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
My name is Allison Weddington and I am the current PGY1 resident at St. Louis Children’s Hospital. Today I am going to be discussing rasburicase in the treatment of tumor lysis syndrome and the controversy surrounding its dosing regimen. .

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. Hematologic Malignancy Related Factors Patient Related Factors
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):

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

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):

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):
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):

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 Precautions
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
Increase Levels/Effects of Allopurinol
Increase Levels/Effects of Other Medications
Loop Diuretics
Thiazide Diuretics
ACE Inhibitors
Azathioprine
6-Mercaptopurine
Cyclophosphamide
Amoxicillin
Ampicillin

22. Allopurinol Dosing Pediatric Dose Adult 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):

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. Rasburicase Warnings 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: $

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): 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 Exclusion 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 Baseline demographics
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 Patient demographics
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 Dec 15;67(24):

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):

49. Evaluation of a Single Fixed Dose of Rasburicase 7
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):

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:

51. Evaluation of a Low, Weight-Based Dose of Rasburicase in Adult Patients for the Treatment or Prophylaxis of Tumor Lysis Syndrome
0.05 mg/kg rasburicase x 1 dose
Median dose = 4.5 mg
Treatment group
Baseline median uric acid: 9.35 mg/dL
Decreased to 3.3 mg/dL – 64.7% decrease
Prophylaxis group
Baseline median uric acid: 6.5 mg/dL
Decreased to 1.45 mg/dL – 77% decrease
8 patients redosed
No changes in serum creatinine
Knoebel R, et al. J Oncol Pharm Pract. 2010;17(3):

52. Fixed-Dose Rasburicase 6mg for Hyperuricemia and Tumor Lysis Syndrome in High Risk Cancer Patients
6mg rasburicase x 1 dose
Baseline median uric acid: 9.2mg/dL
Decreased to 1.8mg/dL on day 3 & 3.8mg/dL on day 7
80.4% decrease in 24 hours
2 patients redosed
1 received 2 additional doses
1 received 3 additional doses
Baseline median serum creatinine: 1.9mg/dL
Decreased to 1.1mg/dL on day 7
Vines AN, et al. Ann Pharmacother. 2010;44:

53. Effectiveness of a Single 3mg Rasburicase Dose for the Management of Hyperuricemia in Patients with Hematological Malignancies
3mg rasburicase x 1 dose
Baseline median uric acid: 9.3 mg/dL
Decreased to 5.3 mg/dL – 45%decrease
51 episodes needed redosed
42 episodes required 1 additional dose
5 episodes required 2 additional doses
4 episodes required 3 additional doses
Baseline serum creatinine : 1.7 mg/dL
28% of patients had renal failure (2.5 mg/dL) at baseline
Decreased to 1.6 mg/dL at 24 hours
Trifilio SM, et al. Bone Marrow Transplant. 2011;46:800-5.

54. Weight Based Dosing vs. Single-Fixed Dosing in Pediatrics
Flat dosing shown to be effective in adults
Same dose and possibly even lower dose should be effective in pediatric patients
Literature is lacking in pediatric population

55. Treatment of Impending Tumor Lysis with Single Dose Rasburicase
3 case summaries in pediatric patients
All diagnosed with acute lymphoblastic leukemia
2 cases given standard dose of rasburicase
Case
White blood count: 198,000/mm3
Uric acid: 11.4mg/dL
Serum creatinine: 0.6mg/dL
Allopurinol and hydration initiated
Rasburicase 4.5 mg (0.08mg/kg) was given
No additional rasburicase doses were needed
Lee A, et al. Ann Pharmacother. 2003;37:

56. Summary
TLS: Oncologic emergency characterized by metabolic disturbances
Identify patient risk and initiate appropriate therapy
Treatment consists of fluids and allopurinol or rasburicase
Studies have shown that a maximum doses of 6mg and 7.5mg is effective in adults

57. Recommendations
Based on the published literature, single-fixed dosing shows to be effective in the adult population
A single-fixed dose of rasburicase 6mg should be administered in adult patients
Dosing in the pediatric population should remain weight-based but with a max dose of 6mg

58. 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 58