Allison Weddington, PharmD PGY1 Pharmacy Resident St. Louis Children’s Hospital November 14, 2011

1. 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

2. 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.

3. 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

4. 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.

5. Other Associated Malignancies • Anaplastic large cell lymphoma • T-cell and B-cell precursor ALL • Acute myeloid leukemia • Chronic lymphocytic leukemia • Multiple myeloma

6. 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

7. Risk of TLS Based on Tumor Type Coiffier B, et al. J Clin Oncol. 2008;26(16):2767-78.

8. Pathophysiology of TLS Hochberg J, et al. Expert Opin Biol Ther. 2008;8(10):1595-604.

9. Clinical Presentation of TLS • Representative of metabolic abnormalities • Hyperkalemia • Hyperphosphatemia • Hypocalcemia • Hyperuricemia

10. Consequences of TLS Hochberg J, et al . Expert Opin Biol Ther. 2008;8(10):1595-604.

11. 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.

12. Treatment Overview • Hydration and diuresis • Urinary alkalinization • Agents acting on uric acid • Allopurinol • Rasburicase

13. 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

14. Urinary Alkalinization • Previous recommendation: Addition of 40 – 80 mEq/L of sodium bicarbonate • Current recommendation: No addition of sodium bicarbonate to fluids

15. Agents Affecting Uric Acid • Allopurinol • Rasburicase

16. Allopurinol Mechanism of Action Coiffier B, et al. J Clin Oncol. 2008;26(16):2767-78.

17. 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

18. Allopurinol Warnings • Contraindications • Hypersensitivity to allopurinol • Precautions • Reduce dose in renal impairment • Rash • Hypersensitivity

19. 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

20. Allopurinol Monitoring • Liver enzyme tests and bilirubin • Renal function • Serum uric acid

21. Allopurinol Drug Interactions

22. 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

23. 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

24. Rasburicase Mechanism of Action Coiffier B, et al. J Clin Oncol. 2008;26(16):2767-78.

25. Rasburicase Pharmacology • Administration • IV only • Pharmacokinetics • Metabolism • Peptide hydrolysis • Half life • 18 hours

26. 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

27. RasburicaseWarnings • Precautions • Maintain adequate hydration • Urinary alkalinization is not recommended • Antibody response risk increases with each dose

28. 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

29. Rasburicase Drug Interactions • No known drug interactions Dosing • IV: 0.2mg/kg/dose daily for 5 days

30. Allopurinol vs. Rasburicase

31. 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

32. Average Wholesale Price • Allopurinol • 100mg tablet: $0.26 • 300mg tablet: $0.70 • Rasburicase • 1.5mg vial: $704.05 • 7.5mg vial: $3520.31

33. 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

34. 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

35. 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

36. 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

37. Design • Retrospective study • Premier Perspective Database to collect data • Rasburicase and allopurinol treated patients were propensity score matched

38. Primary Endpoints • Costs per hospitalization • Length of stay • Duration of critical care

39. 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

40. 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

41. 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

42. Results Eaddy M, et al. Am J Health-Sys Pharm. 2010 Dec 15;67(24):2110-4.

43. 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.”

44. 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

45. Strengths • One of the first studies to look at cost effectiveness of allopurinol and rasburicase in the pediatric population • Primary endpoints were appropriate

46. Applicable Conclusions • Statistically significant results • Mean duration of critical care days • Standard of practice should not be altered based on this study

47. Weight Based Dosing vs. Single-Fixed Dosing in Adults

48. 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.

49. 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.

50. 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.