Glatiramer

5 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 ) • Glatopa can modify immune response ( 5.4 ) • Hepatic Injury: if signs or symptoms of hepatic dysfunction occur, consider discontinuing Glatopa ( 5.5 ) 5.1 Immediate Post-Injection Reaction Approximately 16% of patients exposed to glatiramer acetate injection 20 mg per mL in the five placebo-controlled trials compared to 4% of those on placebo, and approximately 2% of patients exposed to glatiramer acetate injection 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 glatiramer acetate injection 20 mg per mL patients in the five placebo-controlled studies compared to 6% of placebo patients, and approximately 2% of patients exposed to glatiramer acetate injection 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 glatiramer acetate injection 20 mg per mL in the five placebo-controlled trials compared to none on placebo, and 0.5% of patients exposed to glatiramer acetate injection 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. 5.4 Potential Effects on Immune Response Because glatiramer acetate injection can modify immune response, it may interfere with immune functions. For example, treatment with glatiramer acetate injection 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 glatiramer acetate injection does this, but there has not been a systematic evaluation of this risk. Because glatiramer acetate injection 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 glatiramer acetate injection is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with glatiramer acetate injection 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 glatiramer acetate injection 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. 5.5 Hepatic Injury Cases of hepatic injury, some severe, including liver failure and hepatitis with jaundice, have been reported with Glatopa. Hepatic injury has occurred from days to years after initiating treatment with Glatopa. If signs or symptoms of liver dysfunction occur, consider discontinuation of Glatopa.

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 )] • Hepatic Injury [see Warnings and Precautions ( 5.5 )] • In controlled studies of glatiramer acetate injection 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 glatiramer acetate injection 40 mg/mL, most common adverse reactions (≥10% and ≥1.5 times higher than placebo) were: injection site reactions ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Glatiramer Acetate Injection 20 mg per mL per day Among 563 patients treated with glatiramer acetate injection 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 glatiramer acetate injection 20 mg per mL in the placebo-controlled trials. These signs and symptoms were numerically more common in patients treated with glatiramer acetate injection 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 Glatiramer Acetate Injection (20 mg per mL daily) than with Placebo Glatiramer Acetate Injection 20 mg/mL (n=563) % Placebo (n=564) % Blood And Lymphatic System Disorders Lymphadenopathy 7 3 Cardiac Disorders Palpitations 9 4 Tachycardia 5 2 Eye Disorders Eye Disorder 3 1 Diplopia 3 2 Gastrointestinal Disorders Nausea 15 11 Vomiting 7 4 Dysphagia 2 1 General Disorders And Administration Injection Site Erythema 43 10 Site Conditions Injection Site Pain 40 20 Injection Site Pruritus 27 4 Injection Site Mass 26 6 Asthenia 22 21 Pain 20 17 Injection Site Edema 19 4 Chest Pain 13 6 Injection Site Inflammation 9 1 Edema 8 2 Injection Site Reaction 8 1 Pyrexia 6 5 Injection Site Hypersensitivity 4 0 Local Reaction 3 1 Chills 3 1 Face Edema 3 1 Edema Peripheral 3 2 Injection Site Fibrosis 2 1 Injection Site Atrophy Injection site atrophy comprises terms relating to localized lipoatrophy at injection site 2 0 Immune System Disorders Hypersensitivity 3 2 Infections And Infestations Infection 30 28 Influenza 14 13 Rhinitis 7 5 Bronchitis 6 5 Gastroenteritis 6 4 Vaginal Candidiasis 4 2 Metabolism And Nutrition Disorders Weight Increased 3 1 Musculoskeletal And Connective Back Pain 12 10 Tissue Disorders Neoplasms Benign, Malignant And Benign Neoplasm of Skin 2 1 Unspecified (Incl Cysts And Polyps) Nervous System Disorders Tremor 4 2 Migraine 4 2 Syncope 3 2 Speech Disorder 2 1 Psychiatric Disorders Anxiety 13 10 Nervousness 2 1 Renal And Urinary Disorders Micturition Urgency 5 4 Respiratory, Thoracic And Mediastinal Dyspnea 14 4 Disorders Cough 6 5 Laryngospasm 2 1 Skin And Subcutaneous Tissue Rash 19 11 Disorders Hyperhidrosis 7 5 Pruritus 5 4 Urticaria 3 1 Skin Disorder 3 1 Vascular Disorders Vasodilatation 20 5 Adverse reactions which occurred only in 4 to 5 more subjects in the glatiramer acetate injection group than in the placebo group (less than 1% difference), but for which a relationship to glatiramer acetate injection could not be excluded, were arthralgia and herpes simplex. Laboratory analyses were performed on all patients participating in the clinical program for glatiramer acetate injection. Clinically-significant laboratory values for hematology, chemistry, and urinalysis were similar for both glatiramer acetate injection and placebo groups in blinded clinical trials. In controlled trials one patient discontinued treatment due to thrombocytopenia (16 x 10 9 /L), which resolved after discontinuation of treatment. Data on adverse reactions occurring in the controlled clinical trials of glatiramer acetate injection 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 glatiramer acetate injection 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 glatiramer acetate injection 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 glatiramer acetate injection and reported a reaction divided by the total number of patients exposed to glatiramer acetate injection. 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 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. Glatiramer Acetate Injection 40 mg per mL three times per week Among 943 patients treated with glatiramer acetate injection 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 glatiramer acetate injection 40 mg per mL in the blinded, placebo-controlled trial. These signs and symptoms were numerically more common in patients treated with glatiramer acetate injection 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 Glatiramer Acetate Injection (40 mg per mL three times per week) than with Placebo Glatiramer Acetate Injection 40 mg/mL (n=943) % Placebo (n=461) % General Disorders And Administration Site Conditions Injection Site Erythema 22 2 Injection Site Pain 10 2 Injection Site Mass 6 0 Injection Site Pruritus 6 0 Injection Site Edema 6 0 Pyrexia 3 2 Influenza-like Illness 3 2 Injection Site Inflammation 2 0 Chills 2 0 Chest Pain 2 1 Infections And Infestations Nasopharyngitis 11 9 Respiratory Tract Infection Viral 3 2 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 3 0 Vascular Disorders Vasodilatation 3 0 Gastrointestinal Disorders Nausea 2 1 Skin And Subcutaneous Tissue Disorders Erythema 2 0 Rash 2 1 No new adverse reactions appeared in subjects treated with glatiramer acetate injection 40 mg per mL three times per week as compared to subjects treated with glatiramer acetate injection 20 mg per mL per day in clinical trials and during postmarketing experience. Data on adverse reactions occurring in the controlled clinical trial of glatiramer acetate injection 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 glatiramer acetate injection. 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; eructation Hemic and Lymphatic System : thrombocytopenia; lymphoma-like reaction; acute leukemia Hepatobiliary Disorders : cholelithiasis; liver function abnormality; cirrhosis of the liver; hepatitis; hepatic injury [see Warnings and Precautions ( 5.5 )] 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

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available human data on the use of Glatopa in pregnant women are not sufficient to support conclusions about drug-associated risk for major birth defects and miscarriage. Administration of glatiramer acetate by subcutaneous injection to pregnant rats and rabbits resulted in no adverse effects on embryo-fetal or offspring development ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data There are no adequate and well-controlled studies of Glatopa in pregnant women. The available postmarketing reports, case series, and small cohort studies do not provide sufficient information to support conclusions about drug-associated risk for major birth defects and miscarriage. Animal Data 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/m 2 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 Lactation Risk Summary There are no data on the presence of glatiramer acetate in human milk, the effects on breastfed infants, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Glatopa and any potential adverse effects on the breastfed infant from Glatopa or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Glatopa have not been established in patients under 18 years of age. 8.5 Geriatric Use Glatopa 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.