HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use COPAXONE®
`safely and effectively. See full prescribing information for COPAXONE.
`COPAXONE (glatiramer acetate injection) for subcutaneous use
`Initial U.S. Approval: 1996
` RECENT MAJOR CHANGES
`Dosage and Administration, Recommend Dose (2.1)
`01/2014
`Dosage and Administration, Instructions for Use (2.2)
`01/2014
`Warnings and Precautions, Immediate Post-Injection Reaction (5.1)
`01/2014
`Warnings and Precautions, Chest Pain (5.2)
`01/2014
`Warnings and Precautions, Lipoatrophy and Skin Necrosis (5.3)
`01/2014
` INDICATIONS AND USAGE
`COPAXONE is indicated for the treatment of patients with relapsing-forms of multiple
`sclerosis (1).
` DOSAGE AND ADMINISTRATION
`• For subcutaneous injection only; doses are not interchangeable (2.1)
`• COPAXONE 20 mg/mL per day (2.1)
`• COPAXONE 40 mg/mL three times per week (2.1)
`• Before use, allow the solution to warm to room temperature (2.2)
` DOSAGE FORMS AND STRENGTHS
`• Injection: 20 mg/mL in a single-dose prefilled syringe with a white plunger (3)
`• Injection: 40 mg/mL in a single-dose, prefilled syringe with a blue plunger (3)
`
` CONTRAINDICATIONS
`Known hypersensitivity to glatiramer acetate or mannitol (4)
` WARNINGS AND PRECAUTIONS
`• Immediate Post-Injection Reaction (flushing, chest pain, palpitations, anxiety, dysp-
`nea, throat constriction, and/or urticaria), generally transient and self-limiting (5.1)
`• Chest pain, usually transient (5.2)
`• Lipoatrophy and skin necrosis may occur. Instruct patients in proper injection tech-
`nique and to rotate injection sites (5.3)
`• COPAXONE can modify immune response (5.4)
` ADVERSE REACTIONS
`• In controlled studies of COPAXONE 20 mg/mL, most common adverse reactions
`(≥10% and ≥1.5 times higher than placebo) were: injection site reactions, vasodila-
`tation, rash, dyspnea, and chest pain (6.1)
`• In a controlled study of COPAXONE 40 mg/mL, most common adverse reactions
`(≥10% and ≥1.5 times higher than placebo) were: injection site reactions (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact TEVA at 1-800-221-4026 or
`FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
` USE IN SPECIFIC POPULATIONS
`• Nursing Mothers: It is not known if COPAXONE is excreted in human milk (8.3)
`• Pediatric Use: The safety and effectiveness of COPAXONE have not been established
`in patients under 18 years of age (8.4)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
`Revised: 01/2014
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dose
`2.2
`Instructions for Use
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Immediate Post-Injection Reaction
`5.2 Chest Pain
`5.3 Lipoatrophy and Skin Necrosis
`5.4 Potential Effects on Immune Response
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Use in Patients with Impaired Renal Function
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`FULL PRESCRIBING INFORMATION
`COPAXONE (glatiramer acetate injection)
`1 INDICATIONS AND USAGE
`COPAXONE is indicated for the treatment of patients with relapsing forms of multiple
`sclerosis.
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dose
`COPAXONE is for subcutaneous use only. Do not administer intravenously. The dos-
`ing schedule depends on the product strength that is selected. The recommended
`doses are:
`• COPAXONE 20 mg per mL: administer once per day
` or
`• COPAXONE 40 mg per mL: administer three times per week and at least 48 hours apart
`COPAXONE 20 mg per mL and COPAXONE 40 mg per mL are not interchangeable.
`2.2 Instructions for Use
`Remove one blister-packaged prefilled syringe from the refrigerated carton. Let the
`prefilled syringe stand at room temperature for 20 minutes to allow the solution to
`warm to room temperature. Visually inspect the syringe for particulate matter and
`discoloration prior to administration. The solution in the syringe should appear clear,
`colorless to slightly yellow. If particulate matter or discoloration is observed, discard
`the syringe.
`Areas for subcutaneous self-injection include arms, abdomen, hips, and thighs. The
`prefilled syringe is for single use only. Discard unused portions.
`3 DOSAGE FORMS AND STRENGTHS
`• Injection: 20 mg per mL in a single-dose, prefilled syringe with a white plunger. For
`subcutaneous use only.
`• Injection: 40 mg per mL in a single-dose, prefilled syringe with a blue plunger. For
`subcutaneous use only.
`4 CONTRAINDICATIONS
`COPAXONE is contraindicated in patients with known hypersensitivity to glatiramer
`acetate or mannitol.
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Immediate Post-Injection Reaction
`Approximately 16% of patients exposed to COPAXONE 20 mg per mL in the 5
`placebo-controlled trials compared to 4% of those on placebo, and approximately
`2% of patients exposed to COPAXONE 40 mg per mL in a placebo-controlled trial
`compared to none on placebo, experienced a constellation of symptoms immediately
`after injection that included at least two of the following: flushing, chest pain, palpi-
`tations, anxiety, dyspnea, constriction of the throat, and urticaria. In general, these
`symptoms have their onset several months after the initiation of treatment, although
`they may occur earlier, and a given patient may experience one or several episodes
`of these symptoms. Whether or not any of these symptoms actually represent a spe-
`cific syndrome is uncertain. Typically, the symptoms were transient and self-limited
`and did not require treatment; however, there have been reports of patients with
`similar symptoms who received emergency medical care. Whether an immunologic
`or nonimmunologic mechanism mediates these episodes, or whether several similar
`episodes seen in a given patient have identical mechanisms, is unknown.
`5.2 Chest Pain
`Approximately 13% of COPAXONE 20 mg per mL patients in the 5 placebo-controlled
`studies compared to 6% of placebo patients, and approximately 2% of patients
`exposed to COPAXONE 40 mg per mL in a placebo-controlled trial compared to 1% of
`placebo patients, experienced at least one episode of transient chest pain. While some
`of these episodes occurred in the context of the Immediate Post-Injection Reaction
`described above, many did not. The temporal relationship of this chest pain to an
`injection was not always known. The pain was usually transient, often unassociated
`with other symptoms, and appeared to have no clinical sequelae. Some patients expe-
`rienced more than one such episode, and episodes usually began at least 1 month
`after the initiation of treatment. The pathogenesis of this symptom is unknown.
`5.3 Lipoatrophy and Skin Necrosis
`At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis may
`occur. Lipoatrophy occurred in approximately 2% of patients exposed to COPAXONE
`20 mg per mL in the 5 placebo-controlled trials compared to none on placebo, and
`0.5% of patients exposed to COPAXONE 40 mg per mL in a single placebo-controlled
`trial and none on placebo. Skin necrosis has only been observed in the post-marketing
`
`1
`
`
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`COPAXONE® (glatiramer acetate injection)
`setting. Lipoatrophy may occur at various times after treatment onset (sometimes
`after several months) and is thought to be permanent. There is no known therapy
`for lipoatrophy. To assist in possibly minimizing these events, the patient should be
`advised to follow proper injection technique and to rotate injection sites with each
`injection.
`5.4 Potential Effects on Immune Response
`Because COPAXONE can modify immune response, it may interfere with immune
`functions. For example, treatment with COPAXONE may interfere with the recognition
`of foreign antigens in a way that would undermine the body’s tumor surveillance
`and its defenses against infection. There is no evidence that COPAXONE does this,
`but there has not been a systematic evaluation of this risk. Because COPAXONE is
`an antigenic material, it is possible that its use may lead to the induction of host
`responses that are untoward, but systematic surveillance for these effects has not
`been undertaken.
`Although COPAXONE is intended to minimize the autoimmune response to myelin,
`there is the possibility that continued alteration of cellular immunity due to chronic
`treatment with COPAXONE may result in untoward effects.
`Glatiramer acetate-reactive antibodies are formed in most patients receiving glati-
`ramer acetate. Studies in both the rat and monkey have suggested that immune
`complexes are deposited in the renal glomeruli. Furthermore, in a controlled trial of
`125 RRMS patients given COPAXONE 20 mg per mL, subcutaneously every day for
`2 years, serum IgG levels reached at least 3 times baseline values in 80% of patients
`by 3 months of initiation of treatment. By 12 months of treatment, however, 30%
`of patients still had IgG levels at least 3 times baseline values, and 90% had levels
`above baseline by 12 months. The antibodies are exclusively of the IgG subtype and
`predominantly of the IgG-1 subtype. No IgE type antibodies could be detected in any
`of the 94 sera tested; nevertheless, anaphylaxis can be associated with the admin-
`istration of most any foreign substance, and therefore, this risk cannot be excluded.
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reac-
`tion rates observed in the clinical trials of a drug cannot be directly compared to
`rates in the clinical trials of another drug and may not reflect the rates observed in
`clinical practice.
`Incidence in Controlled Clinical Trials
`COPAXONE 20 mg per mL per day
`Among 563 patients treated with COPAXONE in blinded placebo-controlled trials,
`approximately 5% of the subjects discontinued treatment because of an adverse
`reaction. The adverse reactions most commonly associated with discontinuation
`were: injection site reactions, dyspnea, urticaria, vasodilatation, and hypersensitivity.
`The most common adverse reactions were: injection site reactions, vasodilatation,
`rash, dyspnea, and chest pain.
`Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2%
`of patients treated with COPAXONE 20 mg per mL in the placebo-controlled trials.
`These signs and symptoms were numerically more common in patients treated with
`COPAXONE than in patients treated with placebo. Adverse reactions were usually mild
`in intensity.
`Table 1: Adverse reactions in controlled clinical trials with an incidence ≥2% of
`patients and more frequent with COPAXONE (20 mg per mL daily) than with placebo
`COPAXONE
`20 mg/mL
`(n=563)
`7%
`
`Lymphadenopathy
`
`Placebo
`(n=564)
`3%
`
`Blood And Lymphatic
`System Disorders
`Cardiac Disorders
`
`Eye Disorders
`
`Gastrointestinal Disorders
`
`General Disorders And
`Administration Site
`Conditions
`
`Palpitations
`Tachycardia
`Eye Disorder
`Diplopia
`Nausea
`Vomiting
`Dysphagia
`Injection Site Erythema
`Injection Site Pain
`Injection Site Pruritus
`Injection Site Mass
`Asthenia
`Pain
`Injection Site Edema
`Chest Pain
`Injection Site Inflammation
`Edema
`
`9%
`5%
`3%
`3%
`15%
`7%
`2%
`43%
`40%
`27%
`26%
`22%
`20%
`19%
`13%
`9%
`8%
`
`4%
`2%
`1%
`2%
`11%
`4%
`1%
`10%
`20%
`4%
`6%
`21%
`17%
`4%
`6%
`1%
`2%
`
`2
`
`COPAXONE® (glatiramer acetate injection)
`
`Injection Site Reaction
`Pyrexia
`Injection Site
`Hypersensitivity
`Local Reaction
`Chills
`Face Edema
`Edema Peripheral
`Injection Site Fibrosis
`Injection Site Atrophy*
`Hypersensitivity
`Infection
`Influenza
`Rhinitis
`Bronchitis
`Gastroenteritis
`Vaginal Candidiasis
`Weight Increased
`
`Back Pain
`
`COPAXONE
`20 mg/mL
`(n=563)
`8%
`6%
`4%
`
`Placebo
`(n=564)
`1%
`5%
`0%
`
`3%
`3%
`3%
`3%
`2%
`2%
`3%
`30%
`14%
`7%
`6%
`6%
`4%
`3%
`
`12%
`
`1%
`1%
`1%
`2%
`1%
`0%
`2%
`28%
`13%
`5%
`5%
`4%
`2%
`1%
`
`10%
`
`Benign Neoplasm of Skin
`
`2%
`
`1%
`
`Immune System Disorders
`Infections And Infestations
`
`Metabolism And
`Nutrition Disorders
`Musculoskeletal And
`Connective Tissue
`Disorders
`Neoplasms Benign,
`Malignant And Unspecified
`(Incl Cysts And Polyps)
`Nervous System Disorders
`
`Psychiatric Disorders
`
`Skin And Subcutaneous
`Tissue Disorders
`
`2%
`4%
`Tremor
`2%
`4%
`Migraine
`2%
`3%
`Syncope
`1%
`2%
`Speech Disorder
`10%
`13%
`Anxiety
`1%
`2%
`Nervousness
`4%
`5%
`Renal And Urinary Disorders Micturition Urgency
`4%
`14%
`Respiratory, Thoracic And
`Dyspnea
`Mediastinal Disorders
`5%
`6%
`Cough
`1%
`2%
`Laryngospasm
`11%
`19%
`Rash
`5%
`7%
`Hyperhidrosis
`4%
`5%
`Pruritus
`1%
`3%
`Urticaria
`1%
`3%
`Skin Disorder
`5%
`20%
`Vasodilatation
`Vascular Disorders
`*Injection site atrophy comprises terms relating to localized lipoatrophy at injection site
`Adverse reactions which occurred only in 4 to 5 more subjects in the COPAXONE
`group than in the placebo group (less than 1% difference), but for which a relation-
`ship to COPAXONE could not be excluded, were arthralgia and herpes simplex.
`Laboratory analyses were performed on all patients participating in the clinical pro-
`gram for COPAXONE. Clinically-significant laboratory values for hematology, chem-
`istry, and urinalysis were similar for both COPAXONE and placebo groups in blinded
`clinical trials. In controlled trials one patient discontinued treatment due to thrombo-
`cytopenia (16 x109/L), which resolved after discontinuation of treatment.
`Data on adverse reactions occurring in the controlled clinical trials of COPAXONE
`20 mg per mL were analyzed to evaluate differences based on sex. No clinically-
`significant differences were identified. Ninety-six percent of patients in these clinical
`trials were Caucasian. The majority of patients treated with COPAXONE were between
`the ages of 18 and 45. Consequently, data are inadequate to perform an analysis of
`the adverse reaction incidence related to clinically-relevant age subgroups.
`Other Adverse Reactions
`In the paragraphs that follow, the frequencies of less commonly reported adverse
`clinical reactions are presented. Because the reports include reactions observed in
`open and uncontrolled premarketing studies (n= 979), the role of COPAXONE in their
`causation cannot be reliably determined. Furthermore, variability associated with
`
`
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`COPAXONE® (glatiramer acetate injection)
`adverse reaction reporting, the terminology used to describe adverse reactions, etc.,
`limit the value of the quantitative frequency estimates provided. Reaction frequen-
`cies are calculated as the number of patients who used COPAXONE and reported a
`reaction divided by the total number of patients exposed to COPAXONE. All reported
`reactions are included except those already listed in the previous table, those too
`general to be informative, and those not reasonably associated with the use of the
`drug. Reactions are further classified within body system categories and enumerated
`in order of decreasing frequency using the following definitions: Frequent adverse
`reactions are defined as those occurring in at least 1/100 patients and infrequent
`adverse reactions are those occurring in 1/100 to 1/1,000 patients.
`Body as a Whole:
`Frequent: Abscess.
`Infrequent: Injection site hematoma, moon face, cellulitis, hernia, injection site abscess,
`serum sickness, suicide attempt, injection site hypertrophy, injection site melanosis,
`lipoma, and photosensitivity reaction.
`Cardiovascular:
`Frequent: Hypertension.
`Infrequent: Hypotension, midsystolic click, systolic murmur, atrial fibrillation, brady-
`cardia, fourth heart sound, postural hypotension, and varicose veins.
`Digestive:
`Infrequent: Dry mouth, stomatitis, burning sensation on tongue, cholecystitis, colitis,
`esophageal ulcer, esophagitis, gastrointestinal carcinoma, gum hemorrhage, hepato-
`megaly, increased appetite, melena, mouth ulceration, pancreas disorder, pancreati-
`tis, rectal hemorrhage, tenesmus, tongue discoloration, and duodenal ulcer.
`Endocrine:
`Infrequent: Goiter, hyperthyroidism, and hypothyroidism.
`Gastrointestinal:
`Frequent: Bowel urgency, oral moniliasis, salivary gland enlargement, tooth caries,
`and ulcerative stomatitis.
`Hemic and Lymphatic:
`Infrequent: Leukopenia, anemia, cyanosis, eosinophilia, hematemesis, lymphedema,
`pancytopenia, and splenomegaly.
`Metabolic and Nutritional:
`Infrequent: Weight loss, alcohol intolerance, Cushing’s syndrome, gout, abnormal
`healing, and xanthoma.
`Musculoskeletal:
`Infrequent: Arthritis, muscle atrophy, bone pain, bursitis, kidney pain, muscle disor-
`der, myopathy, osteomyelitis, tendon pain, and tenosynovitis.
`Nervous:
`Frequent: Abnormal dreams, emotional lability, and stupor.
`Infrequent: Aphasia, ataxia, convulsion, circumoral paresthesia, depersonalization,
`hallucinations, hostility, hypokinesia, coma, concentration disorder, facial paralysis,
`decreased libido, manic reaction, memory impairment, myoclonus, neuralgia, para-
`noid reaction, paraplegia, psychotic depression, and transient stupor.
`Respiratory:
`Frequent: Hyperventilation and hay fever.
`Infrequent: Asthma, pneumonia, epistaxis, hypoventilation, and voice alteration.
`Skin and Appendages:
`Frequent: Eczema, herpes zoster, pustular rash, skin atrophy, and warts.
`Infrequent: Dry skin, skin hypertrophy, dermatitis, furunculosis, psoriasis, angioedema,
`contact dermatitis, erythema nodosum, fungal dermatitis, maculopapular rash, pigmen-
`tation, benign skin neoplasm, skin carcinoma, skin striae, and vesiculobullous rash.
`Special Senses:
`Frequent: Visual field defect.
`Infrequent: Dry eyes, otitis externa, ptosis, cataract, corneal ulcer, mydriasis, optic
`neuritis, photophobia, and taste loss.
`Urogenital:
`Frequent: Amenorrhea, hematuria, impotence, menorrhagia, suspicious papanico-
`laou smear, urinary frequency, and vaginal hemorrhage.
`Infrequent: Vaginitis, flank pain (kidney), abortion, breast engorgement, breast
`enlargement, carcinoma in situ cervix, fibrocystic breast, kidney calculus, nocturia,
`ovarian cyst, priapism, pyelonephritis, abnormal sexual function, and urethritis.
`COPAXONE 40 mg per mL three times per week
`Among 943 patients treated with COPAXONE 40 mg per mL three times per week in
`a blinded, placebo-controlled trial, approximately 3% of the subjects discontinued
`treatment because of an adverse reaction. The most common adverse reactions were
`injection site reactions, which were also the most common cause of discontinuation.
`Table 2 lists treatment-emergent signs and symptoms that occurred in at least 2%
`of patients treated with COPAXONE 40 mg per mL in the blinded, placebo-controlled
`trial. These signs and symptoms were numerically more common in patients treated
`with COPAXONE 40 mg per mL than in patients treated with placebo. Adverse reac-
`tions were usually mild in intensity.
`
`3
`
`COPAXONE® (glatiramer acetate injection)
`Table 2: Adverse reactions in a controlled clinical trial with an incidence ≥2% of
`patients and more frequent with COPAXONE (40 mg per mL three times per week)
`than with placebo
`
`COPAXONE
`40 mg/mL
`(n=943)
`22%
`10%
`6%
`6%
`6%
`3%
`3%
`2%
`2%
`2%
`11%
`3%
`
`Placebo
`(n=461)
`2%
`2%
`0%
`0%
`0%
`2%
`2%
`0%
`0%
`1%
`9%
`2%
`
`General Disorders And
`Administration Site
`Conditions
`
`Injection Site Erythema
`Injection Site Pain
`Injection Site Mass
`Injection Site Pruritus
`Injection Site Edema
`Pyrexia
`Influenza-like Illness
`Injection Site Inflammation
`Chills
`Chest Pain
`Infections And Infestations Nasopharyngitis
`Respiratory Tract Infection
`Viral
`Dyspnea
`
`3%
`
`0%
`
`Respiratory, Thoracic And
`Mediastinal Disorders
`0%
`3%
`Vasodilatation
`Vascular Disorders
`1%
`2%
`Gastrointestinal Disorders Nausea
`0%
`2%
`Skin And Subcutaneous
`Erythema
`Tissue Disorders
`1%
`2%
`Rash
`No new adverse reactions appeared in subjects treated with COPAXONE 40 mg per mL
`three times per week as compared to subjects treated with COPAXONE 20 mg per mL
`per day in clinical trials and during postmarketing experience. Data on adverse reactions
`occurring in the controlled clinical trial of COPAXONE 40 mg per mL were analyzed to
`evaluate differences based on sex. No clinically significant differences were identified.
`Ninety-eight percent of patients in this clinical trial were Caucasian and the majority
`were between the ages of 18 and 50. Consequently, data are inadequate to perform
`an analysis of the adverse reaction incidence related to clinically-relevant age groups.
`6.2 Postmarketing Experience
`The following adverse events occurring under treatment with COPAXONE 20 mg per
`mL since market introduction and not mentioned above have been identified during
`postapproval use of COPAXONE. Because these events 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.
`Body as a Whole: sepsis; SLE syndrome; hydrocephalus; enlarged abdomen; allergic
`reaction; anaphylactoid reaction
`Cardiovascular System: thrombosis; peripheral vascular disease; pericardial effusion;
`myocardial infarct; deep thrombophlebitis; coronary occlusion; congestive heart fail-
`ure; cardiomyopathy; cardiomegaly; arrhythmia; angina pectoris
`Digestive System: tongue edema; stomach ulcer; hemorrhage; liver function abnor-
`mality; liver damage; hepatitis; eructation; cirrhosis of the liver; cholelithiasis
`Hemic and Lymphatic System: thrombocytopenia; lymphoma-like reaction; acute
`leukemia
`Metabolic and Nutritional Disorders: hypercholesterolemia
`Musculoskeletal System: rheumatoid arthritis; generalized spasm
`Nervous System: myelitis; meningitis; CNS neoplasm; cerebrovascular accident;
`brain edema; abnormal dreams; aphasia; convulsion; neuralgia
`Respiratory System: pulmonary embolus; pleural effusion; carcinoma of lung
`Special Senses: glaucoma; blindness
`Urogenital System: urogenital neoplasm; urine abnormality; ovarian carcinoma;
`nephrosis; kidney failure; breast carcinoma; bladder carcinoma; urinary frequency
`7 DRUG INTERACTIONS
`Interactions between COPAXONE and other drugs have not been fully evaluated.
`Results from existing clinical trials do not suggest any significant interactions of
`COPAXONE with therapies commonly used in MS patients, including the concurrent
`use of corticosteroids for up to 28 days. COPAXONE has not been formally evaluated
`in combination with interferon beta.
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category B.
`Administration of glatiramer acetate by subcutaneous injection to pregnant rats and
`rabbits resulted in no adverse effects on offspring development. There are no ade-
`quate and well-controlled studies in pregnant women. Because animal reproduction
`studies are not always predictive of human response, COPAXONE should be used
`during pregnancy only if clearly needed.
`In rats or rabbits receiving glatiramer acetate by subcutaneous injection during the
`period of organogenesis, no adverse effects on embryo-fetal development were
`
`
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`COPAXONE® (glatiramer acetate injection)
`observed at doses up to 37.5 mg/kg/day (18 and 36 times, respectively, the thera-
`peutic human dose of 20 mg/day on a mg/m2 basis). In rats receiving subcutaneous
`glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout
`lactation, no significant effects on delivery or on offspring growth and development
`were observed.
`8.2 Labor and Delivery
`The effects of COPAXONE on labor and delivery in pregnant women are unknown.
`8.3 Nursing Mothers
`It is not known if glatiramer acetate is excreted in human milk. Because many drugs
`are excreted in human milk, caution should be exercised when COPAXONE is admin-
`istered to a nursing woman.
`8.4 Pediatric Use
`The safety and effectiveness of COPAXONE have not been established in patients
`under 18 years of age.
`8.5 Geriatric Use
`COPAXONE has not been studied in elderly patients.
`8.6 Use in Patients with Impaired Renal Function
`The pharmacokinetics of glatiramer acetate in patients with impaired renal function
`have not been determined.
`11 DESCRIPTION
`Glatiramer acetate, the active ingredient of COPAXONE, consists of the acetate salts
`of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic
`acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427,
`0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate is
`5,000 – 9,000 daltons. Glatiramer acetate is identified by specific antibodies.
`Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine,
`L- lysine and L-tyrosine, acetate (salt). Its structural formula is:
`(Glu, Ala, Lys, Tyr)x • xCH3COOH
`(C5H9NO4 • C3H7NO2 • C6H14N2O2 • C9H11NO3)x • xC2H4O2
`CAS - 147245-92-9
`COPAXONE is a clear, colorless to slightly yellow, sterile, nonpyrogenic solution for sub-
`cutaneous injection. Each 1 mL of COPAXONE solution contains 20 mg or 40 mg of
`glatiramer acetate and the following inactive ingredient: 40 mg of mannitol. The pH of
`the solutions is approximately 5.5 to 7.0. The biological activity of glatiramer acetate is
`determined by its ability to block the induction of experimental autoimmune encephalo-
`myelitis (EAE) in mice.
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`The mechanism(s) by which glatiramer acetate exerts its effects in patients with MS
`are not fully understood. However, glatiramer acetate is thought to act by modifying
`immune processes that are believed to be responsible for the pathogenesis of MS.
`This hypothesis is supported by findings of studies that have been carried out to
`explore the pathogenesis of experimental autoimmune encephalomyelitis, a condi-
`tion induced in animals through immunization against central nervous system derived
`material containing myelin and often used as an experimental animal model of MS.
`Studies in animals and in vitro systems suggest that upon its administration, glati-
`ramer acetate-specific suppressor T-cells are induced and activated in the periphery.
`Because glatiramer acetate can modify immune functions, concerns exist about its
`potential to alter naturally-occurring immune responses. There is no evidence that
`glatiramer acetate does this, but this has not been systematically evaluated [see
`Warnings and Precautions (5.4)].
`12.3 Pharmacokinetics
`Results obtained in pharmacokinetic studies performed in humans (healthy volun-
`teers) and animals support that a substantial fraction of the therapeutic dose deliv-
`ered to patients subcutaneously is hydrolyzed locally. Larger fragments of glatiramer
`acetate can be recognized by glatiramer acetate-reactive antibodies. Some fraction
`of the injected material, either intact or partially hydrolyzed, is presumed to enter the
`lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter
`the systemic circulation intact.
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`In a 2-year carcinogenicity study, mice were administered up to 60 mg/kg/day glati-
`ramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose
`of 20 mg/day on a mg/m2 basis). No increase in systemic neoplasms was observed.
`In males receiving the 60-mg/kg/day dose, there was an increased incidence of fibro-
`sarcomas at the injection sites. These sarcomas were associated with skin damage
`precipitated by repetitive injections of an irritant over a limited skin area.
`In a 2-year carcinogenicity study, rats were administered up to 30 mg/kg/day glati-
`ramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose
`on a mg/m2 basis). No increase in neoplasms was observed.
`Glatiramer acetate was not mutagenic in in vitro (Ames test, mouse lymphoma tk)
`assays. Glatiramer acetate was clastogenic in two separate in vitro chromosomal
`aberration assays in cultured human lymphocytes but not clastogenic in an in vivo
`mouse bone marrow micronucleus assay.
`When glatiramer acetate was administered by subcutaneous injection prior to and
`during mating (males and females) and throughout gestation and lactation (females)
`at doses up to 36 mg/kg/day (18 times the human therapeutic dose on a mg/m2 basis)
`no adverse effects were observed on reproductive or developmental parameters.
`
`4
`
`COPAXONE® (glatiramer acetate injection)
`14 CLINICAL STUDIES
`Evidence supporting the effectiveness of COPAXONE derives from five placebo-controlled
`trials, four of which used a COPAXONE dose of 20 mg per mL per day and one of
`which used a COPAXONE dose of 40 mg per mL three times per week.
`COPAXONE 20 mg per mL per day
`Study 1 was performed at a single center. Fifty patients were enrolled and random-
`ized to receive daily doses of either COPAXONE, 20 mg per mL subcutaneously, or
`placebo (COPAXONE: n=25; placebo: n=25). Patients were diagnosed with RRMS by
`standard criteria, and had had at least 2 exacerbations during the 2 years immedi-
`ately preceding enrollment. Patients were ambulatory, as evidenced by a score of no
`more than 6 on the Kurtzke Disability Scale Score (DSS), a standard scale ranging
`from 0–Normal to 10–Death due to MS. A score of 6 is defined as one at which a
`patient is still ambulatory with assistance; a score of 7 means the patient must use
`a wheelchair.
`Patients were examined every 3 months for 2 years, as well as within several days
`of a presumed exacerbation. To confirm an exacerbation, a blinded neurologist had
`to document objective neurologic signs, as well as document the existence of other
`criteria (e.g., the persistence of the neurological signs for at least 48 hours).
`The protocol-specified primary outcome measure was the proportion of patients in
`each treatment group who remained exacerbation free for the 2 years of the trial, but
`two other important outcomes were also specified as endpoints: the frequency of
`attacks during the trial, and the change in the number of attacks compared with the
`number which occurred during the previous 2 years.
`Table 3 presents the values of the three outcomes described above, as well as several
`protocol-specified secondary measures. These values are based on the intent-to-
`treat population (i.e., all patients who received at least 1 dose of treatment and who
`had at least 1 on-treatment assessment):
`Table 3: Study 1 Efficacy Results
`
`Placebo
`(n=25)
`
`P-Value
`
`COPAXONE
`20 mg/mL
`(n=25)
`14/25 (56%)
`0.6/2 years
`3.2
`
`7/25 (28%)
`2.4/2 years
`1.6
`
`0.085
`0.005
`0.025
`
`% Relapse-Free Patients
`Mean Relapse Frequency
`Reduction in Relapse Rate
`Compared to Prestudy
`0.03
`150
`>700
`Median Time to First Relapse (days)
`0.07
`13/25 (52%)
`20/25 (80%)
`% of Progression-Free* Patients
`*Progression was defined as an increase of at least 1 point on the DSS, persisting for
`at least 3 consecutive months.
`Study