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Zuplenz

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Zuplenz

CLINICAL PHARMACOLOGY

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-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

Pharmacodynamics

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

Absorption

Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. After a single dose of ZUPLENZ (ondansetron) oral soluble film 8 mg under fasting conditions (n=46), the peak plasma concentrations were achieved in 1.3 hours and the mean elimination half-life was 4.6 hours in healthy subjects. The mean (±S.D.) Cmax and AUC were 37.28 (±14.9) ng/mL and 225 (±88.1) ng·h/mL, respectively. In the same study, mean ondansetron Cmax and AUC following administration of 8 mg ZUPLENZ oral soluble film were comparable to those after 8 mg ondansetron ODT (orally disintegrating tablet). The systemic exposure after administration of ZUPLENZ oral soluble film 8 mg with or without water was found to be comparable.

In a study using ondansetron tablets, ondansetron systemic exposure did 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.

Food Effect

When administered with a high fat meal, 8 mg ZUPLENZ (ondansetron) oral soluble film's mean time to peak plasma concentration (tmax) was delayed by approximately 1 hour and its AUC remained similar compared to that of under fasted stated.

Metabolism and Drug Interactions

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 observed1; this resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment for ondansetron is recommended.

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

Excretion

Ondansetron and its metabolites are eliminated via the urine.

Gender Effects

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. It is not known whether these gender-related differences are clinically important.

Table 4: Mean Pharmacokinetic Parameters by Gender in Healthy Volunteers After A Single 8 mg

Gender Mean Weight (kg) n C vmax (ng/mL) Tmax (h) T½ (h) AUC (h•ng/mL)
M 62 39 35.2 1.67 4.54 207
F 56.7 7 49.1 1.7 5.39 323

Elderly

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.

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 to 5.7 hours in healthy subjects. In patients with severe hepatic impairment (Child-Pugh score of 10 or greater)2, 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.

Renal Impairment

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 < 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.

Protein Binding

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.

Clinical Studies

The clinical efficacy of ondansetron, the active ingredient of ZUPLENZ, was assessed in clinical trials as described below.

Chemotherapy-Induced Nausea and Vomiting

Highly Emetogenic Chemotherapy

In 2 randomized, double-blind, monotherapy trials, a single 24 mg ondansetron HCl tablet was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m². Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose ≥ 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 once a day, 8 mg twice a day, and 32 mg once a day in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin _50 mg/m². 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 study 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 oral ondansetron 24 mg once a day experienced no nausea during the 24-hour study 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.

In a second trial, efficacy of the oral ondansetron 24 mg once-a-day regimen in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m², was confirmed.

Moderately Emetogenic Chemotherapy

In 1 double-blind US study in 67 patients, ondansetron HCl tablets 8 mg administered twice a day were significantly more effective than placebo in preventing vomiting induced by cyclophosphamide-based chemotherapy containing doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 5.

Table 5: Emetic Episodes: Treatment Response After Ondansetron HCl Tablets 8 mg Twice A Day

  Ondansetron Tablet 8 mg twice dailya Placebo p Value
Number of patients 33 34
  Treatment response
0 emetic episodes 20 (61%) 2 (6%) < 0.001
1 -2 emetic episodes 6 (18%) 8 (24%)
> 2 emetic episodes/ withdrawn 7 (21%) 24 (71%) < 0.001
Median number of emeticepisodes 0.0 Undefinedb
Number of patients 33 34
Median time to first emetic episode (h) Undefinedc 6.5
a The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8-mg ondansetron HCl tablet was administered twice a day for 2 days after completion of chemotherapy.
b Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes.
c Median undefined since at least 50% of patients did not have any emetic episodes.

In 1 double-blind US study in 336 patients, ondansetron HCl tablets 8 mg administered twice a day were as effective as ondansetron HCl tablets 8 mg administered 3 times a day in preventing nausea and vomiting induced by cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin.

Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 6.

Table 6: Emetic Episodes: Treatment Response After Ondansetron HCl Tablets 8 mg Twice A Day and Three Times A Day

  Ondansetron 8 mg twice dailya Ondansetron 8 mg three times dailyb
Number of patients 165 171
Treatment response
0 emetic episodes 101 (61%) 99 (58%)
1 -2 emetic episodes 16 (10%) 17 (10%)
> 2 emetic episodes/withdrawn 48 (29%) 55 (32%)
Median number of emetic episodes 0.0 0.0
Median time to first emetic episode (h) Undefinedc Undefinedc
Median nausea scores (0-100)d 6 6
a The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8-mg ondansetron HCl tablet was administered twice a day for 2 days after completion of chemotherapy.
b The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. An 8-mg ondansetron HCl tablet was administered three times daily for 2 days after 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.

Retreatment

In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ondansetron HCl tablets 8 mg three times daily during subsequent chemotherapy for a total of 396 retreatment 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.

Pediatrics

Three open-label, uncontrolled, foreign trials have been performed with 182 pediatric patients 4 to 18 years old with cancer who were given a variety of cisplatin or non-cisplatin regimens. In these foreign trials, the initial dose of ondansetron HCl injection ranged from 0.04 mg/kg to 0.87 mg/kg for a total dose of 2.16 mg to 12 mg. This was followed by the administration of ondansetron HCl tablets ranging from 4 mg to 24 mg daily for 3 days. In these studies, 58% of the 170 evaluable patients had a complete response (no emetic episodes) on day 1. Two studies showed the response rates for patients less than 12 years of age who received ondansetron HCl tablets 4 mg three times daily to be similar to those in patients 12 to 18 years of age who received ondansetron HCl tablets 8 mg three times daily. Thus, prevention of emesis in these pediatric patients was essentially the same as for patients older than 18 years of age. Overall, ondansetron HCl tablets were tolerated in these pediatric patients.

Radiation-Induced Nausea and Vomiting

Total Body Irradiation

In a randomized, double-blind study in 20 patients, ondansetron HCl tablets (8 mg given 1.5 hours before each fraction of radiotherapy for 4 days) were 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

Ondansetron was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of ≥ 80 cm² to the abdomen. Patients received the first dose of ondansetron HCl tablets (8 mg) or metoclopramide (10 mg) 1 to 2 hours before radiotherapy. If radiotherapy was given in the morning, 2 additional doses of study treatment were given (1 tablet late afternoon and 1 tablet before bedtime). If radiotherapy was given in the afternoon, patients took only 1 further tablet that day before bedtime. Patients continued the oral medication on a three times daily basis for 3 days.

Daily Fractionated Radiotherapy

Ondansetron was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 135 patients receiving a 1- to 4-week course of fractionated radiotherapy (180 cGy doses) over a field size of > 100 cm² to the abdomen. Patients received the first dose of ondansetron HCl tablets (8 mg) or prochlorperazine (10 mg) 1 to 2 hours before the patient received the first daily radiotherapy fraction, with 2 subsequent doses on a three times a day basis. Patients continued the oral medication on a three times daily basis on each day of radiotherapy.

Postoperative Nausea and Vomiting

Surgical patients who received ondansetron 1 hour before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil, sufentanil, morphine, or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare or gallamine and/or vecuronium, pancuronium, or atracurium; and supplemental isoflurane or enflurane) were evaluated in 2 double-blind studies (1 US study, 1 foreign) involving 865 patients. Ondansetron HCl tablets (16 mg) were significantly more effective than placebo in preventing postoperative nausea and vomiting.

The study populations in all trials thus far consisted of women undergoing inpatient surgical procedures. No studies have been performed in males. No controlled clinical study comparing ondansetron HCl tablets to ondansetron injection has been performed.

Last reviewed on RxList: 11/8/2013
This monograph has been modified to include the generic and brand name in many instances.

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