Elitek

ELITEK- rasburicase
Sanofi-Aventis U.S. LLC

Hemolysis

Do not administer Elitek to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Immediately and permanently discontinue Elitek in patients developing hemolysis. Screen patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting Elitek [see Contraindications (4), Warnings and Precautions (5.2)].

Methemoglobinemia

Elitek can result in methemoglobinemia in some patients. Immediately and permanently discontinue Elitek in patients developing methemoglobinemia [see Contraindications (4), Warnings and Precautions (5.3)].

Interference with Uric Acid Measurements

Elitek enzymatically degrades uric acid in blood samples left at room temperature. Collect blood samples in prechilled tubes containing heparin and immediately immerse and maintain sample in an ice water bath. Assay plasma samples within 4 hours of collection [see Warnings and Precautions (5.4)].

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.

Limitations of Use

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

2 DOSAGE AND ADMINISTRATION

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.

3 DOSAGE FORMS AND STRENGTHS

• For injection: 1.5 mg, lyophilized powder in single-dose vial for reconstitution
• For injection: 7.5 mg, lyophilized powder in single-dose vial for 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)].

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 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 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)]

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)
	AllGrades%	Grades3,4%	AllGrades%	Grades3,4%	AllGrades%	Grades3,4%
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.