Life-threatening anaphylactic reactions have been observed in some patients during or up to 3 hours after ALDURAZYME infusions. Reactions have included: respiratory failure, respiratory distress, stridor, tachypnea, bronchospasm, airway obstruction, hypoxia, hypotension, bradycardia, and urticaria. Interventions have included: resuscitation, mechanical ventilatory support, emergency tracheotomy, hospitalization, and treatment with inhaled beta-adrenergic agonists, epinephrine, and intravenous corticosteroids.
In clinical trials and postmarketing safety experience with ALDURAZYME, approximately 1% of patients experienced severe or serious allergic reactions. In patients with MPS I, pre-existing upper airway obstruction may have contributed to the severity of some reactions. Due to the potential for severe allergic reactions, appropriate medical support should be readily available when ALDURAZYME is administered. Because of the potential for recurrent reactions, some patients who experience initial severe reactions may require prolonged observation.
Patients with an acute illness at the time of ALDURAZYME infusion may be at greater risk for infusion-related reactions. Careful consideration should be given to the patient’s clinical status prior to administration of ALDURAZYME. One patient with acute bronchitis and hypoxia experienced increased tachypnea during the first ALDURAZYME infusion that resolved without intervention. The patient’s respiratory symptoms returned within 30 minutes of completing the infusion and responded to bronchodilator therapy. Approximately 6 hours after the infusion, the patient experienced coughing, then respiratory arrest, and died.
Patients should receive antipyretics and/or antihistamines prior to infusion (see ADVERSE REACTIONS). If an infusion reaction occurs, regardless of pretreatment, decreasing the infusion rate, temporarily stopping the infusion, and/or administration of additional antipyretics and/or antihistamines may ameliorate the symptoms (see ADVERSE REACTIONS).
If anaphylactic or other severe allergic reactions occur, immediately discontinue the infusion of ALDURAZYME and initiate appropriate treatment. Caution should be exercised if epinephrine is being considered for use in patients with MPS I due to the increased prevalence of coronary artery disease in these patients.
The risks and benefits of re-administering ALDURAZYME following an anaphylactic or severe allergic reaction should be considered. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product.
PRECAUTIONS
Information for Patients
Patients should be informed that a registry for MPS I patients has been established in order to better understand the variability and progression of MPS I disease, and to continue to monitor and evaluate treatments. Patients should be encouraged to participate and advised that their participation may involve long-term follow-up.
Patients should be informed that a registry for MPS I patients has been established in order to better understand the variability and progression of MPS I disease, and to continue to monitor and evaluate treatments. Patients should be encouraged to participate and advised that their participation may involve long-term follow-up.
Information regarding the registry program may be found at www.MPSIregistry.com or by calling (800) 745-4447.
Drug Interactions
No formal drug interaction studies have been conducted.
No formal drug interaction studies have been conducted.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies to assess the mutagenic and carcinogenic potential of ALDURAZYME have not 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).
Pregnancy: Category B
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 ALDURAZYME. However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ALDURAZYME should be used during pregnancy only if clearly needed.
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 ALDURAZYME. However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ALDURAZYME should be used during pregnancy only if clearly needed.
Nursing Mothers
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.).
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.).
Pediatric Use
Patients younger than 5 years of age 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 years of age respond differently from older children.
Patients younger than 5 years of age 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 years of age respond differently from older children.
Geriatric Use
Clinical studies of ALDURAZYME did not include patients aged 65 and over. It is not known whether they respond differently from younger patients.
Clinical studies of ALDURAZYME did not include patients aged 65 and over. It is not known whether they respond differently from younger patients.
ADVERSE REACTIONS
The most serious adverse reactions reported with ALDURAZYME during clinical trials and the postmarketing 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 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.
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.
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).
