Elitek

Overdose

The maximum reported overdosage of Elitek is a single dose of 1.3 mg/kg. No adverse events occurred in reported cases of overdosage. Monitor patients who receive an overdose and initiate supportive measures if required.

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.

Elitek is contraindicated in individuals deficient in glucose-6-phosphate dehydrogenase (G6PD).

Undesirable effects

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:

• Anaphylaxis
• Hemolysis
• Methemoglobinemia

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 Elitektreated 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

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.

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. 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.

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 potential fatal outcome have been reported.

Therapeutic indications

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 anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.

Elitek is indicated only for a single course of treatment .

Pharmacodynamic properties

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

Pharmacokinetic properties

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).

Date of revision of the text

Name of the medicinal product

Fertility, pregnancy and lactation

There are no studies of rasburicase in pregnant women. Reproductive toxicity studies in rabbits treated during organogenesis with approximately 10 to 100 times the recommended human dose of rasburicase resulted in teratogenicity, including decreased fetal body weights and heart and great vessel malformations at all dose levels. Multiple heart and great vessel malformations were also observed in offspring of pregnant rats treated with approximately 250 times the recommended human dose of rasburicase. Other adverse effects were observed in rasburicasetreated pregnant rabbits at all dose levels tested and included pre and postimplantation losses, abortions, and decreased uterine weights.

It is unknown whether rasburicase can cross the placental barrier in humans and result in fetal harm. Because of the observed teratogenic effects of rasburicase in animal reproductive studies, use rasburicase during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Qualitative and quantitative composition

• 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

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.

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

Manufactured by: sanofi-aventis U.S. LLC, Bridgewater, NJ 08807, U.S. License No. 1752. Revised: Sep 2017

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

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.

The safety and efficacy of Elitek have been established only for a single course of treatment once daily for 5 days.

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.

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).

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.

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 at a dose 50-fold higher (10 mg/kg) than the recommended human dose.

There are no studies of rasburicase in pregnant women. Reproductive toxicity studies in rabbits treated during organogenesis with approximately 10 to 100 times the recommended human dose of rasburicase resulted in teratogenicity, including decreased fetal body weights and heart and great vessel malformations at all dose levels. Multiple heart and great vessel malformations were also observed in offspring of pregnant rats treated with approximately 250 times the recommended human dose of rasburicase. Other adverse effects were observed in rasburicasetreated pregnant rabbits at all dose levels tested and included pre and postimplantation losses, abortions, and decreased uterine weights.

It is unknown whether rasburicase can cross the placental barrier in humans and result in fetal harm. Because of the observed teratogenic effects of rasburicase in animal reproductive studies, use rasburicase during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

It is not known whether rasburicase is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rasburicase, a decision should be made whether to discontinue nursing or to discontinue rasburicase, taking into account the importance of the drug to the mother.

The safety and efficacy of Elitek was studied in 246 pediatric patients ranging in age from 1 month to 17 years. There were insufficient numbers of patients between 0 and 6 months (n=7) to determine whether they respond differently from 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]).

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.

Dosage (Posology) and method of administration

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.

• 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.

• 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 2-8°C.
  • Discard unused product solution 24 hours following reconstitution.

Interaction with other medicinal products and other forms of interaction

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:

• Anaphylaxis
• Hemolysis
• Methemoglobinemia

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 Elitektreated 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

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.

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. 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.

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 potential fatal outcome have been reported.

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 pre-chilled 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 pre-cooled centrifuge (4°C). Finally, the plasma must be maintained in an ice water bath and analyzed for uric acid within four hours of collection.

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.