Are granisetron (Kytril) 1 mg, tropisetron (Navoban) 2 mg, and ondansetron (Zofran) 4 mg given intr

Fråga: Are granisetron (Kytril) 1 mg, tropisetron (Navoban) 2 mg, and ondansetron (Zofran) 4 mg given intravenously equally effective in preventing post-operative nausea?

Sammanfattning: No direct comparisons have been made between granisetron, tropisetron and ondansetron in the doses recommended for prevention of post-operative nausea. In three randomised controlled studies a higher dose of tropisetron (5 mg) was not superior to ondansetron (4 mg). However, tropisetron seems to give a longer-lasting anti-emetic effect compared to ondansetron, due to a longer half-life. Altogether, there is still no strong evidence of any 5-HT3-inhibitor being superior to the others, and it is not clear whether equipotent doses of the three substances have been established.

Svar: A similar question has previously been answered by the drug information centre and at the time it was concluded that there were no known differences between the three 5-HT3-antagonsists with regard to antiemetic effect. However, this conclusion was drawn from studies in patients undergoing cytostatic treatment, using higher 5-HT3-blocker doses than those recommended for prevention of postoperative nausea (1).

There are clinically important differences between the three drugs with regard to their pharmacokinetics. Ondasetron has a shorter biologic half-life (3-5 hours) compared to tropisetron and granisetron (9 hours). However, the elimination of the latter two drugs is subject to large interindividual variability. In the case of tropisetron, this variability is mainly due to involvement of a polymorphic metabolising enzyme, cytochrome P450 2D6. In individuals lacking this enzyme (slow metabolisers), tropisetron has a half-life of approximately 32 hours and in individuals with gene duplication (ultrarapid metabolisers) one would expect a considerably faster elimination. When given orally, all three substances have a bio-availability of approximately 60 percent (2).

Five double-blind randomised studies have addressed the use of these anti-emetics for post-operative nausea (3,4,5,6,7). In the first of these (n=132), ondansetron 4 mg given intravenously prior to anaesthesia was superior to placebo in preventing nausea during the first 24 postoperative hours after laparoscopic cholecystectomy, while granisetron 3 mg and tropisetron 5 mg were not. The study did not have enough power to formally demonstrate any differences between the three 5-HT3-inhibitors (3).

Two other studies (n=87 and 121) comparing ondansetron 4 mg and tropisetron 5 mg administered intravenously prior to laparoscopic cholecystectomy (4) or gynaecological laparotomy (5) demonstrated time dependent effect differences between the two drugs. Three hours postoperatively, ondansetron had a significantly better anti-emetic effect compared to tropisetron (4), while tropisetron was superior to ondansetron six to sixteen hours postoperatively (4, 5). The apparent difference in effect duration seen in these studies is consistent with ondansetron having a shorter biologic half-life compared to tropisetron (2). A comparison (n=88) between ondansetron 8 mg and tropisetron 5 mg failed to show any differences in anti-emetic effect, except for droperidol rescue medication being needed on average three hours earlier in the tropisetron group compared to the ondansetron group. The subjects of this study were women with a history of post-operative nausea undergoing gynaecological laparoscopic surgery (6).

The fifth study on 5HT3-blockers in postoperative nausea (n=179) investigated the effects of oral pre-medication with tropisetron 5 mg, ondansetron 16 mg or metoclopramide 10 mg in patients undergoing thyroid and parathyroid surgery. During the first two post-operative hours, the frequency of nausea and vomiting in the tropisetron, ondansetron, and metoclopramide groups was 15, 32 and 39 percent, respectively. During this time period, ondansetron was significantly more effective than metoclopramide, while the difference between the two 5-HT3-blockers was judged non-significant (P=0.051). During the first 24 post-operative hours, there were no effect differences between the three groups (7).

The heterogeneity of the above-mentioned studies with regard to patient populations, surgical procedures, 5HT3-blocker doses and outcome measures makes it difficult to draw any certain conclusions from the aggregated data. The question of whether recommended doses are equipotent may be further elucidated by scrutinising the dose-finding studies underlying registrations of these three drugs. However, this lies outside the scope of the current review.