ONDAPHREN

A competitive serotonin type 3 receptor antagonist.

It is effective in the treatment of nausea and vomiting caused by cytotoxic chemotherapy drugs, including cisplatin, and has reported anxiolytic and neuroleptic properties.

Having been developed in the 1980s by GlaxoSmithKline and approved by the US FDA since January 1991, ondansetron has demonstrated a long history of use and efficacy.

Commonly formulated as oral tablets, Oral disintegrating tablets (ODT), and injections, and available as generic products as well, ondansetron continues to see contemporary innovations in its formulation and use, including the development of Oral soluble films that are both discreet in administration and less of a burden in comparison to having patients attempt to swallow pills during emesis.

FDA withdrew its approval for the use of all intravenous drug products containing more than 16 mg of ondansetron hydrochloride in a single dose, due to a high risk of QT prolongation. 8, 9.

In the adult patient population

Oral administered ondansetron tablets and Oral disintegrating tablets (ODT) are indicated for: the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, including high dose (ie. greater than or equal to 50 mg/m2) cisplatin therapy, and radiotherapy

Ondansetron is a highly specific and selective serotonin 5-HT 3 receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors Label, 3, 4.

The serotonin 5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema Label, 3, 4.

The temporal relationship between the emetogenic action of emetogenic drugs and the release of serotonin, as well as the efficacy of antiemetic agents, suggest that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract Label, 3, 4.

The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT 3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting Label, 3, 4.

Moreover, 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 11, 12.

Ondansetron was tested at single doses of 8 mg and 32 mg infused Intravenous over 15 minutes 11, 12.

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 min infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 19.6 msec at 20 min 11, 12.

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 msec at 15 min 11, 12.

The magnitude of

QTc prolongation with ondansetron is expected to be greater if the infusion rate is faster than 15 minutes 11, 12.

The 32 mg intravenous dose of ondansetron must not be administered 11, 12.

No treatment-related effects on the QRS duration or the PR interval were observed at either the 8 or 32 mg dose 11, 12.

An ECG assessment study has not been performed for Oral administered ondansetron 11, 12.

On the basis of pharmacokinetic-pharmacodynamic modelling, an 8 mg oral dose of ondansetron 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) 11, 12.

QTc prolongation at the recommended 5 mg/m2 dose in pediatrics has not been studied, but pharmacokinetic-pharmacodynamic modeling predicts a mean increase of 6.6 ms (90% CI 2.8, 10.7) at maximal plasma concentrations 11, 12.

In healthy subjects, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time 10.

Multiday administration of ondansetron has been shown to slow colonic transit in healthy subjects 10.

Ondansetron has no effect on plasma prolactin concentrations 10.

5-hydroxytryptamine receptor 3A Antagonist.

Ondansetron is absorbed from the gastrointestinal tract and undergoes some limited first-pass metabolism 10.

Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, was recorded as being approximately 56% to 60% 10, 11, 12.

Bioavailability is also slightly enhanced by the presence of food 10.

Ondansetron systemic exposure does not increase proportionately to dose 10.

AUC from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose 10.

This may reflect some reduction of first-pass metabolism at higher oral doses 10.

The volume of distribution of ondansetron has been recorded as being approximately 160 L 5.

In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P450 enzymes, including CYP1A2, CYP2D6 and CYP3A4 10, 11, 12.

In terms of overall ondansetron turnover, CYP3A4 played the predominant role 10, 11, 12.

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 10, 11, 12.

Following oral or

Intravenous administration, ondansetron is extensively metabolised and excreted in the urine and faeces 10, 11, 12.

In humans, less than 10% of the dose is excreted unchanged in the urine 10, 11, 12.

The major urinary metabolites are glucuronide conjugates (45%), sulphate conjugates (20%) and hydroxylation products (10%) 10, 11, 12.

The primary metabolic pathway is subsequently hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation 10, 11, 12.

Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron 10, 11, 12.

Hover over products below to view reaction partners Ondansetron 6-OH-ondansetron 7-OH-ondansetron 8-OH-ondansetron.

Following oral or

Intravenous administration, ondansetron is extensively metabolised and excreted in the urine and faeces 11, 12.

The half-life of ondansetron after either an 8 mg oral dose or intravenous dose was approximately 3-4 hours and could be extended to 6-8 hours in the elderly 11, 12.

The clearance values determined for ondansetron in various patient age groups were recorded as approximately 0.38 L/h/kg in normal adult volunteers aged 19-40 yrs, 0.32 L/h/kg in normal adult volunteers aged 61-74 yrs, 0.26 L/h/kg in normal adult volunteers aged >=75 yrs Label.

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

At present, there is little information concerning overdosage with ondansetron 10, 11, 12.

Nevertheless, there have been certain cases of somewhat idiosyncratic adverse effects associated with particular dosages of ondansetron used 10, 11, 12. “Sudden blindness” (amaurosis) of 2-3 minutes duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron Intravenous as a single dose 10, 11, 12.

Hypotension (and faintness) occurred in another patient that took 48 mg of oral ondansetron 10, 11, 12.

Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed 10, 11, 12.

Neuromuscular abnormalities, autonomic instability, somnolence, and a brief generalized tonic-clonic seizure (which resolved after a dose of benzodiazepine) were observed in a 12-month-old infant who ingested seven or eight 8-mg ondansetron tablets (approximately forty times the recommended 0.1-0.15 mg/kg dose for a pediatric patient) 10, 11, 12.

In all instances, however, the events resolved completely 10, 11, 12.

The safety of ondansetron for use in human pregnancy has not been established 11, 12.

Ondansetron is not teratogenic in animals 11, 12.

However, as animal studies are not always predictive of human response, the use of ondansetron in pregnancy is not recommended 11, 12.

Ondansetron is excreted in the milk of lactating rats 11, 12.

It is not known if it is excreted in human milk, however, nursing is not recommended during treatment with ondansetron 11, 12.

Insufficient information is available to provide dosage recommendations for children 3 years of age or younger 11, 12.