The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:
6.1 Clinical Trials
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 practice.
The data below reflect exposure to Elitek in 265 pediatric and 82 adult patients enrolled in one active-controlled trial (Study 1), two uncontrolled trials (Studies 2 and 3), and an uncontrolled safety trial (n=82). Additional data were obtained from an expanded access program of 356 patients, for whom data collection was limited to serious adverse reactions. Among these 703 patients 63% were male, the median age was 10 years (range 10 days to 88 years), 73% were Caucasian, 9% African, 4% Asian, and 14% other/unknown.
Among the 347 patients for whom all adverse reactions regardless of severity were assessed, the most frequently observed adverse reactions (incidence ≥10%) were vomiting (50%), fever (46%), nausea (27%), headache (26%), abdominal pain (20%), constipation (20%), diarrhea (20%), mucositis (15%), and rash (13%). In Study 1, an active control study, the following adverse reactions occurred more frequently in Elitek-treated subjects than allopurinol-treated subjects: vomiting, fever, nausea, diarrhea, and headache. Although the incidence of rash was similar in the two arms, severe rash was reported only in one Elitek-treated patient.
Further studies, including one-active controlled study (Study 4) and four supportive studies, have been conducted in adult patients. In these studies, Elitek was administered to a total of 434 adult patients [58% male, 42% female; median age 56 years (range 18 years to 89 years); 52% Caucasian, 7% African, 14% Asian, 28% other/unknown].
Of these 434 patients, 275 adult patients with leukemia, lymphoma, or solid tumor malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomized in an open label trial receiving either Elitek alone, Elitek in combination with allopurinol, or allopurinol alone (Study 4).
A drug-related adverse reaction in Study 4 of any grade was experienced in 4.3% of Elitek-treated patients, 5.4% of Elitek/allopurinol-treated patients, and 1.1% of allopurinol-treated patients.
Table 1 presents the per patient incidence of adverse reactions by study arm in Study 4.
Hypersensitivity reactions occurred in 4.3% of Elitek-treated patients and 1.1% of Elitek/allopurinol-treated patients in Study 4. Clinical manifestations of hypersensitivity included arthralgia, injection site irritation, peripheral edema, and rash.
The following serious adverse reactions occurred at a difference in incidence of ≥2% in patients receiving Elitek compared to patients receiving allopurinol in randomized studies (Study 1 and Study 4): pulmonary hemorrhage, respiratory failure, supraventricular arrhythmias, ischemic coronary artery disorders, and abdominal and gastrointestinal infections.
The incidence of anaphylaxis, hemolysis, and methemoglobinemia was less than 1% of the 887 Elitek-treated patients entered on these clinical trials.
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. Elitek can elicit anti-product antibodies that bind to rasburicase and in some instances inhibit the activity of rasburicase in vitro [see Boxed Warning, Warnings and Precautions (5.1)].
In clinical trials of pediatric patients with hematologic malignancies, 24/218 patients tested (11%) developed antibodies by day 28 following Elitek administration as assessed by qualitative ELISA.
Using quasi-quantitative immunoassays in rasburicase naïve adult patients with hematological malignancies, 47/260 (18%) patients were positive for anti-rasburicase immunoglobulin G (IgG), 21/260 (8%) patients were positive for anti-rasburicase neutralizing IgG, and 16/260 (6%) patients were positive for anti-rasburicase immunoglobulin E (IgE) from day 14 to 24 months after 5 daily doses of Elitek.
The incidence of antibody responses detected is highly dependent on the sensitivity and specificity of the assay, which have not been fully evaluated. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including serum sampling, timing and methodology, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Elitek with the incidence of antibodies to other products may be misleading.
6.3 Post-marketing Experience
The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Central nervous system disorders: convulsion, muscle contractions involuntary
Immune system disorders: Cases of anaphylaxis with potential fatal outcome have been reported.
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