-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`•
`Immediate Post-Injection Reaction (flushing, chest pain, palpitations,
`anxiety, dyspnea, 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 patient in proper
`
`
`injection technique and to rotate injection sites daily (5.3)
`• COPAXONE can modify immune response (5.4)
`
`
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`•
`
`In controlled studies, most common adverse reactions (≥10% and ≥1.5
`
`times higher than placebo) were: injection site reactions, vasodilatation,
`rash, dyspnea, and chest pain (6.1)
`
`
`
`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) solution for subcutaneous injection
`Initial U.S. Approval: 1996
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Indications and Usage (1) 2/2009
`
`
`
`
`
`•
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`COPAXONE is indicated for reduction of the frequency of relapses in patients
`with Relapsing-Remitting Multiple Sclerosis, including patients who have
`experienced a first clinical episode and have MRI features consistent with
`multiple sclerosis.
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`•
`For subcutaneous injection only (2.1)
`• Recommended dose: 20 mg/day (2.1)
`• Before use, allow the solution to warm to room temperature (2.2)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`•
`
`Prefilled syringe containing 1 mL solution with 20 mg of glatiramer
`
`acetate (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`Known hypersensitivity to glatiramer acetate or mannitol (4)
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`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: [2/2009]
`
`
`
`Page 1 of 22
`
`Coalition Exhibit 1071
`Coalition v. Biogen
`IPR2015-01993
`
`

`
`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
`
`14.1 Relapsing-Remitting Multiple Sclerosis (RRMS)
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`17.1 Pregnancy
`
`17.2
`Immediate Post-Injection Reaction
`
`17.3 Chest Pain
`
`17.4 Lipoatrophy and Skin Necrosis at Injection Site
`
`17.5
`Instructions for Use
`
`17.6 Storage Conditions of COPAXONE
`
`
`17.7 FDA-Approved Patient Labeling
`
`
`
`
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`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 Responses
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 2 of 22
`
`
`
`
`
`

`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`COPAXONE (glatiramer acetate)
`
`1 INDICATIONS AND USAGE
`COPAXONE is indicated for reduction of the frequency of relapses in patients
`with Relapsing-Remitting Multiple Sclerosis (RRMS), including patients who have
`experienced a first clinical episode and have MRI features consistent with multiple
`sclerosis.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dose
`COPAXONE is for subcutaneous use only. Do not administer intravenously.
`The recommended dose of COPAXONE is 20 mg/day.
`
`2.2 Instructions for Use
`Remove one blister that contains the syringe from the COPAXONE prefilled
`syringes package. Since this product should be refrigerated, let the prefilled syringe
`
`stand at room temperature for 20 minutes to allow the solution to warm to room
`temperature. Inspect the COPAXONE syringe visually for particulate matter and
`discoloration prior to administration, whenever solution and container permit. The
`solution in the syringe should appear clear, colorless to slightly yellow. If particulate
`matter or discoloration is observed, discard the COPAXONE syringe.
`Areas for self-injection include arms, abdomen, hips, and thighs. The prefilled
`syringe is for single use only. Discard unused portions.
`
`3 DOSAGE FORMS AND STRENGTHS
`Single-use prefilled syringe containing 1 mL solution with 20 mg of glatiramer
`acetate and 40 mg of mannitol.
`
`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 in the 5 placebo-
`
`controlled trials compared to 4% of those on placebo experienced a constellation of
`symptoms immediately after injection that included at least two of the following:
`
`flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and
`urticaria. The symptoms were generally transient and self-limited and did not require
`treatment. 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 specific syndrome is uncertain. During the
`
`Page 3 of 22
`
`

`
`postmarketing period, 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 patients in the 5 placebo-controlled
`studies compared to 6% of placebo patients experienced at least one episode of
`what was described as 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 of COPAXONE was
`not always known. The pain was transient (usually lasting only a few minutes), often
`unassociated with other symptoms, and appeared to have no clinical sequelae.
`Some patients experienced 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
`have been reported during the postmarketing experience. 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 daily.
`
`
`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 exposed to
`daily treatment with the recommended dose. 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,
`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
`
`
`
`
`
`2
`
`
`Page 4 of 22
`
`

`
`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 lgG subtype and predominantly of the lgG-1 subtype. No lgE
`type antibodies could be detected in any of the 94 sera tested; nevertheless,
`anaphylaxis can be associated with the administration 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
`reaction 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
`
`
`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 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 than with placebo
`
`
` GA 20 mg
`
`
`
` (N=563)
`7%
`
`9%
`5%
`3%
`3%
`15%
`7%
`2%
`
`Blood And Lymphatic System Disorders
`Cardiac Disorders
`
`Eye Disorders
`
`
`Gastrointestinal Disorders
`
`Lymphadenopathy
`
`
`Palpitations
`Tachycardia
`Eye Disorder
`Diplopia
`
`Nausea
`Vomiting
`Dysphagia
`
`Placebo
`
` (N=564)
`3%
`
`4%
`2%
`1%
`2%
`11%
`4%
`1%
`
`
`
`
`
`3
`
`Page 5 of 22
`
`

`
`
`
`
`
`General Disorders And Administration Site
`Conditions
`
`
`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
`
`
`
`Renal And Urinary Disorders
`Respiratory, Thoracic And Mediastinal
`Disorders
`
`Skin And Subcutaneous Tissue Disorders
`
`2%
`4%
`Tremor
`4%
`Migraine
`3%
`Syncope
`2%
`Speech Disorder
`
`13%
`Anxiety
`2%
`Nervousness
`
`5%
`Micturition Urgency
`14%
`Dyspnea
`
`6%
`Cough
`
`2%
`Laryngospasm
`19%
`Rash
`7%
`Hyperhidrosis
`5%
`Pruritus
`3%
`Urticaria
`3%
`Skin Disorder
`20%
`Vasodilatation
`Vascular Disorders
`*Injection site atrophy comprises terms relating to localized lipoatrophy at injection site
`
`
`
` GA 20 mg
`
` (N=563)
`43%
`40%
`27%
`26%
`22%
`20%
`19%
`13%
`9%
`8%
`8%
`6%
`
`4%
`3%
`
`3%
`3%
`3%
`2%
`
`2%
`3%
`30%
`14%
`
`7%
`
`6%
`
`6%
`4%
`
`3%
`
`12%
`
`Placebo
`
` (N=564)
`10%
`20%
`4%
`
`6%
`21%
`17%
`4%
`
`6%
`1%
`2%
`1%
`5%
`
`0%
`1%
`
`1%
`1%
`2%
`1%
`
`0%
`2%
`28%
`13%
`
`5%
`
`5%
`
`4%
`2%
`
`1%
`
`10%
`
`1%
`2%
`2%
`2%
`1%
`10%
`1%
`4%
`4%
`5%
`1%
`11%
`5%
`4%
`1%
`1%
`5%
`
`Injection Site Erythema
`
`
`
`Injection Site Pain
`Injection Site Pruritus
`Injection Site Mass
`Asthenia
`
`Pain
`Injection Site Edema
`
`Chest Pain
`Injection Site Inflammation
`Edema
`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
`
`
`
`
`
`Benign Neoplasm of Skin
`
`
`
`
`
`
`
`4
`
`
`Page 6 of 22
`
`

`
`Adverse reactions which occurred only in 4-5 more subjects in the
`COPAXONE group than in the placebo group (less than 1% difference), but for
`which a relationship to COPAXONE could not be excluded, were arthralgia and
`herpes simplex.
`Laboratory analyses were performed on all patients participating in the clinical
`program for COPAXONE. Clinically significant laboratory values for hematology,
`chemistry, and urinalysis were similar for both COPAXONE and placebo groups in
`blinded clinical trials. In controlled trials one patient discontinued treatment due to
`thrombocytopenia (16 x109/L), which resolved after discontinuation of treatment.
`Data on adverse reactions occurring in the controlled clinical trials 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 adverse reaction reporting, the terminology used to
`describe adverse reactions, etc., limit the value of the quantitative frequency
`estimates provided. Reaction frequencies 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, injection site fibrosis, moon face, cellulitis,
`generalized edema, 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,
`bradycardia, fourth heart sound, postural hypotension, and varicose veins.
`
`Digestive:
`
`
`
`
`
`5
`
`
`Page 7 of 22
`
`

`
`Infrequent: Dry mouth, stomatitis, burning sensation on tongue, cholecystitis,
`colitis, esophageal ulcer, esophagitis, gastrointestinal carcinoma, gum
`hemorrhage, hepatomegaly, increased appetite, melena, mouth ulceration,
`pancreas disorder, pancreatitis, 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
`disorder, 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, paranoid 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, pigmentation, benign skin neoplasm, skin carcinoma, skin
`striae, and vesiculobullous rash.
`Special Senses:
`Frequent: Visual field defect.
`
`
`
`
`
`6
`
`
`Page 8 of 22
`
`

`
`Infrequent: Dry eyes, otitis externa, ptosis, cataract, corneal ulcer, mydriasis,
`optic neuritis, photophobia, and taste loss.
`
` Urogenital:
`Frequent: Amenorrhea, hematuria, impotence, menorrhagia, suspicious
`papanicolaou 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.
`
`
`6.2 Postmarketing Experience
`
`
`Reports of adverse events occurring under treatment with COPAXONE not
`
`mentioned above that have been received since market introduction and may or may
`not have causal relationship to COPAXONE are listed below. 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;
`injection site hypersensitivity; allergic reaction; anaphylactoid reaction
`
`Cardiovascular System: thrombosis; peripheral vascular disease; pericardial
`effusion; myocardial infarct; deep thrombophlebitis; coronary occlusion; congestive
`heart failure; cardiomyopathy; cardiomegaly; arrhythmia; angina pectoris
`Digestive System: tongue edema; stomach ulcer; hemorrhage; liver function
`abnormality; 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; hay
`fever
`Special Senses: glaucoma; blindness; visual field defect
`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
`
`
`
`
`
`7
`
`
`Page 9 of 22
`
`

`
`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 adequate 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 observed at doses up to 37.5 mg/kg/day (18 and 36 times, respectively, the
`therapeutic 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
`administered 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
`COPAXONE is the brand name for glatiramer acetate (formerly known as
`copolymer-1). Glatiramer acetate, the active ingredient of COPAXONE, consists of
`the acetate salts of synthetic polypeptides, containing four naturally occurring amino
`
`
`
`
`
`8
`
`Page 10 of 22
`
`

`
`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 subcutaneous injection. Each 1 mL of solution contains 20 mg of
`glatiramer acetate and 40 mg of mannitol. The pH range of the solution is
`approximately 5.5 to 7.0. The biological activity of COPAXONE is determined by its
`
`ability to block the induction of experimental autoimmune encephalomyelitis (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 condition 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, glatiramer 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)].
`
`12.2 Pharmacokinetics
`
`Results obtained in pharmacokinetic studies performed in humans (healthy
`volunteers) and animals support that a substantial fraction of the therapeutic dose
`delivered 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
`
`
`
`
`
`9
`
`
`Page 11 of 22
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`

`
`In a 2-year carcinogenicity study, mice were administered up to 60 mg/kg/day
`glatiramer 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 fibrosarcomas 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
`glatiramer 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.
`
`14 CLINICAL STUDIES
`14.1 Relapsing-Remitting Multiple Sclerosis (RRMS)
`
`
`Evidence supporting the effectiveness of COPAXONE in decreasing the
`frequency of relapses derives from 3 placebo-controlled trials, all of which used a
`COPAXONE dose of 20 mg/day.
`Study 1 was performed at a single center. Fifty patients were enrolled and
`randomized to receive daily doses of either COPAXONE, 20 mg 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
`immediately 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 2 presents the values of the three outcomes described above, as well
`as several protocol specified secondary measures. These values are based on the
`
`
`
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`Page 12 of 22
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`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 2: Study 1 Efficacy Results
`
`
`
`
`
`
`
`Study 2 was a multicenter trial of similar design which was performed in 11
`
`US centers. A total of 251 patients (COPAXONE: n=125; placebo: n=126) were
`
`enrolled. The primary outcome measure was the Mean 2-Year Relapse Rate. Table
`
`3 presents the values of this outcome for the intent-to-treat population, as well as
`
`several secondary measures:
`
`
`Table 3: Study 2 Efficacy Results
`
`
`
`
`
`P-Value
`
`
`
`0.055
`
`
`
`0.25
`
`
`
`11
`
`
`COPAXONE
`(N=125)
`
`
`1.19/2 years
`
`
`
`Placebo
`(N=126)
`
`
`1.68 /2 years
`
`
`
`
`
`34/126 (27%)
`
`
`
`
`
`42/125 (34%)
`
`
`
`
`Mean No. of
`Relapses
`
`% Relapse-Free
`Patients
`
`
`
`
`
`
`COPAXONE (N=25)
`
`
`
`14/25 (56%)
`
`
`0.6/2 years
`
`
`3.2
`
`
`>700
`
`
`
`Placebo (N=25)
`
`
`7/25 (28%)
`
`
`2.4/2 years
`
`
`1.6
`
`
`150
`
`
`20/25 (80%)
`
`
`13/25 (52%)
`
`
`
`P-Value
`
`
`0.085
`
`
`0.005
`
`
`0.025
`
`
`0.03
`
`
`0.07
`
`
`% Relapse-Free
`Patients
`
`Mean Relapse
`
`Frequency
`
`Reduction in
`Relapse Rate
`Compared to
`Prestudy
`
`Median Time to First
`Relapse (days)
`
`% 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.
`
`
`Page 13 of 22
`
`

`
`Median Time to First
`Relapse (days)
`
`% of Progression-
`Free Patients
`
`Mean Change in
`DSS
`
`287
`
`
`98/125 (78%)
`
`
`-0.05
`
`198
`
`0.23
`
`
`95/126 (75%)
`
`
` 0.48
`
`
`+0.21
`
`
`0.023
`
`
`
`In both studies, COPAXONE exhibited a clear beneficial effect on relapse
`rate, and it is based on this evidence that COPAXONE is considered effective.
`
`In Study 3, 481 patients who had recently (within 90 days) experienced an
`isolated demyelinating event and who had lesions typical of multiple sclerosis on
`brain MRI were randomized to receive either COPAXONE 20 mg/day (n=243) or
`placebo (n=238). The primary outcome measure was time to development of a
`second exacerbation. Patients were followed for up to three years or until they
`reached the primary endpoint. Secondary outcomes were brain MRI measures,
`including number of new T2 lesions and T2 lesion volume.
`Time to development of a second exacerbation was significantly delayed in
`patients treated with COPAXONE compared to placebo (Hazard Ratio = 0.55; 95%
`confidence interval 0.40 to 0.77; Figure 1). The Kaplan-Meier estimates of the
`percentage of patients developing a relapse within 36 months were 42.9% in the
`placebo group and 24.7% in the COPAXONE group.
`
`Figure 1: Time to Second Exacerbation
`
`
`
`
`
`
`12
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`Page 14 of 22
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`

`
`
`
`%)
`
`Second Exacerbation (
`
`
`
`Patients treated with COPAXONE demonstrated fewer new T2 lesions at the
`last observation (rate ratio 0.41; confidence interval 0.28 to 0.59; p < 0.0001).
`Additionally, baseline-adjusted T2 lesion volume at the last observation was lower
`for patients treated with COPAXONE (ratio of 0.89; confidence interval 0.84 to 0.94;
`p = 0.0001).
`
`Study 4 was a multinational study in which MRI parameters were used both
`as primary and secondary endpoints. A total of 239 patients with RRMS
`(COPAXONE: n=119; and placebo: n=120) were randomized. Inclusion criteria were
`similar to those in the second study with the additional criterion that patients had to
`have at least one Gd-enhancing lesion on the screening MRI. The patients were
`treated in a double-blind manner for nine months, during which they underwent
`monthly MRI scanning. The primary endpoint for the double-blind phase was the
`total cumulative number of T1 Gd-enhancing lesions over the nine months. Table 4
`summarizes the results for the primary outcome measure monitored during the trial
`for the intent-to-treat cohort.
`
`
`
`Table 4: Study 4 MRI Results
`
`
`
`
`COPAXONE
`(N=119)
`11
`
`Placebo
`(N=120)
`17
`
`P-Value
`
`0.0030
`
`Medians of the Cumulative
`Number o