, Volume 41, Issue 4, pp 574–595


Therapeutic Use as an Antiemetic
  • Richard J. Milne
  • Rennie C. Heel
Drug Evaluation

DOI: 10.2165/00003495-199141040-00006

Cite this article as:
Milne, R.J. & Heel, R.C. Drugs (1991) 41: 574. doi:10.2165/00003495-199141040-00006



Ondansetron (GR 38032F) is a highly selective 5- HT3 receptor antagonist, one of a new class of compounds which may have several therapeutic applications. Animal and clinical studies show that ondansetron reduces the 24- hour incidence and severity of nausea and vomiting induced by cytotoxic drugs, including cisplatin, and by single exposure, high dose radiation. Ondansetron is more effective than high dose metoclopramide in the 24 hours following chemotherapy, and preliminary clinical evidence suggests that it is equally effective in the following 4 days. It is also more effective than the ‘moderate’ doses of metoclopramide used to suppress emesis following radiotherapy. The antiemetic efficacy of ondansetron is enhanced by dexamethasone in cisplatintreated patients. Importantly, extrapyramidal effects have not been reported with ondansetron. Further comparisons are required with standard combination antiemetic therapy to complement the data presently available.

Thus, ondansetron is a promising new agent for prophylaxis against nausea and vomiting in chemotherapy and radiotherapy. It may be particularly useful in young and elderly patients who are more susceptible to extrapyramidal symptoms induced by high dose metoclopramide. With its improved tolerability and clinical response profiles, ondansetron represents an important advance in a difficult area of therapeutics.

Pharmacodynamic Properties

Ondansetron is a new carbazole which blocks serotoninergic neurotransmission at serotonin3 (5-HT3) receptors. It is a potent, highly selective and competitive antagonist of the depolarising effects of serotonin in the rat and rabbit isolated vagus nerve and the rat superior cervical ganglion. Ondansetron blocks the depolarising effect of the 5-HT3-selective agonist 2-methyl-5-HT in longitudinal smooth muscle of guinea-pig ileum, and the Bezold-Jarisch reflex response to 2-methyl-5-HT in anaesthetised rats and cats, but has little effect on 5-HT1 and 5-HT2 mediated responses or on α1, β1 muscarinic, nicotinic, histamine1, histamine2 or GABAa receptors. In vitro, it is at least 70 times more potent than metoclopramide at peripheral 5-HT3 receptors, but has no effect on stereotyped movements induced by dopamine agonists.

In animal models parenterally administered ondansetron reduces the incidence of emetic episodes induced by radiation, cyclophosphamide and cisplatin-based chemotherapies. Since both radiation and cisplatin may release serotonin from chromaffin cells in the intestinal mucosa, and since serotonin activates vagal and possibly splanchnic afferent nerves which in turn reflexly induce nausea and vomiting, it has been proposed that ondansetron acts by blocking serotonininduced depolarisation of vagal afferent nerves. It may also block serotoninergic action in the chemoreceptor trigger zone in the area postrema and the nucleus tractus solitarius of the brainstem, which contain 5-HT3 binding sites probably located on vagal afferent nerve terminals. Ondansetron may slow colonie transit times but this effect is unrelated to its antiemetic action. It has no effect on motion sickness or on emesis induced by dopamine receptor agonists.

Pharmacokinetic Properties

Ondansetron can be administered either intravenously or orally. Following oral administration of ondansetron 8mg, peak plasma concentrations of about 30 µg/L are reached in 1 to 1.5 hours. Orally administered ondansetron is about 60% bioavailable in healthy subjects and about 75% bound to plasma proteins. The apparent volume of distribution is large (160L) and the mean elimination half-life is 3 hours. The clearance of ondansetron may be lower in the elderly. In healthy subjects 60% of a single intravenous radiolabelled dose is eliminated by the kidneys and 25% in faeces, mostly as metabolites. Clinically relevant metabolites have not been reported.

Therapeutic Use

Most clinical trials have studied the control of vomiting over the first 24 hours following chemotherapy. Ondansetron has been given either intravenously (IV) or orally, as a loading dose within the first 30 minutes IV or 1 to 2 hours orally prior to chemotherapy, followed by continuous infusion or by 2 or 3 oral or intravenous doses at intervals of 2 to 8 hours.

In a moderate size noncomparative study ondansetron (0.18 mg/kg intravenously 6- or 8-hourly) completely controlled acute vomiting induced by cisplatin-based chemotherapy in 55% of patients, and reduced the number of emetic episodes to fewer than 3 in a further 20% of patients. Ondansetron delayed the onset of emesis from a median of 2.8 hours with placebo to a median of 11.6 hours after administration of cisplatin, and reduced the incidence of emetic episodes 4-fold and the incidence of retching 3-fold during the 24 hours after administration. No cisplatin-treated patients receiving ondansetron required rescue antiemetic therapy compared with 12 of 14 receiving placebo.

Compared with metoclopramide in several studies, including 4 double-blind crossover trials, ondansetron was more effective in ameliorating nausea and vomiting on the day of chemotherapy. In the largest trial complete or major control of emesis (fewer than 3 emetic episodes in 24 hours) was achieved in 75% of patients with ondansetron compared with 42% with metoclopramide. Preliminary evidence suggests that ondansetron is as efficacious as metoclopramide in the 4 days following cisplatin chemotherapy.

In all patients included in one study, ondansetron 8mg orally three times daily provided complete or major protection against vomiting induced by single high dose upper abdominal radiotherapy, and was more effective than metoclopramide 10mg orally three times daily.


Overall, ondansetron is well tolerated by patients receiving radiotherapy or chemotherapy. The most frequently reported adverse event associated with ondansetron is headache, which responds to standard analgesics. However, it is noteworthy that in healthy subjects headache occurred as frequently in placebo recipients as in those receiving ondansetron. Mild constipation or diarrhoea occurs in a small minority of patients. Importantly, extrapyramidal effects such as those produced by metoclopramide would not be expected from the pharmacodynamic profile of ondansetron and have not been reported in clinical trials or in studies with healthy volunteers.

Dosage and Administration

When used to prevent nausea and vomiting induced by highly emetogenic chemotherapeutic regimens a loading dose of ondansetron 8mg infused 30 minutes before cancer therapy, with 2 additional 8mg doses administered at least 4 hours apart, or infusion of 1 mg/h for 24 hours, is recommended. For less emetogenic chemotherapeutic regimens, and for radiotherapy, ondansetron administered orally should be started as a loading dose (8mg) 1 to 2 hours prior to chemotherapy or radiotherapy and continued with 2 additional 8mg doses at 8-hour intervals. All regimens should be followed by 8mg orally for up to 5 days.

Copyright information

© Adis International Limited 1991

Authors and Affiliations

  • Richard J. Milne
    • 1
  • Rennie C. Heel
    • 2
  1. 1.Adis Drug Information ServicesAucklandNew Zealand
  2. 2.Adis International LimitedMairangi Bay, Auckland 10New Zealand