What is the adequate dosage of ondansetron (Zofran) to children about 12 years of age with renal fa

Fråga: What is the adequate dosage of ondansetron (Zofran) to children about 12 years of age with renal failure and who are on regular hemodialysis? These children are treated with ondansetron because of nausea due to chemotherapy, anuria or hemolytic uremic syndrome, respectively.

Sammanfattning: There is a lack of information about the elimination of ondansetron in patients with severe renal failure and treated with hemodialysis. When there is a strong need for this drug, dosing at the lower end of current recommendations and alertness for the observation of possible adverse effects seem warranted.

Svar: Ondansetron is a selective 5-HT3 receptor antagonist which is licensed for the treatment of nausea and vomiting related to cancer chemotherapy and radiotherapy. The antiemetic mechanism is antagonism of 5-HT receptors located in the area postrema and possibly on vagal afferents in the upper gastro-intestinal tract. Ondansetron has a plasma protein binding of 75 per cent, a volume of distribution of 163 +/-25 L and a plasma half-life of approximately 3 hours. Ondansetron is metabolized to hydroxy- and demethylated metabolites, which are subsequently further hydroxylated, glucuronidated and sulfateconjugated. The activity of the metabolites is not known (1). As well CYP2D6 as CYP3A4 are involved in the metabolism of ondansetron (2). Less than 10 per cent of an intravenous dose is recovered unchanged in the urine (1). The plasma clearance is 500 mL/min (3).

Since 10 per cent of the unchanged drug and 75 per cent of hepatic metabolites are excreted in the urine, it has been assumed that the use of ondansetron could be potentially hazardous in patients with reduced renal function (4).

It has been reported that ondansetron has been given on other indications than nausea due to cancer treatment (4,5).

However, there are only sparse data found in an extensive literature search on ondansetron in patients with renal insufficiency. There are eg no studies of the pharmacokinetics in renally healthy patients compared with patients with impaired renal function.

Some sources, like FASS and a standard pharmacological handbook (6), do not recommend dose adjustment in patients with renal failure. However, it could be expected that only small amounts of ondansetron will be removed by hemodialysis, due to the relatively high plasma protein binding in combination with a rather large volume of distribution (7). Furthermore, since the patients are completely or partially anuric, the elimination half-life of the metabolites could theoretically be prolonged, causing higher concentrations of the metabolites. The potential importance of this is difficult to assess.