Glatiramer Acetate

1 INDICATIONS AND USAGE Glatopa is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Glatopa is indicated for the treatment of relapsing-forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults ( 1 ).

2 DOSAGE AND ADMINISTRATION • For subcutaneous injection only; doses are not interchangeable ( 2.1 ) • Glatopa 20 mg/mL per day ( 2.1 ) • Glatopa 40 mg/mL three times per week ( 2.1 ) • Before use, allow the solution to warm to room temperature ( 2.2 ) 2.1 Recommended Dose Glatopa is for subcutaneous use only. Do not administer intravenously. The dosing schedule depends on the product strength that is selected. The recommended doses are: • Glatopa 20 mg per mL: administer once per day or • Glatopa 40 mg per mL: administer three times per week and at least 48 hours apart. Glatopa 20 mg per mL and Glatopa 40 mg per mL are not interchangeable. 2.2 Instructions for Use Remove one blister-packaged pre-filled syringe from the refrigerated carton. Let the pre-filled 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 pre-filled syringe is for single use only. Discard unused portions.

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

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.