2.1 Recommended Dosage

• The recommended dosage of Fabrazyme is 1 mg/kg body weight infused every two weeks as an intravenous infusion.
• Infusion rate:

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  The initial intravenous infusion rate is 0.25 mg/min (15 mg/hour). Slow the infusion rate in the event of infusion-associated reactions [see Warnings and Precautions (5.2)].

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  For patients >30 kg, after patient tolerance to the infusion is well established, increase the infusion rate in increments of 0.05 to 0.08 mg/min (increments of 3 to 5 mg/hour) with each subsequent infusion. The minimum infusion duration is 1.5 hours (based on individual patient tolerability).

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  For patients weighing <30 kg, the maximum infusion rate is 0.25 mg/minute (15 mg/hour).

• Because of the potential for severe infusion-associated reactions, appropriate medical support measures should be readily available when Fabrazyme is administered [see Warnings and Precautions (5.2)].
• Administer antipyretics prior to infusion of Fabrazyme [see Warnings and Precautions (5.2)].
• Rechallenge: 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). 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)].

2.2 Preparation and Administration Instructions

Fabrazyme does not contain any preservatives. Vials are for single use only. Discard any unused product.

Avoid shaking or agitating this product. Do not use filter needles during the preparation of the infusion.

5.1 Anaphylaxis and Hypersensitivity Reactions

In clinical trials and postmarketing safety experience with Fabrazyme, approximately 1% of patients developed anaphylactic or severe hypersensitivity reactions during Fabrazyme infusion.

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)].

Life-threatening anaphylactic and severe hypersensitivity reactions have been observed in patients during Fabrazyme infusions. 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. Interventions have included cardiopulmonary resuscitation, oxygen supplementation, intravenous fluids, hospitalization, and treatment with inhaled beta-adrenergic agonists, epinephrine, and intravenous corticosteroids.

If anaphylactic or severe hypersensitivity reactions occur, immediately discontinue the administration of Fabrazyme and initiate necessary emergency treatment. Because of the potential for severe hypersensitivity reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

The risks and benefits of readministering Fabrazyme following an anaphylactic or severe hypersensitivity reaction should be considered. If a decision is made to readminister the product, ensure that appropriate medical emergency support is available [see Dosage and Administration (2.1) and Adverse Reactions (6.2)].

Physicians should consider testing for IgE antibodies in patients who experienced suspected hypersensitivity reactions 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.

Patients who have had a positive skin test to Fabrazyme or who have tested positive for Fabrazyme-specific IgE antibody 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 support measures readily available [see Dosage and Administration (2.1) and Adverse Reactions (6.2)].

5.2 Infusion-Associated Reactions

In clinical trials of Fabrazyme, 59% of patients experienced infusion-associated reactions 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 Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Most patients in clinical trials were pretreated with acetaminophen. In patients experiencing infusion-associated reactions, pretreatment with an antipyretic and antihistamine is recommended. Infusion-associated reactions occurred in some patients after receiving pretreatment with antipyretics, antihistamines, and oral steroids. Infusion-associated reactions tended to decline in frequency with continued use of Fabrazyme. However, infusion-associated reactions may still occur despite extended duration of Fabrazyme treatment. If an infusion-associated reaction occurs, decrease the infusion rate, temporarily stop the infusion, and consider administrating additional antipyretics, antihistamines, and/or steroids. If severe infusion-associated reactions occur, discontinue administration of Fabrazyme immediately and initiate appropriate medical treatment. Severe reactions are generally managed with administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated. Because of the potential for severe infusion-associated reactions, ensure appropriate medical support measures are readily available when Fabrazyme is administered. Monitor closely patients who have experienced infusion-associated reactions when readministering Fabrazyme. Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion-associated reactions. Monitor closely patients with compromised cardiac function if Fabrazyme is administered to these patients [see Warnings and Precautions (5.1)].

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 administrations 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)].

Patient Registry

Inform patients that a Registry has been established in order to better understand the variability and progression of Fabry disease in the population as a whole and in women [see Use in Specific Populations (8.1)], and to monitor and evaluate long-term treatment effects of Fabrazyme. The Registry will also monitor the effect of Fabrazyme on pregnant women and their offspring. Encourage patients to participate. Advise patients that their participation is voluntary and may involve long-term follow-up. For more information, visit www. registrynxt.com or call 1-800-745-4447, extension 15500.