Elitek Side Effects

Generic Name: rasburicase

Please note - some side effects for Elitek may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Elitek - for the Consumer

Elitek

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Elitek:

Constipation; diarrhea; headache; mouth sores or ulcers; nausea; stomach pain; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Elitek:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blue or gray skin color; chest pain; chills; coughing up blood; dark urine; fever; irregular heartbeat; numbness or tingling of the skin; persistent sore throat; severe dizziness; shortness of breath, trouble breathing, or wheezing; swelling of the hands or feet; weakness; yellowing of the eyes and skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Elitek Side Effects - for the Professional

Elitek

The following serious 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)]

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.

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 %
*Events were reported and graded according to NCI-CTC version 3.0 and presented as preferred terms MedDRA version 10.1. *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 rasburicase 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 rasburicase-treated patients entered on these clinical trials.

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.

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Side Effects by Body System - for Healthcare Professionals

Immunologic

Immunologic side effects associated with the use of rasburicase in healthy volunteers have included reports of development of binding antibodies to rasburicase and neutralizing antibodies.

Metabolic

Metabolic side effects including at least one case of hypocalcemia have been reported.

Gastrointestinal

Gastrointestinal (GI) side effects have been reported the most frequently. These have included vomiting, nausea, abdominal pain, constipation, and diarrhea. Ileus and intestinal obstruction have been reported in less than 1% patients included in studies (n = 703). At least one case of GI hemorrhage has also been reported.

Respiratory

Respiratory side effects have included respiratory distress, pulmonary edema, pulmonary hypertension, and pneumonia.

Cardiovascular

Cardiovascular side effects have been reported rarely. Less than 1% (n = 703) of patients have reported arrhythmia, cardiac failure, cardiac arrest, chest pain, and myocardial infarction.

Renal

Renal side effects have been reported rarely. Acute renal failure has been reported in less than 1% of patients included in the studies (n = 703).

Ocular

Ocular side effects have included reports of retinal hemorrhage.

Hematologic

A 50-year-old male who was admitted to the hospital for new onset seizure, diabetic ketoacidosis, respiratory failure, and acute renal failure experienced hemolytic anemia and methemoglobinemia coincident with rasburicase therapy. He was given one dose of intravenous rasburicase 22.5 mg for acute renal failure secondary to hyperuricemia. Routine arterial blood gas analysis performed after rasburicase was given revealed elevated methemoglobin concentrations, which peaked at 14.7%. Hemolytic anemia developed as evidenced by a reduction in blood hemoglobin from 14.8 to 5.3 g/dL. The patient made a complete recovery following aggressive fluid therapy, blood transfusions, and respiratory support.

Hematologic side effects have included reports of neutropenia (2%), neutropenia with fever (4%), thrombosis, thrombophlebitis, and pancytopenia. At least two cases of methemoglobinemia have also been reported, in addition to a case of hemolytic anemia.

Dermatologic

Dermatologic side effects have included reports of rash (13%) and cellulitis (1% or less).

Nervous system

Nervous system side effects have included headache (1.8%), cerebrovascular disorder, and convulsions.

Musculoskeletal

Musculoskeletal side effects including at least one case of arthralgia and one case of gout have been reported.

Hypersensitivity

Hypersensitivity side effects including allergic reactions have been reported in 0.7% of patients.

Hepatic

Hepatic side effects including increased serum glutamic pyruvate transaminase have been reported. At least 3 cases of increased liver enzymes have also been reported.

Other

Other side effects including fever (1.4% to 5%) and rigors (1.1%) have been reported.

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