RASBURICASE: Single fixed dose or package insert dose?

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RASBURICASE: Single fixed dose or package insert dose?

RASBURICASE: Single

fixed dose or package

insert dose?

Rosalyn P. Sims-McCallum, PharmD

Clinical Pharmacy Specialist Hematology/Oncology

Children’s Hospital of Michigan USA


HYPERURICEMIA

Caused by massive and rapid nucleic

acid catabolism

Uric acid is relatively soluble in plasma

Less soluble when approaching the

renal tubules and collecting ducts

Leading to increased risk of

crystallization in renal tubules…renal

failure


HYPERURICEMIA

Hydration

Alkalinization

Allopurinol

Rasburicase

Treatment


ALLOPURINOL

Allopurinol is a xanthine oxidase

inhibitor that prevents the conversion of

hypoxanthine and xanthine to uric acid

Has no effect on existing uric acid levels


RASBURICASE

Rasburicase (recombinant urate

oxidase)

An enzyme that facilitates the

conversion of uric acid to allantoin that

is renally excreted.

Allantoin is 5 – 10 times more soluble in

urine than uric acid


RASBURICASE

Indicated for the initial management of

plasma uric acid levels in pediatric

patients with leukemia, lymphoma, and

solid tumor malignancies who are

receiving anti-cancer therapy expected

to result in tumor lysis and subsequent

elevation of plasma uric acid.

Package Insert Rasburicase.

Sanofi-Synthelabo. 2004


RASBURICASE

Advantage: Rapidly eliminates uric acid

that is in the plasma

Allopurinol prevents formation of uric

acid only, does nothing for elimination


RASBURICASE

Pharmacokinetics

Half life: 18 hours

Volume of distribution in pediatric pts.

110 – 127 mL/kg

AUC and Cmax increase linearly in the

dosage range of 0.15 – 0.2 mg/kg

No accumulation of drug when given

daily for 5 days

Package Insert. Rasburicase.

Sanofi-Synthelabo.2004


RASBURICASE

0.15 or 0.2 mg/kg IV over 30 minutes

daily for 5 days

Literature shows that some medical

centers are giving just one dose, may

repeat if necessary


RASBURICASE

Single Dose

A single dose of rasburicase is sufficient

for the treatment of hyperuricemia in

patients receiving chemotherapy.

Leuk Res. 2005 Apr;29(4):463-5

Use of single-dose rasburicase in an

obese female.

Ann Pharmacother. 2004 Sep;38(9):1428-31


RASBURICASE

Fixed Dose

Some medical centers are using a fixed

dose regardless of patient weight with

good results.


RASBURICASE

One center successfully corrected uric

acid levels in three pediatric patients

using a single dose of 4.5 mg

Uric acid levels: 13.8, 11.9, 11.4 mg/dL

Range: 0.017 – 0.17 mg/kg

Ann Pharmacother 2003:37:1614-

17


RASBURICASE

6 mg fixed dose for adults

Range: 0.045 – 0.1 mg/kg

Initial uric acid range: 8.7 – 21 mg/dL

Most patients had uric acid levels within

normal range 12 – 18 hours after a

single dose

Pharmacother 2006;26(2):242-

247


RASBURICASE

Normal Range for serum levels of uric

acid is considered to be less than

8 mg/dL


RASBURICASE

Case report of 4.5 mg dose in an adult

patient

0.056 mg/kg given every 12 hours x 2

doses

Initial uric acid level: 20.8 mg/dL

Uric acid levels within normal limits

within 24 hours

Eur J Haematol 2005: 75: 518-521


RASBURICASE

Experience of Northwestern Memorial

Hospital, USA

Retrospective review of 50 adult

patients

Gave the package insert dose in 3 mg

increments every 6 – 8 hr with frequent

monitoring of uric acid, SCr and

electrolytes

Held subsequent doses if uric acid was


RASBURICASE

Experience of Northwestern Memorial

Hospital, USA

44/50 patients had serum uric acid

levels within normal range 24 hours

after the dose

50/50 after 48 hours

Baseline uric acid: 10.4 mg/dL

Steven Trifilio, RPh BMT Tandem

2006


RASBURICASE

Experience of Northwestern Memorial

Hospital, USA

In patients that had a baseline uric acid

of >10.4,

The fixed dose took longer to lower the

uric acid levels to normal range

24 hr uric acid: 9.7

48 hr uric acid: 4.9

Steven Trifilio, RPh BMT Tandem

2006


RASBURICASE

Experience of Northwestern Memorial

Hospital, USA

Conclusions

With the administration of a single low

dose of rasburicase, uric acid was

lowered to the normal range within 24 -

48 hrs

Give a repeat dose of 1.5 – 3 mg if

results not seen within this time frame


RASBURICASE

Concerns with this method

By giving this small dose, the uric acid

is lowered to within therapeutic range,

but it is not completely eliminated

Want the plasma uric acid level as low

as possible in patients at risk for tumor

lysis syndrome


RASBURICASE

Concerns cont’d

Would it be better to give a slightly

higher dose once in order to eliminate

the uric acid completely ?

Half-life of rasburicase is 18 hours the

level would stay very low for a few days


RASBURICASE

Concerns cont’d

Requires frequent blood draws, more

pokes, increased lab costs


RASBURICASE

Experience at Children’s Hospital of

Michigan, USA

For patients < 70 kg, give 0.15 mg/kg x

1 dose

Plasma uric acid level drops to < 0.5

mg/dL within 24 hours

With 18 hour half-life, effect of drug

usually lasts for 2 or 3 days before

trending back up, if at all


RASBURICASE

Experience at Children’s Hospital of

Michigan, USA

For patients >70 kg have started

capping the dose at 10.5 mg (7 vials,

1.5 mg each)


RASBURICASE

Experience at Children’s Hospital of

Michigan, USA

Example: 147 kg 17 year old patient

(IBW: 72 kg)

Calculated dose at 0.15 mg/kg: 22 mg

(using IBW: 10.8 mg)

Gave one 10.5 mg dose: 0.07 mg/kg

(ABW)


RASBURICASE

The study published in Ann

Pharmacother used a single dose in an

obese female adult patient

Used IBW to calculate the single dose

Hypothesized that rasburicase would

not readily distribute to adipose tissue

Ann Pharmacother 2004;38:1428-

31


RASBURICASE

Reasons: low volume of distribution

Protein nature of rasburicase (301

amino acids)

Ann Pharmacother 2004;38:1428-

31


RASBURICASE

Experience at Children’s Hospital of

Michigan, USA

Coincidentally, the dose for the obese

adolescent patient was the IBW dose

0600 labs the next day (less than 24

hours after the dose) uric acid level was


RASBURICASE

Experience at Children’s Hospital of

Michigan, USA

Advantages to this method?

Eliminate need for a repeat dose within

24 to 48 hours, if at all

Since the serum uric acid is below

normal limits, would there be a

decreased risk of a sudden increase in

uric acid with chemotherapy

administration?


RASBURICASE

Conclusions

Very effective at lowering serum uric

acid

Very effective in doses much lower than

what is recommended by the

manufacturer


RASBURICASE

Conclusions

What method of administration is the

BEST?

Package insert dose x 1 ?

4.5 mg fixed dose ?

6 mg fixed dose ?

3 mg incremental doses?

Package insert dose x 1, 10.5 mg max ?


RASBURICASE

Conclusions

Obviously more controlled trials need to

be done in adults and children to help

us to answer this question.

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