NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
`
`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)
`(cid:120)
`COPAXONE 20 mg/mL per day (2.1)
`(cid:120)
`COPAXONE 40 mg/mL three times per week (2.1)
`(cid:120)
`Before use, allow the solution to warm to room temperature (2.2)
`(cid:120)
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Injection: 20 mg/mL in a single-dose prefilled syringe with a white
`(cid:120)
`plunger (3)
`Injection: 40 mg/mL in a single-dose, prefilled syringe with a blue
`plunger (3)
`
`(cid:120)
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`Immediate Post-Injection Reaction (flushing, chest pain, palpitations,
`(cid:120)
`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 patients in proper
`injection technique and to rotate injection sites (5.3)
`COPAXONE can modify immune response (5.4)
`
`(cid:120)
`(cid:120)
`
`(cid:120)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`In controlled studies of COPAXONE 20 mg/mL, most common adverse
`(cid:120)
`reactions ((cid:149)10% and (cid:149)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 ((cid:149)10% and (cid:149)1.5 times higher than placebo) were: injection site
`reactions (6.1)
`
`(cid:120)
`
`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
`(cid:120)
`milk (8.3)
`Pediatric Use: The safety and effectiveness of COPAXONE have not
`been established in patients under 18 years of age (8.4)
`
`(cid:120)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`-------------------------------CONTRAINDICATIONS------------------------------
`Known hypersensitivity to glatiramer acetate or mannitol (4)
`_____________________________________________________________________________________________________________________________________
`
`Revised: 01/2014
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`1
`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.
`
`_____________________________________________________________________________________________________________________________________
`
`Reference ID: 3443331
`
`Page 1 of 31
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`Merck 2060
`TWi v Merck
`IPR2023-00049
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`

`

`NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
`
`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
`dosing schedule depends on the product strength that is selected. The
`recommended doses are:
`
`(cid:120) COPAXONE 20 mg per mL: administer once per day
`or
`(cid:120) 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
`
`(cid:120)
`
`(cid:120)
`
`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.
`
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`NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
`
`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,
`palpitations, 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 post-marketing 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.
`
`Reference ID: 3443331
`
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`NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
`
`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
`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
`
`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
`
`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.
`
`Reference ID: 3443331
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`NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
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`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 (cid:116)2% of
`patients and more frequent with COPAXONE (20 mg per mL daily) than with
`placebo
`
`Blood And Lymphatic System Disorders
`Cardiac Disorders
`
`Eye Disorders
`
`Gastrointestinal Disorders
`
`General Disorders And Administration Site
`Conditions
`
`Immune System Disorders
`Infections And Infestations
`
`Metabolism And Nutrition Disorders
`
`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*
`Hypersensitivity
`Infection
`Influenza
`Rhinitis
`Bronchitis
`Gastroenteritis
`Vaginal Candidiasis
`Weight Increased
`
`COPAXONE
`20 mg/mL
`(n=563)
`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%
`30%
`14%
`7%
`6%
`6%
`4%
`3%
`
`Placebo
`(n=564)
`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%
`2%
`28%
`13%
`5%
`5%
`4%
`2%
`1%
`
`Reference ID: 3443331
`
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`NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
`
`Musculoskeletal And Connective Tissue
`Disorders
`Neoplasms Benign, Malignant And
`Unspecified (Incl Cysts And Polyps)
`Nervous System Disorders
`
`Back Pain
`
`Benign Neoplasm of Skin
`
`Psychiatric Disorders
`
`Renal And Urinary Disorders
`Respiratory, Thoracic And Mediastinal
`Disorders
`
`Skin And Subcutaneous Tissue Disorders
`
`COPAXONE
`20 mg/mL
`(n=563)
`
`Placebo
`(n=564)
`
`12%
`
`10%
`
`1%
`2%
`2%
`2%
`1%
`10%
`1%
`4%
`4%
`5%
`1%
`11%
`5%
`4%
`1%
`1%
`5%
`
`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
`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.
`
`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 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
`
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`NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
`
`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:
`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
`
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`
`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.
`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
`
`Reference ID: 3443331
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`NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
`
`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 (cid:149)2%
`of patients and more frequent with COPAXONE (40 mg per mL three times per
`week) than with placebo
`
`General Disorders And
`Administration Site Conditions
`
`Infections And Infestations
`
`Respiratory, Thoracic and
`Mediastinal Disorders
`Vascular Disorders
`Gastrointestinal Disorders
`Skin And Subcutaneous Tissue
`Disorders
`
`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
`Nasopharyngitis
`Respiratory Tract Infection Viral
`Dyspnea
`
`Vasodilatation
`Nausea
`Erythema
`Rash
`
`COPAXONE
`40 mg/mL
`(n=943)
`22%
`10%
`6%
`6%
`6%
`3%
`3%
`2%
`2%
`2%
`11%
`3%
`
`3%
`3%
`2%
`2%
`2%
`
`Placebo
`(n=461)
`2%
`2%
`0%
`0%
`0%
`2%
`2%
`0%
`0%
`1%
`9%
`2%
`
`0%
`0%
`1%
`0%
`1%
`
`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.
`
`Reference ID: 3443331
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`NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
`
`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 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.
`
`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
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`NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
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`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.
`
`Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine,
`L-lysine and L-tyrosine, acetate (salt). Its structural formula is:
`
`Reference ID: 3443331
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`NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
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`(Glu, Ala, Lys, Tyr)x(cid:404)xCH3COOH
`(C5H9NO4(cid:404)C3H7NO2(cid:404)C6H14N2O2(cid:404)C9H11NO3)x(cid:404)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
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`Reference ID: 3443331
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`NDA 020622/S-089 FDA Approved Labeling Text dated January 28, 2014
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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
`
`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).
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`Reference ID: 3443331
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`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