Aldurazyme Side Effects, and Drug Interactions - laronidase

Aldurazyme Side Effects, and Drug Interactions - laronidase

SIDE EFFECTS

The most serious adverse reaction reported with ALDURAZYME was an anaphylactic reaction consisting of urticaria and airway obstruction, which occurred in one patient. Pre-existing upper airway obstruction may have contributed to the severity of the reaction (see WARNINGS: Hypersensitivity Reactions).

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

The most common adverse reactions requiring intervention were infusion-related reactions, particularly flushing. 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 WHOART 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.

Infusion-related reactions were reported in 7 of 22 patients treated with ALDURAZYME. Infusion-related reactions were not significantly different between the ALDURAZYME treatment group and the placebo group who received infusions of diluent and all components of ALDURAZYME except the laronidase enzyme. The most common infusion-related reactions included flushing, fever, headache and rash. Flushing occurred in 5 patients (23%) receiving ALDURAZYME; the other reactions were less frequent. All reactions were mild to moderate in severity. The frequency of infusion-related reactions decreased with continued use during the open-label extended use period. There was one case of anaphylaxis during the open-label extension period (see WARNINGS and ADVERSE REACTIONS: Immunogenicity). Less common infusion-related reactions include cough, bronchospasm, dyspnea, urticaria, angioedema and pruritus.

Fifty 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 ELISAand 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 WARNINGS: Hypersensitivity Reactions).

Other hypersensitivity reactions were also seen in patients receiving ALDURAZYME (see ADVERSE REACTIONS: Infusion-Related Reactions).

No formal drug interaction studies have been conducted.

Studies to assess the mutagenic and carcinogenic potential of ALDURAZYME have not been conducted. Reproductive studies in rats have not demonstrated impairment of fertility (see PRECAUTIONS: Pregnancy).

Reproduction studies have been performed in male and female rats at doses up to 6.2 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ALDU-RAZYME. However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ALDU-RAZYME should be used during pregnancy only if clearly needed.

It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ALDURAZYME is administered to a nursing woman (See PRECAUTIONS: Information for Patients regarding a registry program. Nursing women are encouraged to participate in this program.).

Patients younger than 5 were not included in the clinical studies because of inability to comply with efficacy outcome assessments. It is not known if children younger than 5 respond differently from older children.

Clinical studies of ALDURAZYME did not include patients aged 65 and over. It is not known whether they respond differently from younger patients.