Allison Weddington, PharmDPGY1 Pharmacy Resident

St. Louis Children’s HospitalNovember 14, 2011

How Much is Too Much?How Much is Too Much?The Use of Rasburicase in The Use of Rasburicase in

the Treatment of Tumor the Treatment of Tumor Lysis SyndromeLysis Syndrome

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.

Goals & ObjectivesGoals & Objectives

Group of metabolic disturbances as a result of intracellular constituents being released into the blood due to lysis of malignant cells

Tumor Lysis Syndrome (TLS) Tumor Lysis Syndrome (TLS) DefinitionDefinition

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

Etiology and IncidenceEtiology and Incidence

Wossman W, et al. Ann Hematol. 2003;82:160.

Hande KR, et al. Am J Med. 1993;94:133-9.

Anaplastic large cell lymphoma T-cell and B-cell precursor ALL Acute myeloid leukemia Chronic lymphocytic leukemia Multiple myeloma

Other Associated MalignanciesOther Associated Malignancies

Rapid tumor cell proliferation

High tumor burden Increased sensitivity

to cytotoxic therapy

Renal dysfunction Hyperuricemia Hyperphosphatemia Acidic urine Dehydration

Risk Factors for TLSRisk Factors for TLSHematologic Malignancy

Related Factors

Patient Related Factors

Risk of TLS Based on Tumor Risk of TLS Based on Tumor TypeType

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

Pathophysiology of TLSPathophysiology of TLS

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

Representative of metabolic abnormalities

Hyperkalemia

Hyperphosphatemia

Hypocalcemia

Hyperuricemia

Clinical Presentation of TLSClinical Presentation of TLS

Consequences of TLSConsequences of TLS

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

Laboratory TLS

Clinical TLS Laboratory TLS plus 1 of the following

Serum creatinine > 1.5 times upper limit of normal Arrhythmias Seizures

Laboratory vs. Clinical TLSLaboratory vs. Clinical TLS

Coiffier B, et al. J Clin Oncol. 2008;26(16):2767-78. Cairo MS, et al. Br J Haematol. 2004;127:3-11.

Hydration and diuresis

Urinary alkalinization

Agents acting on uric acid Allopurinol Rasburicase

Treatment OverviewTreatment Overview

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

Hydration and DiuresisHydration and Diuresis

Previous recommendation: Addition of 40 – 80 mEq/L of sodium bicarbonate

Current recommendation: No addition of sodium bicarbonate to fluids

Urinary AlkalinizationUrinary Alkalinization

Allopurinol

Rasburicase

Agents Affecting Uric AcidAgents Affecting Uric Acid

Allopurinol Mechanism of ActionAllopurinol Mechanism of Action

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

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 PharmacokineticsAllopurinol Pharmacokinetics

Contraindications Hypersensitivity to allopurinol

Precautions Reduce dose in renal impairment Rash Hypersensitivity

Allopurinol WarningsAllopurinol Warnings

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 Adverse EffectsAllopurinol Adverse Effects

Liver enzyme tests and bilirubin

Renal function

Serum uric acid

Allopurinol MonitoringAllopurinol Monitoring

Allopurinol Drug InteractionsAllopurinol Drug Interactions

Increase Levels/Effects of

Allopurinol

Increase Levels/Effects of

Other MedicationsLoop Diuretics

Thiazide Diuretics

ACE Inhibitors

Azathioprine

6-Mercaptopurine

Cyclophosphamide

Amoxicillin

Ampicillin

Pediatric Dose PO: 200mg – 300mg/m2/day divided into 2 – 4

doses

Adult Dose PO: 600mg – 800mg/day divided into 2 – 3

doses

Allopurinol DosingAllopurinol Dosing

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

Disadvantages of AllopurinolDisadvantages of Allopurinol

Rasburicase Mechanism of ActionRasburicase Mechanism of Action

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

Administration IV only

Pharmacokinetics Metabolism

Peptide hydrolysis

Half life 18 hours

Rasburicase PharmacologyRasburicase Pharmacology

Black box warnings and contraindications

Anaphylactic reactions

Hemolytic reactions with glucose-6-phosphate dehydrogenase (G6PD) deficiency

Methemoglobinemia

Interference with uric acid laboratory values

Rasburicase WarningsRasburicase Warnings

Precautions

Maintain adequate hydration

Urinary alkalinization is not recommended

Antibody response risk increases with each dose

RasburicaseRasburicase WarningsWarnings

CNS: fever, headache GI: nausea, vomiting, diarrhea, abdominal

pain Dermatologic: rash Hematologic: hemolysis,

methemoglobinemia Hepatic: ALT increase, hyperbilirubinemia Miscellaneous: antibody formation,

hypersensitivity reactions

Rasburicase Adverse EffectsRasburicase Adverse Effects

No known drug interactions

IV: 0.2mg/kg/dose daily for 5 days

Rasburicase Drug InteractionsRasburicase Drug Interactions

DosingDosing

Allopurinol vs. RasburicaseAllopurinol vs. Rasburicase

Treatment Based on RiskTreatment 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

Allopurinol 100mg tablet: $0.26 300mg tablet: $0.70

Rasburicase 1.5mg vial: $704.05 7.5mg vial: $3520.31

Average Wholesale PriceAverage Wholesale Price

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 PatientCost 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

Cost for Pediatric PatientCost for Pediatric Patient

Eaddy M, Seal B, Tangirala M, Davies E, O’Day K

Am J Health-Sys Pharm. 67(24):2110-4

December 2010

Economic Comparison of Economic Comparison of Rasburicase and Allopurinol for Rasburicase and Allopurinol for

Treatment of Tumor Lysis Treatment of Tumor Lysis Syndrome in Pediatric PatientsSyndrome in Pediatric Patients

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

ObjectiveObjective

Retrospective study

Premier Perspective Database to collect data

Rasburicase and allopurinol treated patients were propensity score matched

DesignDesign

Costs per hospitalization

Length of stay

Duration of critical care

Primary EndpointsPrimary Endpoints

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

MethodsMethods

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

StatisticsStatistics

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

ResultsResults

ResultsResults

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

“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.”

Authors’ ConclusionsAuthors’ Conclusions

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

LimitationsLimitations

One of the first studies to look at cost effectiveness of allopurinol and rasburicase in the pediatric population

Primary endpoints were appropriate

StrengthsStrengths

Statistically significant results Mean duration of critical care days

Standard of practice should not be altered based on this study

Applicable ConclusionsApplicable Conclusions

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

AdultsAdults

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

Single-Dose Rasburicase 6mg in the Single-Dose Rasburicase 6mg in the Management of Tumor Lysis Syndrome Management of Tumor Lysis Syndrome

in Adultsin Adults

McDonnell AM, et al. Pharmacother. 2006;26(6):806-12.

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

Evaluation of a Single Fixed Dose of Evaluation of a Single Fixed Dose of Rasburicase 7.5mg for the Treatment of Rasburicase 7.5mg for the Treatment of

Hyperuricemia in Adults with CancerHyperuricemia in Adults with Cancer

Reeves DJ, et al.. Pharmacother. 2008;28(6):685-90.

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

Single-Dose Rasburicase for Tumor Lysis Single-Dose Rasburicase for Tumor Lysis Syndrome in Adults: Weight-Based ApproachSyndrome in Adults: Weight-Based Approach

Campara M, et al. J Clin Pharm Ther. 2009;34:207-13.

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

Evaluation of a Low, Weight-Based Dose of Evaluation of a Low, Weight-Based Dose of Rasburicase in Adult Patients for the Treatment Rasburicase in Adult Patients for the Treatment

or Prophylaxis of Tumor Lysis Syndromeor Prophylaxis of Tumor Lysis Syndrome

Knoebel R, et al. J Oncol Pharm Pract. 2010;17(3):147-54.

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

Fixed-Dose Rasburicase 6mg for Fixed-Dose Rasburicase 6mg for Hyperuricemia and Tumor Lysis Syndrome in Hyperuricemia and Tumor Lysis Syndrome in

High Risk Cancer PatientsHigh Risk Cancer Patients

Vines AN, et al. Ann Pharmacother. 2010;44:1529-37.

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

Effectiveness of a Single 3mg Rasburicase Dose Effectiveness of a Single 3mg Rasburicase Dose for the Management of Hyperuricemia in Patients for the Management of Hyperuricemia in Patients

with Hematological Malignancieswith Hematological Malignancies

Trifilio SM, et al. Bone Marrow Transplant. 2011;46:800-5.

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

Weight Based Dosing vs. Single-Weight Based Dosing vs. Single-Fixed Dosing in PediatricsFixed Dosing in Pediatrics

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

Treatment of Impending Tumor Treatment of Impending Tumor Lysis with Single Dose RasburicaseLysis with Single Dose Rasburicase

Lee A, et al. Ann Pharmacother. 2003;37:1614-7.

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

SummarySummary

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

RecommendationsRecommendations

Allison Weddington, PharmDPGY1 Pharmacy Resident

St. Louis Children’s HospitalNovember 14, 2011

How Much is Too Much?How Much is Too Much?The Use of Rasburicase in The Use of Rasburicase in

the Treatment of Tumor the Treatment of Tumor Lysis SyndromeLysis Syndrome