Fabrazyme

Boxed Warning XX/2024 Dosage and Administration ( 2.1 ) XX/2024 Warnings and Precautions ( 5.1 ) 2/2024

1 INDICATIONS AND USAGE FABRAZYME ® is indicated for the treatment of adult and pediatric patients 2 years of age and older with confirmed Fabry disease. FABRAZYME is a hydrolytic lysosomal neutral glycosphingolipid-specific enzyme indicated for the treatment of adult and pediatric patients 2 years of age and older with confirmed Fabry disease. ( 1 )

2 DOSAGE AND ADMINISTRATION Administration of FABRAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. ( 2.1 ) The recommended dosage is 1 mg/kg body weight given every two weeks as an intravenous infusion. ( 2.2 ) See the full prescribing information for rechallenge, preparation, storage, and administration instructions. ( 2.3 , 2.4 , 2.5 , 2.6 ) 2.1 Recommendations Prior to FABRAZYME Treatment Administration of FABRAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1) ]. Initiate FABRAZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1) ]. Prior to FABRAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1 , 5.2) ] . FABRAZYME must be reconstituted and diluted prior to use [see Dosage and Administration (2.4) ] 2.2 Recommended Dosage and Administration The recommended dosage of FABRAZYME is 1 mg/kg body weight infused every two weeks as an intravenous infusion. The initial recommended infusion rate is 0.25 mg/min (15 mg/hour) [see Dosage and Administration (2.6) ] . 2.3 Rechallenge Instructions Patients who have had a positive skin test to FABRAZYME or who have tested positive for anti-FABRAZYME IgE may be successfully rechallenged with FABRAZYME. The initial rechallenge administration should be a low dose at a lower infusion rate, e.g., one-half the therapeutic dose (0.5 mg/kg) at 1/25 th of the initial standard recommended rate (0.01 mg/min or 0.6 mg/hr). Once a patient tolerates the infusion, the dose may be increased to reach the approved dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards (doubled every 30 minutes up to a maximum rate of 0.25 mg/minute), as tolerated [see Adverse Reactions (6.2) ] . 2.4 Preparation Instructions Use aseptic technique during preparation. Reconstitute and dilute FABRAZYME in the following manner: Reconstitution Instructions 1. Determine the number of 35 mg and 5 mg FABRAZYME vials to be reconstituted based on actual body weight (kg) and the recommended dose [see Dosage and Administration (2.2) ] . 2. Remove the required number of 35 mg and 5 mg FABRAZYME vials from the refrigerator and allow the vials to sit for approximately 30 minutes at room temperature 20°C to 25°C (68°F to 77°F) before use. 3. Reconstitute each vial by directing the diluent down the inside wall of each vial then gently tilt and roll each vial. Use the following volumes for reconstitution: 7.2 mL of FABRAZYME Sterile Water for Injection into the 35 mg vial. Total extractable amount per vial is 35 mg, 7 mL. 1.1 mL of Sterile Water for Injection into the 5 mg vial. Total extractable amount per vial is 5 mg, 1 mL. 4. Each reconstituted vial will yield a concentration of 5 mg/mL of agalsidase beta. 5. Do not shake or agitate the product. 6. Visually inspect the reconstituted solution in the vials for particulate matter and discoloration. The reconstituted solution should be clear and colorless. Discard if visible particulate matter is present or the solution is discolored. Dilution Instructions 7. Select an appropriate size 0.9% Sodium Chloride Injection infusion bag and prepare by removing a volume equal to the required FABRAZYME volume to achieve a total volume per Table 1. 8. Slowly withdraw the required volume of reconstituted solution from the FABRAZYME vial(s). Discard any unused reconstituted solution remaining in the vial. Table 1: Total Infusion Volume Based on Patient Weight Patient Weight (kg) Total Volume (mL) ≤35 50 35.1 to 70 100 70.1 to 100 250 >100 500 9. Gently inject the FABRAZYME reconstituted solution into the port of the 0.9% Sodium Chloride Injection infusion bag. D …

3 DOSAGE FORMS AND STRENGTHS For injection: 5 mg or 35 mg of agalsidase beta as a white to off-white, lyophilized cake or powder in a single-dose vial for reconstitution. For injection: 5 mg or 35 mg of agalsidase beta as a lyophilized cake or powder in a single-dose vial for reconstitution. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] Infusion-Associated Reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (≥20%) are: upper respiratory tract infection, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at 1-800-633-1610 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 clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in patients in clinical practice. The data described below reflect exposure of 80 patients, ages 16 to 61 years, to 1 mg/kg FABRAZYME every two weeks in two separate double-blind, placebo-controlled clinical trials, for periods ranging from 1 to 35 months (mean 15.5 months). All 58 patients enrolled in one of the two studies continued into an open-label extension study of FABRAZYME treatment for up to 54 additional months. Patients were treated with antipyretics and antihistamines prior to the infusions. Most Common Adverse Reactions Table 2 enumerates adverse reactions that occurred during the double-blind treatment periods of the two placebo-controlled trials (Study 1 and Study 2) [see Clinical Studies (14) ] . The most common adverse reactions reported with FABRAZYME were infusion-associated reactions, (FABRAZYME 59% vs placebo 27%) some of which were severe (FABRAZYME 5.0% vs placebo 1.7%). Infusion-associated reactions are defined as adverse reactions occurring on the same day as the infusion. Common adverse reactions which occurred in ≥20% of patients treated with FABRAZYME and >2.5% compared to placebo are: upper respiratory tract infection, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness and rash. Table 2: Summary of Common Adverse Reactions Reported at rate of at least 5% in FABRAZYME-treated patients and greater than 2.5% compared to placebo-treated patients. in Clinical Trials (Study 1 and 2) of Patients with Fabry Disease Adverse Reaction FABRAZYME (n=80) % Placebo (n=60) % Upper respiratory tract infection Includes reports of upper respiratory infection, nasal congestion, sinusitis, respiratory tract congestion, and pharyngitis. 53 42 Chills Includes reports of chills and feeling cold. 49 13 Pyrexia 39 22 Headache 39 28 Cough 33 25 Paresthesia 31 18 Fatigue 24 17 Peripheral edema 21 7 Dizziness 21 8 Rash 20 10 Pain in extremity 19 8 Myalgia Includes reports of myalgia and muscle spasms. 18 7 Lower respiratory tract infection 18 7 Pain 16 13 Back pain 16 10 Hypertension 14 5 Pruritus 10 3 Tachycardia 9 3 Excoriation 9 2 Increased blood creatinine 9 5 Tinnitus 8 3 Dyspnea 8 2 Fall 6 3 Burning sensation 6 0 Anxiety 6 3 Depression 6 2 Wheezing 6 0 Hypoacusis 5 0 Chest discomfort 5 2 Fungal infection 5 0 Viral infection 5 0 Hot flush 5 0 Most infusion-associated reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, and/or administration of antipyretics, antihistamines, or steroids. Adverse Reactions in Pediatric Patients In Study 3, the safety profile of FABRAZYME in pediatric Fabry disease patients, ages 8 to 16 years, was similar to that seen in adults. The most common adverse reactions (>20%) were headache, abdominal pain, pharyngitis, fever, nausea, vomiting, rhinitis, diarrhea, arthralgia, and dizziness [see Use in Specific Populations (8.4) and Clinical Studies (14) ] . 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the o …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from a pregnancy sub-study within the Fabry Disease registry, post-marketing case reports, and case series with FABRAZYME use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data ). Reproduction studies performed in rats at doses up to 68 times the human dose have revealed no evidence of effects on embryo-fetal 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 adverse outcomes. In the U.S. 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 Available data from a pregnancy sub-study within the Fabry Disease registry, post-marketing case reports, and case series with FABRAZYME use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In the Fabry Disease registry pregnancy sub-study, 33 pregnancies exposed to FABRAZYME prior to or during pregnancy had a known outcome; 5 were reported as exposed in the first trimester. Animal Data The effects of agalsidase beta on embryo-fetal development in rats were evaluated at doses of 3, 10, and 30 mg/kg/day (up to 68 times the human dose of 1 mg/kg every 2 weeks on a body surface area basis) during gestation days 7 to 17. Hepatocellular necrosis consistent with accumulation of test article was evident in maternal livers in the 10 and 30 mg/kg/day groups (23 and 68 times the human dose on a body surface area basis). There were no adverse effects of agalsidase beta on embryo-fetal development in rats. 8.2 Lactation Risk Summary The available human data detected small amounts of agalsidase beta in human milk. Available data from the clinical study, global pharmacovigilance database, and published scientific literature are insufficient to determine the effects of FABRAZYME on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FABRAZYME and any potential adverse effects on the breastfed child from FABRAZYME or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of FABRAZYME have been established in pediatric patients based on adequate and well-controlled studies in adults, a single-arm, open-label study in 16 pediatric patients with Fabry disease aged 8 to 16 years, and additional data in 24 patients with Fabry disease aged 2 to 7 years [see Clinical Pharmacology (12.2) and Clinical Studies (14) ] . The overall safety profile of FABRAZYME was similar between the pediatric and the adult population [see Adverse Reactions (6.1) and Clinical Studies (14) ] . 8.5 Geriatric Use Clinical studies of FABRAZYME did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action FABRAZYME (agalsidase beta) provides an exogenous source of α-galactosidase A in Fabry disease patients. Agalsidase beta is internalized and transported into lysosomes where it exerts enzymatic activity and reduces accumulated GL-3.

11 DESCRIPTION Agalsidase beta is a recombinant human α-galactosidase A enzyme with the same amino acid sequence as the native enzyme. Purified agalsidase beta is a homodimeric glycoprotein with a molecular weight of approximately 100 kD. The mature protein is comprised of two subunits of 398 amino acids (approximately 51 kD), each of which contains three N-linked glycosylation sites. The enzyme α-galactosidase A catalyzes the hydrolysis of GL-3 and other α-galactyl-terminated neutral glycosphingolipids, such as galabiosylceramide and blood group B substances to ceramide dihexoside and galactose. The specific activity of agalsidase beta is approximately 70 U/mg (one unit is defined as the amount of activity that results in the hydrolysis of 1 μmole of a synthetic substrate, p-nitrophenyl-α-D-galactopyranoside, per minute under the assay conditions). Agalsidase beta is produced by recombinant DNA technology in a Chinese hamster ovary mammalian cell expression system. FABRAZYME (agalsidase beta) for injection is intended for intravenous infusion. It is supplied as a sterile, nonpyrogenic, preservative-free, white to off-white, lyophilized cake or powder for reconstitution with Sterile Water for Injection, USP. Each 35 mg vial contains 37 mg of agalsidase beta, as well as 222 mg mannitol, 20.4 mg sodium phosphate monobasic monohydrate, and 59.2 mg sodium phosphate dibasic heptahydrate. Following reconstitution as directed, 35 mg of agalsidase beta (7 mL) may be extracted from each 35 mg vial. Each 5 mg vial contains 5.5 mg of agalsidase beta, as well as 33.0 mg mannitol, 3.0 mg sodium phosphate monobasic monohydrate, and 8.8 mg sodium phosphate dibasic heptahydrate. Following reconstitution as directed, 5 mg of agalsidase beta (1 mL) may be extracted from each 5 mg vial.

16 HOW SUPPLIED/STORAGE AND HANDLING FABRAZYME (agalsidase beta) for injection is supplied as a sterile, nonpyrogenic, white to off-white lyophilized cake or powder in single-dose vials. 35 mg vial: NDC 58468-0040-1 5 mg vial: NDC 58468-0041-1 Refrigerate vials of FABRAZYME at 2°C to 8°C (36°F to 46°F). Do not use FABRAZYME after the expiration date on the vial. This product contains no preservatives. Reconstituted and diluted solutions of FABRAZYME should be used immediately. If immediate use is not possible, the reconstituted and diluted solution may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F) [see Dosage and Administration (2.2) ] .