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
`Warnings and Precautions, Immediate Post-Injection Reaction (5.1) 9/2018
`
` _________________
`
`INDICATIONS AND US AGE
`COPAXONE is indicated for the treatment of patients with relapsing -forms of
`multiple sclerosis (1).
`
` ______________
`DOSAGE AND ADMINIS TRATION
`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)
`
`_______________
`
`
`
` ______________
`WARNINGS AND PRECAUTIONS
`Immediate Post-Injection Reaction (flushing, chest pain,
`palpitations, tachycardia, anxiety, dyspnea, throat constriction,
`and/or urticaria), may occur within seconds to minutes after
`injection and are generally transient and self-limiting (5.1)
`Chest pain, usually transient (5 2)
`Lipoatrophy and skin necrosis may occur. Instruct patients in
`proper injection technique and to rotate injection sites (5.3)
`COPAXONE can modify immune response (5.4)
`
`
`
`
`
`
`
`
`
` __________________
`
`
`
`
`
` ___________________
`
`
`ADVERS E 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, vasodilatation, 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 ADVERS E REACTIONS, contact Teva
`Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
` ______________
`US E IN SPECIFIC POPULATIO NS
`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)
`
`
`
`
`
` ______________
`
`
`
`
`
`
`
`
`
`
`
` _____________
`
`
`
`
`
`DOSAGE FORMS AND S TRENGTHS
`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)
`
`
`
`
`
`
` __________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 1
`
`
`2
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dose
`2.2
`Instructions for Use
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`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
`ADVERS E REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`
`6
`
`7
`8
`
`
`
`
`
`Reference ID: 4317261
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approve d patient labeling.
`
`Revised: 9/2018
`
`Labor and Delivery
`8 2
`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 PHARMACOLOG Y
`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.
`
`1
`
`
`
`Biogen Exhibit 2160
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 29
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`COPAXONE (glatiramer acetate injection) 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 dosing
`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.
`
`
`
`Reference ID: 4317261
`
`2
`
`
`
`Page 2 of 29
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`

`

`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 that may occur immediately (within seconds to
`minutes, with the majority of symptoms observed within 1 hour) after injection and included at
`least two of the following: flushing, chest pain, palpitations, tachycardia, 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 specific 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
`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 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 postmarketing 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.
`
`
`
`Reference ID: 4317261
`
`3
`
`
`
`Page 3 of 29
`
`

`

`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 glatiramer 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 administration of most any
`foreign substance, and therefore, this risk cannot be excluded.
`
`6
`
`ADVERSE REACTIONS
`
`The following serious adverse reactions are described elsewhere in the labeling:
`
`Immediate Post-Injection Reaction [see Warnings and Precautions (5.1)]
` Chest Pain [see Warnings and Precautions (5.2)]
` Lipoatrophy and Skin Necrosis [see Warnings and Precautions (5.3)]
` Potential Effects on Immune Response [see Warnings and Precautions (5.4)]
`
`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 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 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.
`
`
`
`Reference ID: 4317261
`
`4
`
`
`
`Page 4 of 29
`
`

`

`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)
`
`Placebo
`
`(n=564)
`
`Blood And Lymphatic System
`Disorders
`
`Cardiac Disorders
`
`Eye Disorders
`
`Gastrointestinal Disorders
`
`General Disorders And Administration
`Site Conditions
`
`Lymphadenopathy
`
`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
`
`Injection Site Reaction
`
`Pyrexia
`
`Injection Site
`Hypersensitivity
`
`Local Reaction
`
`Chills
`
`Face Edema
`
`Edema Peripheral
`
`Injection Site Fibrosis
`
`Injection Site Atrophy*
`
`7%
`
`9%
`
`5%
`
`3%
`
`3%
`
`15%
`
`7%
`
`2%
`
`43%
`
`40%
`
`27%
`
`26%
`
`22%
`
`20%
`
`19%
`
`13%
`
`9%
`
`8%
`
`8%
`
`6%
`
`4%
`
`3%
`
`3%
`
`3%
`
`3%
`
`2%
`
`2%
`
`3%
`
`4%
`
`2%
`
`1%
`
`2%
`
`11%
`
`4%
`
`1%
`
`10%
`
`20%
`
`4%
`
`6%
`
`21%
`
`17%
`
`4%
`
`6%
`
`1%
`
`2%
`
`1%
`
`5%
`
`0%
`
`1%
`
`1%
`
`1%
`
`2%
`
`1%
`
`0%
`
`
`
`Reference ID: 4317261
`
`5
`
`
`
`Page 5 of 29
`
`

`

`
`
`
`
`Immune System Disorders
`
`Hypersensitivity
`
`Infections And Infestations
`
`Infection
`
`Influenza
`
`Rhinitis
`
`Bronchitis
`
`Gastroenteritis
`
`Vaginal Candidiasis
`
`Metabolism And Nutrition Disorders
`
`Weight Increased
`
`COPAXONE
`20 mg/mL
`(n=563)
`
`Placebo
`
`(n=564)
`
`3%
`
`30%
`
`14%
`
`7%
`
`6%
`
`6%
`
`4%
`
`3%
`
`2%
`
`28%
`
`13%
`
`5%
`
`5%
`
`4%
`
`2%
`
`1%
`
`Back Pain
`
`12%
`
`10%
`
`Musculoskeletal And Connective
`Tissue Disorders
`
`Neoplasms Benign, Malignant And
`Unspecified (Incl Cysts And Polyps)
`
`Nervous System Disorders
`
`Psychiatric Disorders
`
`Benign Neoplasm of Skin
`
`Tremor
`
`Migraine
`
`Syncope
`
`Speech Disorder
`
`Anxiety
`
`Nervousness
`
`2%
`
`4%
`
`4%
`
`3%
`
`2%
`
`13%
`
`2%
`
`5%
`
`14%
`
`6%
`
`2%
`
`19%
`
`7%
`
`5%
`
`3%
`
`3%
`
`20%
`
`1%
`
`2%
`
`2%
`
`2%
`
`1%
`
`10%
`
`1%
`
`4%
`
`4%
`
`5%
`
`1%
`
`11%
`
`5%
`
`4%
`
`1%
`
`1%
`
`5%
`
`Renal And Urinary Disorders
`
`Micturition Urgency
`
`Respiratory, Thoracic And Mediastinal
`Disorders
`
`Skin And Subcutaneous Tissue
`Disorders
`
`Vascular Disorders
`
`Dyspnea
`
`Cough
`
`Laryngospasm
`
`Rash
`
`Hyperhidrosis
`
`Pruritus
`
`Urticaria
`
`Skin Disorder
`
`Vasodilatation
`
`*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 relationship to COPAXONE could
`not be excluded, were arthralgia and herpes simplex.
`
`
`
`Reference ID: 4317261
`
`6
`
`
`
`Page 6 of 29
`
`

`

`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 x10 9/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 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, 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, bradycardia,
`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, hepatomegaly,
`increased appetite, melena, mouth ulceration, pancreas disorder, pancreatitis, rectal
`hemorrhage, tenesmus, tongue discoloration, and duodenal ulcer.
`
`Endocrine:
`
`
`
`Reference ID: 4317261
`
`7
`
`
`
`Page 7 of 29
`
`

`

`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.
`
`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.
`
`
`
`Reference ID: 4317261
`
`8
`
`
`
`Page 8 of 29
`
`

`

`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 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 reactions were usually mild in intensity.
`
`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)
`
`Placebo
`
`(n=461)
`
`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
`
`Respiratory, Thoracic and
`Mediastinal Disorders
`
`Dyspnea
`
`Vascular Disorders
`
`Vasodilatation
`
`Gastrointestinal Disorders
`
`Nausea
`
`Skin And Subcutaneous Tissue
`Disorders
`
`Erythema
`
`Rash
`
`22%
`
`10%
`
`6%
`
`6%
`
`6%
`
`3%
`
`3%
`
`2%
`
`2%
`
`2%
`
`11%
`
`3%
`
`3%
`
`3%
`
`2%
`
`2%
`
`2%
`
`2%
`
`2%
`
`0%
`
`0%
`
`0%
`
`2%
`
`2%
`
`0%
`
`0%
`
`1%
`
`9%
`
`2%
`
`0%
`
`0%
`
`1%
`
`0%
`
`1%
`
`
`
`Reference ID: 4317261
`
`9
`
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`Page 9 of 29
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`

`

`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 reactions have been identified during postapproval use of COPAXONE.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure.
`
`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 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
`
`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.
`
`
`
`Reference ID: 4317261
`
`10
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`Page 10 of 29
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`

`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
`
`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.
`
`
`
`Reference ID: 4317261
`
`11
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`

`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 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 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)].
`
`12.3
`
`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
`
`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
`
`
`
`Reference ID: 4317261
`
`12
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`

`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
`
`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 randomized 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 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 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
`
`
`
`Reference ID: 4317261
`
`13
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`patients who received at least 1 dose of treatment and who had at least 1 on-treatment
`assessment):
`
`Table 3:
`
`Study 1 Efficacy Results
`
`
`
`COPAXONE
`20 mg/mL
`
`(n=25)
`
`% Relapse-Free Patients
`
`14/25 (56%)
`
`Mean Relapse
`Frequency
`
`Reduction in Relapse
`Rate Compared to
`Prestudy
`
`Median Time to First
`Relapse (days)
`
`% of Progression-Free*
`Patients
`
`0.6/2 years
`
`3.2
`
`>700
`
`Placebo
`
`(n=25)
`
`7/25 (28%)
`
`2.4/2 years
`
`1.6
`
`150
`
`P-Value
`
`0.085
`
`0.005
`
`0.025
`
`0.03
`
`0.07
`
`20/25 (80%)
`
`13/25 (52%)
`
`*Progression was defined as an increase of at least 1