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Emerging Drug List
RASBURICASE
AND
HYPERURICEMIA
IN
CANCER PATIENTS
CANADIAN COORDINATING
OFFICE FOR HEALTH
TECHNOLOGY ASSESSMENT
NO. 45
Generic (Trade Name):
Manufacturer:
Indication:
MAY 2003
Rasburicase (ElitekTM)
Sanofi-Synthelabo Canada Inc.
For the treatment and prophylaxis of hyperuricemia in pediatric and adult cancer
patients.1
Current Regulatory
Status:
Rasburicase was approved by the US Food and Drug Administration (FDA) on July 16,
2002 for the initial management of plasma uric acid levels in pediatric patients with
leukemia, lymphoma and solid tumour malignancies who are receiving chemotherapy
that is expected to result in tumour lysis syndrome. Previous to this, it had been launched
in Europe under the brand name Fasturetic®.2 A submission has been made to the
Canadian Therapeutic Products Directorate in reference to rasburicase, and final approval
is pending (David Pao, Sanofi-Synthelabo, Markham, ON: personal communication,
2003 Feb 3). Currently in Canada, it is available via the Special Access Programme.3
Description:
Tumour lysis syndrome is a metabolic disturbance that can lead to increased morbidity
and mortality. It is characterized by various combinations of hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia, resulting from cell destruction during
cancer treatment. This frequently leads to acute renal failure. Tumour lysis syndrome
usually occurs during or shortly after (1 to 5 days) chemotherapy. It is associated with the
treatment of hematologic malignancies including Burkitt's lymphoma, acute lymphoblastic leukemia, and rarely with solid tumours.
Rasburicase, a recombinant urate-oxidase enzyme, converts uric acid into allantoin, a
more soluble by-product of the purine catabolic pathway. The enzyme is administered
intravenously (IV) at a dose of 0.2 mg/kg/day for up to seven days. In a pharmacokinetic
trial using the approved dose for five days, the observed Cmax was 4.5 mg/L, and the
mean elimination half-life was 21.1 hours.1,4
Current Treatment:
Cost:
Prophylaxis in patients at high risk for tumour lysis syndrome consists of maintaining
hydration, alkalinization with sodium bicarbonate, administering allopurinol to reduce
uric acid and monitoring serum chemistry. Acute situations may require hemodialysis
and disruptions in chemotherapy.4
According to the publication The Medical Letter, the cost of five days of therapy is
US$16,762 for a 30-kg child at the lowest usual daily dose (i.e. 0.15 mg/kg). The
November 2002 Drug Topics Red Book Update was apparently used to obtain this figure.5
The Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca)
Emerging Drug List
RASBURICASE
AND
Evidence:
HYPERURICEMIA
IN
CANCER PATIENTS
CANADIAN COORDINATING
OFFICE FOR HEALTH
TECHNOLOGY ASSESSMENT
Rasburicase vs. Standard Treatment: Evidence of comparative efficacy and safety is
available from a single randomized trial. Patients (n=52) aged 0.3 to 17 years with
leukemia or lymphoma were randomized to receive either rasburicase or allopurinol
without blinding. All were scheduled to receive five to seven days of therapy at a dose
of 0.2 mg/kg IV daily or 10 mg/kg po (300 mg/m2) divided every eight hours of rasburicase or allopurinol, respectively after initiation of anti-tumour therapy. In the case of
allopurinol, investigators were allowed to change the allopurinol dose based on their
own practice. Standard hydration and bicarbonate, if required, were allowed.
The protocol defined efficacy endpoints that included occurrence of renal complications,
occurrence of hypertension, occurrence of metabolic abnormalities, incidence of elevated
creatinine and the area under the curve (AUC) of the plasma uric acid concentration in
the first 96 hours of therapy (AUC0-96). The AUC0-96 was the primary efficacy endpoint.
The incidence of renal complications was similar in both arms (one participant in the
allopurinol arm required hemodialysis); the trial was underpowered to detect a statistical
difference for this outcome. The incidence of hypertension was not reported. For both
groups, the mean time from study drug administration to the first dose of induction
chemotherapy was 21 hours. Using intent-to-treat analysis, the mean AUC0-96 was
128 mg/dL/hr (95% CI: 114 to 142) and 329 mg/dL/hr (95% CI: 200 to 458) for rasburicase and allopurinol recipients, respectively (p<0.0001); this translated to 2.6 times less
exposure to uric acid during the first 96 hours of therapy.6
Rasburicase Alone: Pui and colleagues have published the results of non-comparative
trials in children, adolescents and adults, indicating that rasburicase is effective for the
prophylaxis and treatment of hyperuricemia associated with underlying malignancy.7,8
Recently, the updated results from their compassionate-use trial were presented at the
American Society of Clinical Oncology ASCO. The study population which consisted
of 778 patients, both children and adults, showed that all patients "responded" to therapy
administered prophylactically (100%) and most when used as a treatment (98-99%).9
Other trials examining the merits of rasburicase are available in abstract form.4,10-13
Adverse Effects:
According to the product monograph, drawing from the experience of 703 patients, the
commonly reported serious adverse reactions were serious fever (5%), neutropenia with
fever (4%), respiratory distress (3%), sepsis (3%), neutropenia (2%), and mucositis
(2%). A FDA "Black Box" warning appears on the US product monograph warning of
infrequent (<1%) but serious adverse events including anaphylaxis, serious rash, hemolysis, and methemoglobinemia. Rasburicase is contraindicated in those patients with
glucose-6-phosphate dehydrogenase deficiency.14
The Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca)
Emerging Drug List
RASBURICASE
AND
Commentary:
HYPERURICEMIA
IN
CANCER PATIENTS
CANADIAN COORDINATING
OFFICE FOR HEALTH
TECHNOLOGY ASSESSMENT
So far, there is no evidence that rasburicase reduces serious complications or death from
tumour lysis syndrome compared to standard therapy. Unless more data from clinical
trials become available, the effectiveness of this drug will require speculation based on
surrogate endpoints from a single randomized trial of efficacy.
In addition, no comparative data are available for the adult population. A trial "assessing
the respective places of allopurinol and rasburicase in … adult patients" is part of the
manufacturers commitment after licensing according to a European Commision Report.
Accordingly, a Canadian pharmacoeconomic analysis is in development (David Pao:
personal communication, 2003 Feb 3) and will need to overcome these considerable
hurdles in order to reliably aid formulary decisions.
References:
1. Elitek™ (rasburicase) [product monograph]. Markham (ON): Sanofi-Synthelabo Canada Inc.;
2001 Nov.
2. Elitek™ (rasburicase) has been approved by the FDA in the United States [press release]. New York:
Sanofi-Synthelabo Inc.; 2002 Jul 16. Available: http://www.sanofisynthelabous.com/news/2002/20020716.html (accessed 2003 Jan 17).
3. Canadian Investigational and Special Access drug list. Don Mills (ON): Ontario Pharmacists'
Association; 2002.
4. Brant JM. Rasburicase: an innovative new treatment for hyperuricemia associated with tumor lysis
syndrome. Clin J Oncol Nurs 2002;6(1):12-6.
5. Rasburicase (Elitek) for hyperuricemia. Med Lett Drugs Ther 2002;44(1143):96-7.
6. Goldman SC, Holcenberg JS, Finklestein JZ, Hutchinson R, Kreissman S, Johnson FL, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at
high risk for tumor lysis. Blood 2001;97(10):2998-3003.
7. Pui CH, Mahmoud HH, Wiley JM, Woods GM, Leverger G, Camitta B, et al. Recombinant urate
oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma.
J Clin Oncol 2001;19(3):697-704.
8. Pui CH, Jeha S, Irwin D, Camitta B. Recombinant urate oxidase (rasburicase) in the prevention and
treatment of malignancy-associated hyperuricemia in pediatric and adult patients: results of a compassionate-use trial. Leukemia 2001;15(10):1505-9.
9. Pui CH, Jeha S, Irwin D, Shen V, Shenoy S, Blaney S, et al. Recombinant urate oxidase (rasburicase,
Elitek) for prevention and treatment of malignancy-associated hyperuricemia: updated tesults of a compassionate use trial. American Society of Hematology 44th Annual Meeting; 2002 Dec 6-10;
Philadelphia. A2187. Available: http://www.abstracts-on-line.com/abstracts/hemphiladelphia02/windowview.asp?abs=HEM2L_1374&Search=.
10. Rasburicase [Drugdex drug evaluations]. In: Hutchison TA, Shahan DR, editors. DRUGDEX® system.
Greenwood Village (CO): MICROMEDEX (edition expires 3/2003); 2003.
The Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca)
Emerging Drug List
RASBURICASE
AND
HYPERURICEMIA
IN
CANCER PATIENTS
CANADIAN COORDINATING
OFFICE FOR HEALTH
TECHNOLOGY ASSESSMENT
11. Bosly A, Pinkerton CR, McCowage G, Bron D, Sanz MA, Van den Berg H. Recombinant urate oxidase
(rasburicase) is safe and effective in managing hyperuricemia in children and adults: results of a multinational compassionate use trial [abstract]. American Society of Hematology 44th Annual Meeting;
2002 Dec 6-10; Philadelphia. A2187. Available: http://www.abstracts-online.com/abstracts/hemphiladelphia02/windowview.asp?abs=HEM2L_2020&Search=.
12. Coiffier B, Mounier N, Bologna S, Fermé C, Herbrecht R, Tilly H, et al. Final results of the efficacy
and safety of rasburicase (recombinant urate oxydase) for the prevention and treatment of hyperuricemia in patients with aggressive lymphoma (GRAAL 1 Study) [abstract]. American Society of
Hematology 44th Annual Meeting; 2002 Dec 6-10; Philadelphia. A1391. Available:
http://www.abstracts-online.com/abstracts/hemphiladelphia02/windowview.asp?abs=HEM2L_4231&Search=.
13. Jeha S, McDonald L, Irwin D, Krishnamurthy M, Ericson S, Asselin B, et al. Recombinant urate oxidase (Elitek™) is safe and effective in prevention and treatment of malignancy-associated hyperuricemia in adult patients [abstract]. American Society of Hematology 44th Annual Meeting; 2002 Dec
6-10; Philadelphia. A2185. Available: http://www.abstracts-online.com/abstracts/hemphiladelphia02/windowview.asp?abs=HEM2L_4231&Search=.
14. Elitek™ (rasburicase): prescribing information. Rev. New York: Sanofi-Synthelabo Inc.; 2002 Jul.
Available: http://www.sanofi-synthelabous.com/products/pi_elitek/pi_elitek.html (accessed 2003
Jan 17).
This series highlights medical technologies that are not yet in widespread use in Canada and that
may have a significant impact on health care. The contents are based on information from early
experience with the technology; however, further evidence may become available in the future.
These summaries are not intended to replace professional medical advice. They are compiled as
an information service for those involved in planning and providing health care in Canada.
These summaries have not been externally peer reviewed.
ISSN 1496-8398 (online only)
The Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca)