Elitek

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.

4 CONTRAINDICATIONS Elitek is contraindicated in patients with a history of anaphylaxis or severe hypersensitivity to rasburicase or in patients with development of hemolytic reactions or methemoglobinemia with rasburicase [see Boxed Warning , Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Elitek is contraindicated in individuals deficient in glucose-6-phosphate dehydrogenase (G6PD) [see Boxed Warning , Warnings and Precautions (5.2) ] . History of the following reactions to rasburicase: anaphylaxis, severe hypersensitivity, hemolysis, methemoglobinemia. ( 4 ) Glucose-6-phosphate dehydrogenase (G6PD) deficiency. ( 4 )

5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Elitek can cause serious and fatal hypersensitivity reactions including anaphylaxis. In clinical studies, anaphylaxis was reported in <1% patients receiving Elitek. This can occur at any time during treatment including the first dose. Signs and symptoms of these reactions include bronchospasm, chest pain and tightness, dyspnea, hypoxia, hypotension, shock, and urticaria. Immediately and permanently discontinue Elitek administration in any patient developing clinical evidence of a serious hypersensitivity reaction [see Boxed Warning , Contraindications (4) , Adverse Reactions (6.2) ] . The safety and efficacy of Elitek have been established only for a single course of treatment once daily for 5 days. 5.2 Hemolysis Elitek is contraindicated in patients with G6PD deficiency because hydrogen peroxide is one of the major by-products of the conversion of uric acid to allantoin. In clinical studies, hemolysis occurs in <1% patients receiving Elitek; severe hemolytic reactions occurred within 2–4 days of the start of Elitek. Immediately and permanently discontinue Elitek administration in any patient developing hemolysis. Institute appropriate patient monitoring and support measures (e.g., transfusion support). Screen patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting Elitek [see Boxed Warning , Contraindications (4) ] . 5.3 Methemoglobinemia In clinical studies, methemoglobinemia occurred in <1% patients receiving Elitek. These included cases of serious hypoxemia requiring intervention with medical support measures. It is not known whether patients with deficiency of cytochrome b 5 reductase (formerly known as methemoglobin reductase) or of other enzymes with antioxidant activity are at increased risk for methemoglobinemia or hemolytic anemia. Immediately and permanently discontinue Elitek administration in any patient identified as having developed methemoglobinemia. Institute appropriate monitoring and support measures (e.g., transfusion support, methylene-blue administration) [see Boxed Warning , Contraindications (4) ] . 5.4 Laboratory Test Interference At room temperature, Elitek causes enzymatic degradation of the uric acid in blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings. Special sample handling procedure must be followed to avoid ex vivo uric acid degradation [see Boxed Warning , Drug Interactions (7) ] .

7 DRUG INTERACTIONS Laboratory Test Interference At room temperature, Elitek causes enzymatic degradation of the uric acid in blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings. The following special sample handling procedure must be followed to avoid ex vivo uric acid degradation. Uric acid must be analyzed in plasma. Blood must be collected into prechilled tubes containing heparin anticoagulant. Immediately immerse plasma samples for uric acid measurement in an ice water bath. Plasma samples must be prepared by centrifugation in a precooled centrifuge (4°C). Finally, the plasma must be maintained in an ice water bath and analyzed for uric acid within four hours of collection [see Boxed Warning ] . Rasburicase does not metabolize allopurinol, cytarabine, methylprednisolone, methotrexate, 6-mercaptopurine, thioguanine, etoposide, daunorubicin, cyclophosphamide or vincristine in vitro. No metabolic-based drug interactions are therefore anticipated with these agents in patients.

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.

8.1 Pregnancy Risk Summary Based on findings in animals, Elitek may cause fetal harm when administered to pregnant women. In animal reproduction studies, intravenous administration of rasburicase to pregnant rabbits during organogenesis at 5-times the human exposure (based on AUC) at the recommended human dose of 0.2 mg/kg resulted in adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth (see Data ) . The limited available data with Elitek use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal fetal outcomes. Consider the benefits and risks of Elitek and possible risks to the fetus when prescribing Elitek to a pregnant woman. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal data Intravenous administration of rasburicase at doses of 10, 20, or 50 mg/kg/day (approximately 14, 34, and 100 times the exposure at the recommended human dose of 0.2 mg/kg) to pregnant rats from gestation days (GD) 6 to 17 produced multiple heart and great vessel malformations at 50 mg/kg/day (approximately 100 times the exposure at the recommended human dose). Intravenous administration of rasburicase from GD 6 to 19 at doses of 2, 10, or 20 mg/kg/day (approximately 5, 26, and 54 times the exposure at the recommended human dose) to pregnant rabbits produced increased pre and postimplantation loss, abortion, decreased uterine weight, decreased fetal body weights, and heart and great vessel malformations at all dose levels.