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/m 2[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)].
Zuplenz Dosage and Administration
Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer Chemotherapy
The recommended adult oral dosage of Zuplenz (ondansetron) oral soluble film is 24 mg given successively as three 8 mg films administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin ≥50 mg/m 2. Each Zuplenz oral soluble film should be allowed to dissolve completely before administering the next film. [see Dosage and Administration (2.6)]. Multiday, single-dose administration of a 24 mg dosage has not been studied.
Safety and effectiveness of Zuplenz in pediatric patients have not been established for this indication.
Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy
The recommended adult oral dosage is one 8 mg Zuplenz oral soluble film 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 Zuplenz oral soluble film should be administered twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy [see Dosage and Administration (2.6)].
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 Zuplenz oral soluble film given three 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 Zuplenz oral soluble film should be administered three times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy [see Dosage and Administration (2.6)].
Prevention of Nausea and Vomiting Associated With Radiotherapy
The recommended adult oral dosage of Zuplenz oral soluble film is one 8 mg film given three times a day [see Dosage and Administration (2.6)].
For total body irradiation, one 8 mg Zuplenz oral soluble film 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 Zuplenz oral soluble film 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 Zuplenz oral soluble film 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.
Safety and effectiveness of Zuplenz in pediatric patients have not been established for this indication.
Prevention of Postoperative Nausea and/or Vomiting
The recommended adult oral dosage of Zuplenz oral soluble film is 16 mg given successively as two 8 mg films 1 hour before induction of anesthesia. Each Zuplenz oral soluble film should be allowed to dissolve completely before administering the next film [see Dosage and Administration (2.6)].
Safety and effectiveness of Zuplenz in pediatric patients have not been established for this indication.
Dosage Adjustment for Patients with Impaired Hepatic Function
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.
Important Administration Instructions
With dry hands, fold the pouch along the dotted line to expose the tear notch. While still folded, tear the pouch carefully along the edge and remove the Zuplenz oral soluble film from the pouch. Immediately place the film on top of the tongue where it dissolves in 4 to 20 seconds. Once the Zuplenz oral soluble film is dissolved, swallow with or without liquid [see Clinical Pharmacology (12.3)]. Wash hands after taking Zuplenz.
Dosage Forms and Strengths
Zuplenz (ondansetron) oral soluble film is available in 4 mg and 8mg strengths. The thin white opaque films are rectangularly shaped strips with a printed identifier in black ink of “4 mg” for Zuplenz 4 mg or “8 mg” for Zuplenz 8mg.
Contraindications
The concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron.
Zuplenz (ondansetron) oral soluble film is contraindicated for patients known to have hypersensitivity to the drug. Anaphylactic reactions have been reported in patients taking ondansetron.
Warnings and Precautions
Hypersensitivity
Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3 receptor antagonists.
Electrocardiographic Changes
Rarely and predominantly with intravenous ondansetron, transient electrocardiographic changes, including QT interval prolongation, have been reported.
Masking of Progressive Ileus and/or Gastric Distension
The use of Zuplenz in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension.
Effect on Peristalsis
Zuplenz is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction.
Adverse Reactions
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The following adverse events have been reported in clinical trials of patients treated with ondansetron, the active ingredient of Zuplenz. A causal relationship to therapy with ondansetron was unclear in many cases.
Chemotherapy-Induced Nausea and Vomiting
| Adverse Event | Ondansetron 24 mg once daily N=300 | Ondansetron 8 mg twice a day N=124 | Ondansetron 32 mg once daily N=117 |
| Headache | 33 (11%) | 16 (13%) | 17 (15%) |
| Diarrhea | 13 (4%) | 9 (7%) | 3 (3%) |
| Adverse Event | Ondansetron 8 mg twice daily N=242 | Ondansetron 8 mg three times day. N=415 | Placebo N=262 |
| Headache | 58 (24%) | 113 (27%) | 34 (13%) |
| Malaise/fatigue | 32 (13%) | 37 (9%) | 6 (2%) |
| Constipation | 22 (9%) | 26 (6%) | 1 (<1%) |
| Diarrhea | 15 (6%) | 16 (4%) | 10 (4%) |
Central Nervous System: There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving ondansetron.
Hepatic: In 723 patients receiving cyclophosphamide-based chemotherapy in US clinical trials, AST and/or ALT values have been reported to exceed twice the upper limit of normal in approximately 1% to 2% of patients receiving ondansetron HCl tablets. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role of cancer chemotherapy in these biochemical changes cannot be clearly determined. There have been reports of liver failure and death in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.
Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron.
Other: Rare cases of anaphylaxis, bronchospasm, tachycardia, angina (chest pain), hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures have been reported. Except for bronchospasm and anaphylaxis, the relationship to ondansetron was unclear.
Radiation-Induced Nausea and Vomiting
The adverse events reported in patients receiving ondansetron HCl tablets and concurrent radiotherapy were similar to those reported in patients receiving ondansetron HCl tablets and concurrent chemotherapy. The most frequently reported adverse events were headache, constipation, and diarrhea.
Postoperative Nausea and Vomiting
Postmarketing Experience
The following events have been identified during post-approval use of ondansetron. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ondansetron.
Cardiovascular: Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported.
General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been reported. Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable ondansetron.
Hepatobiliary: Liver enzyme abnormalities
Neurology: Oculogyric crisis, appearing alone, as well as with other dystonic reactions
Eye Disorders: Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.
Drug Interactions
Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver [see Clinical Pharmacology (12.3)]. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of available data, no dosage adjustment is recommended for patients on these drugs.
Apomorphine
Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with ondansetron is contraindicated [see Contraindications (4)].
Phenytoin, Carbamazepine, Rifampicin
In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. 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 However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs. 1,3
Tramadol
Although there are no data on pharmacokinetic drug interactions between ondansetron and tramadol, data from two small studies indicate that concomitant use of ondansetron may result in reduced analgesic activity of tramadol. Patients in the studies self administered tramadol more frequently, leading to an increased cumulative dose in patient controlled administration (PCA) of tramadol. 4,5
Chemotherapy
In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.
In a crossover study in 76 pediatric patients, intravenous ondansetron did not increase blood levels of high-dose methotrexate.
Temazepam
The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam.
Antacids
Bioavailability of ondansetron is unaffected by antacids.
Alfentanil and Atracurium
Ondansetron does not alter 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.
USE IN SPECIFIC POPULATIONS
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 16mg/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.
Drug Abuse and Dependence
Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies.
Overdosage
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.
Zuplenz Description
Zuplenz (ondansetron) oral soluble film is a white opaque orally dissolving film designed to be applied on top of the tongue where it will dissolve in 4 to 20 seconds and then is swallowed with saliva.
Zuplenz does not require water to aid dissolution or swallowing.
The active ingredient in Zuplenz is ondansetron base, the racemic form of ondansetron, and a selective blocking agent of the serotonin 5-HT 3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one.
The empirical formula is C 18H19N3O representing a molecular weight of 293.3. Each 4 mg Zuplenz oral soluble film for oral administration contains 4 mg ondansetron base. Each 8 mg Zuplenz oral soluble film for oral administration contains 8 mg ondansetron base. Each Zuplenz oral soluble film also contains the inactive ingredients butylated hydroxyltoluene, calcium carbonate, colloidal silicon dioxide, erythritol, hydroxypropyl methylcellulose, monoammonium glycyrrhizinate, peppermint flavor, polyethylene oxide, sodium bicarbonate, sucralose, titanium dioxide and xanthan gum.
Zuplenz - Clinical Pharmacology
Mechanism of Action Section
Ondansetron is a selective 5-HT 3 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 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.
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.) C max 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 Zuplenz 8 mg was administered with a high fat meal, the mean time to peak plasma concentration (T max) was delayed by approximately 1 hour while AUC was similar to that under fasting conditions. Under the same fed conditions, both Cmax and AUC were comparable between Zuplenz 8 mg and ondansetron ODT 8 mg.
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.
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. The metabolites are observed in the urine.
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.
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 were clinically important.
| Gender | Mean Weight (kg) | n | Cmax (ng/mL) | Tmax (h) | T 1/2 (h) | AUC (h•ng/mL) |
| M F | 62 56.7 | 39 7 | 35.2 49.1 | 1.67 1.7 | 4.54 5.39 | 207 323 |
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.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 mg/kg/day and 30 mg/kg/day, respectively (approximately 5 and 8 times the human dose of 16 mg/day, based on body surface area). Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg/day (approximately 8 times the human dose of 16 mg/day, based on body surface area) did not affect fertility or general reproductive performance of male and female rats.
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/m 2. 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/m 2. 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 no 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/m 2, 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.
In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy w
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