Zuplenz

Before taking ondansetron,

• tell your doctor and pharmacist if you are allergic to ondansetron, alosetron (Lotronex), dolasetron (Anzemet), granisetron (Kytril), palonosetron (Aloxi, in Akynzeo), any other medications, or any of the ingredients in ondansetron tablets or liquid. Ask your pharmacist for a list of the ingredients.
• tell your doctor if you are receiving apomorphine (Apokyn). Your doctor will probably tell you not to take ondansetron if you are receiving this medication.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: certain medications for seizures such as carbamazepine (Carbatrol, Epitol, Equetro, Tegretol) or phenytoin (Dilantin); clarithromycin (Biaxin, in Prevpac); erythromycin (E.E.S., Erythrocin, others); fentanyl (Abstral, Actiq, Duragesic, Fentora, Lazanda, Onsolis, Subsys); lithium (Lithobid); medications for irregular heart beat; medications for mental illness; medications to treat migraines such as almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), and zolmitriptan (Zomig); methylene blue; mirtazapine (Remeron); monoamine oxidase (MAO) inhibitors including isocarboxazid (Marplan), linezolid (Zyvox), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate); moxifloxacin (Avelox); selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, in Symbyax), fluvoxamine (Luvox), paroxetine (Brisdelle, Paxil, Pexeva), and sertraline (Zoloft); and tramadol (Conzip, Ultram, in Ultracet). Your doctor may need to change the doses of your medications or monitor you more carefully for side effects. Many other medications may also interact with ondansetron, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor if you or anyone in your family has or has ever had long QT syndrome (condition that increases the risk of developing an irregular heartbeat that may cause fainting or sudden death), or another type of irregular heart beat or heart rhythm problem, or if you have or have ever had low blood levels of magnesium or potassium in your blood, heart failure (HF; condition in which the heart cannot pump enough blood to other parts of the body), or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking ondansetron, call your doctor.
• if you have phenylketonuria (PKU, an inherited condition in which a special diet must be followed to prevent mental retardation), you should know that the orally disintegrating tablets contain aspartame that forms phenylalanine.

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

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.

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.

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.

Ondansetron and its metabolites are eliminated via the urine.

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

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 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.

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.

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

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.

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

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

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.

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

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.

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.

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.

• Zofran

• Zofran Injection

© Zuplenz Patient Information is supplied by Cerner Multum, Inc. and Zuplenz Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose of this medicine, and you feel nauseated or you vomit, take the missed dose as soon as possible.

Zuplenz is part of the drug class:

• Serotonin 5HT3 antagonists

Prevention of Nausea and Vomiting Associated with Highly Emetogenic Cancer Chemotherapy

Zuplenz (ondansetron) oral soluble film is indicated for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥50 mg/m2 [see Clinical Studies, (14.1)].

Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Cancer Chemotherapy

Zuplenz is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy [see Clinical Studies (14.1)].

Prevention of Nausea and Vomiting Associated with Radiotherapy

Zuplenz is indicated for the prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen [see Clinical Studies (14.2)].

Prevention of Postoperative Nausea and/or Vomiting

Zuplenz is indicated for the prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, Zuplenz is recommended even where the incidence of postoperative nausea and/or vomiting is low [see Clinical Studies (14.3)].

Pregnancy

Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg/day, respectively (approximately 8 and 30 times the human dose of 16 mg/day, based on body surface area), and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well- controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Zuplenz (ondansetron) oral soluble film should be used during pregnancy only if clearly needed.

Nursing Mothers

Ondansetron is excreted in the milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Zuplenz oral soluble film is administered to a nursing woman.

Pediatric Use

Little information is available about dosage in pediatric patients less than 4 years of age. For dosage recommendations in the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy for patients 4 years of age and older [see Dosage and Administration (2.2)]. The safety and effectiveness in pediatric patients have not been established for the following indications: prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, prevention of nausea and vomiting associated with radiotherapy, and prevention of postoperative nausea and/or vomiting.

Geriatric Use

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 were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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. Dosage adjustment is not needed in patients over the age of 65 [see Clinical Pharmacology (12.3)].

Renal Impairment

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

Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater)2, clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life [see Clinical Pharmacology (12.3)]. In such patients, a total daily dose of 8 mg should not be exceeded.

There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose.

In addition to the adverse events listed above, the following events have been described in the setting of ondansetron overdose: "Sudden blindness" (amaurosis) of 2 to 3 minutes' duration plus severe constipation occurred in 1 patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in a patient that took 48 mg of ondansetron HCl tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely.

Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg/kg) in young children. Reported symptoms included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizure. Patients required supportive care, including intubation in some cases, with complete recovery without sequelae within 1 to 2 days.

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.

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.

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 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.

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.

1. Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND) metabolism in humans. Clin Pharmacol Ther. 1997;61:228.
2. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649.
3. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381.
4. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321.
5. Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg. 2002;94:1553-1557.

You should not use Zuplenz if you are also using apomorphine (Apokyn).

You should not use Zuplenz if you are allergic to ondansetron or to similar medicines such as dolasetron (Anzemet), granisetron (Kytril), or palonosetron (Aloxi).

Serious side effects of Zuplenz include blurred vision or temporary vision loss (lasting from only a few minutes to several hours), slow heart rate, trouble breathing, anxiety, agitation, shivering, feeling like you might pass out, and urinating less than usual or not at all. Stop taking Zuplenz and call your doctor at once if you have any of these side effects. Ondansetron may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Get emergency medical help if you have signs of an allergic reaction to Zuplenz: rash, hives; fever, chills, difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• severe constipation, stomach pain, or bloating;

• headache with chest pain and severe dizziness, fainting, fast or pounding heartbeats;

• fast or pounding heartbeats;

• jaundice (yellowing of the skin or eyes);

• blurred vision or temporary vision loss (lasting from only a few minutes to several hours);

• high levels of serotonin in the body - agitation, hallucinations, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting.

Common Zuplenz side effects may include:

• diarrhea or constipation;

• headache;

• drowsiness; or

• tired feeling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.