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Cytotoxic chemotherapy and radiotherapy are associated with the release of serotonin (5-HT) from enterochromaffin cells of the small intestine, presumably initiating a vomiting reflex through stimulation of 5-HT3 receptors located on vagal afferents. Ondansetron may block the initiation of this reflex. Activation of vagal afferents may also cause a central release of serotonin from the chemoreceptor trigger zone of the area postrema, located on the floor of the fourth ventricle. Thus, the antiemetic effect of ondansetron is probably due to the selective antagonism of 5-HT3 receptors on neurons located in either the peripheral or central nervous systems, or both.
The mechanisms of ondansetron's antiemetic action in post-operative nausea and vomiting are not known.
Pharmacodynamics: In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P450 enzymes, including CYP1A2, CYP2D6 and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 enzyme deficiency) will be compensated by others and may result in little change in overall rates of ondansetron clearance.
Electrocardiography: The effect of ondansetron on the QTc interval was evaluated in a double blind, randomized, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron was tested at single doses of 8 mg and 32 mg infused intravenously over 15 minutes. At the highest tested dose of 32 mg, prolongation of the Fridericia-corrected QTc interval (QT/RR0.33 = QTcF) was observed from 15 min to 4 h after the start of the 15-minute infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 19.6 (21.5) msec at 20 min. At the lower tested dose of 8 mg, QTc prolongation was observed from 15 min to 1 h after the start of the 15-minute infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 5.8 (7.8) msec at 15 min. The magnitude of QTc prolongation with ondansetron is expected to be greater if the infusion rate is faster than 15 minutes. The 32 mg IV dose of ondansetron must not be administered.
No treatment-related effects on the QRS duration or the PR interval were observed at either the 8 mg or 32 mg dose. (See Figure 1.)
Click on icon to see table/diagram/imageAn ECG assessment study has not been performed for orally administered ondansetron hydrochloride. On the basis of pharmacokinetic-pharmacodynamic modelling, an 8 mg oral dose of ondansetron hydrochloride is predicted to cause a mean QTcF increase of 0.7 ms (90% CI -2.1, 3.3) at steady-state, assuming a mean maximal plasma concentration of 24.7 ng/mL (95% CI 21.1, 29.0).
The magnitude of QTc prolongation at the recommended 5 mg/m2 dose in pediatrics has not been studied, but pharmacokinetic-pharmacodynamic modelling predicts a mean increase of 6.6 ms (90% CI 2.8, 10.7) at maximal plasma concentrations.
Clinical Trials: Pivotal Comparative Bioavailability Studies: A comparative bioavailability study was performed of Pharmascience Inc., pms-ONDANSETRON (ondansetron hydrochloride) 8 mg tablets, versus the reference product, GlaxoSmithKline Inc., ZOFRAN 8 mg tablets, under fasting conditions. The results are summarized in the following table: See Table 1.
Click on icon to see table/diagram/imageStudy Results: Clinical trial results showing the number and percentage of patients exhibiting a complete response to ondansetron (0 emetic episodes) are shown in the following tables for both post-operative and chemotherapy induced emesis. (See Tables 2, 3 and 4.)
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Click on icon to see table/diagram/imageDetailed Pharmacology: Animal Pharmacology: Pharmacodynamics: The ferret provides an excellent model for demonstrating the antiemetic action of drugs. Emesis can be induced by antineoplastic drugs or whole-body irradiation. Behavioural changes associated with these treatments are noted in these animals and may also provide a parallel for the human experience of nausea.
The antiemetic action of ondansetron has been evaluated in both male and female ferrets given cisplatin (9 to 10 mg/kg), cyclophosphamide (200 mg/kg) or irradiation (2 and 8 Gy, 250 kV). IV doses of ondansetron (0.1 to 1 mg/kg) abolished cisplatin-induced emesis for up to 2 hours. In cyclophosphamide-induced emesis, subcutaneous doses of 0.5 mg/kg ondansetron completely eliminated vomiting, significantly reduced retching and delayed the onset of these responses.
The radiation-induced emesis, 0.5 mg/kg ondansetron alone completely and rapidly eliminated retching and vomiting.
The antiemetic effects of ondansetron (0.1 mg/kg) in combination with dexamethasone (2 to 5 mg/kg) were potentiated in ferrets with cyclophosphamide-induced emesis, compared with ondansetron alone. Ondansetron with dexamethasone produced a significant reduction in retching (65%) and vomiting (72%).
Serotonin receptors of the 5-HT3 type are present both peripherally and on vagal nerve terminals. Ondansetron probably acts by preventing activation of these receptors or receptors located in other regions of the central nervous system. Both the peripheral and central nervous systems appear to be involved since both abdominal vagotomy and microinjection of ondansetron and other 5-HT3 antagonists directly into the area postrema eliminate cisplatin-induced emesis, while 5-HT1-like (methiothepin maleate) and 5-HT2 (ketanserin) antagonists have no effect.
Ondansetron is highly selective for 5-HT3 receptors and shows negligible binding to other receptors such as 5-HT1-like, 5-HT2, α1 and α2 adrenoceptors, β1 and β2 adrenoceptors, D1 and D2 muscarinic, nicotinic, GABAA, H1 and H2 receptors.
The pharmacological specificity of ondansetron may explain the observed lack of extrapyramidal side effects often seen following similar therapy with metoclopramide, which preferentially binds to dopamine receptors of the D2 subtype.
Among its secondary effects, ondansetron has also been shown to cause a dose-dependent increase in the rate of gastric emptying in the guinea pig, which is significant at doses of 0.01 to 0.1 mg/kg. As gastric stasis is frequently associated with nausea, stimulation of gastric motility may be a beneficial action of ondansetron. In the cat, dog and monkey, ondansetron has little effect on heart rate, blood pressure or ECG at IV doses up to 3 mg/kg.
A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of hERG potassium channels at clinically relevant concentrations. Dose-dependent QT prolongation has been observed in a thorough QT study in human volunteers (see Electrocardiography as previously mentioned).
Pharmacokinetics: In mice, rats, rabbits and dogs dosed at 1 mg/kg orally and/or intravenously, the plasma half-life of ondansetron was less than 1 hour, but the half-lives of its metabolites were significantly longer. Peak plasma concentrations of ondansetron in rats and dogs ranged from 351 to 419 ng/mL for the IV dose and 8 to 15 ng/mL for the oral dose. Plasma levels were linear over a 30-fold dose range. In repeat-dose studies there was no apparent accumulation of ondansetron.
Ondansetron is almost completely absorbed in animals, and is rapidly metabolized by N-demethylation and hydroxylation of the indole ring, followed by conjugation with glucuronic acid and sulphate. There is significant first-pass metabolism after oral doses.
Ondansetron and its metabolites are rapidly and widely distributed in tissues, reaching higher levels than the corresponding plasma levels. In the rat and dog, ondansetron binds reversibly to tissues containing melanin and elastin. In rats and man, plasma protein binding is about 73%, while it is slightly lower in the dog (60%). Ondansetron and its metabolites cross the blood-brain barrier to only a slight extent.
Human Pharmacology: Pharmacodynamics: In vivo pharmacodynamic studies have investigated the effects of ondansetron on gastric emptying, small bowel transit time and oesophageal motility.
Both oral (16 mg t.i.d) and IV (5 to 10 mg) doses of ondansetron failed to produce a significant effect on gastric emptying in both healthy volunteers and in patients suffering from delayed gastric emptying. However, in one study IV doses of 8 mg did increase gastric emptying in over half the volunteers tested.
IV infusion of either 1 mg or 5 mg ondansetron tended to increase small bowel transit times and single IV doses of 10 mg ondansetron have been reported to decrease sphincter pressure in the lower oesophagus in some subjects.
In psychomotor testing ondansetron does not impair performance nor cause sedation.
Pharmacokinetics: Pharmacokinetic studies in human volunteers showed peak plasma levels of 20 to 30 ng/mL at around 1.5 hours after an 8 mg oral dose of ondansetron. An 8 mg infusion of ondansetron resulted in peak plasma levels of 80 to 100 ng/mL. Repeat dosing of an 8 mg tablet every 8 hours for 6 days increased the peak plasma value to 40 ng/mL. A continuous IV infusion of 1 mg/hour after the initial 8 mg loading dose of ondansetron maintained plasma levels over 30 ng/mL during the following 24-hour period.
The absolute bioavailability of ondansetron in humans was approximately 60% and the plasma protein binding was approximately 73%.
Following oral or IV administration, ondansetron is extensively metabolised and excreted in the urine and faeces. In humans, less than 10% of the dose is excreted unchanged in the urine. The major urinary metabolites are glucuronide conjugates (45%), sulphate conjugates (20%) and hydroxylation products (10%).
The half-life of ondansetron after either an 8 mg oral dose or IV dose was approximately 3 to 4 hours and may be extended to 6 to 8 hours in the elderly.
Mean plasma concentration-time curves for ondansetron following 8 mg and 32 mg dose are shown as follows: See Figure 2.
Click on icon to see table/diagram/imageIn a pharmacokinetic study of 16 epileptic patients maintained chronically on carbamazepine or phenytoin, reduction in AUC, Cmax and t½ of ondansetron was observed. This resulted in a significant increase in clearance. However, on the basis of the inter-subject variability in the available data, no dosage adjustment can be recommended (see Drug-Drug Interactions under Interactions).
Early Phase I studies in healthy elderly volunteers showed a slight age-related decrease in clearance, and an increase in half-life of ondansetron. However, wide inter-subject variability resulted in considerable overlap in pharmacokinetic parameters between young (< 65 years of age) and elderly subjects (≥ 65 years of age) and there were no overall differences in safety or efficacy observed between young and elderly cancer patients enrolled in CINV clinical trials. (See Use in Elderly under Dosage & Administration.)
Based on more recent ondansetron plasma concentrations and exposure-response modeling, a greater effect on QTcF is predicted in patients ≥ 75 years of age compared to young adults. Specific dosing information is provided for patients over 65 years of age and over 75 years of age for IV dosing. (See Use in Elderly under Dosage & Administration.)
Toxicology: Acute Toxicity: Single doses of ondansetron up to the LD50 in mice and in rats were generally well-tolerated. Reactions, including tremor and convulsive behaviour, occurred only at near lethal levels. (See Table 5.)
Click on icon to see table/diagram/imageAll deaths resulted from the acute effects of treatment, the observed clinical signs being consistent with the central nervous system effects associated with behavioural depression. These effects were not associated with any apparent histopathological changes in the brain. No target organ toxicity was identified.
Long-Term Toxicity: Subacute Toxicity Studies: See Table 6.
Click on icon to see table/diagram/imageMaximum daily dose levels in rats were found to be higher when doses were gradually increased. Identical doses were rapidly lethal to rats not previously exposed to ondansetron. Post-dosing reactions, in both rats and dogs, included ataxia, exophthalmia, mydriasis, tremor and respiratory changes. Increases in liver enzymes (SGPT and SGOT) were noted at high dose levels. Dogs dosed at 6.75 mg/kg/day intravenously exhibited vein irritancy in the form of constriction and thickening, creating resistance to needle penetration. The changes were noted after seven days treatment but were reversed by decreasing the dose concentration.
Chronic Toxicity: See Table 7.
Click on icon to see table/diagram/imageCarcinogenicity Studies: See Table 8.
Click on icon to see table/diagram/imageThere was no evidence of a tumourigenic effect of ondansetron in any tissue.
Mutagenicity Studies: No evidence of mutagenicity was observed in microbial mutagen tests using mutant strains of Salmonella typhimurium, Escherichia coli or Saccharomyces cerevisiae, with or without a rat-liver post-mitochondrial metabolizing system.
There was also no evidence of damage to genetic material noted in in vitro V-79 mammalian cell mutation studies, in vitro chromosome aberration tests using human peripheral lymphocytes, or in vivo chromosome aberration assays in mouse bone marrow.
Reproduction and Teratology: Ondansetron was not teratogenic in rats and rabbits at dosages up to the maximum non-convulsive level, (rat: 15 mg/kg/day, rabbit: 30 mg/kg/day; the maternal dose was approximately 6 and 24 times the maximum recommended human oral dose of 24 mg/day, respectively, based on body surface area). No adverse effects on pregnancy or fetal and post-natal development were detected in rats and no fetal abnormalities were observed in rabbits after oral administration of ondansetron.
A slight maternal toxicity was observed at the highest dose level in IV organogenesis (4.0 mg/kg/day) studies in the rabbit. Effects included maternal body weight loss and increased incidence of early fetal death. In a rat fertility study, there was a dose-related decrease in the proportion of surviving pups of the F2 generation; however, the significance of this is unclear.
Administration of ondansetron to pregnant rats and rabbits indicated there was fetal exposure to low levels of ondansetron and its metabolites. Ondansetron is retained in the fetal eye presumably bound to melanin. In rats, the transfer of ondansetron and its metabolites into breast milk was extensive. The concentration of unchanged ondansetron in breast milk was higher than in corresponding plasma samples.
Daily administration of ondansetron at dosages up to 15 mg/kg/day to pregnant rats (a maternal dose of approximately 6 times the maximum recommended human oral dose of 24 mg/day, based on body surface area) from day 17 of pregnancy to litter day 22 had no effects on pregnancy of the parental generation or on post-natal development and mating of the F1 generation. Fetal development of the F2 generation was comparable to controls; however, the number of implantations and viable foetuses was reduced in the highest dosage group when compared with controls.
Microbiology: Not applicable.
