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 1/25th 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:

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.

5.1 Hypersensitivity Reactions Including Anaphylaxis

Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with enzyme replacement therapies, including FABRAZYME. 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)].

Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of FABRAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Prior to FABRAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. 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.

6.1 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.

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 (1/25th 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

8.2 Lactation

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.

12.2 Pharmacodynamics

In Study 1, baseline mean values for plasma GL-3 were similar in the FABRAZYME (14.4 µg/mL) and the placebo (14.7 µg/mL) treatment groups. In the FABRAZYME treatment group, all 29 patients experienced normalization of plasma GL-3 levels (≤7.03 µg/mL) and they maintained normal plasma GL-3 levels for up to 60 months of treatment. Follow-up heart and kidney biopsies were assessed at month 54 in only 8 of the 44 patients, which showed sustained GL-3 clearance in the capillary endothelium of the kidney in 8 patients, and sustained GL-3 clearance in the capillary endothelium of the heart in 6 patients. The reduction in tissue GL-3 is summarized in the clinical studies section (Table 4) [see Clinical Studies (14)].

In Study 2, patients in the FABRAZYME treatment group had mean plasma GL-3 levels that decreased from 9.0 µg/mL at baseline (N=49) to 4.8 µg/mL at one year (N=37) and 4.8 µg/mL at two years (N=18). In the placebo group, the mean plasma GL-3 was 9.1 µg/mL at baseline (N=31), 8.8 µg/mL at one year (N=21), and 9.4 µg/mL at two years (N=7).

In Study 3, at baseline, all 14 males had elevated plasma GL-3 levels (i.e., >7.03 µg/mL), whereas the two female patients had normal plasma GL-3 levels. At weeks 24 and 48 of treatment, all 14 males had plasma GL-3 within the normal range. The two female patients' plasma GL-3 levels remained normal through study week 48. Histological evaluation of the capillary endothelium (vasculature), deep vessel endothelium, deep vessel smooth muscle cells, and perineurium of biopsied skin was conducted using histochemistry with light microscopy. Scoring was on a scale of 0 to 3 (0 defined as none; 1 as mild, 2 as moderate, and 3 as severe). At baseline, 12 of the 14 males had GL-3 inclusions present on skin biopsy (scores 1, 2, or 3) and all 12 achieved GL-3 inclusion scores of 0 at weeks 24 and 48 of treatment. The two females had no GL-3 inclusions in skin at baseline.

In Study 5, in an analysis of 24 FABRAZYME-treated pediatric patients with Fabry disease aged 2 to <8 years at FABRAZYME initiation and with elevated plasma GL-3 levels (i.e., >7.03 μg/mL) at baseline, plasma GL-3 levels fell within the normal range (i.e., ≤7.03 μg/mL) in 91% (20/22), 95% (18/19), and 92% (12/13) of patients at 6, 12, and 24 months, respectively.

12.3 Pharmacokinetics

The pharmacokinetics of FABRAZYME in clinical studies with adult and pediatric patients with Fabry disease is summarized in Table 3.

FABRAZYME exhibited nonlinear pharmacokinetics following intravenous infusions at 0.3 (30% of the approved recommended dosage), 1 mg/kg, and 3 mg/kg (3 times the approved recommended dosage) in adult patients. The area under the plasma concentration-time curve (AUCinf) and the maximum plasma concentration (Cmax) increased greater than dose proportional with increasing doses. The AUCinf and Cmax following multiple dose administrations were comparable to their values at the first dose.

In pediatric patients 8 to 16 years of age with body weight ranging from 27 to 65 kg, the AUCinf and Cmax following multiple dose administrations were higher compared to their values at the first dose. The increased plasma concentrations following multiple dose administration in pediatric patients could be due to formation of antidrug antibodies; however, such impact was not observed in adult patients [see Adverse Reactions (6.2) and Use in Specific Populations (8.4)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no animal or human studies to assess the carcinogenic or mutagenic potential of FABRAZYME. A study to evaluate the effects of agalsidase beta on fertility and general reproduction was performed in male and female rats at doses up to 10 mg/kg/day (23 times the human dose, on a body surface area basis). There were no adverse effects of agalsidase beta on fertility and early embryonic development in rats.

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)].

Hypersensitivity Reactions Including Anaphylaxis and Infusion-Associated Reactions (IARs)

Advise the patient and caregiver that life-threatening hypersensitivity reactions, including anaphylaxis, and IARs may occur with FABRAZYME treatment.

Advise the patient or caregiver that anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.

Inform the patient and caregiver of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis, and IARs and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1, 5.2)].

FABRAZYME Exposure During Pregnancy or Lactation

Advise a pregnant or lactating woman exposed to FABRAZYME to report FABRAZYME exposure to her healthcare provider and by calling 1-800-633-1610, option 1 [see Use in Specific Populations (8.1., 8.2)].

Patient Registry

Inform the patient and/or caregiver that a registry has been established for Fabry patients in order to better understand the variability and progression of Fabry disease in the population as a whole, and in women along with monitoring and evaluating long-term treatment effects of FABRAZYME. Additionally, the registry also monitors the effect of FABRAZYME on pregnant women and their offspring. Encourage the patient and/or caregiver to contact the registry program by visiting www. registrynxt.com or by calling 1-800-745-4447, extension 15500.