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How Much is Too Much? The Use of Rasburicase in the Treatment of Tumor Lysis Syndrome. Allison Weddington, PharmD PGY1 Pharmacy Resident St. Louis Children’s Hospital November 14, 2011. Goals & Objectives.
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How Much is Too Much?The Use of Rasburicase in the Treatment of Tumor Lysis Syndrome Allison Weddington, PharmD PGY1 Pharmacy Resident St. Louis Children’s Hospital November 14, 2011
Goals & Objectives • Describe the clinical background of tumor lysis syndrome, including risk factors and disease presentation. • Compare and contrast rasburicase versus allopurinol in the treatment of tumor lysis syndrome. • Assess the cost effectiveness of rasburicase compared to allopurinol. • Critique the current dosage regimen for rasburicase and formulate possible alternative dosing regimens.
Tumor Lysis Syndrome (TLS) Definition • Group of metabolic disturbances as a result of intracellular constituents being released into the blood due to lysis of malignant cells
Etiology and Incidence • Non-Hodgkin’s lymphomas (NHL) • Acute lymphoblastic leukemia (ALL) • Overall incidence • 42% of Non-Hodgkin’s lymphoma patients • 16.1% of Burkitt’s lymphoma and leukemia pediatric patients Hande KR, et al. Am J Med. 1993;94:133-9. Wossman W, et al. Ann Hematol. 2003;82:160.
Other Associated Malignancies • Anaplastic large cell lymphoma • T-cell and B-cell precursor ALL • Acute myeloid leukemia • Chronic lymphocytic leukemia • Multiple myeloma
Risk Factors for TLS Hematologic Malignancy Related Factors Patient Related Factors • Rapid tumor cell proliferation • High tumor burden • Increased sensitivity to cytotoxic therapy • Renal dysfunction • Hyperuricemia • Hyperphosphatemia • Acidic urine • Dehydration
Risk of TLS Based on Tumor Type Coiffier B, et al. J Clin Oncol. 2008;26(16):2767-78.
Pathophysiology of TLS Hochberg J, et al. Expert Opin Biol Ther. 2008;8(10):1595-604.
Clinical Presentation of TLS • Representative of metabolic abnormalities • Hyperkalemia • Hyperphosphatemia • Hypocalcemia • Hyperuricemia
Consequences of TLS Hochberg J, et al . Expert Opin Biol Ther. 2008;8(10):1595-604.
Laboratory vs. Clinical TLS • Laboratory TLS • Clinical TLS • Laboratory TLS plus 1 of the following • Serum creatinine > 1.5 times upper limit of normal • Arrhythmias • Seizures Coiffier B, et al. J Clin Oncol. 2008;26(16):2767-78. Cairo MS, et al. Br J Haematol. 2004;127:3-11.
Treatment Overview • Hydration and diuresis • Urinary alkalinization • Agents acting on uric acid • Allopurinol • Rasburicase
Hydration and Diuresis • Initiate 1 – 2 days prior to chemotherapy • Administer D5 ½ NS or D5 ¼ NS + Sodium Bicarbonate • Rate: 2 – 3L/m2/day • Monitor • Specific gravity • Urine output parameters
Urinary Alkalinization • Previous recommendation: Addition of 40 – 80 mEq/L of sodium bicarbonate • Current recommendation: No addition of sodium bicarbonate to fluids
Agents Affecting Uric Acid • Allopurinol • Rasburicase
Allopurinol Mechanism of Action Coiffier B, et al. J Clin Oncol. 2008;26(16):2767-78.
Allopurinol Pharmacokinetics • Metabolism • Hepatic metabolism • Metabolized to active metabolite, oxypurinol • Elimination • Renally • Dose adjust for renal impairment • Half life • Allopurinol: 1 – 3 hours • Oxypurinol: 18 – 30 hours
Allopurinol Warnings • Contraindications • Hypersensitivity to allopurinol • Precautions • Reduce dose in renal impairment • Rash • Hypersensitivity
Allopurinol Adverse Effects • GI: nausea, vomiting, diarrhea, abdominal pain, dyspepsia, and irritation • Dermatologic: pruritic maculopapular rash, Stevens-Johnson syndrome, toxic epidermal necrolysis • Hepatic: hepatitis, hyperbilirubinemia, liver enzyme elevations • Renal: renal impairment, acute tubular necrosis, and interstitial nephritis
Allopurinol Monitoring • Liver enzyme tests and bilirubin • Renal function • Serum uric acid
Allopurinol Dosing • Pediatric Dose • PO: 200mg – 300mg/m2/day divided into 2 – 4 doses • Adult Dose • PO: 600mg – 800mg/day divided into 2 – 3 doses
Disadvantages of Allopurinol • Does not work on preexisting uric acid • May take up to 3 days before effects are seen • May cause xanthinuria • Interacts with chemotherapy medications • Adjust in renal impairment
Rasburicase Mechanism of Action Coiffier B, et al. J Clin Oncol. 2008;26(16):2767-78.
Rasburicase Pharmacology • Administration • IV only • Pharmacokinetics • Metabolism • Peptide hydrolysis • Half life • 18 hours
Rasburicase Warnings • Black box warnings and contraindications • Anaphylactic reactions • Hemolytic reactions with glucose-6-phosphate dehydrogenase (G6PD) deficiency • Methemoglobinemia • Interference with uric acid laboratory values
RasburicaseWarnings • Precautions • Maintain adequate hydration • Urinary alkalinization is not recommended • Antibody response risk increases with each dose
Rasburicase Adverse Effects • CNS: fever, headache • GI: nausea, vomiting, diarrhea, abdominal pain • Dermatologic: rash • Hematologic: hemolysis, methemoglobinemia • Hepatic: ALT increase, hyperbilirubinemia • Miscellaneous: antibody formation, hypersensitivity reactions
Rasburicase Drug Interactions • No known drug interactions Dosing • IV: 0.2mg/kg/dose daily for 5 days
Treatment Based on Risk • Low Risk • Hydration + Monitoring of TLS labs • Intermediate Risk • Hydration + Allopurinol • May consider initial management with a single dose of rasburicase in the pediatric population • High Risk • Hydration + Rasburicase
Average Wholesale Price • Allopurinol • 100mg tablet: $0.26 • 300mg tablet: $0.70 • Rasburicase • 1.5mg vial: $704.05 • 7.5mg vial: $3520.31
Cost for Pediatric Patient • 7 year old– weight 23kg and height 111.7cm; BSA: 0.84m2 • Allopurinol dose: 300mg/m2/day • Patient’s dose: 252mg daily x 7 days • Allopurinol cost: $4.90 • Rasburicase dose: 0.2mg/kg daily x 5 days • Patient’s dose: 4.5mg daily x 5 days • Rasburicase cost: $10,560.75 • Rasburicase cost/day: $2,112.15
Cost for Pediatric Patient • 16 year old– weight 100kg and height 170cm; BSA 2.17m2 • Allopurinol dose: 300mg/m2/day • Patient’s dose: 650mg daily x 7 days • Allopurinol cost: $11.62 • Rasburicase dose: 0.2mg/kg daily x 5 days • Patient’s dose: 20mg daily x 5 days • Rasburicase cost: $49,284.10 • Rasburicase cost/day: $9,856.82
Economic Comparison of Rasburicase and Allopurinol for Treatment of Tumor Lysis Syndrome in Pediatric Patients Eaddy M, Seal B, Tangirala M, Davies E, O’Day K Am J Health-Sys Pharm. 67(24):2110-4 December 2010
Objective • Compare the economic outcomes, including hospitalization costs, length of stay, and duration of critical care, of pediatric patients receiving rasburicase or allopurinol for tumor lysis syndrome
Design • Retrospective study • Premier Perspective Database to collect data • Rasburicase and allopurinol treated patients were propensity score matched
Primary Endpoints • Costs per hospitalization • Length of stay • Duration of critical care
Methods • Inclusion criteria • Pediatric patients • Diagnosis of lymphoma or leukemia • Received allopurinol or rasburicase within 2 days of hospital admission • Exclusion criteria • Age > 18 years • Received hemodialysis on hospital admission
Statistics • Primary outcome differences • Assessed using the γ-distributed generalized linear models with a log-link function • Baseline demographics • Categorical variables • Chi-Square • Continuous variables • T-test • Significance level set at 0.05
Results • 126 patients were included in analysis • 63 rasburicase treated patients matched with 63 allopurinol treated patients • Patient demographics • Groups were not similar in regards to provider type, admission source, and critical care admission on day 1 • Average age: 7.4 years old • 27% females and 73% males
Results Eaddy M, et al. Am J Health-Sys Pharm. 2010 Dec 15;67(24):2110-4.
Authors’ Conclusions • “Examination of claims from a large hospital database showed that treatment with rasburicase, compared with allopurinol, was associated with a significant reduction in critical care days but not with a significant difference in mean LOS or total cost.”
Limitations • Lack of randomization • Possible confounding factors • No account for patient acuity • Greater percent of patients in the rasburicase treated group considered critical care admissions • Clinical outcomes not assessed between groups • Small sample size
Strengths • One of the first studies to look at cost effectiveness of allopurinol and rasburicase in the pediatric population • Primary endpoints were appropriate
Applicable Conclusions • Statistically significant results • Mean duration of critical care days • Standard of practice should not be altered based on this study
Single-Dose Rasburicase 6mg in the Management of Tumor Lysis Syndrome in Adults • 6 mg rasburicase x 1 dose • Baseline median uric acid: 11.7mg/dL • Decreased to 2 mg/dL • 82.9% decrease within 24 hours • 1 patient redosed • 8 patients presented with secondary renal dysfunction • 7 returned to baseline McDonnell AM, et al. Pharmacother. 2006;26(6):806-12.
Evaluation of a Single Fixed Dose of Rasburicase 7.5mg for the Treatment of Hyperuricemia in Adults with Cancer • 0.15 mg/kg vs. 7.5 mg dose • Average dose in control group = 12 mg • Uric acid measured at 12 and 24 hours • 5 patients redosed in control group • 1 patient redosed in 7.5 mg group • No changes in serum creatinine Reeves DJ, et al.. Pharmacother. 2008;28(6):685-90.
Single-Dose Rasburicase for Tumor Lysis Syndrome in Adults: Weight-Based Approach • Dose based on ideal or adjusted body weight • Average dose = 11 mg • Baseline mean uric acid: 11.4 mg/dL • Decreased to 1.4 mg/dL • 89.7% decrease in 24 hours • No patients required second dose • Mean serum creatinine at baseline: 2.3 mg/dL • Decreased in 13 patients • 1 increased > 0.5 mg/dL • 2 increased > 0.1 mg/dL but < 0.5 mg/dL Campara M, et al. J Clin Pharm Ther. 2009;34:207-13.