`•
`•
`•
`
`Anaphylaxis and other allergic reactions. (5.4)
`Flu-Like Symptom Complex. (5.5)
`Leukopenia: monitor CBC. (5.6, 5.8)
`Liver enzymes abnormalities: monitor liver function tests. (5.7,
`5.8)
`• Monitor thyroid function tests every 6 months in patients with
`history of thyroid dysfunction. (5.8)
`
`-------------------ADVERSE REACTIONS----------------------
`In controlled studies with interferon beta-1b, the most common adverse
`reactions (at least 2% more than placebo) were: Lymphopenia, neutropenia,
`leukopenia, lymphadenopathy, headache, insomnia, incoordination,
`hypertension, dyspnea, abdominal pain, increased liver enzymes, rash, skin
`disorder, hypertonia, myalgia, urinary urgency, metrorrhagia, impotence,
`injection site reaction, asthenia, flu-like symptom complex, pain, fever, chills,
`peripheral edema, chest pain, malaise, and injection site necrosis (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-
`1088 or www.fda.gov/medwatch
`
`-------------------DRUG INTERACTIONS----------------------
`No formal drug interaction studies have been conducted. (7)
`
`-------------USE IN SPECIFIC POPULATIONS-------------
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`Nursing Mothers: use EXTAVIA with caution. (8.3)
`Pediatric Use: Safety and efficacy not established in patients under
`18 years of age. (8.3)
`Geriatric Use: Safety and efficacy not established in patients age
`65 years or older. (8.4)
`
`•
`•
`•
`
`•
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`
`
`
`
`
`
`
` Revised: 08/2009
`
`
`
` *
`
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Depression
`17.2 Injection Site Reactions, Including Necrosis
`17.3 Allergic Reactions and Anaphylaxis
`17.4 Flu-like Symptoms
`17.5 Pregnancy
`17.6 Instruction on Self-injection Technique and Procedures
`Medication Guide
`
` Sections or subsections omitted from the full prescribing information are not
`listed
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use Extavia
`safely and effectively. See full prescribing information for Extavia.
`
`Extavia (Interferon beta-1b) Kit for subcutaneous use
`Initial U.S. Approval: 1993
`
`--------------INDICATIONS AND USAGE---------------------
`Extavia is an interferon beta indicated for the treatment of relapsing forms of
`multiple sclerosis to reduce 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 subcutaneous use only. (2)
`The recommended dose is 0.25 mg injected subcutaneously every
`other day. Generally, start at 0.0625 mg (0.25 mL) subcutaneously
`every other day, and increase over a six week period to 0.25 mg
`(1 mL) every other day. (2)
`Instruct patients in the use of aseptic technique when administering
`Extavia. (17.6)
`
`•
`•
`
`•
`
`-----------DOSAGE FORMS AND STRENGTHS------------
`Lyophilized powder containing 0.3 mg of Interferon beta-1b, 15 mg Albumin
`(Human), USP, and 15 mg Mannitol, USP. (3).
`
`---------------------CONTRAINDICATIONS-------------------
`History of hypersensitivity to natural or recombinant interferon beta, Albumin
`(Human), USP, or any other component of the formulation. (4)
`
`---------------WARNINGS AND PRECAUTIONS------------
`Depression and suicide: advise patients to immediately report any
`symptom of depression and/or suicidal ideation; consider
`discontinuation of Extavia if depression occurs. (5.1)
`Injection site necrosis: do not administer Extavia into affected area
`until it is fully healed; if multiple lesions occur, therapy should be
`discontinued until healing occurs. (5.2)
`Injection site reactions. (5.3)
`
`•
`
`•
`
`•
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Depression and Suicide
`5.2 Injection Site Necrosis
`5.3 Injection Site Reactions
`5.4 Anaphylaxis
`5.5 Flu-Like Symptom Complex
`5.6 Leukopenia
`5.7 Hepatic enzymes elevations
`5.8 Laboratory Tests
`5.9 Albumin (Human), USP
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`6.2 Postmarketing Experience
`6.3 Immunogenicity
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`
`Page 1 of 25
`
`YEDA EXHIBIT NO. 2099
`MYLAN PHARM. v YEDA
`IPR2015-00643
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`EXTAVIA (Interferon beta-1b) is indicated for the treatment of relapsing forms of multiple sclerosis to reduce
`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.
`
`
`
`Volume
`
`2 DOSAGE AND ADMINISTRATION
`The recommended dose of EXTAVIA is 0.25 mg injected subcutaneously every other day.
`Generally, patients should be started at 0.0625 mg (0.25 mL) subcutaneously every other day, and increased
`over a six week period to 0.25 mg (1 mL) every other day (see Table 1).
`Table 1. Schedule for Dose Titration
`Recommended
`EXTAVIA
`Titration
`Dose
`0.25 mL
`25%
`0.0625 mg
`Weeks 1-2
`0.5 mL
`50%
`0.125 mg
`Weeks 3-4
`0.75 mL
`75%
`0.1875 mg
`Weeks 5-6
`1 mL
`100%
`0.25 mg
`Week 7+
`To reconstitute lyophilized EXTAVIA for injection, attach the prefilled syringe containing the diluent (Sodium
`Chloride, 0.54% Solution) to the EXTAVIA vial using the vial adapter. Slowly inject 1.2 mL of diluent into the
`EXTAVIA vial. Gently swirl the vial to dissolve the drug completely; do not shake. Foaming may occur during
`reconstitution or if the vial is swirled or shaken too vigorously. If foaming occurs, allow the vial to sit
`undisturbed until the foam settles. Visually inspect the reconstituted product before use; discard the product if it
`contains particulate matter or is discolored. Keeping the syringe and vial adapter in place, turn the assembly
`over so that the vial is on top. Withdraw the appropriate dose of EXTAVIA solution. Remove the vial from the
`vial adapter before injecting EXTAVIA. One mL of reconstituted EXTAVIA solution contains 0.25 mg of
`Interferon beta-1b/mL.
`EXTAVIA is intended for use under the guidance and supervision of a physician. It is recommended that
`physicians or qualified medical personnel train patients in the proper technique for self-administering
`subcutaneous injections. Patients should be advised to rotate sites for subcutaneous injections (see Patient
`Counseling Information 17.6). Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like
`symptoms on treatment days. EXTAVIA should be visually inspected for particulate matter and discoloration
`prior to administration.
`
`3 DOSAGE FORMS AND STRENGTHS
`EXTAVIA is supplied as a lyophilized powder containing 0.3 mg of Interferon beta-1b, 15 mg Albumin
`(Human), USP, and 15 mg Mannitol, USP. Drug is packaged in a clear glass, single-use vial (3 mL capacity). A
`pre-filled single-use syringe containing 1.2 mL of diluent (Sodium Chloride, 0.54% solution), two alcohol prep
`pads, and one vial adapter with attached 27 gauge needle are included for each vial of drug. EXTAVIA and the
`diluent are for single-use only. Unused portions should be discarded. Store at room temperature.
`
`Page 2 of 25
`
`YEDA EXHIBIT NO. 2099
`MYLAN PHARM. v YEDA
`IPR2015-00643
`
`
`
` 4
`
` CONTRAINDICATIONS
`EXTAVIA is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon
`beta, Albumin (Human), USP, or any other component of the formulation.
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Depression and Suicide
`EXTAVIA (Interferon beta-1b) should be used with caution in patients with depression, a condition that is
`common in people with multiple sclerosis. Depression and suicide have been reported to occur with increased
`frequency in patients receiving interferon compounds, including Interferon beta-1b. Patients treated with
`EXTAVIA 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 EXTAVIA therapy should be
`considered.
`In the four randomized controlled studies there were three suicides and eight suicide attempts among the 1532
`patients in the Interferon beta-1b treated groups compared to one suicide and four suicide attempts among the
`965 patients in the placebo groups.
`5.2 Injection Site Necrosis
`Injection site necrosis (ISN) has been reported in 4% of patients in controlled clinical trials [see Adverse
`Reactions (6.1)]. Typically, injection site necrosis occurs within the first four months of therapy, although post-
`marketing reports have been received of ISN occurring over one year after initiation of therapy. Necrosis may
`occur at a single or multiple injection sites. The necrotic lesions are typically three cm or less in diameter, but
`larger areas have been reported. Generally the necrosis has extended only to subcutaneous fat. However, there
`are also reports of necrosis extending to and including fascia overlying muscle. In some lesions where biopsy
`results are available, vasculitis has been reported. For some lesions debridement and, infrequently, skin grafting
`have been required.
`As with any open lesion, it is important to avoid infection and, if it occurs, to treat the infection. Time to healing
`was varied depending on the severity of the necrosis at the time treatment was begun. In most cases healing was
`associated with scarring.
`Some patients have experienced healing of necrotic skin lesions while Interferon beta-1b therapy continued;
`others have not. Whether to discontinue therapy following a single site of necrosis is dependent on the extent of
`necrosis. For patients who continue therapy with EXTAVIA after injection site necrosis has occurred,
`EXTAVIA should not be administered into the affected area until it is fully healed. If multiple lesions occur,
`therapy should be discontinued until healing occurs.
`Patient understanding and use of aseptic self-injection techniques and procedures should be periodically
`reevaluated, particularly if injection site necrosis has occurred.
`5.3 Injection Site Reactions
`In controlled clinical trials, injection site reactions occurred in 78% of patients receiving Interferon beta-1b with
`injection site necrosis in 4%. Injection site inflammation (42%), injection site pain (16%), injection site
`hypersensitivity (4%), injection site necrosis (4%), injection site mass (2%), injection site edema (2%) and non-
`specific reactions were significantly associated with Interferon beta-1b treatment . The incidence of injection
`site reactions tended to decrease over time. Approximately 69% of patients experienced the event during the
`first three months of treatment, compared to approximately 40% at the end of the studies.
`5.4 Anaphylaxis
`Anaphylaxis has been reported as a rare complication of Interferon beta-1b use. Other allergic reactions have
`included dyspnea, bronchospasm, tongue edema, skin rash and urticaria [see Adverse Reactions (6.1)].
`
`Page 3 of 25
`
`YEDA EXHIBIT NO. 2099
`MYLAN PHARM. v YEDA
`IPR2015-00643
`
`
`
`
`5.5 Flu-Like Symptom Complex
`In controlled clinical trials, the rate of flu-like symptom complex was approximately 57%. The incidence
`decreased over time, with only 10% of patients reporting flu-like symptom complex at the end of the studies.
`The median duration of flu-like symptom complex in Study l was 7.5 days [see Clinical Studies (14)].
`5.6 Leukopenia
`In controlled clinical trials, leukopenia was reported in 18% of patients receiving Interferon beta-1b, leading to
`a reduction of the dose of Interferon beta-1b in some patients [see Adverse Reactions (6.1)]. Monitoring of
`complete blood and differential white blood cell counts is recommended [see Warnings and Precautions (5.8)].
`5.7 Hepatic enzymes elevations
`In controlled clinical trials, elevations of SGPT to greater than five times baseline value were reported in 12%
`of patients receiving Interferon beta-1b, and increase of SGOT to greater than five times baseline value were
`reported in 4% of patients receiving Interferon beta-1b, leading to dose-reduction or discontinuation of
`treatment in some patients [see Adverse Reactions (6.1)]. Monitoring of liver function tests is recommended
`[see Warnings and Precautions (5.8)].
`5.8 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 at regular intervals (one, three, and six months) following introduction of EXTAVIA
`therapy, and then periodically thereafter in the absence of clinical symptoms. Thyroid function tests are
`recommended every six months in patients with a history of thyroid dysfunction or as clinically indicated.
`Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with
`differential and platelet counts.
`5.9 Albumin (Human), USP
`This product contains albumin, a derivative of human blood. Based on effective donor screening and product
`manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk
`for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of
`transmission of viral diseases or CJD have ever been identified for albumin.
`
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`In all studies, the most serious adverse reactions with Interferon beta-1b were depression, suicidal ideation and
`injection site necrosis (see Warnings and Precautions). The incidence of depression of any severity was
`approximately 30% in both Interferon beta-1b-treated patients and placebo-treated patients. Anaphylaxis and
`other allergic reactions have been reported in patients using Interferon beta-1b [see Warnings and Precautions
`(5.4)]. The most commonly reported adverse reactions were lymphopenia (lymphocytes<1500/mm3), injection
`site reaction, asthenia, flu-like symptom complex, headache, and pain. The most frequently reported adverse
`reactions resulting in clinical intervention (e.g., discontinuation of Interferon beta-1b, adjustment in dosage, or
`the need for concomitant medication to treat an adverse reaction symptom) were depression, flu-like symptom
`complex, injection site reactions, leukopenia, increased liver enzymes, asthenia, hypertonia, and myasthenia.
`Because clinical trials are conducted under widely varying conditions and over varying lengths of time, adverse
`reaction rates observed in the clinical trials of Interferon beta-1b cannot be directly compared to rates in clinical
`trials of other drugs, and may not reflect the rates observed in practice. The adverse reaction information from
`clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug
`use and for approximating rates.
`The data described below reflect exposure to Interferon beta-1b in the four placebo controlled trials of 1407
`patients with MS treated with 0.25 mg or 0.16 mg/m2, including 1261 exposed for greater than one year. The
`
`Page 4 of 25
`
`YEDA EXHIBIT NO. 2099
`MYLAN PHARM. v YEDA
`IPR2015-00643
`
`
`
` population encompassed an age range from 18 – 65 years. Sixty-four percent (64%) of the patients were female.
`The percentages of Caucasian, Black, Asian, and Hispanic patients were 94.8%, 3.5%, 0.1%, and 0.7%,
`respectively.
`The safety profiles for Interferon beta-1b-treated patients with SPMS and RRMS were similar. Clinical
`experience with Interferon beta-1b in other populations (patients with cancer, HIV positive patients, etc.)
`provides additional data regarding adverse reactions; however, experience in non-MS populations may not be
`fully applicable to the MS population.
`Table 2 enumerates adverse events and laboratory abnormalities that occurred among all patients treated with
`0.25 mg or 0.16 mg/m2 Interferon beta-1b every other day for periods of up to three years in the four placebo
`controlled trials (Study 1-4) at an incidence that was at least 2.0% more than that observed in the placebo
`patients (System Organ Class, MedDRA v. 8.0).
`Table 2. Adverse Reactions and Laboratory Abnormalities
`System Organ Class MedDRA v. 8.0 #
`Placebo
`Adverse Reaction
`(n=965)
`
`Blood and lymphatic system disorders
`Lymphocytes count decreased (< 1500/mm3) x
`66%
`Absolute neutrophil count decreased (< 1500/mm3) x
`5%
`White blood cell count decreased (< 3000/mm3) x
`4%
`Lymphadenopathy
`3%
`
`Nervous system disorders
`Headache
`43%
`Insomnia
`16%
`Incoordination
`15%
`
`Vascular disorders
`Hypertension
`4%
`
`Respiratory, thoracic and mediastinal disorders
`Dyspnea
`3%
`
`Gastrointestinal disorders
`Abdominal pain
`11%
`
`Hepatobiliary disorders
`Alanine aminotransferase increased(SGPT > 5 times baseline)x
`4%
`Aspartate aminotransferase increased(SGOT > 5 times baseline)x
`1%
`
`Skin and subcutaneous tissue disorders
`Rash
`15%
`Skin disorder
`8%
`
`Musculoskeletal and connective tissue disorders
`Hypertonia
`33%
`Myalgia
`14%
`
`Renal and urinary disorders
`Urinary urgency
`8%
`
`Reproductive system and breast disorders
`Metrorrhagia*
`7%
`Impotence**
`6%
`
`General disorders and administration site conditions
`Injection site reaction (various kinds ) 0
`26%
`Asthenia
`48%
`Flu-like symptoms (complex)§
`37%
`
`Interferon beta-1b
`(n=1407)
`
`86%
`13%
`13%
`6%
`
`50%
`21%
`17%
`
`6%
`
`6%
`
`16%
`
`12%
`4%
`
`21%
`10%
`
`40%
`23%
`
`11%
`
`9%
`8%
`
`78%
`53%
`57%
`
`Page 5 of 25
`
`YEDA EXHIBIT NO. 2099
`MYLAN PHARM. v YEDA
`IPR2015-00643
`
`
`
`
`
`42%
`35%
`Pain
`31%
`19%
`Fever
`21%
`9%
`Chills
`12%
`10%
`Peripheral edema
`9%
`6%
`Chest pain
`6%
`3%
`Malaise
`4%
`0%
`Injection site necrosis
`# except for "injection site reaction (various kinds)o" and "flu-like symptom complex§" the most appropriate MedDRA term is used to describe a
`certain reaction and its synonyms and related conditions.
`x laboratory abnormality
`* pre-menopausal women
`** men
`o "Injection site reaction (various kinds)" comprises all adverse events occurring at the injection site (except injection site necrosis), i.e., the
`following terms: injection site reaction, injection site hemorrhage, injection site hypersensitivity, injection site inflammation, injection site mass,
`injection site pain, injection site edema and injection site atrophy.
`§ "Flu-like symptom complex" denotes flu syndrome and/or a combination of at least two AEs from fever, chills, myalgia, malaise, sweating.
`Laboratory Abnormalities
`In the four clinical trials, leukopenia was reported in 18% and 6% of patients in Interferon beta-1b- and
`placebo-treated groups, respectively. No patients were withdrawn or dose reduced for neutropenia in Study 1.
`Three percent (3%) of patients in Studies 2 and 3 experienced leukopenia and were dose-reduced. Monitoring of
`complete blood and differential white blood cell counts is recommended [see Warnings and Precautions (5.6,
`5.8)].
`Other abnormalities included increase of SGPT to greater than five times baseline value (12%), and increase of
`SGOT to greater than five times baseline value (4%). In Study 1, two patients were dose reduced for increased
`hepatic enzymes; one continued on treatment and one was ultimately withdrawn. In Studies 2 and 3, 1.5% of
`Interferon beta-1b patients were dose-reduced or interrupted treatment for increased hepatic enzymes. In Study
`4, 1.7% of patients were withdrawn from treatment due to increased hepatic enzymes, two of them after a dose
`reduction. In Studies 1-4, nine (0.6%) patients were withdrawn from treatment with Interferon beta-1b for any
`laboratory abnormality, including four (0.3%) patients following dose reduction. Monitoring of liver function
`tests is recommended [see Warnings and Precautions (5.7, 5.8)].
`6.2 Postmarketing Experience
`The following adverse events have been observed during postmarketing experience with Interferon beta-1b and
`are classified within body system categories:
`Blood and lymphatic system disorders: Anemia, Thrombocytopenia
`Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction
`Metabolism and nutrition disorders: Hypocalcemia, Hyperuricemia, Triglyceride increased, Anorexia, Weight
`decrease
`Psychiatric disorders: Confusion, Depersonalization, Emotional lability
`Nervous system disorders: Ataxia, Convulsion, Paresthesia, Psychotic symptoms
`Cardiac disorders: Cardiomyopathy
`Vascular disorders: Deep vein thrombosis, Pulmonary embolism
`Respiratory, thoracic and mediastinal disorders: Bronchospasm, Pneumonia
`Gastrointestinal disorders: Pancreatitis, Vomiting
`Hepatobiliary disorders: Hepatitis, Gamma GT increased
`Skin and subcutaneous tissue disorders: Pruritus, Skin discoloration, Urticaria
`
`Page 6 of 25
`
`YEDA EXHIBIT NO. 2099
`MYLAN PHARM. v YEDA
`IPR2015-00643
`
`
`
` Renal and urinary disorders: Urinary tract infection, Urosepsis
`General disorders and administration site conditions: Fatal capillary leak syndrome*.
`*The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated
`with the development of this syndrome.
`6.3 Immunogenicity
`As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples were monitored for the
`development of antibodies to Interferon beta-1b during Study 1 [see Clinical Studies (14)]. In patients receiving
`0.25 mg every other day 56/124 (45%) were found to have serum neutralizing activity at one or more of the
`time points tested. In Study 4 [see Clinical Studies (14)], neutralizing activity was measured every 6 months
`and at end of study. At individual visits after start of therapy, activity was observed in 16.5% up to 25.2% of the
`Interferon beta-1b treated patients. Such neutralizing activity was measured at least once in 75 (29.9%) out of
`251 Interferon beta-1b patients who provided samples during treatment phase; of these, 17 (22.7%) converted to
`negative status later in the study.
`Based on all the available evidence, the relationship between antibody formation and clinical safety or efficacy
`is not known.
`These data reflect the percentage of patients whose test results were considered positive for antibodies to
`Interferon beta-1b using a biological neutralization assay that measures the ability of immune sera to inhibit the
`production of the interferon-inducible protein, MxA. Neutralization assays 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 Interferon
`beta-1b with the incidence of antibodies to other products may be misleading.
`Anaphylactic reactions have rarely been reported with the use of Interferon beta-1b [see Warnings and
`Precautions (5.4)].
`
`7 DRUG INTERACTIONS
`No formal drug interaction studies have been conducted with Interferon beta-1b. In the placebo controlled
`studies in MS, corticosteroids or ACTH were administered for treatment of relapses for periods of up to 28 days
`in patients (N=664) receiving Interferon beta-1b.
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category C: There are no adequate and well-controlled studies of Interferon beta-1b in pregnant
`women; however, spontaneous abortions while on treatment were reported in four patients participating in the
`Interferon beta-1b RRMS clinical trial. Interferon beta-1b should be used during pregnancy only if the potential
`benefit justifies the potential risk to the fetus.
`When Interferon beta-1b (doses ranging from 0.028 to 0.42 mg/kg) was administered to pregnant rhesus
`monkeys throughout the period of organogenesis (gestation days 20 to 70), a dose-related abortifacient effect
`was observed. The low effect dose is approximately 3 times the recommended human dose of 0.25 mg on a
`body surface are (mg/m2) basis. A no-effect dose for embryo-fetal developmental toxicity in rhesus monkeys
`was not established.
`8.3 Nursing Mothers
`It is not known whether Interferon beta-1b is excreted in human milk. Because many drugs are excreted in
`human milk and because of the potential for serious adverse reactions in nursing infants from Interferon beta-
`1b, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the
`importance of drug to the mother.
`
`Page 7 of 25
`
`YEDA EXHIBIT NO. 2099
`MYLAN PHARM. v YEDA
`IPR2015-00643
`
`
`
`
`8.4 Pediatric Use
`Safety and efficacy in pediatric patients have not been established.
`8.5 Geriatric Use
`Clinical studies of Interferon beta-1b did not include sufficient numbers of patients aged 65 and over to
`determine whether they respond differently than younger patients.
`
`10 OVERDOSAGE
`Safety of doses higher than 0.25 mg every other day has not been adequately evaluated. The maximum amount
`of Interferon beta-1b that can be safely administered has not been determined.
`
`11 DESCRIPTION
`EXTAVIA® (Interferon beta-lb) is a purified, sterile, lyophilized protein product produced by recombinant
`DNA techniques. Interferon beta-1b is manufactured by bacterial fermentation of a strain of Escherichia coli
`that bears a genetically engineered plasmid containing the gene for human interferon betaser17. The native gene
`was obtained from human fibroblasts and altered in a way that substitutes serine for the cysteine residue found
`at position 17. Interferon beta-1b has 165 amino acids and an approximate molecular weight of 18,500 daltons.
`It does not include the carbohydrate side chains found in the natural material. EXTAVIA contains the same
`active ingredients as other Interferon beta-1b products. For this reason, these products should not be given
`concomitantly.
`The specific activity of EXTAVIA is approximately 32 million international units (IU)/mg Interferon beta-lb.
`Each vial contains 0.3 mg of Interferon beta-lb. The unit measurement is derived by comparing the antiviral
`activity of the product to the World Health Organization (WHO) reference standard of recombinant human
`interferon beta. Mannitol, USP and Albumin (Human), USP (15 mg each/vial) are added as stabilizers.
`Lyophilized EXTAVIA is a sterile, white to off-white powder, for subcutaneous injection after reconstitution
`with the diluent supplied (Sodium Chloride, 0.54% Solution).
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`The mechanism of action of Interferon beta-1b 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. Four major groups of interferons have been distinguished: alpha, beta,
`gamma and lambda. Interferons-alpha and -beta comprise the Type I interferons, interferon-gamma is the sole
`Type II interferon, and interferon-lambda is designated as Type III interferon. Type I interferons have
`considerably overlapping but also distinct biologic activities. The bioactivities of IFNs are mediated by their
`interactions with specific receptors found on the surfaces of human cells. Differences in bioactivites induced by
`IFNs likely reflect divergences in the signal transduction process induced by IFN-receptor binding.
`Interferon beta-1b receptor binding induces the expression of proteins that are responsible for the pleiotropic
`bioactivities of Interferon beta-1b. A number of these proteins (including neopterin, β2-microglobulin, MxA
`protein, and IL-10) have been measured in blood fractions from Interferon beta-1b-treated patients and
`Interferon beta-1b-treated healthy volunteers. Immunomodulatory effects of Interferon beta-1b include the
`enhancement of suppressor T cell activity, reduction of pro-inflammatory cytokine production, down-regulation
`of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system. It is not known
`if these effects play an important role in the observed clinical activity of Interferon beta-1b in multiple sclerosis
`(MS).
`
`Page 8 of 25
`
`YEDA EXHIBIT NO. 2099
`MYLAN PHARM. v YEDA
`IPR2015-00643
`
`
`
`
`12.3 Pharmacokinetics
`Because serum concentrations of Interferon beta-1b are low or not detectable following subcutaneous
`administration of 0.25 mg or less of Interferon beta-1b, pharmacokinetic information in patients with MS
`receiving the recommended dose of Interferon beta-1b is not available. Following single and multiple daily
`subcutaneous administrations of 0.5 mg Interferon beta-1b to healthy volunteers (N=12), serum Interferon beta-
`1b concentrations were generally below 100 IU/mL. Peak serum Interferon beta-1b concentrations occurred
`between one to eight hours, with a mean peak serum interferon concentration of 40 IU/mL. Bioavailability,
`based on a total dose of 0.5 mg Interferon beta-1b given as two subcutaneous injections at different sites, was
`approximately 50%.
`After intravenous administration of Interferon beta-1b (0.006 mg to 2.0 mg), similar pharmacokinetic profiles
`were obtained from healthy volunteers (N=12) and from patients with diseases other than MS (N=142). In
`patients receiving single intravenous doses up to 2.0 mg, increases in serum concentrations were dose
`proportional. Mean serum clearance values ranged from 9.4 mL/min•kg -1 to 28.9 mL/min•kg-1 and were
`independent of dose. Mean terminal elimination half-life values ranged from 8.0 minutes to 4.3 hours and mean
`steady-state volume of distribution values ranged from 0.25 L/kg to 2.88 L/kg. Three-times-a-week intravenous
`dosing for two weeks resulted in no accumulation of Interferon beta-1b in sera of patients. Pharmacokinetic
`parameters after single and multiple intravenous doses of Interferon beta-1b were comparable.
`Following every other day subcutaneous administration of 0.25 mg Interferon beta-1b in healthy volunteers,
`biologic response marker levels (neopterin, β2- microglobulin, MxA protein, and the immunosuppressive
`cytokine, IL-10) increased significantly above baseline six-twelve hours after the first Interferon beta-1b dose.
`Biologic response marker levels peaked between 40 and 124 hours and remained elevated above baseline
`throughout the seven-day (168-hour) study. The relationship between serum Interferon beta-1b levels or
`induced biologic response marker levels and the clinical effects of Interferon beta-1b in multiple sclerosis is
`unknown.
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenesis: Interferon beta-1b has not been tested for its carcinogenic potential in animals.
`Mutagenesis: Interferon beta-1b was not genotoxic in the in vitro Ames bacterial test or the in vitro
`chromosomal aberration assay in human peripheral blood lymphocytes. Interferon beta-1b treatment of mouse
`BALBc-3T3 cells did not result in increased transformation frequency in an in vitro model of tumor
`transformation.
`Impairment of fertility: Administration of Interferon beta-1b (doses of up to 0.33 mg/kg) to normally cycling
`female rhesus monkeys had no apparent adverse effects on either menstrual cycle duration or associated
`hormonal profiles (progesterone and estradiol) when administered over three consecutive menstrual cycles. The
`highest dose tested is approximately 30 times the recommended human dose of 0.25 mg on a body surface area
`(mg/m2) basis. The potential for other effects on fertility or reproductive performance was not evaluated.
`
`14 CLINICAL STUDIES
`The clinical effects of Interferon beta-1b were studied in four randomized, multicenter, double-blind, placebo-
`controlled studies in patients with multiple sclerosis.
`The effectiveness of Interferon beta-1b in relapsing-remitt