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:
A 26-week, double-blind, placebo-controlled clinical study (study 1) of Aldurazyme was conducted in 45 patients 6-43 years with MPS I, 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 Aldurazyme IV 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 oedema), hypotension, paresthesia, feeling hot, hyperhidrosis, tachycardia, vomiting, back pain and cough. Other reported adverse reactions included bronchospasm, dyspnea, urticaria and pruritus.
Table 4 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 (see Table 4).
Click on icon to see table/diagram/image
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). 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.
: In clinical trials, 99-102 patients (97%) treated with Aldurazyme were positive for immunoglobulin G (IgG) antibodies to Aldurazyme. The clinical significance of antibodies to Aldurazyme, including the potential for product neutralization, is not known. Potential for antibody neutralization of cellular uptake has not been assessed.
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 Aldurazyme-specific IgG binding antibodies reported as titers (57 patients) or optical density units per microliter (OD/microliter) (42 patients), and confirmed by radio-immunoprecipitation (RIP). The relationship of Aldurazyme antibody concentration in titer units and OD/microliter units has not been established.
Nine (9) patients in study 1 and study 2, collectively, who experienced severe infusion reactions were tested for Aldurazyme-specific immunoglobulin E (IgE) antibodies and complement activation. IgE testing was performed by enzyme-linked immunosorbent assay (ELISA), and complement activation was measured by the Quidel Enzyme Immunoassay. One of the 9 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 (study 3) tested positive for IgE.
Other allergic reactions were also seen in patients receiving Aldurazyme (see Adverse Reactions).
In the post-marketing 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 rechallenged. 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.
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 post-marketing experience with Aldurazyme, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock and laryngeal oedema.
Adverse reactions resulting in death reported in the post-marketing 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 common adverse reactions included fatigue, oedema 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.