Fabrazyme

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. Do not inject into the airspace within the infusion bag. 10. Gently invert the infusion bag to mix the solution. Do not shake or agitate the product. After dilution, the solution will have a final concentration of 0.2 to 0.7 mg/mL of agalsidase beta. 2.5 Storage Instructions for the Reconstituted and Diluted Product Dilute the reconstituted solution without delay and use immediately. If immediate use is not possible, the reconstituted and diluted solution may be stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours. 2.6 Administration Instructions The initial recommended infusion rate is 0.25 mg/min (15 mg/hour). For patients weighing: 30 kg or more, in the absence of hypersensitivity and/or infusion-associated reactions (IARs), increase the infusion rate in increments of 0.05 to 0.08 mg/min (3 to 5 mg/hour) with each subsequent infusion. The minimum infusion duration is 1.5 hours (based on individual patient tolerability) [see Dosage and Administration (2.6) ] . Less than 30 kg, the maximum infusion rate is 0.25 mg/minute (15 mg/hour) [see Dosage and Administration (2.6) ] . Do not infuse FABRAZYME in the same intravenous line with other products. Administer FABRAZYME using an in-line low protein binding 0.2 µm filter.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Infusion-Associated Reactions : If a severe infusion-associated reaction occurs, discontinue FABRAZYME immediately and initiate appropriate medical treatment. ( 5.2 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in FABRAZYME-treated patients. In clinical trials and postmarketing safety experience with FABRAZYME, approximately 1% of patients developed anaphylaxis or severe hypersensitivity reactions. Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion. In clinical trials with FABRAZYME, 10 of 238 patients developed IgE antibodies or skin test reactivity specific to FABRAZYME. Two of six patients in the rechallenge study discontinued treatment with FABRAZYME prematurely due to recurrent infusion-associated reactions. Four serious infusion-associated reactions occurred in three patients during FABRAZYME infusions, including bronchospasm, urticaria, hypotension, and development of FABRAZYME-specific antibodies. Other infusion-associated reactions occurring in more than one patient during the study included rigors, hypertension, nausea, vomiting, and pruritus. Higher incidences of hypersensitivity reactions were observed in adult patients with persistent anti-FABRAZYME antibodies and in adult patients with high antibody titer compared to that in antibody-negative adult patients [see Adverse Reactions (6.2) ] . Prior to FABRAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Administration of FABRAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Initiate FABRAZYME in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue FABRAZYME and immediately initiate appropriate medical treatment, including use of epinephrine. Consider the risks and benefits of re-administering FABRAZYME following severe hypersensitivity reactions (including anaphylaxis). Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur. Consider testing for IgE antibodies in FABRAZYME-treated patients who experienced severe hypersensitivity reactions, including anaphylaxis and consider the risks and benefits of continued treatment in patients with anti-FABRAZYME IgE antibodies. There are no marketed tests for antibodies against FABRAZYME. If testing is warranted, contact Genzyme Corporation at 1-800-745-4447 [see Adverse Reactions (6.2) ] . Patients who have had a positive skin test to FABRAZYME or who have tested positive for FABRAZYME-specific IgE antibodies have been rechallenged with FABRAZYME using a rechallenge protocol. Rechallenge of these patients should only occur under the direct supervision of qualified personnel with appropriate medical monitoring and support measures readily available [see Dosage and Administration (2.3) and Adverse Reactions (6.2) ] . 5.2 Infusion-Associated Reactions In clinical trials of FABRAZYME, 59% of patients experienced infusion-associated reactions (IARs) during FABRAZYME administration, some of which were severe. Infusion-associated reactions are defined as adverse reactions occurring on the same day as the infusion. The incidence of infusion-associated reactions was higher in patients who were positive for anti-FABRAZYME antibodies than in patients who were negative for anti-FABRAZYME antibodies [see Adverse Reactions (6.2) ] . Severe infusion-associated reactions experienced by more than one patient in clinical trials of FABRAZYME included chills, vomiting, hypotension, and paresthesia. Other infusion-associated reactions included pyrexia, feeling hot or cold, dyspnea, nausea, flushing, headache, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, urticaria, bradycardia, and somnolence [see Adverse Reactions (6.1) ] . Prior to FABRAZYME administration, consider pre-treatment with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of infusion-associated reactions (IARs). However, IARs may still occur in patients after receiving pre-treatment. IARs tended to decline in frequency with continued use of FABRAZYME. However, IARs may still occur despite extended duration of FABRAZYME treatment. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily during FABRAZYME administration. If a severe IAR occurs, discontinue FABRAZYME immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering FABRAZYME following a severe IAR and monitor patients closely upon re-administration of FABRAZYME. If a mild or moderate IAR occurs, consider temporarily holding the infusion, slowing the infusion rate, and/or reducing the FABRAZYME dosage. Patients with advanced Fabry disease may have compromised cardiac function which may predispose them to a higher risk of severe complications from IARs. Closely monitor patients with compromised cardiac function if FABRAZYME is administered to these patients.

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 observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to FABRAZYME in the studies described below with the incidence of antibodies in other studies or to other agalsidase beta products may be misleading. Patients with classic Fabry disease in Study 1, Study 2, and extension studies were tested at multiple time points for antibodies to agalsidase beta during the 55 to 58-month period. Approximately 83% (110 of 133) of adult patients receiving agalsidase beta developed antibodies; 77% (102/133) of patients developed neutralizing antibody (NAb) that inhibited in vitro agalsidase beta catalytic activity, which declined over time, and 6% (8/133) of patients developed NAb that inhibited cellular uptake. In pediatric patients with Fabry disease in Study 3 receiving the recommended dose who were 8 to <16 years of age, antibodies to agalsidase beta were detected in approximately 69% (11/16) of patients. Most patients who developed antibodies did so within the first 3 months of treatment. Antibody titers generally declined over time. Approximately 18% of adult patients who developed antibodies became antibody negative by 74 weeks (median time) from the time of seroconversion; however, none of the pediatric patients became antibody negative. Female patients generally had lower incidence of antibodies and lower antibody titers compared to male patients. In Study 5, patients with truncating GLA mutations had higher incidence of antibodies and higher antibody titers compared to patients with nontruncating GLA mutations. Patients with plasma α-galactosidase A activity ≤1.5 nmol/hr/mL had higher incidence of antibodies and higher antibody titers compared to patients with plasma α-galactosidase A activity >1.5 nmol/hr/mL. In general, over 90% of adult and pediatric patients treated with agalsidase beta achieved and maintained normalization of plasma globotriaosylceramide (GL-3) levels irrespective of developing antibodies to agalsidase beta. Study 4 was an open-label, rechallenge study to evaluate the safety of FABRAZYME treatment in patients who had a positive skin test to FABRAZYME or who had tested positive for FABRAZYME-specific IgE antibodies. In this study, six adult male patients, who had experienced multiple or recurrent infusion-associated reactions during previous clinical trials of FABRAZYME, were rechallenged with FABRAZYME administered as a graded infusion for up to 52 weeks of treatment. The initial two rechallenge doses of FABRAZYME were administered as a 0.5 mg/kg dose per week at an initial infusion rate of 0.01 mg/min for the first 30 minutes (1/25 th the usually recommended maximum infusion rate). The infusion rate was doubled every 30 minutes thereafter, as tolerated, for the remainder of the infusion up to a maximum rate of 0.25 mg/min. If the patient tolerated the infusion, the dose was increased to 1 mg/kg every two weeks and the infusion rate was increased by slow upwards titration [see Dosage and Administration (2.1) ] . Pretreatment was not permitted for at least the first 4 infusions in order to allow early recognition of acute systemic hypersensitivity reactions. Four of the six patients treated in this study received at least 26 weeks of FABRAZYME (2 patients received 26 weeks and 2 patients received 52 weeks), and two patients discontinued prematurely due to recurrent infusion-associated reactions [see Warnings and Precautions (5.1 , 5.2) ] . Testing for IgE antibodies was performed in approximately 60 patients in clinical trials who experienced moderate to severe infusion-associated reactions or in whom mast cell activation was suspected. Seven of these patients tested positive for FABRAZYME-specific IgE antibodies or had a positive skin test to FABRAZYME. Patients who have had a positive skin test to FABRAZYME, or who have tested positive for FABRAZYME-specific IgE antibodies in clinical trials with FABRAZYME have been rechallenged [see Dosage and Administration (2.1) and Warnings and Precautions (5.1 , 5.2) ] . The incidences of hypersensitivity reactions were 51% (41/80) and 60% (25/42) in adult patients with persistent anti-FABRAZYME antibodies and in adult patients with high antibody titer, respectively, compared to 30% (7/23) in antibody-negative adult patients [see Warnings and Precautions (5.1) ] . The incidence of infusion-associated reactions was 76% (84/110) in antibody-positive adult patients compared to 30% (7/23) in antibody-negative adult patients. The incidence of infusion-associated reactions was 46% (5/11) in antibody positive pediatric patients compared to 20% (1/5) in antibody negative pediatric patients [see Warnings and Precautions (5.2) ] . 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of FABRAZYME. 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. Cardiovascular: cardiorespiratory arrest, cardiac failure, myocardial infarction, palpitations Hypersensitivity reactions: anaphylaxis [see Warnings and Precautions (5.1) ] , localized angioedema (including auricular swelling, eye swelling, dysphagia, lip swelling, edema, pharyngeal edema, face swelling, and swollen tongue), and bronchospasm General: hyperhidrosis, asthenia, infusion site reaction Lymphatic: lymphadenopathy Musculoskeletal: arthralgia Neurologic: cerebrovascular accident, hypoesthesia, oral hypoesthesia Pulmonary: respiratory failure, hypoxia Renal: renal failure Vascular: leukocytoclastic vasculitis

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.