Laronidase

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 information on the compatibility of diluted ALDURAZYME with glass containers. Dilute ALDURAZYME in the following manner using aseptic technique: Determine the infusion bag volume and number of ALDURAZYME vials to be diluted based on actual body weight in kg and the recommended dose [see Dosage and Administration (2.2) ] . Round the number of vials up to the next whole number. Remove the appropriate number of ALDURAZYME vials from the refrigerator and allow the vials to reach room temperature 20°C to 25°C (68°F to 77°F) before use. Do not heat or microwave the vials. Visually inspect the solution in each vial for particulate matter and discoloration. The ALDURAZYME solution should be clear to slightly opalescent and colorless to pale yellow. Some translucency may be present in the solution. Discard if the solution is discolored or if visible particulate matter is present. Withdraw and discard a volume of the 0.9% Sodium Chloride Injection from an infusion bag, equal to the volume of ALDURAZYME to be added. Slowly withdraw the calculated volume of ALDURAZYME from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature ALDURAZYME, rendering it biologically inactive. Discard any unused solution remaining in the vial. Slowly add the ALDURAZYME solution to the 0.9% Sodium Chloride Injection solution through the port of the infusion bag and avoid agitation. Do not use a filter needle. Gently rotate the infusion bag to ensure proper distribution of ALDURAZYME. Do not shake the infusion bag. 2.5. Storage Instruction for the Diluted Solution If the diluted ALDURAZYME solution is not used immediately: Refrigerate the diluted solution at 2°C to 8°C (36°F to 46°F) for up to 36 hours. Discard any unused ALDURAZYME diluted solution after 36 hours. Do not store the diluted solution at room temperature. The solution must be infused within 8 hours after removal from the refrigerator, inclusive of the total infusion time, or discarded. 2.6 Administration Instructions Use an infusion set equipped with a low-protein-binding, 0.2 micron, in-line filter to administer the diluted ALDURAZYME solution. The total volume of infusion [see Dosage and Administration (2.2) ] should be administered over approximately 3 to 4 hours as tolerated per the infusion rate steps outlined in Table 1 below. At the end of the infusion, flush the infusion line with 0.9% Sodium Chloride Injection, using the same infusion rate as the one used for the last part of the infusion. Do not infuse ALDURAZYME in the same intravenous line with other products. Table 1: Incremental Infusion Rate Steps and Volumes for ALDURAZYME ® Infusion by Patient Weight Patient Weight Range Total Infusion Volume Step 1 10 mcg/kg/hr Step 2 20 mcg/kg/hr Step 3 50 mcg/kg/hr Step 4 100 mcg/kg/hr Step 5 200 mcg/kg/hr Infusion Rate in mL/hour ≥2 to <4 kg 50 mL 1 2 4 8 16 ≥4 to <20 kg 100 mL 2 4 8 16 32 ≥20 kg 250 mL 5 10 20 40 80 Start infusion at rate in Step 1. In the absence of infusion-associated reactions after vital sign assessment, increase infusion rate sequentially per the steps in Table 1 every 15 minutes to reach the target rate in Step 5. Continue Step 5 until infusion is completed. The total infusion time is approximately 3 to 4 hours.

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 body weight once weekly for up to 182 weeks. The most serious adverse reactions reported with ALDURAZYME infusions in Study 2 were anaphylactic and hypersensitivity reactions [see Warnings and Precautions (5) ] . One patient had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both ALDURAZYME-specific IgG and IgE binding antibodies and complement activation. The most common adverse reactions requiring intervention were infusion reactions reported in 49% (22 of 45) of patients treated with ALDURAZYME. The most common adverse reactions reported in patients who received ALDURAZYME were rash (13%), flushing (11%), pyrexia (11%), headache (9%), abdominal pain or discomfort (9%), and injection site reaction (9%). Less commonly reported infusion reactions included nausea (7%), diarrhea (7%), feeling hot or cold (7%), vomiting (4%), pruritus (4%), arthralgia (4%), and urticaria (4%). Additional common adverse reactions included back pain and musculoskeletal pain. Clinical Trials in Patients 6 Years and Younger Study 3 was a 52-week, open-label, uncontrolled study of 20 MPS I patients, ages 6 months to 5 years old (at enrollment). Sixteen patients were clinically assessed as having the Hurler form, and 4 had the Hurler-Scheie form. All 20 patients received ALDURAZYME at 0.58 mg/kg of body weight once weekly for 26 weeks and up to 52 weeks. All patients were treated with antipyretics and antihistamines prior to the infusions. The nature and severity of infusion reactions were similar between the older and less severely affected patients (Studies 1 and 2) and the younger, more severely affected patients (Study 3). The most commonly reported adverse reactions in Study 3 were infusion reactions reported in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), blood pressure increased (10%), tachycardia (10%), and oxygen saturation decreased (10%). Other commonly reported infusion reactions occurring in ≥5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritus, and rash. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ALDURAZYME. 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. In postmarketing experience with ALDURAZYME, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock [see Warnings and Precautions (5.1) ] and laryngeal edema. Adverse reactions resulting in death reported in the postmarketing setting with ALDURAZYME treatment included cardiorespiratory arrest, respiratory failure, cardiac failure, and pneumonia. These events have been reported in MPS I patients with underlying disease [see Warnings and Precautions (5.3) ]. Additional adverse reactions included fatigue, peripheral edema, erythema and cyanosis. There have been a small number of reports of extravasation in patients treated with ALDURAZYME. There have been no reports of tissue necrosis associated with extravasation. Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions Including Anaphylaxis In the MPS I Registry and other postmarketing setting, laronidase-specific IgE and/or IgG antibodies appeared to be associated with anaphylaxis and suspected hypersensitivity reactions in ALDURAZYME-treated patients [see Clinical Pharmacology (12.6) ].

12.3 Pharmacokinetics The pharmacokinetics of laronidase were evaluated in 6-year-old or older patients (N=10 to 12) with MPS I who received 0.58 mg/kg of body weight once weekly of ALDURAZYME as a 4-hour infusion in the placebo-controlled clinical study (Study 1). After the 1 st , 12 th , and 26 th weekly infusions, the mean maximum plasma concentrations (C max ) ranged from 1.2 to 1.7 mcg/mL for the 3 time points. The mean area under the plasma concentration-time curve (AUC ∞ ) ranged from 4.5 to 6.9 mcg ∙ hour/mL. The mean volume of distribution (V z ) ranged from 0.24 to 0.60 L/kg. Mean plasma clearance (CL) ranged from 1.7 to 2.7 mL/min/kg, and the mean elimination half-life (t 1/2 ) ranged from 1.5 to 3.6 hours. The pharmacokinetics of laronidase were evaluated in 6-year-old or younger patients (N=7 to 9) with MPS I disease who received 0.58 mg/kg of body weight once weekly of ALDURAZYME as a 4-hour infusion in the open label clinical study (Study 3). After the 26 th infusion, the 95% confidence interval of the geometric mean values of PK parameters ranged from 0.6 to 1.6 mcg/mL for the maximum plasma concentrations (C max ), from 1.3 to 4.4 mcg ∙ hour/mL for area under the plasma concentration-time curve (AUC ∞ ), from 0.12 to 0.56 L/kg for volume of distribution (V z ), from 2.2 to 7.7 mL/min/kg for plasma clearance (CL), and from 0.3 to 1.9 hours for elimination half-life (t 1/2 ).