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Vomizen

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Vomizen uses


1 INDICATIONS AND USAGE

Vomizen is a 5-HT3 receptor antagonist indicated for:

1.1 Prevention of Nausea and Vomiting Associated with Highly Emetogenic Cancer Chemotherapy

Vomizen (ondansetron) oral soluble film is indicated for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥50 mg/m2 .

1.2 Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Cancer Chemotherapy

Vomizen is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy .

1.3 Prevention of Nausea and Vomiting Associated with Radiotherapy

Vomizen 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 .

1.4 Prevention of Postoperative Nausea and/or Vomiting

Vomizen 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, Vomizen is recommended even where the incidence of postoperative nausea and/or vomiting is low .

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2 DOSAGE AND ADMINISTRATION

2.1 Prevention of Nausea and Vomiting Associated with Highly Emetogenic Cancer Chemotherapy

Adults

The recommended adult oral dosage of Vomizen (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/m2. Each Vomizen 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.

Pediatrics

Safety and effectiveness of Vomizen in pediatric patients have not been established for this indication.

2.2 Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Cancer Chemotherapy

Adults

The recommended adult oral dosage is one 8 mg Vomizen 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 Vomizen oral soluble film should be administered twice a day for 1 to 2 days after completion of chemotherapy .

Pediatrics

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 Vomizen 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 Vomizen oral soluble film should be administered three times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy .

2.3 Prevention of Nausea and Vomiting Associated with Radiotherapy

Adults

The recommended adult oral dosage of Vomizen oral soluble film is one 8 mg film given three times a day .

For total body irradiation, one 8 mg Vomizen 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 Vomizen 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 Vomizen 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.

Pediatrics

Safety and effectiveness of Vomizen in pediatric patients have not been established for this indication.

2.4 Prevention of Postoperative Nausea and/or Vomiting

Adults

The recommended adult oral dosage of Vomizen oral soluble film is 16 mg given successively as two 8 mg films 1 hour before induction of anesthesia. Each Vomizen oral soluble film should be allowed to dissolve completely before administering the next film .

Pediatrics

Safety and effectiveness of Vomizen in pediatric patients have not been established for this indication.

2.5 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 . In such patients, a total daily dose of 8 mg should not be exceeded.

2.6 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 Vomizen 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 Vomizen oral soluble film is dissolved, swallow with or without liquid . Wash hands after taking Vomizen.

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3 DOSAGE FORMS AND STRENGTHS

Vomizen (ondansetron) oral soluble film is available in 4 mg and 8 mg strengths. The thin white opaque films are rectangularly shaped strips with a printed identifier in black ink of “4 mg” for Vomizen 4 mg or “8 mg” for Vomizen 8 mg.

4 CONTRAINDICATIONS

The concomitant use of apomorphine with Vomizen is contraindicated based on reports of profound hypotension and loss of consciousness when apomorphine was administered with Vomizen.

Vomizen (ondansetron) oral soluble film is contraindicated for patients known to have hypersensitivity to the drug. Anaphylactic reactions have been reported in patients taking Vomizen.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity

Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. Vomizen (ondansetron) oral soluble film should be discontinued immediately at the first sign of hypersensitivity.

5.2 Electrocardiographic Changes

ECG changes including QT interval prolongation have been seen in patients receiving Vomizen. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using Vomizen. Avoid Vomizen in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation.

5.3 Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of Vomizen alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of Vomizen and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Vomizen and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Vomizen is used concomitantly with other serotonergic drugs [see Drug Interactions (7.3), Overdosage (10.), Patient Counseling Information (17.)].

5.4 Masking of Progressive Ileus and/or Gastric Distension

The use of Vomizen in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension.

5.5 Effect on Peristalsis

Vomizen is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction.

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6 ADVERSE REACTIONS


To report SUSPECTED ADVERSE REACTIONS, contact Galena Biopharma, Inc., Portland, OR, 97239, at 1 855 636 5710 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials 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 Vomizen, the active ingredient of Vomizen. A causal relationship to therapy with Vomizen was unclear in many cases.

Chemotherapy-Induced Nausea and Vomiting

Vomizen Vomizen Vomizen
24 mg once daily 8 mg twice daily 32 mg once daily
Adverse Event N=300 N=124 N=117
Headache 33 (11%) 16 (13%) 17 (15%)
Diarrhea 13 (4%) 9 (7%) 3 (3%)
Vomizen Vomizen Placebo
8 mg twice daily 8 mg three times daily
Adverse Event N=242 N=415 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 Vomizen.

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 Vomizen 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 Vomizen.

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 Vomizen was unclear.

Radiation-Induced Nausea and Vomiting

The adverse events reported in patients receiving Vomizen HCl tablets and concurrent radiotherapy were similar to those reported in patients receiving Vomizen HCl tablets and concurrent chemotherapy. The most frequently reported adverse events were headache, constipation, and diarrhea.

Postoperative Nausea and Vomiting

a Adverse Events: With the exception of headache, rates of these events were not significantly different in the Vomizen and placebo groups.
b Patients were receiving multiple concomitant perioperative and postoperative medications.
Vomizen 16 mg Placebo
Adverse Event a,b N=550 N=531
Headache 49 (9%) 27 (5%)
Hypoxia 49 (9%) 35 (7%)
Pyrexia 45 (8%) 34 (6%)
Dizziness 36 (7%) 34 (6%)
Gynecological disorder 36 (7%) 33 (6%)
Anxiety/agitation 33 (6%) 29 (5%)
Urinary retention 28 (5%) 18 (3%)
Pruritus 27 (5%) 20 (4%)

6.2 Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of oral formulations of Vomizen. Because these events are reported voluntarily from a population of unknown 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 Vomizen.

Cardiovascular: Rarely and predominantly with intravenous Vomizen, 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 Vomizen.

Hepatobiliary: Liver enzyme abnormalities

Lower Respiratory: Hiccups

Neurology: Oculogyric crisis, appearing alone, as well as with other dystonic reactions

Skin: Urticaria

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.

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7 DRUG INTERACTIONS

Vomizen does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver.

7.1 Apomorphine

Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with Vomizen, the concomitant use of apomorphine with Vomizen is contraindicated [see Contraindications (4)].

7.2 Phenytoin, Carbamazepine, Rifampicin

In patients treated with potent inducers of CYP3A4, the clearance of Vomizen was significantly increased and Vomizen blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for Vomizen is recommended for patients on these drugs.1,3

7.3 Serotonergic Drugs

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagoinists and other serotonergic drugs, including selective serotonin reuptake inhibitor (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) .

7.4 Tramadol

Although there are no data on pharmacokinetic drug interactions between Vomizen and tramadol, data from two small studies indicate that concomitant use of Vomizen 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 of tramadol.4,5

7.5 Chemotherapy

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

In a crossover study in 76 pediatric patients, intravenous Vomizen did not increase blood levels of high-dose methotrexate.

7.6 Temazepam

The co-administration of Vomizen had no effect on the pharmacokinetics and pharmacodynamics of temazepam.

7.7 Antacids

Bioavailability of Vomizen is unaffected by antacids

7.8 Alfentanil and Atracurium

Vomizen 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.

8 USE IN SPECIFIC POPULATIONS

8.1 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 Vomizen. There are, however, no adequate and well- controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Vomizen (ondansetron) oral soluble film should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

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

8.4 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 . 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.

8.5 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)].

8.6 Renal Impairment

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

8.7 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.

9 DRUG ABUSE AND DEPENDENCE

Animal studies have shown that Vomizen is not discriminated as a benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies.

10 OVERDOSAGE

There is no specific antidote for Vomizen 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 Vomizen overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes' duration plus severe constipation occurred in 1 patient that was administered 72 mg of Vomizen intravenously as a single dose. Hypotension (and faintness) occurred in a patient that took 48 mg of Vomizen 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 Vomizen (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.

11 DESCRIPTION

Vomizen (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.

Vomizen does not require water to aid dissolution or swallowing.

The active ingredient in Vomizen is Vomizen base, the racemic form of Vomizen, and a selective blocking agent of the serotonin 5-HT3 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 C18H19N3O representing a molecular weight of 293.3. Each 4-mg Vomizen oral soluble film for oral administration contains 4 mg Vomizen base. Each 8-mg Vomizen oral soluble film for oral administration contains 8 mg Vomizen base. Each Vomizen oral soluble film also contains the inactive ingredients butylated hydroxytoluene, calcium carbonate, colloidal silicon dioxide, erythritol, hypromellose, monoammonium glycyrrhizinate, peppermint flavor, polyethylene oxide, sodium bicarbonate, sucralose, titanium dioxide and xanthan gum.

Figure 1

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Vomizen is a selective 5-HT3 receptor antagonist. While its mechanism of action has not been fully characterized, Vomizen 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 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.

12.2 Pharmacodynamics

In normal volunteers, single intravenous doses of 0.15 mg/kg of Vomizen had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of Vomizen has been shown to slow colonic transit in normal volunteers. Vomizen has no effect on plasma prolactin concentrations.

12.3 Pharmacokinetics

Absorption

Vomizen is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. After a single dose of Vomizen (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 Vomizen Cmax and AUC following administration of 8 mg Vomizen oral soluble film were comparable to those after 8 mg Vomizen ODT (orally disintegrating tablet). The systemic exposure after administration of Vomizen oral soluble film 8 mg with or without water was found to be comparable.

In a study using Vomizen tablets, Vomizen 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 Vomizen (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.

Distribution

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

Metabolism and Excretion

Vomizen 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 Vomizen is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall Vomizen turnover, CYP3A4 played the predominant role.

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

Drug Interactions

Vomizen does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver.

Because Vomizen is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inhibitors of these enzymes may change the clearance and, hence, the half-life of Vomizen. On the basis of available data, no dosage adjustment is recommended for patients on these drugs. Based on the multiplicity of metabolic enzymes capable of metabolizing Vomizen, 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 Vomizen elimination.

On the basis of available limited data, no dosage adjustment for Vomizen is recommended for patients on inhibitors of a single CYP enzyme.

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

Specific Populations

Gender

Gender differences were shown in the disposition of Vomizen 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.

Gender Mean Weight (kg) n C max (ng/mL) T max (h) T 1/2

(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 Vomizen. However, Vomizen 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenic effects were not seen in 2-year studies in rats and mice with oral Vomizen 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). Vomizen was not mutagenic in standard tests for mutagenicity. Oral administration of Vomizen 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.

14 CLINICAL STUDIES

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

14.1 Chemotherapy-Induced Nausea and Vomiting

Highly Emetogenic Chemotherapy

In 2 randomized, double-blind, monotherapy trials, a single 24 mg Vomizen 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 Vomizen 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 Vomizen 24 mg once- a-day group, 55% in the Vomizen 8 mg twice-a-day group, and 55% in the Vomizen 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 Vomizen 24 mg once a day experienced no nausea during the 24-hour study period, compared with 36% of patients in the oral Vomizen 8 mg twice-a-day group and 50% in the oral Vomizen 32 mg once-a-day group.

In a second trial, efficacy of the oral Vomizen 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, Vomizen 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.

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 Vomizen 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.
Vomizen
Tablet
8 mg twice daily a 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 emetic episodes 0.0 Undefinedb
Median time to first emetic episode (h) Undefinedc 6.5

In 1 double-blind US study in 336 patients, Vomizen HCl tablets 8 mg administered twice a day were as effective as Vomizen 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.

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 Vomizen 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
Vomizen 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.
Vomizen 8 mg twice daily a Vomizen 8 mg three times daily b
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

Retreatment

In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with Vomizen 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 Vomizen 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 Vomizen 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 Vomizen HCl tablets 4 mg three times daily to be similar to those in patients 12 to 18 years of age who received Vomizen 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, Vomizen HCl tablets were tolerated in these pediatric patients.

14.2 Radiation-Induced Nausea and Vomiting

Total Body Irradiation

In a randomized, double-blind study in 20 patients, Vomizen 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

Vomizen 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 Vomizen 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

Vomizen 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 Vomizen 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.

14.3 Postoperative Nausea and Vomiting

Surgical patients who received Vomizen 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. Vomizen 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 Vomizen HCl tablets to Vomizen injection has been performed.

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

Vomizen (ondansetron) oral soluble film 4 mg and Vomizen (ondansetron) oral soluble film 8 mg, are supplied as thin rectangular white opaque films in individual foil-foil sealed child resistant pouches. Individual films are identified by “4 mg” or “8 mg”, according to the respective strengths, which is printed using pharmaceutical grade edible ink.

Individual pouches of Vomizen 4 mg oral soluble film are packaged in boxes of 10 (NDC 57881-444-10) and packaged in boxes of 1 (NDC 57881-444-01). Individual pouches of Vomizen 8 mg oral soluble film are packaged in boxes of 10 (NDC 57881-448-10) and packaged in boxes of 1 (NDC 57881-448-01).

Store at controlled room temperature 20° to 25°C (68° to 77°F). Store pouches in cartons. Keep product in pouch until ready to use.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

Advise patients to carefully read the “Patient Information” and “Instructions for Use” accompanying each package of Vomizen (ondansetron) oral soluble film.

Inform patients that Vomizen may cause serious cardiac arrhythmias such as QT prolongation. Instruct patients to tell their healthcare provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode.

Inform patients that the chances of developing severe cardiac arrhythmias such as QT prolongation and Torsade de Pointes are higher in the following people:


Inform patients that Vomizen film may cause headache, malaise/fatigue, constipation, and diarrhea. The patient should report the use of all medications, especially apomorphine or any drug of the 5HT3 antagonist class, to their health care provider. Concomitant use of apomorphine and Vomizen may cause a significant drop in blood pressure and loss of consciousness.

Inform patients that Vomizen may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. The patient should report any hypersensitivity reactions to this and other 5-HT3 receptor antagonists to their health care provider.

Instruct patients on how to use Vomizen films:

The patient should keep the film in the pouch until ready to use and not to chew or swallow the film. With dry hands, the patient should fold the pouch along the dotted line to expose the tear notch. While still folded, the patient should tear the pouch carefully along the edge and remove the Vomizen oral soluble film from the pouch. The patient should immediately place the film on top of the tongue where it dissolves in 4 to 20 seconds, then swallow with saliva. Once the film dissolves, the patient may swallow liquid but it is not required. The patient should wash his hands after taking Vomizen.

Patient Information

Vomizen ® (ZOO-plenz)

(ondansetron)

Oral Soluble Film

What is Vomizen ® ?

Vomizen is a prescription medicine that is used in adults to prevent nausea and vomiting:


In children 4 years of age and older, Vomizen is only used to prevent nausea and vomiting that happens with certain cancer chemotherapy medicines.

It is not known if Vomizen is safe and works in children to prevent nausea and vomiting with radiation therapy, or nausea and vomiting that may happen after surgery in children.

Who should not take Vomizen? Do not take Vomizen if you:


What should I tell my doctor before taking Vomizen? Before you take Vomizen, tell you doctor if you:


Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how Vomizen works, and Vomizen may affect how other medicines work. Taking Vomizen with certain other medicines may cause serious side effects. Especially tell your doctor if you take:


Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Vomizen?


Read the Instructions for Use at the end of this Patient Information for information about the right way to take Vomizen.

What should I avoid while taking Vomizen?

Vomizen may cause dizziness. Do not drive, operate machinery, or do other dangerous activities until you know how Vomizen affects you.

What are the possible side effects of Vomizen?

Vomizen may cause serious side effects, including:


The most common side effects of Vomizen include:


These are not all the possible side effects of Vomizen. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Vomizen?


Keep Vomizen and all medicines out of the reach of children.

General information about the safe and effective use of Vomizen

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Vomizen for a condition for which it was not prescribed. Do not give Vomizen to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your doctor or pharmacist for information about Vomizen that is written for health professionals.

For more information, go to www. ZUPLENZ.com or call 1 855 636 5710.

What are the ingredients in Vomizen?

Active ingredient: Vomizen

Inactive ingredients: butylated hydroxytoluene, calcium carbonate, colloidal silicon dioxide, erythritol, hypromellose, monoammonium glycyrrhizinate, peppermint flavor, polyethylene oxide, sodium bicarbonate, sucralose, titanium dioxide and xanthan gum.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Monosol Rx, LLC

Warren, NJ 07059

Manufactured for:

Galena Biopharma, Inc.

Portland, OR 97239

Distributed by:

Galena Biopharma, Inc. Portland, OR 97239

Revised: September 2014

Instructions for Use

Vomizen ® (ZOO-plenz)

(ondansetron)

Oral Soluble Film

Step 1. Keep the Vomizen film in the foil pouch until ready to use. Use Vomizen film right away after you take it out of the pouch.

Step 2. Make sure your hands are dry.

Step 3. Fold the pouch along the dotted line to expose the tear notch. See Figure A.

Principal Display Panel - 4 mg

Principal Display Panel - Box Label

TO OPEN: Fold along dotted line and

tear down at slit along the arrow.

PHYSICIAN SAMPLE

NOT FOR SALE

NDC 57881-444-01

Vomizen ®

(ondansetron) oral soluble film

4 mg

Rx only

1 Film

Principal Display Panel - 8 mg

Principal Display Panel - Box Label

TO OPEN: Fold along dotted line and

tear down at slit along the arrow.

PHYSICIAN SAMPLE

NOT FOR SALE

NDC 57881-448-01

Vomizen ®

(ondansetron) oral soluble film

8 mg

Rx only

1 Film

Vomizen pharmaceutical active ingredients containing related brand and generic drugs:


Vomizen available forms, composition, doses:


Vomizen destination | category:


Vomizen Anatomical Therapeutic Chemical codes:


Vomizen pharmaceutical companies:


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References

  1. Dailymed."ZUPLENZ (ONDANSETRON) FILM, SOLUBLE [GALENA BIOPHARMA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."ONDANSETRON: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "ondansetron". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Vomizen?

Depending on the reaction of the Vomizen after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Vomizen not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Vomizen addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Vomizen, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Vomizen consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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