ALDURAZYME

1 INDICATIONS AND USAGE ALDURAZYME ® is indicated for the treatment of: adult and pediatric patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and patients with the Scheie form of MPS I who have moderate to severe symptoms. ALDURAZYME is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for the treatment of adult and pediatric patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for the treatment of patients with the Scheie form of MPS I who have moderate to severe symptoms. ( 1 ) Limitations of Use: The risks and benefits of treating mildly affected patients with the Scheie form have not been established. ( 1 ) ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder. ( 1 ) Limitations of Use The safety and effectiveness of treating mildly affected patients with the Scheie form have not been established. The effect of ALDURAZYME on central nervous system manifestations of the disorder has not been determined.

2 DOSAGE AND ADMINISTRATION For pretreatment recommendations, see Full Prescribing Information. ( 2.1 ) The recommended dosage is 0.58 mg/kg administered once weekly as an intravenous infusion. ( 2.2 ) For dosage and administration modifications due to hypersensitivity reactions or infusion-associated reactions (IARs), see Full Prescribing Information. ( 2.3 ) For instructions on preparation, storage, and administration, see Full Prescribing Information. ( 2.4 , 2.5 , 2.6 ) 2.1 Recommendations Prior to ALDURAZYME Treatment Premedication Prior to ALDURAZYME administration, consider premedicating with antihistamines, with or without antipyretics, 60 minutes before the start of infusion [see Warnings and Precautions (5.1 , 5.4) ]. Medical Support Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during ALDURAZYME administration. 2.2 Recommended Dosage and Administration The recommended dosage of ALDURAZYME is 0.58 mg/kg (actual body weight) administered once weekly as an intravenous infusion. ALDURAZYME injection must be diluted with 0.9% Sodium Chloride Injection to a final volume of 50 mL, 100 mL or 250 mL as determined by the patient's body weight and cardiopulmonary condition: Patients with a body weight equal to or greater than 2 kg and less than 4 kg should receive a total volume of 50 mL; patients with a body weight equal to or greater than 4 kg and up to 20 kg should receive a total volume of 100 mL; and those patients with a body weight greater than 20 kg should receive a total volume of 250 mL [see Dosage and Administration (2.6) ]. For patients with underlying cardiac or respiratory compromise and weighing up to 30 kg, physicians may consider diluting ALDURAZYME in a volume of 100 mL and administering at a decreased infusion rate [see Dosage and Administration (2.6) ]. The initial infusion rate of ALDURAZYME is 10 mcg/kg/hr and may be increased every 15 minutes during the first hour, as tolerated, to a maximum infusion rate of 200 mcg/kg/hr. The maximum rate is then maintained for the remainder of the infusion (2 to 3 hours) [see Dosage and Administration (2.6) , Warnings and Precautions (5.2 , 5.3) ] . If one or more doses are missed, restart ALDURAZYME treatment as soon as possible and maintain the 1-week interval between infusions thereafter. Do not double a dose to compensate for a missed dose. 2.3 Administration Modifications due to Hypersensitivity or Infusion Associated Reaction In the event of a severe hypersensitivity reaction (e.g. anaphylaxis) or severe infusion-associated reaction (IAR), immediately discontinue ALDURAZYME administration and initiate appropriate medical treatment. For additional recommendations in the event of a severe hypersensitivity reaction, [ see Warnings and Precautions (5.1) ]. In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, consider temporarily holding the infusion for 15 to 30 minutes, or slowing the infusion rate by 25% to 50% [ see Dosage and Administration (2.6) ] , and initiating appropriate medical treatment [see Warnings and Precautions (5.1 , 5.4) ] . If symptoms persist despite holding or slowing the infusion, stop the infusion and monitor the patient. Consider re-initiating the infusion within 7 to 14 days using the incremental rate steps table [see Dosage and Administration (2.6) ] , up to 25% or 50% of the rate at which the reaction occurred with appropriate premedication. If symptoms subside after holding the infusion, resume infusion at a 25% to 50% reduced rate as tolerated. Alternatively, if symptoms subside after slowing the infusion, complete infusion at the reduced rate as tolerated. Starting with next infusion, increase the infusion rate by increments of 25% as tolerated until the recommended infusion rate is reached. Closely monitor the patient. 2.4 Preparation Instructions Prepare ALDURAZYME using low-protein-binding containers. There is no i…

5 WARNINGS AND PRECAUTIONS Risk of Acute Respiratory Complications: Patients with acute febrile or respiratory illness at the time of ALDURAZYME infusion may be at greater risk for infusion reactions. Consider delaying ALDURAZYME infusion. Sleep apnea is common in MPS I patients. Consider evaluating airway patency prior to initiation of treatment with ALDURAZYME. Appropriate respiratory support should be available during infusion. ( 5.2 ) Risk of Acute Cardiorespiratory Failure: Patients susceptible to fluid overload may be at increased risk for serious exacerbation of their cardiac or respiratory status during infusions. Consider a decreased total infusion volume and infusion rate when administering ALDURAZYME to these patients. Appropriate medical monitoring and support measures should be available during infusion. ( 2.2 , 5.3 ) Infusion Reactions: If severe IARs occur, discontinue ALDURAZYME and initiate appropriate medical treatment. ( 5.4 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis have been reported in patients during or up to 3 hours after ALDURAZYME infusions. Some of these reactions were life-threatening and included respiratory failure, respiratory distress, stridor, tachypnea, bronchospasm, obstructive airways disorder, hypoxia, hypotension, bradycardia, and urticaria. In clinical studies and postmarketing safety experience with ALDURAZYME, approximately 1% of patients experienced severe or serious hypersensitivity reactions. In patients with MPS I, pre-existing upper airway obstruction may have contributed to the severity of some reactions. Prior to ALDURAZYME administration, consider premedicating patients with antihistamines, with or without antipyretics, 60 minutes before the start of infusion. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during ALDURAZYME administration. Because of the potential for recurrent reactions, some patients who experience initial severe reactions may require prolonged observation. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue ALDURAZYME immediately and initiate appropriate medical treatment. Exercise caution if epinephrine is being considered for use in patients with MPS I due to the increased prevalence of coronary artery disease in these patients. Interventions have included resuscitation, mechanical ventilatory support, emergency tracheotomy, hospitalization, and treatment with inhaled beta-adrenergic agonists, epinephrine, and intravenous corticosteroids [see Adverse Reactions (6) ]. Consider the risks and benefits of re-administering ALDURAZYME following severe hypersensitivity reactions (including anaphylaxis). Patients may be rechallenged using slower infusion rates. In patients with severe hypersensitivity reaction, desensitization measures to ALDURAZYME may be considered. If the decision is made to readminister ALDURAZYME, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the rate may be increased to reach the recommended rate. If a mild or moderate hypersensitivity reaction occurs, consider temporarily holding the infusion or slowing the infusion rate [see Dosage and Administration (2.3) ]. 5.2 Acute Respiratory Complications Associated with Administration One patient with acute bronchitis and hypoxia experienced increased tachypnea during the first ALDURAZYME infusion that resolved without intervention. The patient's respiratory symptoms returned within 30 minutes of completing the infusion and responded to bronchodilator therapy. Approximately 6 hours after the infusion, the patient experienced coughing, then respiratory arrest, and died. Patients with an acute febrile or respiratory illness at the time of ALDURAZYME infusion may be at greater risk for infusion reactions. Careful consideration should be given to the patient's clinical status prior to administration …

4 CONTRAINDICATIONS None. None. ( 4 )

8.1 Pregnancy Pregnancy Exposure Registry An MPS I Registry has been established. Pregnant women with MPS I and healthcare providers are encouraged to contact the pregnancy sub-registry by visiting www.registrynxt.com or calling 1-800-745-4447 ext. 15500. Risk Summary Available data from the MPS I Registry pregnancy sub-registry, published case reports, and the global pharmacovigilance database with ALDURAZYME use in more than 30 pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The continuation of treatment for MPS I during pregnancy should be individualized to the pregnant woman. Untreated MPS I may result in adverse pregnancy and infant outcomes ( see Clinical Considerations ). No evidence of fetal harm has been observed in rats when laronidase was administered during organogenesis at doses up to 6.2 times the recommended human dose (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Pregnancy can exacerbate preexisting clinical manifestations of MPS and lead to adverse pregnancy outcomes for both mother and fetus. Data Animal Data When laronidase was administered to pregnant female rats during organogenesis (gestation days [GD] 7-17) at doses of 0, 0.036, 0.36 or 3.6 mg/kg/day intravenously (equivalent to 7.3, 73.1, 730.8 units/kg/day) decreased maternal body weight gains and food consumption were observed with no corresponding effects on reproductive and litter parameters including number and distribution of corpora lutea, implantations and early and late resorptions at doses up to 3.6 mg/kg/day (6.2 times the recommended human dose of 0.58 mg/kg on a mg/kg basis). Laronidase has not been evaluated for effects on embryo-fetal development in any other species.

6 ADVERSE REACTIONS Serious and or clinically significant adverse reactions described elsewhere in labeling include: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] Acute Respiratory Complications Associated with Administration [see Warnings and Precautions (5.2) ] Acute Cardiorespiratory Failure [see Warnings and Precautions (5.3) ] Infusion-Associated Reactions [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥10%) in patients: 6 months of age and older are: infusion reactions (pyrexia, chills, blood pressure increased, tachycardia, and oxygen saturation decreased). ( 6.1 ) 6 years and older are: rash, upper respiratory tract infection, injection site reaction, hyperreflexia, paresthesia, flushing, and poor venous access. ( 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 . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Serious adverse reactions reported with ALDURAZYME treatment during clinical trials were anaphylactic and hypersensitivity reactions. The most common adverse reactions were infusion reactions. The frequency of infusion reactions decreased over time with continued use of ALDURAZYME, and the majority of reactions were classified as being mild to moderate in severity. Clinical Trials in Patients 6 Years and Older A 26-week, double-blind, placebo-controlled clinical study (Study 1) of ALDURAZYME was conducted in 45 patients with MPS I, ages 6 to 43 years old, gender evenly distributed (N=23 females and 22 males). Of these 45 patients, 1 was clinically assessed as having Hurler form, 37 Hurler-Scheie, and 7 Scheie. Patients were randomized to receive either 0.58 mg/kg intravenously of ALDURAZYME per week for 26 weeks or placebo. All patients were treated with antipyretics and antihistamines prior to the infusions. Infusion reactions were reported in 32% (7 of 22) of ALDURAZYME-treated patients. The most common adverse reactions reported in patients who received ALDURAZYME were flushing, pyrexia, headache, and rash. Flushing occurred in 5 patients (23%) receiving ALDURAZYME; the other reactions were less frequent. Less common infusion reactions included angioedema (including face edema), hypotension, paresthesia, feeling hot, hyperhidrosis, tachycardia, vomiting, back pain, and cough. Other reported adverse reactions included bronchospasm, dyspnea, urticaria and pruritus. Table 2 enumerates adverse reactions and selected laboratory abnormalities that occurred during the 26-week placebo-controlled study (Study 1) that were reported in at least 2 patients more in the ALDURAZYME group than in the placebo group. Table 2: Adverse Reactions that Occurred in at Least 2 Patients More in the ALDURAZYME Group than in the Placebo Group Among Adult and Pediatric Patients with MPS I in Study 1 ALDURAZYME N=22 n (%) Placebo N=23 n (%) Blood and lymphatic system disorders Thrombocytopenia 2 (9) 0 Eye disorders Corneal opacity 2 (9) 0 General disorders and administration site conditions Chest pain 2 (9) 0 Face edema 2 (9) 0 Gravitational edema 2 (9) 0 Injection site pain 2 (9) 0 Injection site reaction 4 (18) 2 (9) Hepatobiliary disorders Hyperbilirubinemia 2 (9) 0 Infections and infestations Abscess 2 (9) 0 Upper respiratory tract infection 7 (32) 4 (17) Nervous system disorders Hyperreflexia 3 (14) 0 Paresthesia 3 (14) 1 (4) Skin and subcutaneous tissue disorders Rash 8 (36) 5 (22) Vascular disorders Hypotension 2 (9) 0 Poor venous access 3 (14) 0 All 45 patients who completed the placebo-controlled study (Study 1) continued treatment in an open-label, uncontrolled extension study (Study 2). All patients received ALDURAZYME 0.58 mg/kg of bod…