Tropisetron

Publisher Website
Google Scholar
Abstract
Tropisetron is a serotonin (5-hydroxytryptamine; 5-HT) antagonist that is primarily used in the prevention of chemotherapy-induced nausea and vomiting. Antagonism of 5-HT3 binding sites in the peripheral and central nervous system is the probable mechanism of prevention of acute nausea and vomiting. Effects on delayed nausea and vomiting are less well understood as these are probably not mediated solely by 5-HT3 receptors. Tropisetron monotherapy is effective for the control of acute, and to a lesser extent delayed, nausea and vomiting in patients receiving moderately to severely emetogenic chemotherapy. The combination of dexamethasone and tropisetron is more effective than monotherapy. Complete control of cisplatin-induced nausea and vomiting was obtained in 69 to 97% of patients receiving the combination compared with 46 to 80% receiving tropisetron monotherapy in randomised trials. There were generally no significant differences between the control of acute or delayed nausea and vomiting provided by tropisetron, ondansetron or granisetron in randomised, comparative trials. The antiemetic efficacy of tropisetron was maintained over multiple cycles of chemotherapy. Most comparative studies showed tropisetron monotherapy to be more effective than metoclopramide in controlling acute nausea and vomiting, with the exception of 1 study which showed similar efficacy. However, high dose metoclopramide plus dexamethasone provided similar control of delayed emesis to tropisetron plus dexamethasone. Tropisetron is also effective in children, including those who responded poorly to previous antiemetic treatment. Tropisetron and ondansetron generally have similar efficacies in this population. The drug enhanced patients’ quality of life and was well tolerated by adults and children alike. The recommended oral and IV dosage of tropisetron is 5mg once daily; there is no increase in efficacy with doses >5mg. Conclusions: Tropisetron is similar to other 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting in both adults and children. It is suitable as first-line therapy (combined with a corticosteroid) for the prevention of acute nausea and vomiting in patients treated with moderately to severely emetogenic chemotherapeutic agents. This combination is also moderately effective in the prevention of delayed nausea and vomiting. Tropisetron is a serotonin (5-hydroxytryptamine; 5-HT) antagonist that is primarily used in the treatment of patients with chemotherapy-induced nausea and vomiting. It has high affinity and specificity for 5-HT3 receptors; blockade of 5-HT3 binding sites in the peripheral and central nervous system is the probable mechanism of prevention of acute nausea and vomiting. Effects on delayed nausea and vomiting are less well understood as these are probably not mediated solely by 5-HT3 receptors. Tropisetron antagonised the emetic response in animal models of cisplatin-induced vomiting. Tropisetron is rapidly and almost completely absorbed (≫95% of a 100mg dose within 2.2 hours) after oral administration, with absolute bioavailabilities of 52% for a 20mg dose and 66% for a 100mg dose. It has a large volume of distribution (attributed to its lipophilicity) and protein binding of 59 to 71%. Tropisetron is metabolised predominantly in the liver into inactive metabolites. The plasma terminal elimination half-life (t½) of tropisetron was about 8 hours in extensive metabolisers and about 30 to 40 hours in poor metabolisers of the drug. Although liver cirrhosis reduces the metabolic clearance of tropisetron and moderate to severe renal impairment reduces its nonrenal clearance, dosage adjustments in these populations are not necessary. Plasma t½ of tropisetron was unaffected by age in children, but in children aged 3 to 6 years plasma clearance was lower and the area under the plasma drug concentration-time curve higher than in those aged 10 to 15 years. Tropisetron mono therapy is effective for the control of acute, and to a lesser extent delayed, nausea and vomiting in patients receiving moderately to severely emetogenic chemotherapy. The drug was most effective in patients who had received no previous chemotherapy, in adults aged >50 years and in men. There were generally no significant differences in the control of acute and delayed nausea and vomiting between tropisetron, ondansetron or granisetron monotherapies in randomised, comparative trials. Control of acute nausea and vomiting was maintained over multiple cycles of chemotherapy with all 3 agents. The combination of dexamethasone and tropisetron is more effective than tropisetron monotherapy. Complete control of cisplatin-induced acute vomiting was obtained in 69 to 97% of patients receiving the combination compared with 46 to 80% receiving tropisetron monotherapy in randomised trials. The combination of tropisetron and dexamethasone also provided greater protection against delayed emesis (51 to 81%) than tropisetron monotherapy (27 to 59%). However, much of this benefit may be attributable to dexamethasone, as delayed nausea and vomiting were only slightly better controlled (≤13% and ≤6% improvement, respectively) with tropisetron plus dexamethasone compared with dexamethasone monotherapy. The combination of tropisetron and dexamethasone was also more effective in patients whose nausea and vomiting had previously not been well controlled with tropisetron monotherapy. Complete control of acute and delayed vomiting occurred in as many as 80% of patients treated with the combination compared with ≤64% (acute) and ≤70% (delayed vomiting) of those receiving tropisetron monotherapy in randomised double-blind studies. The antiemetic efficacy of tropisetron monotherapy was generally greater than that of metoclopramide, although high dose metoclopramide plus dexamethasone provided equivalent control of delayed nausea and vomiting to tropisetron plus dexamethasone. Results of a number of noncomparative trials indicated that tropisetron is effective in children, including those who had responded poorly to previous antiemetic treatment. Furthermore, comparative data suggest that tropisetron and ondansetron generally have similar antiemetic efficacy in this population. Tropisetron was usually administered at a daily dosage of 0.2 mg/kg up to a maximum of 5mg. In a trial involving 131 children aged 10 weeks to 21 years, complete response (no nausea or vomiting) was observed on day 1 in 67% of patients; delayed vomiting was controlled in 60% of all cycles of intravenous chemotherapy. Improvements in quality of life with regard to nausea and vomiting during chemotherapy have been reported with tropisetron 5 and 10mg in 2 randomised, double-blind, multicentre trials. Food intake was not significantly affected during chemotherapy. Nurses considered tropisetron to be highly beneficial in over 85% of patients who received 5 days’ treatment. Tropisetron was generally well tolerated by adults, being associated with adverse events commonly caused by 5-HT3 antagonists. Adverse events were usually mild, the most frequent being headache (≤18% of patients), constipation (≤7.6%) and fatigue (≤3.5%). The drug was also well tolerated by children; adverse events showed a similar pattern to that seen in adults. Tropisetron has not been shown to potentiate the adverse effects of cisplatin or other chemotherapeutic agents. Laboratory and ECG data are generally unaffected by the recommended dosage of tropisetron. Review of >80 000 patients treated with tropisetron revealed no reports of marked extrapyramidal effects. In a trial involving 201 patients, metoclopramide was associated with a significantly higher incidence of adverse events than tropisetron. In direct comparisons of tropisetron with other 5-HT3 antagonists, tolerability profiles of all agents were very similar. Tropisetron is available in capsule form (5mg) for oral administration and in ampoules containing 2 or 5mg for oral or intravenous use. The recommended dosage for oral or intravenous administration is 5mg once daily for 6 days in adults and 0.2 mg/kg (up to a maximum of 5mg) in children aged >2 years. It is recommended that tropisetron be given intravenously shortly before chemotherapy on day 1, either as an infusion (diluted) or as a slow (≥1 minute) injection, and orally each morning before food thereafter. However, oral doses may be substituted in practice for the initial intravenous dose, and therapy is generally not continued for the full 6 days because of the demonstrated equivalence with 5-HT3 receptor antagonists of single and multiple doses and oral and intravenous regimens. The combination of tropisetron and dexamethasone is more effective than monotherapy and this is expected practice with moderately to highly emetogenic chemotherapy.