ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in labeling:Anaphylaxis and Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Infusion-Associated Reactions [see Warnings and Precautions (5.2)] Anaphylaxis and Hypersensitivity Reactions [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 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of 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 mg/kg Fabrazyme every two weeks in two separate double-blind, placebo-controlled clinical trials, for periods ranging from 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 ReactionsTable enumerates adverse reactions that occurred during the double-blind treatment periods of the two placebo-controlled trials (Study 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 lists the common adverse reactions (>=5%).Table 2: Summary of Common Adverse ReactionsReported at rate of at least 5% in Fabrazyme-treated patients and greater than 2.5% compared to placebo-treated patients. in Clinical Trials (study and 2) of Patients with Fabry DiseaseAdverse ReactionFabrazyme(n=80)%Placebo(n=60)% Upper respiratory tract infectionIncludes reports of upper respiratory infection, nasal congestion, sinusitis, respiratory tract congestion, and pharyngitis. 5342 ChillsIncludes reports of chills and feeling cold. 4913 Pyrexia3922 Headache3928 Cough3325 Paresthesia3118 Fatigue2417 Peripheral edema217 Dizziness218 Rash2010 Pain in extremity198 MyalgiaIncludes reports of myalgia and muscle spasms. 187 Lower respiratory tract infection187 Pain1613 Back pain1610 Hypertension145 Pruritus103 Tachycardia93 Excoriation92 Increased blood creatinine95 Tinnitus83 Dyspnea82 Fall63 Burning sensation60 Anxiety63 Depression62 Wheezing60 Hypoacusis50 Chest discomfort52 Fungal infection50 Viral infection50 Hot flush50Most 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 PatientsIn Study 3, the safety profile of Fabrazyme in pediatric Fabry disease patients, ages 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 receiving the recommended dose who were 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 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 -galactosidase activity <=1.5 nmol/hr/mL had higher incidence of antibodies and higher antibody titers compared to patients with plasma -galactosidase 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 was an open-label, rechallenge study to evaluate the safety of Fabrazyme treatment in patients who had 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 graded infusion for up to 52 weeks of treatment. The initial two rechallenge doses of Fabrazyme were administered as 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 maximum rate of 0.25 mg/min. If the patient tolerated the infusion, the dose was increased to 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 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 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 positive skin test to Fabrazyme. Patients who have had 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiovascular: cardiorespiratory arrest, cardiac failure, myocardial infarction, palpitationsHypersensitivity 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 bronchospasmGeneral: hyperhidrosis, asthenia, infusion site reactionLymphatic: lymphadenopathyMusculoskeletal: arthralgiaNeurologic: cerebrovascular accident, hypoesthesia, oral hypoesthesiaPulmonary: respiratory failure, hypoxiaRenal: renal failureVascular: leukocytoclastic vasculitis. 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Fabrazyme (agalsidase beta) provides an exogenous source of -galactosidase 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 ug/mL) and the placebo (14.7 ug/mL) treatment groups. In the Fabrazyme treatment group, all 29 patients experienced normalization of plasma GL-3 levels (<=7.03 ug/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 of the 44 patients, which showed sustained GL-3 clearance in the capillary endothelium of the kidney in patients, and sustained GL-3 clearance in the capillary endothelium of the heart in 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 ug/mL at baseline (N=49) to 4.8 ug/mL at one year (N=37) and 4.8 ug/mL at two years (N=18). In the placebo group, the mean plasma GL-3 was 9.1 ug/mL at baseline (N=31), 8.8 ug/mL at one year (N=21), and 9.4 ug/mL at two years (N=7).In Study 3, at baseline, all 14 males had elevated plasma GL-3 levels (i.e., >7.03 ug/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 scale of to (0 defined as none; as mild, as moderate, and 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 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 to <8 years at Fabrazyme initiation and with elevated plasma GL-3 levels (i.e., >7.03 ug/mL) at baseline, plasma GL-3 levels fell within the normal range (i.e., <=7.03 ug/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), mg/kg, and 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 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)].Table 3: Fabrazyme Pharmacokinetic SummaryDoseRegimenMean Infusion Length (min)Infusion number(n=patients)AUCinf ug min/mLCmax ug/mLHalf-lifeminCLmL/min/kgVssVss volume of distribution at steady state. mL/kgAll data reported as the mean +- standard deviation.Study FB9702-01: Phase 1/2 Study in Adult Patients with Fabry Disease0.3 mg/kgq14 days 51321 (n=3)79 +- 240.6 +- 0.292 +- 274.1 +- 1.2225 +- 621285 (n=3)74 +- 300.6 +- 0.278 +- 674.6 +- 2.2330 +- 2311 mg/kgq14 days 51151 (n=3)496 +- 1375.0 +- 1.167 +- 122.1 +- 0.7112 +- 131205 (n=2)466 +- 3824.74 +- 4.345 +- 33.2 +- 2.6243 +- 2363 mg/kgq14 days 51291 (n=2)4168 +- 140129.7 +- 14.6102 +- 40.8 +- 0.381 +- 453005 (n=2)4327 +- 207419.8 +- 5.887 +- 210.8 +- 0.4165 +- 80Study 1: Phase Study in Adult Patients with Fabry Disease1 mg/kgq14 days 112801-3 (n=11)649 +- 2263.5 +- 1.689 +- 201.8 +- 0.8120 +- 802807 (n=11)372 +- 2232.1 +- 1.1482 +- 254.9 +- 5.6570 +- 71030011 (n=11)784 +- 5213.5 +- 2.2119 +- 492.3 +- 2.2280 +- 230Study 3: Phase Study in Pediatric Patients with Fabry Disease1 mg/kgq14 days 242081 (n=8-9)344 +- 3072.2 +- 1.986 +- 275.8 +- 4.61097 +- 91211112 (n=15)1007 +- 6884.9 +- 2.4130 +- 411.6 +- 1.2292 +- 18510824 (n=9-10)1238 +- 5477.1 +- 4.4151 +- 591.1 +- 0.8247 +- 146.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of Fabrazyme were assessed in four clinical studies in patients with Fabry disease and one matched analysis based on data from observational studies.Study was randomized, double-blind, placebo-controlled, multinational, multicenter study of 58 patients with Fabry disease (56 males and females), ages 16 to 61 years, all naive to enzyme replacement therapy [see Clinical Pharmacology (12.2)]. Patients were randomized 1:1 to receive either Fabrazyme mg/kg every weeks or placebo for 20 weeks. Patients had median age of 24 years in the placebo group and 33 years in the Fabrazyme group at baseline. At baseline, all patients had plasma GAL activity below the detection limit and 79% had leukocyte GAL activity below the detection limit. The median plasma GL-3 at baseline was 14.4 ng/uL in the placebo group and 14.7 ng/uL in the Fabrazyme group with the overall range of <1.2 to 36 ng/uL. The median eGFR at baseline was 98.5 mL/hr in the placebo group and 83.0 mL/hr in the Fabrazyme group (overall range 24 to 153 mL/hr). All patients were pretreated with acetaminophen and an antihistamine. Oral steroids were an additional option to the pretreatment regimen for patients who exhibited severe or recurrent infusion-associated reactions. Tissue biopsy specimens (kidney, heart, skin) were evaluated at baseline and at week 20 by light microscopy for the presence and number of GL-3 inclusions using semi-quantitative methodology. Renal interstitial capillaries were scored based on the number of GL-3 inclusions on scale of to (0 defined as nearly none or trace, defined as mild, defined as moderate, and defined as severe). The primary endpoint was the proportion of patients in either group with renal capillary GL-3 inclusion score of zero at week 20. In the Fabrazyme group, 20 of 29 (69%) patients achieved score of zero while of 29 placebo-treated patients achieved score of zero (p<0.001). Similar reductions in GL-3 inclusions were observed in the capillary endothelium of the heart and skin (Table 4). All 58 patients who completed Study were subsequently treated with Fabrazyme mg/kg every two weeks in an open-label extension study. After six months of open-label treatment, most patients with available biopsy data achieved GL-3 inclusion score of in capillary endothelium (Table 4).Table 4: Proportion of Patients with Tissue GL-3 Inclusion Score of Zero (study and open-label treatment)20 weeks of randomized treatment in study 16 months of Fabrazyme open-label treatmentPlacebo(n=29) Fabrazyme(n=29) Placebo/Fabrazyme(n=29)Results reported where biopsies were available. Fabrazyme/Fabrazyme(n=29) Kidney0/2920/2924/2423/25Heart1/2921/2913/1819/22Skin1/2929/2925/2626/27Study was randomized (2:1 Fabrazyme to placebo), double-blind, placebo-controlled, multinational, multicenter study of 82 patients (72 males and 10 females) with Fabry disease, all naive to enzyme replacement therapy [see Clinical Pharmacology (12.2)]. Of the 82 enrolled patients, 51 and 31 patients were randomized to the Fabrazyme and placebo groups, respectively. Patients were 20 to 72 years of age with median age of 45 years at baseline, median age of 36 years at Fabry disease diagnosis, and at median of 10 years at symptom onset. The median plasma GL-3 at baseline was 9.3 ug/mL in the placebo group and 8.9 ug/mL in the Fabrazyme group with the overall range of 2.8 to 18.9 ug/mL. At baseline, patients had median plasma GAL activity 1.5 nmol/hour/mL (range: to 1.5), leukocyte GAL activity 1.8 nmol/hour/mL (range: to 4.0), eGFR 52 mL/min/1.73 m2 (range: 25 to 113), and protein to creatinine ratio 0.9 mg/mg (range: to 7.3). Patients received either mg/kg Fabrazyme IV or placebo every two weeks for up to 35 months (median follow-up 18.5 months). The primary efficacy endpoint was the time to first occurrence of clinically significant event (renal, cardiac, or cerebrovascular event, or death). total of 14 of 51 (28%) Fabrazyme-treated patients and 13 of 31 (42%) placebo-treated patients experienced clinically significant event (HR 0.57, 95% CI: 0.27, 1.22).Study (Pediatric Study) was an open-label, single-arm, multinational, multicenter study in 16 pediatric patients with Fabry disease (14 males, females), aged to 16 years (median 12 years) [see Clinical Pharmacology (12.2)]. At baseline, patients had median plasma GAL activity 0.2 nmol/hour/mL (range: 0.0, 2.0) and median leukocyte GAL activity 0.5 nmol/hour/mg (range: 0.0, 12.5). All 14 males had elevated plasma GL-3 levels (i.e., >7.03 ug/mL) at baseline, whereas the two females had normal plasma GL-3 levels. Median eGFR was normal (112.1 mL/min/1.73 m2) at baseline and did not change during treatment, and median urinary protein was 151.0 mg/24 hr (range: 70.0, 431.0). All patients received Fabrazyme mg/kg every two weeks for up to 48 weeks.Study was long-term, observational study assessing the rate of decline in renal function (eGFR slope) in 122 patients with Fabry disease aged 16 years and older treated with Fabrazyme. Treated patients were matched 1:1 based on age (at Fabrazyme initiation), sex, Fabry disease subtype (classic or non-classic), and baseline eGFR to historical cohort of untreated patients with Fabry disease. The median follow-up time was years in the untreated group and 4.5 years in the treated group (maximum follow-up time years in both groups). In the matched cohort, the median age (at Fabrazyme initiation) was 35 years, 72% of patients were male, 84% of patients had the classic Fabry disease subtype, and the median baseline eGFR was 93 mL/min/1.73 m2. The estimated mean eGFR slope was -1.5 mL/min/1.73 m2/year in the Fabrazyme-treated group and -3.2 mL/min/1.73 m2/year in the untreated group (eGFR slope difference: 1.7 mL/min/1.73 m2/year; 95% CI: 0.5, 3.0).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of 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 mg/kg Fabrazyme every two weeks in two separate double-blind, placebo-controlled clinical trials, for periods ranging from 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 ReactionsTable enumerates adverse reactions that occurred during the double-blind treatment periods of the two placebo-controlled trials (Study 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 lists the common adverse reactions (>=5%).Table 2: Summary of Common Adverse ReactionsReported at rate of at least 5% in Fabrazyme-treated patients and greater than 2.5% compared to placebo-treated patients. in Clinical Trials (study and 2) of Patients with Fabry DiseaseAdverse ReactionFabrazyme(n=80)%Placebo(n=60)% Upper respiratory tract infectionIncludes reports of upper respiratory infection, nasal congestion, sinusitis, respiratory tract congestion, and pharyngitis. 5342 ChillsIncludes reports of chills and feeling cold. 4913 Pyrexia3922 Headache3928 Cough3325 Paresthesia3118 Fatigue2417 Peripheral edema217 Dizziness218 Rash2010 Pain in extremity198 MyalgiaIncludes reports of myalgia and muscle spasms. 187 Lower respiratory tract infection187 Pain1613 Back pain1610 Hypertension145 Pruritus103 Tachycardia93 Excoriation92 Increased blood creatinine95 Tinnitus83 Dyspnea82 Fall63 Burning sensation60 Anxiety63 Depression62 Wheezing60 Hypoacusis50 Chest discomfort52 Fungal infection50 Viral infection50 Hot flush50Most 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 PatientsIn Study 3, the safety profile of Fabrazyme in pediatric Fabry disease patients, ages 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)].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage is mg/kg body weight given every two weeks as an intravenous infusion. (2.1)Ensure appropriate medical support is available when Fabrazyme is administered because of the potential for anaphylaxis and severe infusion-associated reactions. (2.1, 5.1, 5.2)Administer antipyretics prior to infusion. (2.1)See the full prescribing information for the recommended infusion rate. (2.1). The recommended dosage is mg/kg body weight given every two weeks as an intravenous infusion. (2.1). Ensure appropriate medical support is available when Fabrazyme is administered because of the potential for anaphylaxis and severe infusion-associated reactions. (2.1, 5.1, 5.2). Administer antipyretics prior to infusion. (2.1). See the full prescribing information for the recommended infusion rate. (2.1). 2.1Recommended Dosage. The recommended dosage of Fabrazyme is mg/kg body weight infused every two weeks as an intravenous infusion.Infusion rate:-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)].-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 to mg/hour) with each subsequent infusion. The minimum infusion duration is 1.5 hours (based on individual patient tolerability).-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 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 low dose at 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 patient tolerates the infusion, the dose may be increased to reach the approved dose of mg/kg and the infusion rate may be increased by slowly titrating upwards (doubled every 30 minutes up to maximum rate of 0.25 mg/minute), as tolerated [see Adverse Reactions (6.2)].. The recommended dosage of Fabrazyme is mg/kg body weight infused every two weeks as an intravenous infusion.. Infusion rate:-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)].-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 to mg/hour) with each subsequent infusion. The minimum infusion duration is 1.5 hours (based on individual patient tolerability).-For patients weighing <30 kg, the maximum infusion rate is 0.25 mg/minute (15 mg/hour). -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)].. -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 to mg/hour) with each subsequent infusion. The minimum infusion duration is 1.5 hours (based on individual patient tolerability).. -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 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 low dose at 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 patient tolerates the infusion, the dose may be increased to reach the approved dose of mg/kg and the infusion rate may be increased by slowly titrating upwards (doubled every 30 minutes up to maximum rate of 0.25 mg/minute), as tolerated [see Adverse Reactions (6.2)].. 2.2Preparation 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.. Reconstitution and Dilution (using Aseptic Technique)Allow Fabrazyme vials and diluent to reach room temperature prior to reconstitution (approximately 30 minutes). The number of 35 mg and mg vials needed is based on the patients body weight (kg) and the recommended dose of mg/kg.Select combination of 35 mg and mg vials so that the total number of mg is equal to or greater than the patients number of kg of body weight.Reconstitute each 35 mg vial of Fabrazyme by slowly injecting 7.2 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield 5 mg/mL clear, colorless solution (total extractable amount per vial is 35 mg, mL).Reconstitute each mg vial of Fabrazyme by slowly injecting 1.1 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield 5 mg/mL clear, colorless solution (total extractable amount per vial is mg, mL).Visually inspect the reconstituted vials for particulate matter and discoloration. Do not use the reconstituted solution if there is particulate matter or if it is discolored.The reconstituted solution should be further diluted with 0.9% Sodium Chloride Injection, USP to total volume based on patient weight specified in Table below. Prior to adding the volume of reconstituted Fabrazyme required for the patient dose, remove an equal volume of 0.9% Sodium Chloride Injection, USP from the infusion bag.Table 1: Total Infusion Volume Based on Patient WeightPatient Weight (kg)Minimum Total Volume (mL)<=355035.1 to 7010070.1 to 100250>100500Patient dose (in mg) 5 mg/mL Number of mL of reconstituted Fabrazyme required for patient doseExample: Patient dose 80 mg80 mg 5 mg/mL 16 mL of FabrazymeSlowly withdraw the reconstituted solution from each vial up to the total volume required for the patient dose. Inject the reconstituted Fabrazyme solution directly into the Sodium Chloride solution. Do not inject in the airspace within the infusion bag. Discard any vial with unused reconstituted solution. Gently invert infusion bag to mix the solution, avoiding vigorous shaking and agitation.Do not infuse Fabrazyme in the same intravenous line with other products.Administer Fabrazyme using an in-line low protein binding 0.2 um filter.. Allow Fabrazyme vials and diluent to reach room temperature prior to reconstitution (approximately 30 minutes). The number of 35 mg and mg vials needed is based on the patients body weight (kg) and the recommended dose of mg/kg.Select combination of 35 mg and mg vials so that the total number of mg is equal to or greater than the patients number of kg of body weight.. Reconstitute each 35 mg vial of Fabrazyme by slowly injecting 7.2 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield 5 mg/mL clear, colorless solution (total extractable amount per vial is 35 mg, mL).Reconstitute each mg vial of Fabrazyme by slowly injecting 1.1 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield 5 mg/mL clear, colorless solution (total extractable amount per vial is mg, mL).. Visually inspect the reconstituted vials for particulate matter and discoloration. Do not use the reconstituted solution if there is particulate matter or if it is discolored.. The reconstituted solution should be further diluted with 0.9% Sodium Chloride Injection, USP to total volume based on patient weight specified in Table below. Prior to adding the volume of reconstituted Fabrazyme required for the patient dose, remove an equal volume of 0.9% Sodium Chloride Injection, USP from the infusion bag.Table 1: Total Infusion Volume Based on Patient WeightPatient Weight (kg)Minimum Total Volume (mL)<=355035.1 to 7010070.1 to 100250>100500Patient dose (in mg) 5 mg/mL Number of mL of reconstituted Fabrazyme required for patient doseExample: Patient dose 80 mg80 mg 5 mg/mL 16 mL of FabrazymeSlowly withdraw the reconstituted solution from each vial up to the total volume required for the patient dose. Inject the reconstituted Fabrazyme solution directly into the Sodium Chloride solution. Do not inject in the airspace within the infusion bag. Discard any vial with unused reconstituted solution. Gently invert infusion bag to mix the solution, avoiding vigorous shaking and agitation.. Do not infuse Fabrazyme in the same intravenous line with other products.. Administer Fabrazyme using an in-line low protein binding 0.2 um filter.. Storage of Reconstituted SolutionUse reconstituted and diluted solutions of Fabrazyme immediately. If immediate use is not possible, the reconstituted and diluted solution may be stored for up to 24 hours at 2C to 8C (36F to 46F).

IMMUNOGENICITY.

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 receiving the recommended dose who were 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 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 -galactosidase activity <=1.5 nmol/hr/mL had higher incidence of antibodies and higher antibody titers compared to patients with plasma -galactosidase 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 was an open-label, rechallenge study to evaluate the safety of Fabrazyme treatment in patients who had 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 graded infusion for up to 52 weeks of treatment. The initial two rechallenge doses of Fabrazyme were administered as 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 maximum rate of 0.25 mg/min. If the patient tolerated the infusion, the dose was increased to 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 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 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 positive skin test to Fabrazyme. Patients who have had 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)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In Study 1, baseline mean values for plasma GL-3 were similar in the Fabrazyme (14.4 ug/mL) and the placebo (14.7 ug/mL) treatment groups. In the Fabrazyme treatment group, all 29 patients experienced normalization of plasma GL-3 levels (<=7.03 ug/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 of the 44 patients, which showed sustained GL-3 clearance in the capillary endothelium of the kidney in patients, and sustained GL-3 clearance in the capillary endothelium of the heart in 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 ug/mL at baseline (N=49) to 4.8 ug/mL at one year (N=37) and 4.8 ug/mL at two years (N=18). In the placebo group, the mean plasma GL-3 was 9.1 ug/mL at baseline (N=31), 8.8 ug/mL at one year (N=21), and 9.4 ug/mL at two years (N=7).In Study 3, at baseline, all 14 males had elevated plasma GL-3 levels (i.e., >7.03 ug/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 scale of to (0 defined as none; as mild, as moderate, and 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 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 to <8 years at Fabrazyme initiation and with elevated plasma GL-3 levels (i.e., >7.03 ug/mL) at baseline, plasma GL-3 levels fell within the normal range (i.e., <=7.03 ug/mL) in 91% (20/22), 95% (18/19), and 92% (12/13) of patients at 6, 12, and 24 months, respectively.

PHARMACOKINETICS SECTION.

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), mg/kg, and 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 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)].Table 3: Fabrazyme Pharmacokinetic SummaryDoseRegimenMean Infusion Length (min)Infusion number(n=patients)AUCinf ug min/mLCmax ug/mLHalf-lifeminCLmL/min/kgVssVss volume of distribution at steady state. mL/kgAll data reported as the mean +- standard deviation.Study FB9702-01: Phase 1/2 Study in Adult Patients with Fabry Disease0.3 mg/kgq14 days 51321 (n=3)79 +- 240.6 +- 0.292 +- 274.1 +- 1.2225 +- 621285 (n=3)74 +- 300.6 +- 0.278 +- 674.6 +- 2.2330 +- 2311 mg/kgq14 days 51151 (n=3)496 +- 1375.0 +- 1.167 +- 122.1 +- 0.7112 +- 131205 (n=2)466 +- 3824.74 +- 4.345 +- 33.2 +- 2.6243 +- 2363 mg/kgq14 days 51291 (n=2)4168 +- 140129.7 +- 14.6102 +- 40.8 +- 0.381 +- 453005 (n=2)4327 +- 207419.8 +- 5.887 +- 210.8 +- 0.4165 +- 80Study 1: Phase Study in Adult Patients with Fabry Disease1 mg/kgq14 days 112801-3 (n=11)649 +- 2263.5 +- 1.689 +- 201.8 +- 0.8120 +- 802807 (n=11)372 +- 2232.1 +- 1.1482 +- 254.9 +- 5.6570 +- 71030011 (n=11)784 +- 5213.5 +- 2.2119 +- 492.3 +- 2.2280 +- 230Study 3: Phase Study in Pediatric Patients with Fabry Disease1 mg/kgq14 days 242081 (n=8-9)344 +- 3072.2 +- 1.986 +- 275.8 +- 4.61097 +- 91211112 (n=15)1007 +- 6884.9 +- 2.4130 +- 411.6 +- 1.2292 +- 18510824 (n=9-10)1238 +- 5477.1 +- 4.4151 +- 591.1 +- 0.8247 +- 146.

SPL UNCLASSIFIED SECTION.

2.1Recommended Dosage. The recommended dosage of Fabrazyme is mg/kg body weight infused every two weeks as an intravenous infusion.Infusion rate:-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)].-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 to mg/hour) with each subsequent infusion. The minimum infusion duration is 1.5 hours (based on individual patient tolerability).-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 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 low dose at 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 patient tolerates the infusion, the dose may be increased to reach the approved dose of mg/kg and the infusion rate may be increased by slowly titrating upwards (doubled every 30 minutes up to maximum rate of 0.25 mg/minute), as tolerated [see Adverse Reactions (6.2)].. The recommended dosage of Fabrazyme is mg/kg body weight infused every two weeks as an intravenous infusion.. Infusion rate:-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)].-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 to mg/hour) with each subsequent infusion. The minimum infusion duration is 1.5 hours (based on individual patient tolerability).-For patients weighing <30 kg, the maximum infusion rate is 0.25 mg/minute (15 mg/hour). -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)].. -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 to mg/hour) with each subsequent infusion. The minimum infusion duration is 1.5 hours (based on individual patient tolerability).. -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 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 low dose at 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 patient tolerates the infusion, the dose may be increased to reach the approved dose of mg/kg and the infusion rate may be increased by slowly titrating upwards (doubled every 30 minutes up to maximum rate of 0.25 mg/minute), as tolerated [see Adverse Reactions (6.2)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Exposure RegistryPregnant women and women of reproductive potential should be encouraged to enroll in the Fabry patient registry. The registry will monitor the effect of Fabrazyme on pregnant women and their offspring. For more information, visit www.registrynxt.com or call 1-800-745-4447, extension 15500.. Risk SummaryAvailable data from postmarketing case reports and case series with Fabrazyme use in pregnant women have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. 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 estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have 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. Animal dataThe 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 mg/kg every weeks on body surface area basis) during gestation days 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 body surface area basis). There were no adverse effects of agalsidase beta on embryo-fetal development in rats.. 8.2 Lactation. Risk SummaryThere are no data on the presence of agalsidase beta in either human or animal milk, the effects of the drug on the breastfed infant, or on milk production.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Fabrazyme and any potential adverse effects on the breastfed child from Fabrazyme or from the underlying maternal condition.Lactating women with Fabry disease treated with Fabrazyme should be encouraged to enroll in the Fabry registry [see Use in Specific Populations (8.1)].. 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, single-arm, open-label study in 16 pediatric patients with Fabry disease aged to 16 years, and additional data in 24 patients with Fabry disease aged to 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Anaphylaxis and Hypersensitivity Reactions: Life-threatening anaphylactic and severe hypersensitivity reactions have occurred during Fabrazyme infusions. If severe hypersensitivity or anaphylactic reactions occur, immediately discontinue the infusion and provide necessary emergency treatment. Readministration to patients who have previously experienced severe or serious hypersensitivity reactions to Fabrazyme should be done only after careful consideration of the risks and benefits of continued treatment, and only under the direct supervision of qualified personnel with appropriate medical support measures readily available. (5.1)Infusion-Associated Reactions: Pretreat patients who experience infusion-associated reactions with an antipyretic and antihistamine. If an infusion-associated reaction occurs, decrease the infusion rate, temporarily stop the infusion, and consider administration of additional antipyretics, antihistamines, and/or steroids. If severe infusion-associated reaction occurs, discontinue the infusion and initiate appropriate anaphylaxis treatment. (5.2). Anaphylaxis and Hypersensitivity Reactions: Life-threatening anaphylactic and severe hypersensitivity reactions have occurred during Fabrazyme infusions. If severe hypersensitivity or anaphylactic reactions occur, immediately discontinue the infusion and provide necessary emergency treatment. Readministration to patients who have previously experienced severe or serious hypersensitivity reactions to Fabrazyme should be done only after careful consideration of the risks and benefits of continued treatment, and only under the direct supervision of qualified personnel with appropriate medical support measures readily available. (5.1). Infusion-Associated Reactions: Pretreat patients who experience infusion-associated reactions with an antipyretic and antihistamine. If an infusion-associated reaction occurs, decrease the infusion rate, temporarily stop the infusion, and consider administration of additional antipyretics, antihistamines, and/or steroids. If severe infusion-associated reaction occurs, discontinue the infusion and initiate appropriate anaphylaxis treatment. (5.2). 5.1Anaphylaxis 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 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 positive skin test to Fabrazyme or who have tested positive for Fabrazyme-specific IgE antibody have been rechallenged with Fabrazyme using 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)].. 5.2Infusion-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 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)].