-----------------------------------------CONTRAINDICATIONS ---------------------------------------
`
`
` History of hypersensitivity to natural or recombinant interferon beta, albumin or any
`
`other component of the formulation (4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`---------------------------------WARNINGS AND PRECAUTIONS----------------------------------
`Depression, Suicide, and Psychotic Disorders: advise patients to immediately
`
`
`
`report any symptoms of depression, suicidal ideation, and/or psychosis; consider
`discontinuation of AVONEX if depression occurs (5.1)
`Hepatic Injury: monitor liver function tests; monitor patients for signs and
`symptoms of hepatic injury; consider discontinuation of AVONEX if hepatic injury
`occurs (5.2, 5.8)
`Anaphylaxis and Other Allergic-Reactions: Discontinue if occurs (5.3)
`Congestive Heart Failure: monitor patients with pre-existing significant cardiac
`disease for worsening of cardiac symptoms (5.4)
`
`Decreased Peripheral Blood Counts: monitor complete blood count (5.5, 5.8)
`Autoimmune Disorders: consider discontinuation of AVONEX if new autoimmune
`disorder occurs (5.7, 5.8)
`
`
`-----------------------------------------ADVERSE REACTIONS ----------------------------------------
`The most common adverse reactions (at least 5% more frequent on AVONEX than on
`placebo) were flu-like symptoms including chills, fever, myalgia, and asthenia. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Biogen Idec at 1-800-456-
`
`2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`-----------------------------------USE IN SPECIFIC POPULATIONS---------------------- -----------
`Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
`
`
`
`Revised: 2/2012
`
`
`
`
`
`11
`
`
`
`12
`
`13
`
`
`
`DESCRIPTION
`11.1 AVONEX Lyophilized Powder Vial
`
`AVONEX Single-Use Prefilled Syringe
`11.2
`11.3 AVONEX PEN Single-Use Prefilled Autoinjector
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
` Pharmacodynamics
`12.2
`
`
`12.3
` Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`CLINICAL STUDIES
`HOW SUPPLIED/STORAGE AND HANDLING
`16.1 AVONEX Lyophilized Powder Vial
`16.2
`AVONEX Single-Use Prefilled Syringe
`16.3 AVONEX PEN Single-Use Prefilled Autoinjector
`PATIENT COUNSELING INFORMATION
`17.1 Instruction on Self-injection Technique and Procedures
`17.2 Pregnancy
`
`17.3 Depression
`
`17.4 Liver Disease
`
`
`17.5 Allergic Reactions and Anaphylaxis
`
`
`17.6 Congestive Heart Failure
`
`17.7 Seizures
`
`17.8 Flu-like Symptoms
`
`
`
`
`*Sections or subsections omitted from the Full Prescribing Information are not listed.
`
`
`14
`
`16
`
`
`
`17
`
`
`
`
`
`
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use AVONEX safely
`
`
` and effectively. See full prescribing information for AVONEX.
`
` AVONEX (interferon beta-1a) injection, for intramuscular injection
`Initial U.S. Approval: 1996
`
`
`
`
`--------------------------------------INDICATIONS AND USAGE -------------------------------------
`
` AVONEX is an interferon beta 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. (1)
`
`
`---------------------------------DOSAGE AND ADMINISTRATION ---------------------------------
`For intramuscular use only (2.1)
`
`
`
`
`Recommended dose: 30 micrograms once a week (2.1)
`
`
`
`AVONEX may be titrated, starting with 7.5 micrograms for first week, to reduce
`
`
`
`
`flu-like symptoms (2.1)
`Increase dose by 7.5 micrograms each week for next 3 weeks until
`
`recommended dose of 30 micrograms (2.1)
`
`See patient instructions for use for complete administration instructions (2.2)
`
`Perform first injection under the supervision of an appropriately qualified health
`
`care professional (2.2)
`Analgesics and/or antipyretics on treatment days may help ameliorate flu-like
`
`symptoms (2.3)
`
`
`
`
`
`
`
`
`
`
`
`
`---------------------------------DOSAGE FORMS AND STRENGTH --------------------------------
` For Injection: 30 micrograms lyophilized powder in a single-use vial (3)
`
` Injection: 30 micrograms per 0.5 mL solution in single-use prefilled syringe (3)
`
` Injection: Single-use prefilled autoinjector containing 0.5 mL solution with 30 mcg
`
`(3)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`2.1 Dosing Information
`2.2 Important Administration Instructions (All Dosage Forms)
`2.3 Premedication for Flu-like Symptoms
` DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1 Depression, Suicide, and Psychotic Disorders
`5.2 Hepatic Injury
`5.3 Anaphylaxis and Other Allergic-Reactions
`5.4 Congestive Heart Failure
`5.5 Decreased Peripheral Blood Counts
`5.6 Seizures
`5.7 Autoimmune Disorders
`5.8 Laboratory Tests
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
` USE IN SPECIFIC POPULATIONS
` 8.1 Pregnancy
` 8.3 Nursing Mothers
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`
`
`
`
`1
`2
`
`
`3
`4
`
`5
`
`
`
`
`6
`
`
`8
`
`
`
`
`
`
`
`
`Reference ID: 3093577
`
`Page 1 of 19
`
`Coalition Exhibit 1064
`Coalition v. Biogen
`IPR2015-01993
`
`
`
`

`

`
`
`
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`
`Dosing Information
`
`AVONEX® (interferon beta-1a) Intramuscular Injection
`FULL PRESCRIBING INFORMATION
`
`1
`
`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.
`
`2
`
`
`2.1
`
`AVONEX is administered intramuscularly.
`
`The recommended dose is 30 micrograms once a week. To reduce the incidence and severity
`of flu-like symptoms that may occur when initiating AVONEX therapy at a dose of
`
`30 micrograms, AVONEX may be started at a dose of 7.5 micrograms and the dose may be
`
`increased by 7.5 micrograms each week for the next three weeks until the recommended dose
`of 30 micrograms is achieved (see Table 1). An AVOSTARTGRIP™ kit containing 3 titration
`devices can be used for titration and is to be used only with AVONEX Prefilled Syringes.
`
`
`
`
`
` Table 1: Schedule for Dose Titration
`
`AVONEX Dose1
`Recommended Dose
`
`
`
`1/4 dose
`7.5 micrograms
`Week 1
`1/2 dose
`15 micrograms
`Week 2
`3/4 dose
`22.5 micrograms
`Week 3
`full dose
`30 micrograms
`Week 4+
`1 Dosed once a week, intramuscularly
`
`Important Administration Instructions (All Dosage Forms)
`
`
`2.2
`
`All AVONEX dosage forms are single-use (injection of reconstituted solution, prefilled syringe,
`and prefilled autoinjector). See Patient’s Instructions for Use for complete administration
`instructions.
`
`
`The first AVONEX injection should be performed under the supervision of an appropriately
`qualified health care professional. If patients or caregivers are to administer AVONEX, train
`them in the proper intramuscular injection technique and assess their ability to inject
`intramuscularly to ensure the proper administration of AVONEX.
`
`Advise patients and caregivers to:
`rotate sites for intramuscular injections with each injection to minimize the likelihood of
`
`
`injection site reactions
`
` NOT inject into an area of the body where the skin is irritated, reddened, bruised,
`
`
`
`
`Reference ID: 3093577
`
`2
`
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`Page 2 of 19
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`

`

`
`
`
`
`infected or scarred in any way
`
` Check the injection site after 2 hours for redness, swelling, or tenderness
`
` Contact their doctor or nurse if they have a skin reaction and it does not clear up in a few
`days
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`
`A 25 gauge, 1” needle for intramuscular injection with AVONEX prefilled syringe or injection of
`reconstituted solution may be substituted for the 23 gauge, 1 ¼” needle by the healthcare
`provider, if deemed appropriate. A 25 gauge, 5/8” needle specific to the prefilled autoinjector is
`supplied with the AVONEX PEN Administration Dose Pack. DO NOT use any other needle with
`
`the autoinjector.
`
`Use safe disposal procedures for needles and syringes. Do not re-use needles, syringes,
`
`prefilled syringes, or autoinjectors. Following the administration of each titrated dose, discard
`any remaining product.
`
`2.3 Premedication for Flu-like Symptoms
`
`Concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like
`
`symptoms associated with AVONEX use.
`
`
`3
`
`
` For injection: 30 micrograms lyophilized powder in a single-use vial
`
` Injection: 30 micrograms per 0.5 mL solution in a single-use prefilled syringe
`
`
` Injection: 30 micrograms per 0.5 mL solution in a single-use prefilled autoinjector
`
`4
`
`
`
`AVONEX is contraindicated in patients with a history of hypersensitivity to natural or
`recombinant interferon beta, or any other component of the formulation [see Warnings and
`Precautions (5.3)].
`
`
`The lyophilized vial formulation of AVONEX is contraindicated in patients with a history of
`hypersensitivity to albumin (human).
`
`5
`
`
`5.1
`
`
`Patients treated with AVONEX and their caregivers should be advised to report immediately any
`symptoms of depression, suicidal ideation, and/or psychosis to their prescribing physicians. If a
`
`
`patient develops depression or other severe psychiatric symptoms, cessation of AVONEX
`therapy should be considered.
`
`Depression and suicide have been reported to occur with increased frequency in patients
`receiving AVONEX. In Study 1, the incidence of depression was similar in placebo-treated and
`in AVONEX-treated patients, but suicidal tendency was seen more frequently in AVONEX-
`treated patients (4% in AVONEX group vs. 1% in placebo group). In Study 2, there was a
`greater incidence of depression in AVONEX-treated patients than in placebo-treated patients
`(20% in AVONEX group vs. 13% in placebo group) [see Clinical Studies (14)].
`
`WARNINGS AND PRECAUTIONS
`
`Depression, Suicide, and Psychotic Disorders
`
`
`
`Reference ID: 3093577
`
`3
`
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`Page 3 of 19
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`

`
`
`
`
`
`Hepatic Injury
`
`Anaphylaxis and Other Allergic-Reactions
`
`
`Additionally, there have been post-marketing reports of depression, suicidal ideation, and/or
`development of new or worsening of other pre-existing psychiatric disorders, including
`psychosis. For some of these patients, symptoms of depression improved upon cessation of
`AVONEX.
`
`5.2
`
`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 starting AVONEX, or before starting
`hepatotoxic drugs. Patients should be monitored for signs of hepatic injury [see Warnings and
`
`Precautions (5.8)].
`
`5.3
`
`
`Anaphylaxis has been reported as a rare complication of AVONEX use. Other allergic reactions
`have included dyspnea, orolingual edema, skin rash and urticaria. Discontinue AVONEX if
`anaphylaxis or other allergic reactions occur.
`
`5.4
`
`Patients with pre-existing congestive heart failure should be monitored for worsening of their
`cardiac condition during initiation of and continued treatment with AVONEX. While beta
`interferons do not have any known direct cardiac toxicity, during the post-marketing period
`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 etiologies being established. In some cases, these events have been temporally related to
`the administration of AVONEX. In some of these instances recurrence upon rechallenge was
`observed.
`
`
`5.5
`
`Decreased peripheral blood counts in all cell lines, including rare pancytopenia and
`thrombocytopenia, have been reported from postmarketing experience in AVONEX-treated
`patients [see Adverse Reactions (6.2)]. In some cases, platelet counts were below
`10,000/microliter. Some cases recurred with rechallenge [see Adverse Reactions (6.2)].
`Patients should be monitored for symptoms or signs of decreased blood counts.
`
`5.6
`
`Seizures have been temporally associated with the use of beta interferons in clinical trials and
`postmarketing safety surveillance. In the two placebo-controlled studies in multiple sclerosis
`(Studies 1 and 2), 4 patients receiving AVONEX experienced seizures, while no seizures occurred
`in the placebo group [see Clinical Studies (14)]. Three of these 4 patients had no prior history of
`
`seizure [see Adverse Reactions (6.1)]. It is not known whether these events were related to the
`effects of multiple sclerosis alone, to AVONEX, or to a combination of both.
`
`Congestive Heart Failure
`
`Decreased Peripheral Blood Counts
`
`Seizures
`
`
`
`Reference ID: 3093577
`
`4
`
`
`Page 4 of 19
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`

`
`
`
`
`Autoimmune Disorders
`
`
`Laboratory Tests
`
`
`ADVERSE REACTIONS
`
`
`5.7
`
`Post-marketing reports of autoimmune disorders of multiple target organs in AVONEX-treated
`patients included idiopathic thrombocytopenia, hyper- and hypothyroidism, and rare cases of
`autoimmune hepatitis. If AVONEX-treated patients develop a new autoimmune disorder,
`consider stopping the therapy.
`
`5.8
`
`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 and Precautions (5.2, 5.5, 5.7)]. 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.
`
`6
`
`The following serious adverse reactions are discussed in more detail in other sections of
`labeling:
` Depression, Suicide, and Psychotic Disorders [see Warnings and Precautions (5.1)]
`
` Hepatic Injury [see Warnings and Precautions (5.2)]
`
` Anaphylaxis and Other Allergic-Reactions [see Warnings and Precautions (5.3)]
`
`
` Congestive Heart Failure [see Warnings and Precautions (5.4)]
`
` Decreased Peripheral Blood Counts [see Warnings and Precautions (5.5)]
`
`
` Seizures [see Warnings and Precautions (5.6)]
` Autoimmune Disorders [see Warnings and Precautions (5.7)]
` Laboratory Tests [see Warnings and Precautions (5.8)]
`
`
`Clinical Trials Experience
`
`
`6.1
`
`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.
`
`Among 351 patients with relapsing forms of MS treated with AVONEX 30 micrograms (including
`319 patients treated for 6 months and 288 patients treated for greater than one year) the most
`commonly reported adverse reactions (at least 5% more frequent on AVONEX than on placebo)
`were flu-like symptoms. Symptoms can include chills, fever, myalgia and asthenia occurring
`within hours to days following an injection. Most people who take AVONEX have flu-like
`symptoms early during the course of therapy. Usually, these symptoms last for a day after the
`injection. For many people, these symptoms lessen or go away over time. The most frequently
`
`reported adverse reactions resulting in clinical intervention (for example, discontinuation of
`AVONEX or the need for concomitant medication to treat an adverse reaction symptom) were
`flu-like symptoms and depression.
`
`
`
`
`Reference ID: 3093577
`
`5
`
`
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`

`

`
`
`
`
`Table 2 enumerates adverse reactions that occurred with AVONEX-treated patients at an
`incidence of at least 2% more than that observed in the placebo-treated patients in the pooled
`placebo-controlled studies in patients with relapsing forms of MS [see Clinical Studies (14)].
`
`
`Table 2
`
`Adverse Reactions in the Placebo-Controlled Studies
`
`
`
`
`Adverse Reaction
`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
`
`
`
`
`
`Placebo
`AVONEX
`
`(N = 333)
` (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%
`
`
`
`
`
`58%
`49%
`23%
`24%
`20%
`19%
`8%
`8%
`7%
`6%
`5%
`3%
`3%
`
`18%
`14%
`
`14%
`14%
`8%
`
`23%
`
`29%
`9%
`
`
`
`17%
`3%
`
`4%
`
`
`
`4%
`
`6%
`4%
`
`
`
`Reference ID: 3093577
`
`6
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`

`
`
`
`
` Migraine
`
` Vasodilation
`
`
`
`
`
` 3%
` 0%
`
`5%
`
`2%
`
`
`Postmarketing Experience
`
`USE IN SPECIFIC POPULATIONS
`
`
`Pregnancy
`
`
` Immunogenicity
`
` Anaphylaxis and other allergic reactions have occurred in AVONEX-treated patients [see
`
`Warnings and Precautions (5.3)]. As with all therapeutic proteins, there is a potential for
`immunogenicity. In studies assessing immunogenicity in multiple sclerosis patients
`administered AVONEX for at least 1 year, 5% (21 of 390 patients) showed the presence of
`neutralizing antibodies at one or more times.
`These data reflect the percentage of patients whose test results were considered positive for
`
` antibodies to AVONEX using a two-tiered assay (ELISA binding assay followed by an antiviral
`cytopathic effect assay), and are highly dependent on the sensitivity and specificity of the assay.
`Additionally, the observed incidence of neutralizing activity in an assay may be influenced by
`several factors including sample handling, timing of sample collection, concomitant medications,
`and underlying disease. For these reasons, comparison of the incidence of antibodies to
`AVONEX with the incidence of antibodies to other products may be misleading.
`
`6.2
`
`The following additional adverse reactions have been identified during post-approval use of
`AVONEX. Because these reactions are reported voluntarily from a population of uncertain size,
`it is not always possible to reliably estimate their frequency or establish a causal relationship to
`drug exposure.
`
`
` Menorrhagia and metrorrhagia
`
` Rash (including vesicular rash)
`
` Rare cases of injection site abscess or cellulitis requiring surgical intervention
`
`8
`
`
`8.1
`
`
`Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women.
`AVONEX should be used during pregnancy only if the potential benefit justifies the potential risk
`
`to the fetus.
`
`In pregnant monkeys given interferon beta at 100 times the recommended weekly human dose
`(based upon a body surface area [mg/m2] 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 mg/m2).
`
`8.3
`
`It is not known whether AVONEX is excreted in human milk.
`
`8.4
`
`Safety and effectiveness in pediatric patients have not been established.
`
`Nursing Mothers
`
`
`
`Pediatric Use
`
`
`
`Reference ID: 3093577
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`Geriatric Use
`
`DESCRIPTION
`
`
`8.5
`
`Clinical studies of AVONEX did not include sufficient numbers of patients aged 65 and over to
`determine whether they respond differently than younger patients.
`
`11
`
`AVONEX is a 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 AVONEX is identical to that of natural human interferon beta.
`
`
`Using the World Health Organization (WHO) International Standard for Interferon, AVONEX has
`
`a specific activity of approximately 200 million international units of antiviral activity per
`mg of interferon beta-1a determined specifically by an in vitro cytopathic effect bioassay
`using lung carcinoma cells (A549) and Encephalomyocarditis virus (ECM). AVONEX
`
`30 micrograms contains approximately 6 million international units 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.
`
`
`
`11.1 AVONEX Lyophilized Powder Vial
`
`A vial of AVONEX is 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 micrograms 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.
`
`11.2 AVONEX Single-Use Prefilled Syringe
`
`
`
`A prefilled syringe of AVONEX is a sterile liquid for intramuscular injection. Each 0.5 mL
`
`(30 microgram dose) of AVONEX in a prefilled glass syringe contains 30 micrograms of
`interferon beta-1a, 0.79 mg Sodium Acetate Trihydrate, USP; 0.25 mg Glacial Acetic Acid, 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.
`
`11.3 AVONEX PEN Single-Use Prefilled Autoinjector
`
`AVONEX PEN is a sterile liquid for intramuscular injection in a prefilled glass syringe
`surrounded by an autoinjector. Each 0.5 mL (30 microgram dose) in the AVONEX PEN
`contains 30 micrograms of interferon beta-1a, 0.79 mg Sodium Acetate Trihydrate, USP;
`0.25 mg Glacial Acetic Acid, 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.
`
`12
`
`12.1 Mechanism of Action
`
`
`CLINICAL PHARMACOLOGY
`
`
`
`Reference ID: 3093577
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`
`The mechanism of action by which AVONEX exerts its effects in patients with multiple sclerosis
`is unknown.
`
`
`12.2 Pharmacodynamics
`
`Interferons (IFNs) are a family of naturally occurring proteins, produced by eukaryotic cells in
`
`response to viral infection and other biologic agents. Three major types of interferons have been
`defined: type I (IFN-alpha, beta, epsilon, kappa and omega), type II (IFN–gamma) and type III
`(IFN-lambda). Interferon-beta is a member of the type I subset of interferons. The type I
`interferons have considerably overlapping but also distinct biologic activities. The bioactivities of
`all IFNs, including IFN-beta, are induced via their binding to specific receptors on the
`membranes of human cells. Differences in the bioactivites induced by the three major subtypes
`of IFNs likely reflect differences in the signal transduction pathways induced by signaling
`through their cognate receptors.
`
`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', 5'­
`oligoadenylate synthetase, β2-microglobulin, and neopterin. These products have been
`measured in the serum and cellular fractions of blood collected from patients treated with
`
`AVONEX.
`
`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 maximally were increased by 48 hours after intramuscular injection of
`AVONEX and remained elevated for 1 week. However, no relationship has been established
`between absolute levels of IL-10 and clinical outcome in multiple sclerosis.
`
`12.3 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 micrograms through 75 micrograms have been investigated. Serum levels of AVONEX as
`
`measured by antiviral activity are slightly above detectable limits following a 30 microgram
`intramuscular dose, and increase with higher doses.
`
`
`After an intramuscular 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 intramuscular administration due to prolonged absorption from
`
`the intramuscular site. Systemic exposure, as determined by AUC and Cmax values, is greater
`
`following intramuscular 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 β2-microglobulin) are induced by AVONEX
`
`
`following parenteral doses of 15 micrograms through 75 micrograms 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
`
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`CLINICAL STUDIES
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`NONCLINICAL TOXICOLOGY
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`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.
`
`13
`
`
`
`13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`Carcinogenesis: The carcinogenic potential of AVONEX has not been tested in animals.
`
`Mutagenesis: Interferon beta was not mutagenic when tested in an in vitro bacterial reverse
`mutation (Ames) test or in an in vitro cytogenetic assay in human lymphocytes.
`
`Impairment of Fertility: In monkeys administered interferonbeta by subcutaneous injection (8 to
`15 doses of 1.25 mcg/kg or 50 mcg/kg) over the course of one menstrual cycle, menstrual
`irregularities, anovulation, and decreased serum progesterone levels were observed at the
`higher dose. These effects were reversible after discontinuation of drug. The no-effect dose
`(1.25 mcg/kg) is approximately 2 times the recommended weekly dose in humans (30 mcg) on
`a mg/m2 basis.
`
`14
`
`The clinical effects of AVONEX in patients with relapsing forms of multiple sclerosis (MS) were
`studied in two randomized, multicenter, double-blind, placebo-controlled studies in patients with
`MS (Studies 1 and 2). Safety and efficacy of treatment with AVONEX beyond 3 years is not
`known.
`
`
`In Study 1, 301 patients received either 30 micrograms of AVONEX (n=158) or placebo (n=143)
`by intramuscular injection once weekly. Patients 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. The EDSS is a scale that quantifies disability in patients with MS and ranges from 0
`(normal neurologic exam) to 10 (death due to MS). Patients with chronic progressive multiple
`sclerosis were excluded from this study.
`
`Disability
`
`The primary outcome assessment was time to progression in disability, measured as an
`increase in the EDSS score of at least 1 point that was sustained for at least 6 months. An
`increase in EDSS score reflects accumulation of disability. This endpoint was used to help
`
`distinguish permanent increase in disability from a transient increase due to an exacerbation.
`
`As shown in Figure 1, the time to onset of sustained progression in disability was significantly
`longer in AVONEX-treated patients than in placebo-treated patients in Study 1 (p = 0.02). The
`percentage of patients progressing by the end of 2 years was 35% for placebo-treated patients
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`and 22% for AVONEX-treated patients. This represents a 37% relative reduction in the risk of
`accumulating disability in the AVONEX-treated group compared to the placebo-treated group.
`
`
`
`Figure 1: Time to Onset of Sustained Disability Progression in
`Figure 1
`Patients with MS in Study 11
`
`Onset of Sustained Disability Progression by Time on Stu
`
` (Kaplan-Meier Methodology)
`
`
`AVONEX
`
`Placebo
`
`P = 0.02
`
`
`( 35% )
`
`( 22% )
`
`
`
`50
`
`
`40
`
`
`30
`
`
`20
`
`
`10
`10
`
`0
`
`
`Percentage of Patients Progressing
`
` 0
`
`
`26
`
`
`52
`Weeks
`Weeks
`
`78
`
`
`104
`
`1 Kaplan-Meier Methodology; Disability progression was defined as at least a 1 point increase in EDSS score
`
`
`
`
`
`sustained for at least 6 months.
`
`
`
`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 the AVONEX and
`
`
`
`placebo groups in confirmed change for patients with at least 2 scheduled visits (p = 0.006).
`
`
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`Figure 2
`Figure 2: Confirmed Chang
`S from Study Entry to End ofe in EDS
`
`Confirmed EDSS Change from Study Entry to End of Study
`Study 1
`
`
`
`
` AVONEX® (N 150)=
`
`
`
`AVONE (N=150 X )
`
`Placebo (N 136)=
`
`
`Placebo (N=1 36)
`
`P=0.006
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Percentage of Patients
`
`
`
`0
`
`0.5
`
`1.0
`
`1.5
`-0.5
`# -1.0
`≤ -1.0
`Better
`Worse
`Confirmed Change from Baseline EDSS
`Confirmed Change from Baseline EDSS
`
` $ 2.0
`≥ 2.0
`
`
`
`
`
`
`Exacerbations
`
`The rate and frequency of MS exacerbations were 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 3).
`
`MRI Results
`
`Gadolinium (Gd)-enhanced and T2-weighted magnetic resonance imaging (MRI) scans of the
`brain were obtained in most patients at baseline and at the end of 1 and 2 years of treatment.
`Secondary outcomes included Gd-enhanced lesion number and volume, and T2-weighted
`lesion volume. Gd-enhancing lesions