Data from FDA - Curated by EPG Health - Last updated 18 December 2019

Indication(s)

1 INDICATIONS AND USAGE ALDURAZYME ® (laronidase) is indicated for patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established. ALDURAZYME has been shown to improve pulmonary function and walking capacity. ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder. ALDURAZYME is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established. ALDURAZYME has been shown to improve pulmonary function and walking capacity. ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder (1).

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions
6 ADVERSE REACTIONS The most commonly reported infusion reactions occurring in at least 10% of patients 6 months of age and older were pyrexia, chills, blood pressure increased, tachycardia, and oxygen saturation decreased (6). The most frequently occurring adverse reactions occurring in at least 10% of patients 6 years and older are rash, upper respiratory tract infection, injection site reaction, hyperreflexia, paresthesia, flushing, and poor venous access. To report SUSPECTED ADVERSE REACTIONS, contact: Genzyme at 1-800-745-4447, or FDA at 1-800-FDA-1088 or go to 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. The most serious adverse reactions reported with ALDURAZYME treatment during clinical trials were anaphylactic and allergic reactions. Most adverse reactions reported in clinical trials were considered disease-related and unrelated to study drug. 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. Most infusion reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, with or without administering additional treatments including antihistamines, antipyretics, or both. 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 IV 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 commonly reported infusion reactions regardless of treatment group 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 3 enumerates adverse reactions and selected laboratory abnormalities that occurred during the placebo-controlled study (Study 1) that were reported in at least 2 patients more in the ALDURAZYME group than in the placebo group. Table 3: Summary of Adverse Reactions that Occurred in 2 Patients More in the ALDURAZYME® Group than in the Placebo Group in the 26-Week Placebo-controlled Study (Study 1) MedDRA System Organ Class (SOC) MedDRA Preferred Term (N=22) ALDURAZYME n (%) (N=23) Placebo 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 allergic reactions [see Warnings and Precautions (5) ]. The most common adverse reactions requiring intervention were infusion reactions reported in 49% (22 of 45) of patients treated with ALDURAZYME. The most commonly reported infusion reactions included 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 most commonly reported serious adverse events (regardless of relationship) reported with ALDURAZYME infusions in Study 3 were otitis media (20%), and central venous catheterization required for ALDURAZYME infusion (15%). The nature and severity of infusion reactions were similar between the older and less severely affected patients in Studies 1 and 2, and the younger, more severely affected patients in 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 Immunogenicity In clinical trials, 99 of 102 patients (97%) treated with ALDURAZYME were positive for IgG antibodies to ALDURAZYME. No correlation was demonstrated between the presence of IgG anti-ALDURAZYME antibodies and therapeutic response (6 MWT and FVC) or the occurrence of allergic reactions. Potential for antibody neutralization of cellular uptake has not been assessed. No consistent association was demonstrated between the presence of antibodies that neutralize enzymatic activity and therapeutic response. The data reflect the percentage of patients whose test results were considered positive for antibodies to ALDURAZYME using a specific enzyme-linked immunosorbent assay (ELISA) and confirmed by radio-immunoprecipitation (RIP). ALDURAZYME IgG antibodies were reported as titers. Drug specific antibody was detected in 42 of the 45 patients (93.3%) treated in Study 1 and Study 2. The mean time to seroconversion was 51 days in patients 6 years and older. In Study 3, all patients (100%) 5 years old or younger developed IgG antibodies against ALDURAZYME with a mean time to seroconversion of 26 days [see Clinical Studies (14) for the Study populations]. Nine patients in Study 1 and Study 2, collectively, who experienced severe infusion reactions were tested for ALDURAZYME-specific IgE antibodies and complement activation. IgE testing was performed by ELISA, and complement activation was measured by the Quidel Enzyme Immunoassay. One of the nine patients had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both ALDURAZYME-specific IgE binding antibodies and complement activation. None of the patients in the open-label clinical study of patients 5 years old or younger (Study 3) tested positive for IgE. Other allergic reactions were also seen in patients receiving ALDURAZYME [see Adverse Reactions (6) ]. In the postmarketing setting, approximately 1% of patients experienced severe or serious infusion allergic reactions and tested positive for IgE. Of these IgE-positive patients, some have discontinued treatment, but some have been successfully re-challenged. The clinical significance of IgE antibodies has not been established. As with all the therapeutic proteins, there is potential for immunogenicity. The incidence 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 ALDURAZYME with the incidence of antibodies to other products may be misleading. 6.3 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 Boxed Warning and Warnings and Precautions (5) ] 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 significant underlying disease. Additional adverse reactions included fatigue, edema peripheral, 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION 0.58 mg/kg of body weight administered once weekly as an intravenous (IV) infusion (2). 2.1 Recommended Dose The recommended dosage regimen of ALDURAZYME is 0.58 mg/kg of body weight administered once weekly as an intravenous (IV) infusion. Pretreatment is recommended 60 minutes prior to the start of the infusion and may include antihistamines, antipyretics, or both [ see Warnings and Precautions (5) ]. Each vial of ALDURAZYME provides 2.9 milligrams (mg) of laronidase in 5.0 milliliters (mL) of solution and is intended for single dose only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 mL or 250 mL, using aseptic techniques. The final volume of the infusion is determined by the patient’s body weight. Patients with a body weight of 20 kg or less should receive a total volume of 100 mL. Patients with a body weight greater than 20 kg should receive a total volume of 250 mL [see Dosage and Administration (2.2) ]. 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 (2.2), Warnings and Precautions (5.3) and Adverse Reactions (6.3) ]. 2.2 Instructions for Use Prepare and use ALDURAZYME according to the following steps. Use aseptic techniques. Prepare ALDURAZYME using low-protein-binding containers and administer with a low-protein-binding infusion set equipped with an in-line, low-protein-binding 0.2 micrometer (µm) filter. There is no information on the compatibility of diluted ALDURAZYME with glass containers. Determine the number of vials to be diluted based on the patient's weight and the recommended dose of 0.58 mg/kg, using the following equation: Patient's weight (kg) x 1 mL/kg of ALDURAZYME = Total number of mL of ALDURAZYME Total number of mL of ALDURAZYME ÷ 5 mL per Vial = Total number of Vials. Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not heat or microwave vials. Before withdrawing the ALDURAZYME from the vial, visually inspect 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. Do not use if the solution is discolored or if there is particulate matter in the solution. Withdraw and discard a volume of the 0.9% Sodium Chloride Injection, USP from the infusion bag, equal to the volume of ALDURAZYME concentrate 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. Slowly add the ALDURAZYME solution to the 0.9% Sodium Chloride Injection, USP using care to avoid agitation of the solutions. Do not use a filter needle. Gently rotate the infusion bag to ensure proper distribution of ALDURAZYME. Do not shake the solution. The entire infusion volume (100 mL for patients weighing 20 kg or less and 250 mL for patients weighing greater than 20 kg) should be delivered over approximately 3 to 4 hours. The initial infusion rate of 10 µg/kg/hr may be incrementally increased every 15 minutes during the first hour, as tolerated, until a maximum infusion rate of 200 µg/kg/hr is reached. The maximum rate is then maintained for the remainder of the infusion (2-3 hours), as outlined in Tables 1 and 2. Administer the diluted ALDURAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter. Table 1: Incremental Rates for 100 mL ALDURAZYME® Infusion (For use with Patients Weighing 20 kg or Less) Infusion Rate Criteria for Increasing Infusion Rate 2 mL/hr x 15 minutes (10 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 4 mL/hr x 15 minutes (20 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 8 mL/hr x 15 minutes (50 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 16 mL/hr x 15 minutes (100 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 32 mL/hr x ~3 hours (200 μg/kg/hr) For the remainder of the infusion. Table 2: Incremental Rates for 250 mL ALDURAZYME® Infusion (For use with Patients Weighing Greater than 20 kg) Infusion Rate Criteria for Increasing Infusion Rate 5 mL/hr x 15 minutes (10 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 10 mL/hr x 15 minutes (20 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 20 mL/hr x 15 minutes (50 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 40 mL/hr x 15 minutes (100 μg/kg/hr) Obtain vital signs, if stable then increase the rate to... 80 mL/hr x ~3 hours (200 μg/kg/hr) For the remainder of the infusion. ALDURAZYME does not contain any preservatives; therefore, after dilution with saline, the infusion bags should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 36 hours. Other than during infusion, room temperature storage of diluted solution is not recommended. Any unused product or waste material should be discarded and disposed of in accordance with local requirements. ALDURAZYME must not be administered with other medicinal products in the same infusion. The compatibility of ALDURAZYME in solution with other products has not been evaluated.
Use in special populations
8 USE IN SPECIFIC POPULATIONS A registry for pregnant women is available. Pregnant women with MPS I should be encouraged to enroll in the MPS I Registry. For more information, visit www.registrynxt.com or call 1-800-745‑4447 ext. 15500 (8.1). 8.1 Pregnancy Pregnancy Registry An MPS I Registry has been established and pregnant women with MPS I should be encouraged to enroll in the pregnancy sub-registry. For more information, visit www.registrynxt.com or call 1-800-745-4447 ext. 15500. Risk Summary Limited available data with ALDURAZYME use in pregnant women are insufficient to inform drug-associated risk of adverse developmental outcomes. ALDURAZYME should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the fetus. 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 estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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 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 IV (equivalent to 7.3, 73.1, 730.8 U/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. Based on the results of this study, the maternal NOAEL was 0.036 mg (73.1 U)/kg/day and the developmental NOAEL was 3.6 mg (730.8 U)/kg/day or 6.2 times the recommended human dose. Laronidase has not been evaluated for effects on embryo-fetal development in any other species. 8.2 Lactation Lactating women with MPS I are encouraged to enroll in the MPS I Registry. For more information, visit www.registrynxt.com or call 1-800-745-4447 ext.15500. Risk Summary There are insufficient data on the presence of ALDURAZYME in human milk, the effects on milk production, or the effects on the breastfed infant. ALDURAZYME should be used during breastfeeding only if the potential benefits to the mother outweigh the potential risks, including those to the breastfed child. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALDURAZYME and any potential adverse effects on the breastfed child from ALDURAZYME or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ALDURAZYME was assessed in a 52-week, open-label, uncontrolled clinical study in 20 patients with MPS I, ages 6 months to 5 years old, and was found to be similar to the safety and effectiveness of ALDURAZYME in pediatric patients 6 to 18 years, and adults [see Adverse Reactions (6) and Clinical Studies (14) ]. 8.5 Geriatric Use Clinical studies of ALDURAZYME did not include patients aged 65 and over. It is not known whether they respond differently from younger patients.

More information

Category Value
Authorisation number BLA125058
Agency product number WP58SVM6R4
Orphan designation No
Product NDC 58468-0070
Date Last Revised 01-12-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 403822
Marketing authorisation holder Genzyme Corporation
Warnings WARNING: RISK OF ANAPHYLAXIS Life-threatening anaphylactic reactions have been observed in some patients during ALDURAZYME® infusions. Therefore, appropriate medical support should be readily available when ALDURAZYME is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions and require additional monitoring. WARNING: RISK OF ANAPHYLAXIS See full prescribing information for complete boxed warning. Life-threatening anaphylactic reactions have been observed in some patients during ALDURAZYME infusions. Therefore, appropriate medical support should be readily available when ALDURAZYME is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions and require additional monitoring.