SETRON

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.

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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.

Ondansetron is contraindicated in patients: known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any of the components of the formulation receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness Patients known to have hypersensitivity (e.g., anaphylaxis) to ondansetron or any components of the formulation.

Concomitant use of apomorphine.

See full prescribing information for the recommended dosage in adults and pediatrics Patients with severe hepatic impairment: do not exceed a total daily dose of 8 mg 2.1 Dosage The recommended dosage regimens for adult and pediatric patients are described in Table and Table 2, respectively.

Corresponding doses of ondansetron tablets may be used interchangeably.

Table 1: Adult Recommended Dosage Regimen for Prevention of Nausea and Vomiting Indication Dosage Regimen Highly Emetogenic Cancer Chemotherapy A single 24 mg dose administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin greater than or equal to 50 mg/m 2 Moderately Emetogenic Cancer Chemotherapy 8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8 mg dose 8 hours after the first dose.

Then administer 8 mg twice a day (every 12 hours) for to 2 days after completion of chemotherapy.

For total body irradiation: 8 mg administered to 2 hours before each fraction of radiotherapy each day. For single high-dose fraction radiotherapy to the abdomen: 8 mg administered to 2 hours before radiotherapy, with subsequent 8 mg doses every 8 hours after the first dose for to 2 days after completion of radiotherapy.

For daily fractionated radiotherapy to the abdomen: 8 mg administered to 2 hours before radiotherapy, with subsequent 8 mg doses every 8 hours after the first dose for each day radiotherapy is given.

Postoperative 16 mg administered 1 hour before induction of anesthesia.

Table 2: Pediatric Recommended Dosage Regimen for Prevention of Nausea and Vomiting Indication Dosage Regimen Moderately Emetogenic Cancer Chemotherapy to 17 years of age: 8 mg administered 30 minutes before the start of chemotherapy, with a subsequent 8 mg dose 8 hours after the first dose.

Then administer 8 mg twice a day (every 12 hours) for to 2 days after completion of chemotherapy. 4 to 11 years of age: 4 mg administered 30 minutes before the start of chemotherapy, with a subsequent 4 mg dose and 8 hours after the first dose.

Then administer 4 mg three times a day for to 2 days after completion of chemotherapy. 2.2 Dosage in Hepatic Impairment In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), do not exceed a total daily dose of 8 mg.

Ondansetron Tablets Ondansetron Tablets Ondansetron tablets

USP, 4 mg (ondansetron hydrochloride USP, equivalent to 4 mg of ondansetron) are white, round, biconvex, film coated tablets debossed “R” on one side and “153” on other side and are supplied in blistercards of 30, 15, 10, 12, and 5.

Blistercards of 30 NDC 0615-8185-39 Blistercards of 15 NDC 0615-8185-05 Blistercards of 10 NDC 0615-8185-10 Blistercards of 12 NDC 0615-8185-12 Blistercards of 5 NDC 0615-8185-00 Ondansetron tablets USP, 8 mg (ondansetron hydrochloride USP, equivalent to 8 mg of ondansetron) are yellow, round, biconvex, film coated tablets debossed “R” on one side and “154” on other side.

Ondansetron tablets

USP, 16 mg (ondansetron hydrochloride USP, equivalent to 16 mg of ondansetron) are white, round, biconvex, film coated tablets debossed “R” on one side and “155” on other side.

USP, 24 mg (ondansetron hydrochloride USP, equivalent to 24 mg of ondansetron) are pink, round, biconvex, film coated tablets debossed “R” on one side and “156” on other side.

Store at 20°-25°C (68°-77°F) .

Dispense in tight container as defined in the USP.

Store blisters in cartons.

Published epidemiological studies on the association between ondansetron use and major birth defects have reported inconsistent findings and have important methodological limitations that preclude conclusions about the safety of ondansetron use in pregnancy.

Available postmarketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes.

Reproductive studies in rats and rabbits did not show evidence of harm to the fetus when ondansetron was administered during organogenesis at approximately and 24 times the maximum recommended human oral dose of 24 mg/day, based on body surface area (BSA), respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, miscarriages, or other adverse outcomes.

In the

US general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Available data on ondansetron use in pregnant women from several published epidemiological studies preclude an assessment of a drug-associated risk of adverse fetal outcomes due to important methodological limitations, including the uncertainty of whether women who filled a prescription actually took the medication, the concomitant use of other medications or treatments, recall bias, and other unadjusted confounders.

Ondansetron exposure in utero has not been associated with overall major congenital malformations in aggregate analyses.

One large retrospective cohort study examined 1970 women who received a prescription for ondansetron during pregnancy and reported no association between ondansetron exposure and major congenital malformations, miscarriage, stillbirth, preterm delivery, infants of low birth weight, or infants small for gestational age.

Two large retrospective cohort studies and one case-control study have assessed ondansetron exposure in the first trimester and risk of cardiovascular defects with inconsistent findings.

Relative risks (RR) ranged from 0.97 (95% CI 0.86 to 1.10) to 1.62 (95% CI 1.04, 2.54).

A subset analysis in one of the cohort studies observed that ondansetron was specifically associated with cardiac septal defects (RR 2.05, 95% CI 1.19, 3.28); however, this association was not confirmed in other studies.

Several studies have assessed ondansetron and the risk of oral clefts with inconsistent findings.

A retrospective cohort study of 1.8 million pregnancies in the US Medicaid Database showed an increased risk of oral clefts among 88,467 pregnancies in which oral ondansetron was prescribed in the first trimester (RR 1.24, 95% CI 1.03, 1.48), but no such association was reported with intravenous ondansetron in 23,866 pregnancies (RR 0.95, 95% CI 0.63, 1.43).

In the subgroup of women who received both forms of administration, the RR was 1.07 (95% CI 0.59, 1.93).

Two case-control studies, using data from birth defects surveillance programs, reported conflicting associations between maternal use of ondansetron and isolated cleft palate (OR 1.6 [95% CI 1.1, 2.3] and 0.5 [95% CI 0.3, 1.0]).

It is unknown whether ondansetron exposure in utero in the cases of cleft palate occurred during the time of palate formation (the palate is formed between the 6th and 9th weeks of pregnancy).

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of ondansetron up to 15 mg/kg/day and 30 mg/kg/day, respectively, during the period of organogenesis.

With the exception of a slight decrease in maternal body weight gain in the rabbits, there were no significant effects of ondansetron on the maternal animals or the development of the offspring.

At doses of 15 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal exposure margin was approximately and 24 times the maximum recommended human oral dose of 24 mg/day, respectively, based on BSA.

In a pre-and postnatal developmental toxicity study, pregnant rats received oral doses of ondansetron up to 15 mg/kg/day from Day of pregnancy to litter Day 21.

With the exception of a slight reduction in maternal body weight gain, there were no effects upon the pregnant rats and the pre-and postnatal development of their offspring, including reproductive performance of the mated F1 generation.

At a dose of 15 mg/kg/day in rats, the maternal exposure margin was approximately 6 times the maximum recommended human oral dose of 24 mg/day, based on BSA.

The safety and effectiveness of orally administered ondansetron have been established in pediatric patients 4 years and older for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

Use of ondansetron in these age-groups is supported by evidence from adequate and well-controlled studies of ondansetron in adults with additional data from 3 open-label, uncontrolled, non-US trials in 182 pediatric patients aged to 18 years with cancer who were given a variety of cisplatin or noncisplatin regimens.

Additional information on the use of ondansetron in pediatric patients may be found in ondansetron Injection prescribing information.

• prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy.

• prevention of nausea and vomiting associated with radiotherapy.

• prevention of postoperative nausea and/or vomiting.

Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US-and foreign-controlled clinical trials, for which there were subgroup analyses, 938 (19%) were aged 65 years and older.

No overall differences in safety or effectiveness were observed between subjects 65 years of age and older and younger subjects.

A reduction in clearance and increase in elimination half-life were seen in patients older than 75 years compared with younger subjects.

There were an insufficient number of patients older than 75 years of age and older in the clinical trials to permit safety or efficacy conclusions in this age-group.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No dosage adjustment is needed in elderly patients.