascular disorder, postural hypotension, pul-
`monary embolus, spider angioma, telangiectasia, vas-
`
`Table 3
`Adverse Events and Selected Laboratory Abnormalities
`in the Placebo-Controtled Study
`
`Placebo
`AVONEX™
`
`Adverse Event
`(N = 143}
`(N = 158)
`Body as a Whole
`Headache
`Fiu-like symptoms
`(otherwise unspecified)*
`Pain
`Fever*
`Asthenia
`Chills*
`Infection
`Abdominatpain
`Chest pain
`injection site reaction
`Malaise
`Injection site inflammation
`Hypersensitivity reaction
`Ovarian cyst
`Cardiovascular System
`Syncope
`Vasodilation
`Digestive System
`Nausea
`Diarrhea
`Dyspepsia
`Anorexia
`Hemic and Lymphatic System
`Anemia*
`Eosinophils > 10%
`HCT (%) < 32 (females)
`or < 37 (males)
`Ecchymosisinjection site
`Metabolic and
`Nutritional Disorders
`SGOT 23x ULN
`Musculoskeletal System
`Muscle ache*
`Arthraigia
`Nervous System
`Sleep difficult
`Dizziness
`Muscle spasm
`Suicidal tendency
`Seizure
`Speech disorder
`Ataua
`Respiratory System
`Upperrespiratory tract infection
`Sinusitis
`Oyspnea
`Skin and Appendages
`Urticaria
`Alopecia
`Nevus
`Herpes zoster
`Herpes simplex
`Special Senses
`Otitis media
`Hearing decreased
`Urogenital
`2%
`Vaginitis
`*Significantly associated with AVONEX™ treatment(p < 0.05).
`
`57%
`40%
`20%
`13%
`13%
`7%
`6%
`6%
`4%
`1%
`3%
`0%
`0%
`0%
`
`2%
`1%
`
`23%
`10%
`7%
`6%
`
`3%
`4%
`1%
`1%
`
`1%
`
`15%
`5%
`
`16%
`13%
`6%
`1%
`0%
`0%
`0%
`
`28%
`17%
`3%
`
`2%
`1%
`0%
`2%
`1%
`
`5%
`0%
`
`67%
`61%
`24%
`23%
`21%
`21%
`11%
`9%
`6%
`4%
`4%
`3%
`3%
`3%
`
`4%
`4%
`
`33%
`16%
`11%
`7%
`
`8%
`5%
`3%
`2%
`
`3%
`
`34%
`9%
`
`19%
`15%
`7%
`4%
`3%
`3%
`2%
`
`31%
`18%
`6%
`
`5%
`4%
`3%
`3%
`2%
`
`6%
`3%
`
`4%
`
`Cular disorder; Digestive System:blood in stool. colitis.
`constipation, diverticulitis, dry mouth, gallbladder disor-
`der, gastritis, gastrointestinal hemorrhage, gingivitis.
`gum hemorrhage, hepatoma, hepatomegaly. increased
`appetite, intestinal perforation. intestinal obstruction.
`Periodontal abscess, periodontitis. proctitis.
`thirst.
`tongue disorder: Endocrine System: hypothyroidism:
`Hemic and Lymphatic System: coagulation time
`increased, ecchymosis, lymphadenopathy. petechia.
`
`Metabolic and Nutritional Disorders: abnormal heal-
`ing, dehydration, hypoglycemia, hypomagnesemia.
`hypokalemia; Musculoskeletal System:arthritis, bone
`Pain, myasthenia, osteonecrosis, synovitis; Nervous
`System: abnormal gait, amnesia, Bell’s Palsy, clumsi-
`ness, depersonalization, drug dependence,facial paral-
`ysis,
`hyperesthesia,
`increased
`libido,
`neurosis.
`Psychosis; Respiratory System: emphysema, hemopt-
`ysis, hiccup, hyperventilation,
`laryngitis, pharyngeal
`edema, pneumonia; Skin and Appendages:basalcell
`Carcinoma,blisters, cold clammy skin, contact dermati-
`tis, erythema, furunculosis, genital pruritus, nevus, seb-
`orrhea, skin ulcer, skin discoloration; Special Senses:
`abnormal vision, conjunctivitis, earache, eye pain,
`labyrinthitis, vitreous
`floaters: Urogenital: breast
`fibroadenosis, breast mass, dysuria, epididymitis, fibro-
`Cystic change of the breast, fibroids, gynecomastia.
`hematuria, kidney calculus, kidney pain, leukorrhea,
`menopause, nocturia, pelvic inflammatory disease,
`Penis disorder, Peyronies Disease, polyuria, post-
`menopausal
`hemorrhage,
`prostatic
`disorder,
`Pyelonephritis, testis disorder, urethral pain, urinary
`urgency, urinary retention, urinary incontinence, vaginal
`hemorrhage.
`Serum Neutralizing Activity
`Throughout the placebo-controlled multiple sclerosis
`Study, serum samples from patients were monitored for
`the developmentofInterferon beta-1a neutralizing activ-
`ity. During the study, 24% of AVONEX™-treated
`Patients were found to have serum neutralizing activity
`at one or more time points tested. Fifteen percent of
`AVONEX™-treated patients tested positive for neutraliz-
`
`ing activity at a level at which no placebo patient tested
`Positive. The significance of the appearance of serum
`neutralizing activity is unknown.
`DRUG ABUSE AND DEPENDENCE
`There is no evidence that abuse or dependence
`occurs with AVONEX™(Interferon beta-1a) therapy.
`However, the risk of dependence has not been system-
`atically evaluated.
`
`.
`
`DOSAGE AND ADMINISTRATION
`The recommended dosage of AVONEX™ (Interferon
`beta-1a) for the treatmentof relapsing forms of multiple
`sclerosis is 30 mcg injected intramuscularly once a
`week(see Figure 3).
`AVONEX™js intended for use under the guidance and
`supervision of a physician. Patients mayself-inject only
`if their physician determines thatit is appropriate and
`with medical follow-up, as necessary, after proper train-
`ing in intramuscularinjection technique.
`
`Petitioner TWi Pharms., Inc.
`EX1021, Page 3 of 4
`
`Petitioner TWi Pharms., Inc.
`EX1021, Page 3 of 4
`
`

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`
`Reconstitution with dituent vial
`1. Remove the cap from the vial of
`AVONEX™andvial of diluent, and
`Clean the rubber stopper of each
`vial with an alcohol wipe.
`
`2. Removethe small protective cover
`from the syringe with a counter-
`clockwise turn.
`
`‘~
`
`
`
`
`5. Pull back the syringe plunger
`
`4. Remove the MICRO PIN"
`Saveforlater use.
`
`
`cover.
`
`a
`
`
`
`to the 1.1 cc mark.
`
`
`«1.1¢c
`
`6. Push the MICRO PIN* down
`through the center of the
`rubberstopperof the
`
`diluentvial.
`
`
`
`
`
`,
`HOW SUPPLIED
`AVONEX™(interferon beta-1a) is supplied as a lyo-
`Philized powder in a single-use vial containing 33 mcg
`(6.6 million |U) of Interferon beta-1a, 16.5 mg Albumin
`Human, USP, 6.4 mg Sodium Chloride, USP. 6.3 mg
`Dibasic Sodium Phosphate, USP, and 1.3 mg Mono-
`basic Sodium Phosphate, USP, andis preservative-free.
`Diluent is supplied in a single-use vial (Sterile Water
`for
`injection, USP, preservative-free). Reconstitute
`AVONEX™with 1.1 mL(cc) of diluent and swirl gently to
`dissolve (approximate pH 7.3). Withdraw 1.0 mL (cc) for
`administration.
`/
`AVONEX™is available in the following package con-
`figuration (NDC-59627-001-03): Package (Admini-
`Stration Pack) containing 4 Administration Dose Packs
`(each containing one vial of AVONEX™, one 10 mL
`(10 cc) diluent vial, two alcohol wipes, one 3 cc syringe,
`One Micro Pin®* vial access pin, one needle and one
`adhesive bandage).
`Stability and Storage
`Vials of AVONEX™(Interferon beta-1a) must be stored
`ina 2-8°C (36-46°F) refrigerator. Should refrigeration be
`unavailable, AVONEX™can be stored at 25°C (77°F) for
`@ period of up to 30 days. DO NOT EXPOSE TO HIGH
`TEMPERATURES. DO NOT FREEZE. Do not use
`beyond the expiration date stamped on the vial.
`Following reconstitution, it is recommended the product
`be used as soon as possible within 6 hours stored at
`2-8°C (36- 46°F). DO NOT FREEZE.
`REFERENCES
`1. Jacobs LD, et af, Ann Neurol 1996; 39: 285-294.
`2. Kurtzke JF. Neurol 1983; 33: 1444-1452.
`
`IC
`
`AVONEX™(INTERFERON BETA-1a)
`Manufactured by:
`BIOGEN, INC.
`14 Cambridge Center
`Cambridge, MA 02142 USA
`©1996 Biogen, Inc. All rights reserved.
`1-800-456-2255
`
`* AVONEX™(Interferon beta-1a) must be kept coic
`Be sure to storeit in a refrigerator before and atter
`reconstitution. Do not freeze.
`If refrigeration is not
`available, AVONEX™ can be stored before reconsti-
`tution at 25°C (77°F) for up to 30 days. Whenstoring
`outside of a refrigerator, do not allow AVONEX™to
`be exposed to high temperatures as may occur in a
`glove compartment or on a windowsill.
`¢ For treatment of multiple sclerosis, AVONEX™
`mustbe injected into the muscte (intramuscular injec-
`tion).
`
`U.S. Patent Pending
`|63000-1 (5/96)
`
`Caution: Federal law prohibits dispensing without pre-
`scription.
`
`“Micro Pin® is the trademark of B. Braun MedicalInc.
`Patient Information
`AVONEX™(Interferon beta-1a) is intended for use
`under the guidance and supervision of a physician. If
`your physician recommendsself-injection, you shouid
`be instructed in the preparation of AVONEX™ for
`administration and in the technique of self-injection. Do
`not attempt seif-administration until you are sure that
`you understand the requirements for preparing the
`product and giving aninjection to yourself.
`AVONEX™mustbe used as prescribed by your physi-
`cian. However,if you miss a dose, ta