CLINICAL PHARMACOLOGY

Pharmacodynamics

Ondansetron is a selective 5-HT3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine- receptor antagonist. Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron's antiemetic action is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic acid) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the vomiting reflex.

In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or pretreatment with a serotonin 5-HT3 receptor antagonist.

In normal volunteers, 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. Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations.

Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied.

Pharmacokinetics

Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, is approximately 56%.

Ondansetron systemic exposure does not increase proportionately to dose. AUC from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses. Bioavailability is also slightly enhanced by the presence of food but unaffected by antacids.

Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. 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.

In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 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 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, Cmax, and T½ of ondansetron was observed.1 This resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment for ondansetron is recommended (**see PRECAUTIONS:**Drug Interactions).

In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.

Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of ondansetron's absorption is greater in women than men. Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron levels. These higher plasma levels may in part be explained by differences in body weight between men and women. It is not known whether these gender-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables 1 and 2 taken from 2 studies.

Table 1. Pharmacokinetics in Normal Volunteers: Single 8-mg Ondansetron Hydrochloride Tablet Dose

Age-group (years)	Mean Weight (kg)	n	Peak Plasma Concentration (ng/mL)	Time of Peak Plasma Concentration (h)	Mean Elimination Half-life (h)	Systemic Plasma Clearance L/h/kg	Absolute Bioavailability
18-40 M F	69 62.7	6 5	26.2 42.7	2 1.7	3.1 3.5	0.403 0.354	0.483 0.663
61-74 M F	77.5 60.2	6 6	24.1 52.4	2.1 1.9	4.1 4.9	0.384 0.255	0.585 0.643
≥75 M F	78 67.6	5 6	37 46.1	2.2 2.1	4.5 6.2	0.277 0.249	0.619 0.747

Table 2. Pharmacokinetics in Normal Volunteers: Single 24-mg Ondansetron Hydrochloride Tablet Dose

Age-group (years)	Mean Weight (kg)	n	Peak Plasma Concentration (ng/mL	Time of Peak Plasma Concentration (h)	Mean Elimination Half-life (h)
18-43 M F	84.1 71.8	8 8	125.8 194.4	1.9 1.6	4.7 5.8

A reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy was similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly.

In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.

Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of ondansetron. However, ondansetron oral mean plasma clearance was reduced by about 50% in patients with severe renal impairment (creatinine clearance less than 30 mL/min). This reduction in clearance is variable and was not consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is warranted.

Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes.

Four- and 8-mg doses of either ondansetron hydrochloride oral solution or ondansetron orally disintegrating tablets are bioequivalent to corresponding doses of ondansetron hydrochloride tablets and may be used interchangeably. One 24-mg ondansetron hydrochloride tablet is bioequivalent to and interchangeable with three 8-mg ondansetron hydrochloride tablets.

DOSAGE AND ADMINISTRATION

Instructions for Use/Handling Ondansetron Orally Disintegrating Tablets

Do not attempt to push ondansetron orally disintegrating tablets through the foil backing. With dry hands, PEEL BACK the foil backing of 1 blister and GENTLY remove the tablet. IMMEDIATELY place the ondansetron orally disintegrating tablet on top of the tongue where it will dissolve in seconds, then swallow with saliva. Administration with liquid is not necessary.

Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer Chemotherapy

The recommended adult oral dosage of ondansetron hydrochloride tablets is 24-mg administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin ≥ 50 mg/m2. Multiday, single-dose administration of a 24 mg dosage has not been studied.

** Pediatric Use**

There is no experience with the use of 24-mg dosage in pediatric patients.

** Geriatric Use**

The dosage recommendation is the same as for the general population.

Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy

The recommended adult oral dosage is one 8-mg ondansetron hydrochloride tablet or one 8-mg ondansetron orally disintegrating tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ondansetron hydrochloride oral solution given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose.

One 8-mg ondansetron hydrochloride tablet or one 8-mg ondansetron orally disintegrating tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ondansetron hydrochloride oral solution should be administered twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.

** Pediatric Use**

For pediatric patients 12 years of age and older, the dosage is the same as for adults. For pediatric patients 4 through 11 years of age, the dosage is one 4-mg ondansetron hydrochloride tablet or one 4-mg ondansetron orally disintegrating tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of ondansetron hydrochloride oral solution given 3 times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 4-mg ondansetron hydrochloride tablet or one 4-mg ondansetron orally disintegrating tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of ondansetron hydrochloride oral solution should be administered 3 times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy.

** Geriatric Use**

The dosage is the same as for the general population.

Prevention of Nausea and Vomiting Associated With Radiotherapy, Either Total Body Irradiation, or Single High-Dose Fraction or Daily Fractions to the Abdomen

The recommended oral dosage is one 8-mg ondansetron hydrochloride tablet or one 8-mg ondansetron orally disintegrating tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ondansetron hydrochloride oral solution given 3 times a day.

For total body irradiation, one 8-mg ondansetron hydrochloride tablet or one 8-mg ondansetron orally disintegrating tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ondansetron hydrochloride oral solution should be administered 1 to 2 hours before each fraction of radiotherapy administered each day.

For single high-dose fraction radiotherapy to the abdomen, one 8-mg ondansetron hydrochloride tablet or one 8-mg ondansetron orally disintegrating tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ondansetron hydrochloride oral solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy.

For daily fractionated radiotherapy to the abdomen, one 8-mg ondansetron hydrochloride tablet or one 8-mg ondansetron orally disintegrating tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ondansetron hydrochloride oral solution should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given.

** Pediatric Use**

There is no experience with the use of ondansetron hydrochloride tablets, ondansetron orally disintegrating tablets, or ondansetron hydrochloride oral solution in the prevention of radiation-induced nausea and vomiting in pediatric patients.

** Geriatric Use**

The dosage recommendation is the same as for the general population.

Postoperative Nausea and Vomiting

The recommended dosage is 16 mg given as two 8-mg ondansetron hydrochloride tablets or two 8-mg ondansetron orally disintegrating tablets or 20 mL (4 teaspoonfuls equivalent to16 mg of ondansetron) of ondansetron hydrochloride oral solution 1 hour before induction of anesthesia.

** Pediatric Use**

There is no experience with the use of ondansetron hydrochloride tablets, ondansetron orally disintegrating tablets, or ondansetron hydrochloride oral solution in the prevention of postoperative nausea and vomiting in pediatric patients.

** Geriatric Use**

The dosage is the same as for the general population.

Dosage Adjustment for Patients With Impaired Renal Function

The dosage recommendation is the same as for the general population. There is no experience beyond first-day administration of ondansetron.

Dosage Adjustment for Patients With Impaired Hepatic Function

In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life. In such patients, a total daily dose of 8 mg should not be exceeded.