Glatiramer Acetate

1 INDICATIONS AND USAGE Glatiramer acetate injection 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. Glatiramer acetate injection 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 ) Glatiramer acetate injection 20 mg/mL per day ( 2.1 ) Glatiramer acetate injection 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 Glatiramer acetate injection is for subcutaneous use only [see Dosage and Administration (2.2) ] . Do not administer intravenously. The dosing schedule depends on the product strength that is selected. The recommended doses are: • Glatiramer acetate injection 20 mg per mL: administer once per day or • Glatiramer acetate injection 40 mg per mL: administer three times per week and at least 48 hours apart Glatiramer acetate injection 20 mg per mL and glatiramer acetate injection 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. Using an autoinjector that is not compatible for use with Ajenat’s glatiramer acetate injection may increase the risk for medication errors, such as dose omission or administration of a partial dose [see Warnings and Precautions (5.7) ] .

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 ( 5.2 ) Chest pain, usually transient ( 5.3 ) Lipoatrophy and skin necrosis may occur. Instruct patients in proper injection technique and to rotate injection sites ( 5.4 ) Glatiramer acetate can modify immune response ( 5.5 ) Hepatic Injury: if signs or symptoms of hepatic dysfunction occur, consider discontinuing glatiramer acetate ( 5.6 ) Glatiramer Acetate Products and Administration Errors: Using an optional autoinjector that is not compatible for use with Ajenat’s glatiramer acetate injection may increase the risk for medication errors, such as dose omission or administration of a partial dose. ( 5.7 ) 5.1 Anaphylactic Reactions Life-threatening and fatal anaphylaxis has been reported with glatiramer acetate injection [see Adverse Reactions ( 6.2 )]. Glatiramer acetate injection is contraindicated in patients with a history of hypersensitivity reactions to glatiramer acetate injection, including anaphylaxis [see Contraindications ( 4 )] . Anaphylaxis can occur at any time following initiation glatiramer acetate injection therapy, from as early as after the first dose, up to years after initiation of treatment. Anaphylaxis occurred within an hour of a glatiramer acetate injection in most of the reported cases. Some signs and symptoms of anaphylactic reactions may overlap with those of immedicate post-injection reactiongs [see Warnings and Precautions ( 5.2 )]. All patients receiving treatment with glatiramer acetate injection and caregivers should be informed about the signs and symptoms of anaphylactic reactions, and that they must seek immediate emergency medical care in case of experiencing such symptoms. If an anaphylactic reaction occurs, treatment with glatiramer acetate injection must be immediately discontinued. Unless a clear alternative etiology is identified, glatiramer acetate injection must be permanently discontinued [see Contraindications ( 4 )]. 5.2 Immediate Post-Injection Reaction Approximately 16% of patients exposed to glatiramer acetate injection 20 mg per mL in the 5 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. These events are termed immediate post-injection reactions. The symptoms of an immediate post-injetcion reaction may overlap with those of anaphylaxis; prompt identification of anaphylaxis is important to avoid a delay in treatment. In general, symptoms of an immediate post-injection reaction have 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 developed fatal anaphylaxis and/or 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. 5.3 Chest Pain Approximately 13% of glatiramer acetate injection 20 mg per mL patients in the 5 placebo-controlled studies compared to 6% of placebo patients, and approximately 2% of patients exposed to glatiramer acetate…

4 CONTRAINDICATIONS Glatiramer acetate injection is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol. Reactions have included anaphylaxis [see Warning and Precautions ( 5.1 )] . Known hypersensitivity to glatiramer acetate or mannitol ( 4 )

8.1 Pregnancy Risk Summary Available data from pharmacovigilance and published observational studies over decades of use with glatiramer acetate during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes ( see Data ). Administration of glatiramer acetate by subcutaneous injection to pregnant rats and rabbits resulted in no adverse effects on embryofetal or offspring development (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other outcomes. 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 Data from pharmacovigilance and published observational studies have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes when glatiramer acetate was used during pregnancy. However, the published comparative observational studies have methodological limitations, such as short exposure duration during pregnancy, confounding, selection bias, and exposure misclassification. Animal Data In rats or rabbits receiving glatiramer acetate by subcutaneous injection during the period of organogenesis, no adverse effects on embryofetal 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.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Anaphylactic Reactions [see Warnings and Precautions (5.1) ] • Immediate Post-Injection Reaction [see Warnings and Precautions (5.2) ] • Chest Pain [see Warnings and Precautions (5.3) ] • Lipoatrophy and Skin Necrosis [see Warnings and Precautions (5.4) ] • Potential Effects on Immune Response [see Warnings and Precautions (5.5) ] • Hepatic Injury [see Warnings and Precautions (5.6) ] 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 Ajenat Pharmaceuticals, LLC at +1-727-234-8872 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 Site Conditions Injection Site Erythema 43 10 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 Tissue Disorders Back Pain 12 10 Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps) Benign Neoplasm of Skin 2 1 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 Disorders Dyspnea 14 4 Cough 6 5 Laryngospasm 2 1 Skin and Subcutaneous Tissue Disorders Rash 19 11 Hyperhidrosi…