Rasburicase

1 INDICATIONS AND USAGE Elitek is indicated for the initial management of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid. Elitek is a recombinant urate-oxidase indicated for initial management of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid. ( 1 ) Limitations of use: Elitek is indicated only for a single course of treatment. ( 1 ) Limitations of Use Elitek is indicated only for a single course of treatment [see Warnings and Precautions (5.1) ] .

2 DOSAGE AND ADMINISTRATION Administer at 0.2 mg/kg as an intravenous infusion over 30 minutes daily for up to 5 days. ( 2.1 ) Do not administer as an intravenous bolus. ( 2.3 ) 2.1 Dosage The recommended dose of Elitek is 0.2 mg/kg as a 30-minute intravenous infusion daily for up to 5 days. Dosing beyond 5 days or administration of more than one course is not recommended. 2.2 Reconstitution Procedure Elitek must be reconstituted with the diluent provided in the carton. Reconstitute the 1.5 mg vial of Elitek with 1 mL of diluent. Reconstitute the 7.5 mg vial of Elitek with 5 mL of diluent. Mix by swirling gently. Do not shake or vortex. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard solution if particulate matter is visible or product is discolored. 2.3 Further Dilution and Administration Administer Elitek as an intravenous infusion only: Inject the calculated dose of reconstituted Elitek solution into an infusion bag containing the appropriate volume of 0.9% sterile sodium chloride, to achieve a final total volume of 50 mL. Infuse over 30 minutes through a separate line or flush line with at least 15 mL of normal saline prior to and after Elitek infusion. Do not use filters during infusion of reconstituted Elitek drug product. Store reconstituted or diluted solution at 2°C–8°C. Discard unused product solution 24 hours following reconstitution.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the prescribing information: Anaphylaxis [see Boxed Warning , Contraindications (4) , Warnings and Precautions (5.1) ] Hemolysis [see Boxed Warning , Contraindications (4) , Warnings and Precautions (5.2) ] Methemoglobinemia [see Boxed Warning , Contraindications (4) , Warnings and Precautions (5.3) ] Most common adverse reactions (incidence ≥20%), when used concomitantly with anticancer therapy are vomiting, nausea, fever, peripheral edema, anxiety, headache, abdominal pain, constipation, diarrhea, hypophosphatemia, pharyngolaryngeal pain, and increased alanine aminotransferase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 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. Table 1: Per-Patient Incidence of Selected Adverse Reactions by Study Arm in Study 4 Adverse Reaction Events were reported and graded according to NCI-CTC version 3.0 and presented as preferred terms MedDRA version 10.1. Elitek (n=92) Elitek/Allopurinol (n=92) Allopurinol (n=91) All Grades % Grades 3,4 % All Grades % Grades 3,4 % All Grades % Grades 3,4 % Overall incidence ≥10% in any Elitek arm and the difference between any Elitek arm versus the allopurinol arm ≥5%. Nausea 57.6 1.1 60.9 1.1 54.9 2.2 Peripheral edema 50 2.2 43.5 3.3 42.9 6.6 Vomiting 38 1.1 37 0 30.8 1.1 Anxiety 23.9 3.3 17.4 0 17.6 0 Abdominal pain 21.7 3.3 33.7 4.3 25.3 2.2 Hypophosphatemia 17.4 4.3 22.8 6.5 16.5 6.6 Hyperbilirubinemia 16.3 3.3 14.1 2.2 7.7 4.4 Pharyngolaryngeal pain 14.1 1.1 20.7 0 9.9 0 Sepsis 12 5.4 7.6 6.5 4.4 4.4 Fluid overload 12 0 6.5 0 3.3 1.1 Increased alanine aminotransferase 10.9 3.3 27.2 4.3 17.6 2.2 Hyperphosphatemia 9.8 0 15.2 0 8.8 1.1 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 antiproduct 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-naive 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 Postmarketing Experience The following adverse reactions have been identified from clinical trials and/or postmarketing 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 fatal outcome have been reported.

12.3 Pharmacokinetics The pharmacokinetics of rasburicase was evaluated in both pediatric and adult patients with leukemia, lymphoma or other hematological malignancies. Rasburicase exposure, as measured by AUC 0–24 hr and C max , tended to increase with a dose range from 0.15 to 0.2 mg/kg. The mean terminal half-life was similar between pediatric and adult patients and ranged from 15.7 to 22.5 hours. The mean volume of distribution of rasburicase ranged from 110 to 127 mL/kg in pediatric patients and from 75.8 to 138 mL/kg in adult patients, respectively. Minimal accumulation of rasburicase (<1.3-fold) was observed between days 1 and 5 of dosing. In adults, age, gender, baseline liver enzymes and creatinine clearance did not impact the pharmacokinetics of rasburicase. A cross-study comparison revealed that after administration of rasburicase at 0.15 or 0.20 mg/kg, the geometric mean values of body-weight normalized clearance were approximately 40% lower in Japanese (n=20) than that in Caucasians (n=22).