12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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-hydroxyindoleacetic acid (5-HIAA) 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.

12.2 Pharmacodynamics

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. Multiday administration of ondansetron has been shown to slow colonic transit in healthy subjects. Ondansetron has no effect on plasma prolactin concentrations.

Cardiac Electrophysiology

QTc interval prolongation was studied in a double-blind, single-intravenous dose, placebo-and positive-controlled, crossover trial in 58 healthy subjects. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline correction was 19.5 (21.8) milliseconds and 5.6 (7.4) milliseconds after 15minute intravenous infusions of 32 mg and 8 mg of ondansetron injection, respectively. A significant exposure-response relationship was identified between ondansetron concentration and ΔΔQTcF. Using the established exposure-response relationship, 24 mg infused intravenously over 15 minutes had a mean predicted (95% upper prediction interval) ΔΔQTcF of 14.0 (16.3) milliseconds. In contrast, 16 mg infused intravenously over 15 minutes using the same model had a mean predicted (95% upper prediction interval) ΔΔQTcF of 9.1 (11.2) milliseconds. In this study, the 8 mg dose infused over 15 minutes did not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption
Ondansetron is 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. The area under curve (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.

Food Effects: Bioavailability is also slightly enhanced by the presence of food.

Distribution
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.

Elimination

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

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.

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

Specific Populations
Age: Geriatric Population: A reduction in clearance and increase in elimination half-life are seen in patients older than 75 years compared to younger subjects [see Use in Specific Populations (8.5)].

Sex: Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of absorption are 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 concentrations. These higher plasma concentrations may in part be explained by differences in body weight between men and women. It is not known whether these sex-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables 5 and 6.

Table 5: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of a Ondansetron 8 mg Tablet

Age- group ** (years)** ** Sex (M/F)**	** 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	69.0 62.7	6 5	26.2 42.7	2.0 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	78.0 67.6	5 6	37.0 46.1	22 21	4.5 6.2	0.277 0.249	0.619 0.747

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Table 6: Pharmacokinetics in Male and Female Healthy Subjects After a Single Dose of a Ondansetron 24 mg Tablet

Age- group ** (years)** ** Sex (M/F)**	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

Renal Impairment: Renal impairment is not expected to significantly influence the total clearance of ondansetron as renal clearance represents only 5% of the overall clearance. However, the mean plasma clearance of ondansetron was reduced by about 50% in patients with severe renal impairment (creatinine clearance less than 30 mL/min). The reduction in clearance was variable and not consistent with an increase in half-life [see Use in Specific Populations (8.7)].

Hepatic Impairment: In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared with 5.7 hours in healthy subjects. In patients with severe hepatic impairment (Child-Pugh 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 [see Dosage and Administration (2.2), Use in Specific Populations (8.6)].

Drug Interaction Studies

CYP3A4 Inducers: Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic trial of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, a reduction in AUC, Cmax, and t½ of ondansetron was observed. This resulted in a significant increase in the clearance of ondansetron. However, this increase is not thought to be clinically relevant [see Drug Interactions (7.2)]. Chemotherapeutic Agents: Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron [see Drug Interactions (7.4)].

Antacids: Concomitant administration of antacids does not alter the absorption of ondansetron.****

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14 CLINICAL STUDIES

14.1 Prevention of Chemotherapy-Induced Nausea and Vomiting

Highly Emetogenic Chemotherapy
In 2 randomized, double-blind, monotherapy trials, a single 24 mg oral dose of ondansetron tablets was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m2. Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose greater than or equal to 50 mg/m2 in the historical-placebo comparator, experienced vomiting in the absence of antiemetic therapy.

The first trial compared oral doses of ondansetron 24 mg as a single dose, 8 mg every 8 hours for 2 doses, and 32 mg as a single dose in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin greater than or equal to 50 mg/m2. The first or single dose was administered 30 minutes prior to chemotherapy. A total of 66% of patients in the ondansetron 24 mg once-a- day group, 55% in the ondansetron 8 mg twice-a-day group, and 55% in the ondansetron 32 mg once-a-day group, completed the 24-hour trial period with 0 emetic episodes and no rescue antiemetic medications, the primary endpoint of efficacy. Each of the 3 treatment groups was shown to be statistically significantly superior to a historical placebo control.

In the same trial, 56% of patients receiving a single 24 mg oral dose of ondansetron experienced no nausea during the 24-hour trial period, compared with 36% of patients in the oral ondansetron 8 mg twice-a-day group (P = 0.001) and 50% in the oral ondansetron 32 mg once-a-day group. Dosage regimens of ondansetron tablets 8 mg twice daily and 32 mg once daily are not recommended for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy [see Dosage and Administration (2.1)].

In a second trial, efficacy of a single 24 mg oral dose of ondansetron tablets for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m2, was confirmed.

Moderately Emetogenic Chemotherapy

A randomized, placebo-controlled, double-blind trial was conducted in the US in 67 patients receiving a cyclophosphamide-based chemotherapy regimen containing doxorubicin. The first 8 mg dose of ondansetron tablets was administered 30 minutes before the start of chemotherapy, with a subsequent dose 8 hours after the first dose, followed by 8 mg of ondansetron tablets twice a day for 2 days after the completion of chemotherapy.

Ondansetron tablets were significantly more effective than placebo in preventing vomiting. Treatment response was based on the total number of emetic episodes over the 3-day trial period. The results of this trial are summarized in Table 7:

Table 7: Emetic Episodes - Treatment Response in Patients Receiving Moderately Emetogenic Chemotherapy (Cyclophosphamide-based Regimen Containing Doxorubicin)

a Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes. b Median undefined since at least 50% of patients did not have any emetic episodes.
	Ondansetron ** Tablets** ** (n = 33)**	Placebo ** (n = 34)**	P**** Value****
Treatment response 0 Emetic episodes 1 to 2 Emetic episodes More than 2 emetic episodes/withdrawn	20 (61%) 6 (18%) 7 (21%)	2 (6%) 8 (24%) 24 (71%)	<0.001 <0.001
Median number of emetic episodes	0.0	Undefineda
Median time to first emetic episode (hours)	Undefined b	6.5

In a double-blind US trial in 336 patients receiving a cyclophosphamide-based chemotherapy regimen containing either methotrexate or doxorubicin, ondansetron tablets 8 mg administered twice a day, was as effective as ondansetron tablets 8 mg administered 3 times a day in preventing nausea and vomiting. Ondansetron Tablets 8 mg three times daily is not a recommended regimen for the treatment of moderately emetogenic chemotherapy [see Dosage and Administration (2.1)].

Treatment response was based on the total number of emetic episodes over the 3-day trial period. See Table 8 for the details of the dosage regimens studied and results of this trial.

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Table 8: Emetic Episodes: Treatment Response After Ondansetron Tablets Administered Twice a Day and Three Times a Day

a The first 8 mg dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent 8 mg dose 8 hours after the first dose, followed by 8 mg administered twice a day for 2 days after the completion of chemotherapy. b The first 8 mg dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent 8 mg doses at 4 hours and 8 hours after the first dose, followed by 8 mg administered 3 times a day for 2 days after the completion of chemotherapy. c Median undefined since at least 50% of patients did not have any emetic episodes. d Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.
	Ondansetron Tablets
	8 mg Twice Daily****a (n = 165)	8 mg Three Times a Day****b (n = 171)
Treatment response 0 Emetic episodes 1-2 Emetic episodes More than 2 emetic episodes/withdrawn	101 (61%) 16 (10%) 48 (29%)	99 (58%) 17 (10%) 55 (32%)
Median number of emetic episodes	0.0	0.0
Median time to first emetic episode (h)	Undefined c	Undefined c
Median nausea scores (0-100)d	6	6

Re-treatment

In single-arm trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ondansetron tablets 8 mg three times daily during subsequent chemotherapy for a total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) of the re-treatment courses, and only 1 to 2 emetic episodes occurred in 43 (11%) of the re-treatment courses.

Pediatric Trials
Three open-label, single-arm, non-US trials have been performed with 182 pediatric patients aged 4 to 18 years with cancer who were given a variety of cisplatin or non cisplatin regimens. The initial dose of ondansetron tablets injection ranged from 0.04 to 0.87 mg per kg (total dose of 2.16 mg to 12 mg) followed by the administration of oral doses of ondansetron tablets ranging from 4 to 24 mg daily for 3 days. In these trials, 58% of the 170 evaluable patients had a complete response (no emetic episodes) on Day 1. In 2 trials the response rates to ondansetron tablets 4 mg three times a day in patients younger than 12 years was similar to ondansetron tablets 8 mg three times daily in patients 12 to 18 years. Prevention of emesis in these pediatric patients was essentially the same as for adults.

14.2 Radiation-Induced Nausea and Vomiting

Total Body Irradiation

In a randomized, placebo-controlled, double-blind trial in 20 patients, 8 mg of ondansetron tablets administered 1.5 hours before each fraction of radiotherapy for 4 days was significantly more effective than placebo in preventing vomiting induced by total body irradiation. Total body irradiation consisted of 11 fractions (120 cGy per fraction) over 4 days for a total of 1,320 cGy. Patients received 3 fractions for 3 days, then 2 fractions on Day 4.

Single High-dose Fraction Radiotherapy

In an active-controlled, double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of greater than or equal to 80 cm2 to the abdomen, ondansetron tablets was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes). Patients received the first dose of ondansetron tablets (8 mg) or metoclopramide (10 mg) 1 to 2 hours before radiotherapy. If radiotherapy was given in the morning, 8 mg of ondansetron tablets or 10 mg of metoclopramide was administered in the late afternoon and repeated again before bedtime. If radiotherapy was given in the afternoon, patients took 8 mg of ondansetron tablets or 10 mg of metoclopramide only once before bedtime. Patients continued the doses of oral medication three times daily for 3 days.

Daily Fractionated Radiotherapy
In an active-controlled, double-blind trial in 135 patients receiving a 1-to 4-week course of fractionated radiotherapy (180 cGy doses) over a field size of greater than or equal to 100 cm2 to the abdomen, ondansetron tablets was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes). Patients received the first dose of ondansetron tablets (8 mg) or prochlorperazine (10 mg) 1 to 2 hours before the first daily radiotherapy fraction, with subsequent 8 mg doses approximately every 8 hours on each day of radiotherapy.

14.3 Postoperative Nausea and/or Vomiting

In two placebo-controlled, double-blind trials (one conducted in the US and the other outside the US) in 865 females undergoing inpatient surgical procedures, ondansetron tablets 16 mg as a single dose or placebo was administered one hour before the induction of general balanced anesthesia (barbiturate, opioid, nitrous oxide, neuromuscular blockade, and supplemental isoflurane or enflurane), ondansetron tablets were significantly more effective than placebo in preventing postoperative nausea and vomiting.
No trials have been performed in males.