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Ondansetron is a selective 5-HT3 receptor antagonist which has previously been reported in the Journal to be a promising new agent for use as prophylaxis against nausea and vomiting caused by chemotherapy and radiotherapy. Since the publication of this original review, further studies have been published that show ondansetron to be an effective antiemetic agent in patients receiving chemotherapy and radiotherapy. Several studies have shown ondansetron to be a more effective antiemetic agent than high-dose metoclopramide in patients with emesis induced by high- and low-dose cisplatin treatment, and noncisplatin chemotherapy-induced emesis. The drug as monotherapy does not appear to offer any advantage over alternative therapies against delayed high-dose cisplatin-induced nausea and vomiting; however, extremely limited data suggest that ondansetron plus dexamethasone may be useful in this indication.
Trials have shown combination therapy with ondansetron and dexamethasone to be significantly more effective than both ondansetron monotherapy and a standard antiemetic regimen comprising metoclopramide, dexamethasone and diphenhydramine against acute high-dose cisplatin-induced emesis.
Results from a number of small scale trials suggest that ondansetron may be an effective treatment for chemotherapy-induced emesis refractory to conventional antiemetic therapy. Ondansetron also appears to be more effective against refractory emesis induced by noncisplatin chemotherapy than that induced by cisplatin chemotherapy.
Several trials have shown ondansetron to be more effective than placebo as prophylaxis against postoperative nausea and vomiting; a further trial has shown single-dose ondansetron to be significantly more effective than single-dose droperidol or metoclopramide in this indication. In addition, several trials have shown ondansetron to be more effective than placebo as treatment for nausea and vomiting that has commenced postoperatively.
The overall incidence of adverse events in ondansetron recipients during chemotherapy-induced emesis studies was 36%. Headache and constipation are the most common adverse events during ondansetron therapy.
Thus, recent data affirms the efficacy of ondansetron in the treatment of acute chemotherapy-induced nausea and vomiting and shows it to be especially efficacious when combined with dexamethasone. It appears that the drug will also have a substantial role in the prophylaxis and treatment of postoperative nausea and vomiting.
Ondansetron is a carbazole which produces antiemetic and antinauseant effects via competitive and selective antagonism of serotonin3 (5-HT3) receptors. The drug has no clinically relevant effects on 5-HT1- and 5-HT2-mediated responses or α1, β1, muscarinic, nicotinic, histamine1 and GABAA receptors. Ondansetron is more than 70-fold more active than metoclopramide at peripheral 5-HT3 receptors. It has been proposed that ondansetron exerts its antiemetic and antinauseant effects via blockade of serotonin-induced depolarisation of vagal afferent nerves. Blockade of 5-HT3 binding sites in the chemoreceptor trigger zone and the nucleus tractus solitarius of the brainstem may also be involved.
A peak plasma ondansetron concentration of approximately 30 μg/L occurs 1 to 1.5 hours after oral administration of an 8mg dose. The drug is about 60% bioavailable following oral administration to healthy volunteers and is 70 to 76% protein bound. The apparent volume of distribution is 160L and the mean elimination half-life is 3 hours. Ondansetron undergoes extensive hepatic metabolism, and renal clearance accounts for less than 5% of the total clearance.
Several dose-finding studies have now shown that ondansetron administered as a single 8 to 32mg intravenous dose is as effective as formerly recommended multiple administration or infusion regimens of the drug in patients receiving chemotherapy with high doses (50 to 120 mg/m2) of cisplatin.
Several investigations have shown ondansetron to be at least as effective as high-dose metoclopramide for the treatment of high-dose cisplatin-induced emesis and to have a less troublesome adverse effect profile. In one large controlled trial, ondansetron and metoclopramide completely controlled vomiting in 54/136 (40%) and 41/138 (30%) evaluable patients, respectively.
Several well controlled trials have shown combination therapy with ondansetron and dexamethasone to be significantly more effective than ondansetron alone against acute high-dose cisplatin-induced emesis. The same combination has been shown to be significantly more effective than a standard antiemetic regimen comprising metoclopramide, dexamethasone and diphenhydramine.
The efficacy of oral ondansetron against delayed high-dose cisplatin-induced emesis has been evaluated in a phase II study. Ondansetron completely controlled delayed nausea in only 3 (15%) patients over the entire study period. A further study has failed to find a significant difference between placebo and ondansetron with regard to overall complete control of vomiting.
Data regarding the antiemetic efficacy of ondansetron in patients receiving low repeated doses of cisplatin are limited. However, 2 double-blind studies have shown ondansetron, either alone or in combination with dexamethasone, to control emesis more effectively than metoclopramide (alone or in combination with dexamethasone) in this indication.
Results from a number of small scale trials suggest that ondansetron may be an effective treatment for chemotherapy-induced emesis refractory to conventional antiemetic therapy. Oral ondansetron 8mg three times a day also has been shown to be an effective antiemetic in patients undergoing fractionated upper abdominal radiation.
Ondansetron has been investigated as treatment for postoperative nausea and vomiting. The drug has been studied either as prophylaxis prior to surgery or as rescue antiemetic therapy after vomiting has commenced postoperatively. Ondansetron 8 and 16mg orally have been shown to prevent postoperative nausea and vomiting significantly more effectively than placebo and ondansetron 1mg. Controlled trials to date have shown ondansetron to control postoperative vomiting significantly more effectively than placebo in women undergoing gynaecological procedures. A further study has shown a single 8mg intravenous dose of ondansetron administered prior to induction of anaesthesia to significantly reduce postoperative emesis compared with placebo in men and women undergoing thyroid surgery. A double-blind trial has shown ondansetron to be significantly more effective than droperidol or metoclopramide as prophylaxis against postoperative vomiting in women undergoing dilatation and curettage.
Additional double-blind placebo-controlled trials have shown intravenous ondansetron to be an effective rescue antiemetic for patients who develop postoperative nausea and vomiting.
Headache and constipation are the most common adverse effects experienced by patients receiving ondansetron. Of these, headache is more prevalent.
Overall, 36% of ondansetron recipients participating in single dose comparative chemotherapy-induced emesis studies experienced adverse events compared with 50, 41 and 23% of metoclopramide, placebo and dexamethasone recipients, respectively.
Headache, dizziness and drowsiness were the most commonly reported adverse effects in patients who participated in US-based postoperative nausea and vomiting trials. These events occurred with similar frequency in both ondansetron and placebo recipients.
Recently, there have been isolated case reports of extrapyramidal reactions possibly attributable to ondansetron.
Dosage and Administration
Based on recent dose-finding studies, a single dose of intravenous ondansetron 8 to 32mg can now be recommended for patients about to undergo highly emetogenic chemotherapy.
In patients undergoing moderately emetogenic chemotherapy and high-dose radiotherapy, ondansetron 8mg can be given either intravenously or orally immediately prior to treatment, or 1 to 2 hours prior to treatment, respectively, followed by 8mg orally every 12 hours.
Studies evaluating the efficacy of ondansetron as prophylaxis against postoperative nausea and vomiting have used either oral or intravenous routes of administration. Based on dose-finding studies evaluating 1, 8 and 16mg doses, 4mg intravenously appears to be the optimal dose. Studies with orally administered ondansetron for the prevention of postoperative nausea and vomiting have found that 8mg three times daily is the optimal dose for this indication. An intravenous 4mg dose appears to be optimal as treatment for nausea and vomiting occurring after surgery.
The recommended ondansetron dose for children is 5 mg/m2 intravenously before chemotherapy, 4mg orally 12 hours thereafter followed by 4mg orally twice a day for ⩽5 days.
Adjustment of ondansetron dosage and frequency of administration is not required in elderly patients or those with renal impairment. However, the total daily dose should not exceed 8mg in patients with moderate to severe hepatic impairment.
KeywordsOndansetron Metoclopramide Postoperative Nausea Emetogenic Chemotherapy Antiemetic Regimen
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