Limitations of Use

Elitek is indicated only for a single course of treatment [see Warnings and Precautions (5.1)].

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.

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 b5 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)].

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*	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%.
* Events were reported and graded according to NCI-CTC version 3.0 and presented as preferred terms MedDRA version 10.1.
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.

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of Elitek have been established in pediatric patients ages 1 month to 17 years for initial management of plasma uric acid levels in 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 was studied in 246 pediatric patients. There were insufficient numbers of patients between 0 and 6 months (n=7) to determine whether they respond differently than older children. Mean uric acid AUC0–96 hr was higher in children <2 years of age (n=24; 150 ± s.e. 16 mg hr/dL) than those age 2 to 17 years (n=222; 108 ± s.e. 4 mg hr/dL). Children <2 years of age had a lower rate of achieving normal uric acid concentration by 48 hours (83% [95% CI: 62, 95]) than those 2 to 17 years (93% [95% CI: 89, 95]).

8.5 Geriatric Use

Of the total number of adults treated with Elitek (n=434) in clinical studies, 30% were aged 65 and over while 8% were aged 75 and over. No overall differences in pharmacokinetics, safety, and effectiveness were observed between the elderly and younger patients.

12.1 Mechanism of Action

In humans, uric acid is the final step in the catabolic pathway of purines. Rasburicase catalyzes enzymatic oxidation of poorly soluble uric acid into an inactive and more soluble metabolite (allantoin).

12.2 Pharmacodynamics

The measurement of plasma uric acid was used to evaluate the effectiveness of rasburicase in clinical studies. Following administration of either 0.15 or 0.20 mg/kg rasburicase daily for up to 5 days, plasma uric acid levels decreased within 4 hours and were maintained below 7.5 mg/dL in 98% of adult and 90% of pediatric patients for at least 7 days. There was no evidence of a dose response effect on uric acid control for doses between 0.15 and 0.20 mg/kg rasburicase.

In preclinical in vivo studies, rasburicase did not affect the activity of isoenzymes CYP1A, CYP2A, CYP2B, CYP2C, CYP2E, and CYP3A, suggesting no induction or inhibition potential. Clinically relevant P450-mediated drug-drug interactions are therefore not anticipated in patients treated with the recommended Elitek dose and dosing schedule.

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 AUC0–24 hr and Cmax, 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).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies in animals to evaluate tumorigenic potential of rasburicase have not been performed. Rasburicase was not mutagenic in the Ames, unscheduled DNA synthesis, chromosome analysis, mouse lymphoma, and micronucleus tests.

Rasburicase did not affect reproductive performance or fertility in male or female rats with an exposure 11-times greater at a dose of 10 mg/kg than the recommended human dose of 0.2 mg/kg.

14.1 Pediatrics

Elitek was administered in three studies to 265 patients with acute leukemia or non-Hodgkin's lymphoma. These clinical studies were largely limited to pediatric patients (246 of 265). Elitek was administered as a 30-minute infusion once (n=251) or twice (n=14) daily at a dose of 0.15 or 0.2 mg/kg/dose (total daily dose 0.2–0.4 mg/kg/day). Elitek was administered prior to and concurrent with antitumor therapy, which consisted of either systemic chemotherapy (n=196) or steroids (n=69).

14.2 Studies in Adults

A total of 342 adults with either leukemia, lymphoma, or other hematologic malignancy received Elitek in five studies (one randomized study, Study 4, and four uncontrolled studies). Across the five studies, Elitek was administered at a dose of 0.15 mg/kg/day (n=38) or 0.2 mg/kg/day (n=304).

Study 4 was a randomized (1:1:1), multi-center, open-label study conducted in patients with leukemia, lymphoma, and solid tumor malignancies at risk for hyperuricemia and TLS. A total of 275 adult patients received at least one dose of study drug. The median age was 56 years, 62% were males, 80% were Caucasian, 66% had leukemia, 29% had lymphoma; 18% were hyperuricemic (uric acid >7.5 mg/dL) at study entry. Patients in Arm A received Elitek for 5 days (n=92). Patients in Arm B received Elitek from day 1 through day 3 followed by oral allopurinol from day 3 through day 5 (overlap on day 3: Elitek and allopurinol administered approximately 12 hours apart) (n=92). Patients in Arm C received oral allopurinol for 5 days (n=91). Elitek was administered at the dose of 0.2 mg/kg/day as a 30-minute infusion once daily. Allopurinol was administered orally at the dose of 300 mg once a day. Patients were eligible for the study if they were either at high risk or potential risk for TLS. The major endpoint of this study was the uric acid response rate defined as the proportion of patients with plasma uric acid levels ≤7.5 mg/dL from day 3 to day 7, after initiation of antihyperuricemic treatment.

Table 2 presents the response rates in the three treatment arms. The response rate in arm A was significantly greater than in arm C (p=0.0009). The response rate was higher for arm B compared to arm C; this difference was not statistically significant.

Table 2: Summary of Response Rates

	Arm A Elitek n=92	Arm B Elitek/ Allopurinol n=92	Arm C Allopurinol n=91
Response Rate % (95% CI)	87% (80%, 94%)	78% (70%, 87%)	66% (56%, 76%)
Nonresponse Rate %	13%	22%	34%
Failed to control uric acid	0	0	11%
Hyperuricemic treatment extended beyond 5 days	0	6.5%	4.4%
Missing uric acid samples	13%	15%	19%

There were no patients with documented failure to control uric acid in arms A or B. In arm C, 34% of patients did not have a uric acid response; 11% due to failure to control uric acid and 4.4% due to the need for extended antihyperuricemic treatment.

Box and whisker plots of uric acid over time for the patient population (Figure 2) show that in the two arms containing Elitek, uric acid levels were ≤2 mg/dL in 96% of patients at 4 hours of the day 1 dose.

Figure 2: Uric Acid Concentration Over Time – Patient Population Box and Whisker Plot

How Supplied

NDC 0024-5150-10: One carton contains 3 single-dose vials each containing 1.5 mg of rasburicase and 3 ampules each containing 1 mL diluent.

NDC 0024-5151-75: One carton contains 1 single-dose vial containing 7.5 mg of rasburicase and 1 ampule containing 5 mL diluent.

Storage and Handling

The lyophilized drug product and the diluent for reconstitution should be stored at 2°C-8°C (36°F-46°F). Do not freeze. Protect from light.

Hypersensitivity Reactions

Instruct patients to notify their physician immediately if any of the following occur: allergic reaction, bronchospasm, chest pain or tightness, dyspnea, hypoxia, hypotension, shock or urticaria [see Boxed Warning, Warnings and Precautions (5.1)].

Lactation

Advise females not to breastfeed during treatment with Elitek and for at least 2 weeks after the last dose [see Use in Specific Populations (8.2)].