Aldurazyme Drug Information

• 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.
• Limitations of Use: The risks and benefits of treating mildly affected patients with the Scheie form have not been established. ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder. 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.

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. Medical Support Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during ALDURAZYME administration.

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. 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.

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). 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.

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,. 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%, and initiating appropriate medical treatment.

If symptoms persist despite holding or slowing the infusion, stop the infusion and monitor the patient. 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.

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.

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.

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 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 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.

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. 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 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.

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. Additional common adverse reactions included back pain and musculoskeletal pain.

Sixteen patients were clinically assessed as having the Hurler form, and 4 had the Hurler-Scheie form. 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). Other commonly reported infusion reactions occurring in ≥5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritus, and rash.

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 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. 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.

Pregnancy 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 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 7-17) at doses of 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.

Pediatric Use The safety and effectiveness of ALDURAZYME have been established for the treatment of pediatric patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and the treatment of pediatric patients with the Scheie form of MPS I who have moderate to severe symptoms. The safety and effectiveness ALDURAZYME for the treatment of mildly affected pediatric patients with the Scheie form have not been established. Use of ALDURAZYME for these indications is supported by evidence from an adequate and well-controlled clinical study (Study1) with an open label extension (Study 2) in adult and pediatric patients with MPS I, and from an open label, uncontrolled clinical study in pediatric patients with MPS I, 6 months to 5 years of age (Study 3).

The safety and effectiveness of ALDURAZYME in pediatric patients 6 months of age to 5 years of age was found to be similar to pediatric patients 6 to 18 years of age and adults for these indications.