ALDURAZYME

Human recombinant alpha-L-iduronidase, 628 residues (mature form), produced by recombinant DNAtechnology in a Chinese hamster ovary cell line.

Laronidase is a glycoprotein with a molecular weight of approximately 83 kD.

The predicted amino acid sequence of the recombinant form, as well as the nucleotide sequence that encodes it, are identical to a polymorphic form of human a-L-iduronidase.

It contains 6 N-linked oligosaccharide modification sites.

For the treatment of mucopolysaccharidosis

Laronidase is used to treat mucopolysaccharide storage disorders (specifically mucopolysaccharidosis 1 or Hurlers syndrome) caused by deficiencies of alpha-L-iduronidase.

Reduced or absent a-L-iduronidase activity results in the accumulation of the GAG substrates, dermatan sulfate and heparan sulfate, throughout the body and leads to widespread cellular, tissue, and organ dysfunction.

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For pretreatment recommendations, see Full Prescribing Information.

The recommended dosage is 0.58 mg/kg administered once weekly as an intravenous infusion.

For dosage and administration modifications due to hypersensitivity reactions or infusion-associated reactions (IARs), see Full Prescribing Information.

For instructions on preparation, storage, and administration, see Full Prescribing Information. 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.

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.

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. 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, .

In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, consider temporarily holding the infusion for 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.

Consider re-initiating the infusion within to 14 days using the incremental rate steps table, 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.

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.

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 should be administered over approximately 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.

Step 5 until infusion is completed.

The total infusion time is approximately to 4 hours.

(laronidase) injection is supplied as a colorless to pale yellow, clear to slightly opalescent solution in single-dose, clear Type I glass vial.

Each vial contains 2.9 mg/5 mL (0.58 mg/mL) of laronidase.

The closure consists of a siliconized butyl stopper and an aluminum seal with a plastic flip-off cap.

ALDURAZYME is available as

One single-dose vial in a carton (NDC 58468-0070-1) Refrigerate vials of ALDURAZYME at 2°C to 8°C (36°F to 46°F).

Do not freeze or shake.

Protect from light.

This product contains no preservatives.

Refrigerate vials of

ALDURAZYME at 2°C to 8°C (36°F to 46°F).

Do not freeze or shake.

Protect from light.

This product contains no preservatives.

Registry has been established.

Pregnant women with MPS

I and healthcare providers are encouraged to contact the pregnancy sub-registry by visiting 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.

I may result in adverse pregnancy and infant outcomes.

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.

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.

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.

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.

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).

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

Clinical studies of

ALDURAZYME did not include patients 65 years of age and older to determine if they respond differently from younger patients.