The most serious adverse reactions reported with ALDURAZYME during clinical trials and the post-marketing period were anaphylactic and allergic reactions (see BOXED WARNING and WARNINGS: Anaphylaxis and Allergic Reactions).

The most common adverse reactions associated with ALDURAZYME treatment in the clinical studies were upper respiratory tract infection, rash, and injection site reaction.

In clinical studies, the most common adverse reactions requiring intervention were infusion-related reactions reported in 32% (7 of 22) of patients treated with ALDURAZYME. The most common infusion-related reactions were flushing, fever, headache, and rash. Flushing occurred in 5 patients (23%) receiving ALDURAZYME; the other reactions were less frequent. Infusion-related reactions were not significantly different between the ALDURAZYME treatment group and the placebo treatment group who received infusions of diluent and all components of ALDURAZYME except the laronidase enzyme. All reactions were classified as being mild to moderate in severity. The frequency of infusion-related reactions decreased with continued use during the open-label extended use period. Less common infusion-related reactions include cough, bronchospasm, dyspnea, urticaria, angioedema and pruritus. Most infusion-related reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, and/or administering additional antipyretics and/or antihistamines.

The data described below reflect exposure to 0.58 mg/kg of ALDURAZYME for 26 weeks in a placebo-controlled double-blind study in 45 patients with MPS I (N=22 ALDURAZYME, and N=23 placebo). All 45 patients continued into an open-label study of ALDURAZYME treatment for an additional 36 weeks. An additional 10 patients participated in a Phase 1 open-label study with continued infusions for up to 3 years. The population in the placebo-controlled study was evenly distributed for gender (N=23 females and 22 males) and ranged in ages from 6 to 43 years. Of the 45 patients in the placebo-controlled study, 1 was clinically assessed as having Hurler form, 37 Hurler-Scheie, and 7 Scheie. All patients were treated with antipyretics and antihistamines prior to the infusions.

Because clinical trials are conducted under widely varying and controlled conditions, the observed adverse reaction rates may not predict the rates observed in patients in clinical practice.

Table 2 enumerates adverse events and selected laboratory abnormalities that occurred during the placebo-controlled trial in at least 2 patients more in the ALDURAZYME group than was observed in the placebo group. Reported adverse events have been classified using standard

WHO ART terms. Observed adverse events in the Phase 1 study and the open-label treatment period following the controlled study were not different in nature or severity.

Table 2: Number and (%) of Patients with Adverse Events and Selected Laboratory Abnormalities in the Placebo-Controlled Study

In postmarketing experience with ALDURAZYME, severe and serious infusion-related reactions have been reported, some of which were life-threatening (see BOXED WARNING and WARNINGS: Anaphylaxis and Allergic Reactions). The most frequently reported adverse reactions (using MedDRA terminology) included chills, vomiting, nausea, arthralgia, diarrhea, tachycardia, abdominal pain, blood pressure increased, and oxygen saturation decreased.

Immunogenicity

In clinical studies, 50 of 55 patients (91%) treated with ALDURAZYME were positive for antibodies to laronidase. The clinical significance of antibodies to ALDURAZYME is not known, including the potential for product neutralization.

The data reflect the percentage of patients whose test results were considered positive for antibodies to ALDURAZYME using an enzyme-linked immunosorbent assay (ELISA) for laronidase-specific IgG binding antibodies, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibodies in an assay may be influenced by several factors including 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.

Four patients in the controlled study who experienced severe infusion-related 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 four patients had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both ALDURAZYME specific IgE binding antibodies and complement activation (see BOXED WARNING and WARNINGS: Anaphylaxis and Allergic Reactions).

Other allergic reactions were also seen in patients receiving ALDURAZYME (see ADVERSE REACTIONS).

No formal drug interaction studies have been conducted.

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