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
diseaserelated 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 and Older
A 26-week, double-blind, placebo-controlled clinical study
(Study 1) of ALDURAZYME was conducted in 45 patients with MPS I, ages 6 to 43
years old, 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 IV 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 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 edema), hypotension, paresthesia, feeling hot,
hyperhidrosis, tachycardia, vomiting, back pain, and cough. Other reported
adverse reactions included bronchospasm, dyspnea, urticaria and pruritus.
Table 3 enumerates adverse reactions and selected
laboratory abnormalities that occurred during the placebocontrolled study
(Study 1) that were reported in at least 2 patients more in the ALDURAZYME
group than in the placebo group.
Table 3: Summary of Adverse Reactions that Occurred in
2 Patients More in the ALDURAZYME® Group than in the Placebo Group in the
26-Week Placebo-controlled Study (Study 1)
|MedDRA System Organ Class (SOC) MedDRA Preferred Term
|Blood and lymphatic system disorders
| Corneal opacity
|General disorders and administration site conditions
| Chest pain
| Face edema
| Gravitational edema
| Injection site pain
| Injection site reaction
|Infections and infestations
| Upper respiratory tract infection
|Nervous system disorders
|Skin and subcutaneous tissue disorders
| Poor venous access
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.
Clinical Trials in Patients 6 Years and Younger
Study 3 was a 52-week, open-label, uncontrolled study of
20 MPS I patients, ages 6 months to 5 years old (at enrollment). Sixteen
patients were clinically assessed as having the Hurler form, and 4 had the
Hurler-Scheie form. All 20 patients received ALDURAZYME at 0.58 mg/kg of body
weight once weekly for 26 weeks and up to 52 weeks. All patients were treated
with antipyretics and antihistamines prior to the infusions.
The most commonly reported serious adverse events
(regardless of relationship) reported with ALDURAZYME infusions in Study 3 were
otitis media (20%), and central venous catheterization required for ALDURAZYME infusion
The nature and severity of infusion reactions were
similar between the older and less severely affected patients in Studies 1 and
2, and the younger, more severely affected patients in Study 3. The most
commonly reported adverse reactions in Study 3 were infusion reactions reported
in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), blood
pressure increased (10%), tachycardia (10%), and oxygen saturation decreased (10%).
Other commonly reported infusion reactions occurring in ≥ 5% of patients
were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary),
pruritus, and rash.
In clinical trials, 99 of 102 patients (97%) treated with
ALDURAZYME were positive for IgG antibodies to ALDURAZYME. No correlation was
demonstrated between the presence of IgG anti-ALDURAZYME antibodies and
therapeutic response (6 MWT and FVC) or the occurrence of allergic reactions.
Potential for antibody neutralization of cellular uptake has not been assessed.
No consistent association was demonstrated between the presence of antibodies
that neutralize enzymatic activity and therapeutic response.
The data reflect the percentage of patients whose test
results were considered positive for antibodies to ALDURAZYME using a specific
enzyme-linked immunosorbent assay (ELISA) and confirmed by
radioimmunoprecipitation (RIP). ALDURAZYME IgG antibodies were reported as
titers. Drug specific antibody was detected in 42 of the 45 patients (93.3%)
treated in Study 1 and Study 2. The mean time to seroconversion was 51 days in
patients 6 years and older. In Study 3, all patients (100%) 5 years old or
younger developed IgG antibodies against ALDURAZYME with a mean time to seroconversion
of 26 days [see Clinical Studies for the Study populations].
Nine patients in Study 1 and Study 2, collectively, who
experienced severe infusion 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
nine 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 openlabel clinical
study of patients 5 years old or younger (Study 3) tested positive for IgE.
Other allergic reactions were also seen in patients
receiving ALDURAZYME [see ADVERSE REACTIONS].
In the postmarketing 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 re-challenged. 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
In postmarketing experience with ALDURAZYME, severe and
serious infusion reactions have been reported, some of which were
life-threatening, including anaphylactic shock [see BOXED WARNING and WARNINGS
AND PRECAUTIONS] 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 significant underlying disease.
Additional adverse reactions included fatigue, edema
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.
No information provided.