Taliglucerase alfa

12.1 Mechanism of Action Gaucher disease is an autosomal recessive disorder caused by mutations in the human glucocerebrosidase gene, which results in a reduced activity of the lysosomal enzyme glucocerebrosidase. Glucocerebrosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency results in accumulation of substrate glucocerebroside primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells," which accumulate in the liver, spleen and bone marrow. ELELYSO, an enzyme replacement therapy, is a recombinant analog of human lysosomal glucocerebrosidase that catalyzes the hydrolysis of glucocerebroside to glucose and ceramide, reducing the amount of accumulated glucocerebroside. ELELYSO uptake into cellular lysosomes is mediated by binding of ELELYSO mannose oligosaccharide chains to specific mannose receptors on the cell surface leading to internalization and subsequent transport to the lysosomes.

1 INDICATIONS AND USAGE ELELYSO is indicated for the treatment of patients 4 years of age and older with a confirmed diagnosis of Type 1 Gaucher disease. ELELYSO is a hydrolytic lysosomal glucocerebroside-specific enzyme indicated for the treatment of patients 4 years and older with a confirmed diagnosis of Type 1 Gaucher disease ( 1 ).

2 DOSAGE AND ADMINISTRATION Recommendations Prior to ELELYSO Treatment ( 2.1 ): • Administration of ELELYSO should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Recommended Dosage in Patients 4 Years and Older ( 2.2 ): • Treatment-naïve : 60 units/kg administered every other week as a 60- to 120-minute intravenous infusion. • Patients switching from imiglucerase : Initiate ELELYSO intravenous treatment (60- to 120-minute infusion) with the same units/kg imiglucerase dosage and subsequently administer ELELYSO every other week. Dosage adjustments can be based on achievement and maintenance of each patient’s therapeutic goals. Preparation and Administration ( 2.3, 2.4, 2.5 ): • Reconstitute, dilute and administer under the supervision of a healthcare professional. • See Full Prescribing Information for complete instructions. 2.1 Recommendations Prior to ELELYSO Treatment Administration of ELELYSO should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1) ] . Initiate ELELYSO in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1) ] . To reduce the risk of hypersensitivity reactions, consider pretreatment with antihistamines and/or corticosteroids [see Warnings and Precautions (5.1) ] . 2.2 Recommended Dosage in Patients 4 Years and Older Treatment-Naïve Patients 4 Years of Age and Older The recommended dosage of ELELYSO is 60 units/kg (based on actual body weight) administered every other week as a 60- to 120-minute intravenous infusion. Patients 4 Years of Age and Older Switching from Imiglucerase If it is acceptable to switch from a stable imiglucerase dosage to ELELYSO, initiate ELELYSO intravenous treatment (60- to 120-minute infusion) with the same units/kg imiglucerase dosage and subsequently administer ELELYSO every other week. Dosage adjustments can be made based on achievement and maintenance of each patient's therapeutic goals. 2.3 Preparation Instructions ELELYSO should be reconstituted, diluted, and administered under the supervision of a healthcare professional. Prepare ELELYSO according to the following steps using aseptic technique: a. Determine the number of vials to be reconstituted based on the patient's weight in kg and the recommended dose [see Dosage and Administration (2.2) ] . Round the number of vials up to the next whole number. b. Remove the required number of vials from the refrigerator. Do not leave these vials at room temperature longer than 24 hours prior to reconstitution. Do not heat or microwave these vials. c. Reconstitute each vial of ELELYSO with 5.1 mL of Sterile Water for Injection, USP to yield a reconstituted product with a concentration of 40 units/mL and an extractable volume of 5 mL. (1) Upon reconstitution, mix vials gently. DO NOT SHAKE. (2) Prior to further dilution, visually inspect the reconstituted solution in the vials for particulate matter and discoloration. The solution should be clear and colorless. Discard if particulate matter is present or the solution is discolored. d. Withdraw the calculated dose of drug from the appropriate number of vials and dilute with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 to 200 mL. Discard any unused reconstituted solution. (1) For pediatric patients 4 years of age and older, use a final volume of 100 to 120 mL. (2) For adult patients, may use a final volume of 130 to 150 mL. However, if the volume of reconstituted product alone is equal to or greater than 130 to 150 mL, then the final volume should not exceed 200 mL. e. Mix the diluted solution gently. DO NOT SHAKE. Since this is a protein solution, slight flocculation (described as translucent fibers) occurs occasionally after dilution. f. Discard any unused diluted solution. 2.4 Storage and Handling of the Reconstituted and Diluted Solution • If the reconstituted ELELYSO vial is not used immediately, refrigerate at 2 °C to 8 °C (36 °F to 46 °F) for up to 24 hours (under protection from light) or store at controlled room temperature at 20 °C to 25 °C (68 °F to 77 °F) for up to 4 hours (without protection from light). • If the diluted solution is not administered immediately, refrigerate at 2 °C to 8 °C (36 °F to 46 °F) for up to 24 hours (under protection from light). • The total storage time for the reconstituted and diluted solution should not exceed 24 hours. Discard the unused reconstituted or diluted solution after 24 hours from the start of preparation. • Do not freeze. 2.5 Administration Instructions After reconstitution and dilution, administer via intravenous infusion over a minimum of 60 minutes and with an in-line low protein-binding 0.2 micron filter. • For pediatric patients who weigh (based on actual body weight): o Less than 30 kg use an

6 ADVERSE REACTIONS The most common adverse reactions are: • Treatment-Naïve Adults (≥5%): headache, arthralgia, fatigue, nausea, dizziness, abdominal pain, pruritus, flushing, vomiting, urticaria ( 6.1 ). • Patients who Switched from Imiglucerase, after 9 Months on Treatment (≥10%): arthralgia, headache, pain in extremity ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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. Adverse Reactions from Clinical Trials of ELELYSO as Initial Therapy • Clinical Trial in Adult Patients The safety of ELELYSO at dosages of either 30 units/kg (n=16) (50% of the recommended dosage) [see Dosage and Administration (2.1) ] or 60 units/kg (n=16) administered intravenously every other week was assessed in 32 adult treatment-naïve patients (aged 19 to 74 years) with Type 1 Gaucher disease in a 9-month double-blind, randomized clinical trial (Trial 1) [see Clinical Studies (14) ] . Table 1 presents the adverse reactions that occurred in these ELELYSO-treated patients. Table 1: Adverse Reactions in ≥5% of Treatment-Naïve Adult Patients Treated with ELELYSO Preferred Term Treatment-Naïve Adults (N=32) n (%) Headache 6 (19) Arthralgia 4 (13) Fatigue 3 (9) Nausea 3 (9) Dizziness 3 (9) Abdominal pain 2 (6) Pruritus 2 (6) Flushing 2 (6) Vomiting 2 (6) Urticaria 2 (6) • Clinical Trial in Pediatric Patients 16 Years of Age and Younger The safety of ELELYSO at dosages of either 30 units/kg (n=4) (50% of the recommended dosage) [see Dosage and Administration (2.1) ] or 60 units/kg (n=5) administered intravenously every other week was assessed in 9 pediatric treatment-naïve patients (aged 2 to 13 years) with Type 1 Gaucher disease in a 12-month randomized clinical trial (Trial 2) [see Clinical Studies (14) ] . The most common adverse reaction (≥10%) was vomiting, which occurred in 4 of 9 patients. Two patients developed hypersensitivity reactions; 1 patient experienced severe vomiting and gastrointestinal inflammation, and 1 experienced mild throat irritation and chest discomfort. Both patients responded to treatment with antihistamines and continued ELELYSO treatment. Adverse Reactions in a Clinical Trial in Patients Who Switched from Imiglucerase to ELELYSO The safety of ELELYSO was assessed in 31 patients (26 adult and 5 pediatric patients), ages 6 to 66 years old, with Type 1 Gaucher disease who had previously been receiving imiglucerase treatment for a minimum of 2 years (Trial 3). ELELYSO was administered intravenously every other week for 9 months at the same number of units as each patient's previous imiglucerase dose. Table 2 presents the adverse reactions in these ELELYSO-treated patients. Table 2: Adverse Reactions in ≥10% of ELELYSO-Treated Patients Who Switched from Imiglucerase to ELELYSO (after 9 months on treatment) Preferred Term Adult and Pediatric Patients Switched from Imiglucerase (N=31) n (%) Arthralgia 4 (13) Headache 4 (13) Pain in extremity 3 (10) Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions Trials 1, 2, and 3 evaluated ELELYSO enzyme replacement therapy (ERT)-naïve and ERT-experienced adult and pediatric patients with Gaucher disease [see Clinical Studies (14.1, 14.2) ] . In patients with Type 1 Gaucher disease, hypersensitivity reactions occurred in 36% (9/25) of ELELYSO-treated patients who developed ADA during the treatment period and in 15% (6/41) of ELELYSO-treated patients who did not develop ADA during the treatment period [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.6) ] . Of the 9 ELELYSO-treated patients who tested positive for ADA and who developed hypersensitivity reactions, 2 patients had anaphylaxis and 1 additional patient discontinued ELELYSO due to hypersensitivity reactions. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ELELYSO. Because these reactions include those reported voluntarily from a population of uncertain size in addition to those from postmarketing studies, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: • Gastrointestinal disorders : Vomiting, diarrhea • General disorders and administration site conditions : Fatigue • Immune system disorders : Anaphylaxis [see Warnings and Precautions (5.1) ] , Type III immune mediated fixed drug eruption • Musculoskeletal and connective tissue disorders : Back pain