ZUPLENZ (ondansetron)

ZUPLENZ (ondansetron) oral soluble film

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ZUPLENZ (ondansetron)

The active ingredient in ZUPLENZ is ondansetron base, the racemic form of ondansetron, 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]-4Hcarbazol-4-one.

The empirical formula is C18H19N3O 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 hydroxytoluene, calcium carbonate, colloidal silicon dioxide, erythritol, hypromellose, monoammonium glycyrrhizinate, peppermint flavor, polyethylene oxide, sodium bicarbonate, sucralose, titanium dioxide and xanthan gum.

Indications and usage

ZUPLENZ is a 5-HT3 receptor antagonist indicated for the prevention of:

  • nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m2 , in adults.
  • nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy in adults and pediatric patients 4 years of age and older.
  • nausea and vomiting associated with radiotherapy in adult patients receiving either total body irradiation, single high-dose fraction to abdomen, or daily fractions to the abdomen.
  • postoperative nausea and/or vomiting in adults.

Dosage and administration

IndicationDosage Regimen
Highly Emetogenic Cancer ChemotherapyA single 24-mg dose (administered successively as three 8-mg films) 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin greater than or equal to 50 mg/m2 . Allow each film to dissolve completely before administering the next film
Moderately Emetogenic CancerAn 8-mg dose administered 30 minutes before the start of chemotherapy, with a subsequent 8-mg dose 8 hours after the first dose.
RadiotherapyFor total body irradiation: An 8-mg dose administered 1 to 2 hours before each fraction of radiotherapy each day.
For single high-dose fraction radiotherapy to the abdomen: An 8-mg dose administered 1 to 2 hours before radiotherapy, with subsequent 8-mg doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy.
For daily fractionated radiotherapy to the abdomen: An 8-mg dose administered 1 to 2 hours before radiotherapy, with subsequent 8-mg doses every 8 hours after the first dose for each day radiotherapy is given.
PostoperativeA single 16-mg dose (administered successively as two 8-mg films) 1 hour before induction of anesthesia. Allow each film to dissolve completely before administering the next film
Moderately Emetogenic Cancer Chemotherapy12 to 17 years of age: A 8-mg dose administered 30 minutes before the start of chemotherapy, with a subsequent 8-mg dose 8 hours after the first dose.
Then administer 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.
4 to 11 years of age: A 4-mg dose administered 30 minutes before the start of chemotherapy, with a subsequent 4-mg dose at 4 and 8 hours after the first dose.
Then, administer 4 mg three times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy.

Recommended Dosage in Patients with Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), do not exceed a total daily dose of 8 mg

Important Preparation and Administration Instructions

  1. With dry hands, fold the pouch along the dotted line to expose the tear notch.
  2. While still folded, tear the pouch carefully along the edge and remove the ZUPLENZ oral soluble film from the pouch.
  3. Immediately place the film on top of the tongue where it dissolves in 4 to 20 seconds.
  4. Once the ZUPLENZ oral soluble film is dissolved, swallow with or without liquid. ZUPLENZ may be taken with or without food.
  5. Wash hands after taking ZUPLENZ.

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.

Contraindications

ZUPLENZ is contraindicated in patients:

  • known to have hypersensitivity (e.g., anaphylaxis) to ondansetron
  • receiving concomitant apomorphine due to the risk of profound hypotension and loss of consciousness

Warnings and precautions

Hypersensitivity reactions, including anaphylaxis and bronchospasm: Discontinue ZUPLENZ if suspected. Monitor and treat promptly per standard of care until signs and symptoms resolve.

QT interval prolongation and Torsades de Pointes: Avoid in patients with congenital long QT syndrome; monitor with electrocardiograms (ECGs) if concomitant electrolyte abnormalities, congestive heart failure or arrhythmias or use of other QT prolonging drugs.

Serotonin syndrome: Reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. If such symptoms occur, discontinue ZUPLENZ and initiate supportive treatment. If concomitant use of ZUPLENZ with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome.

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Masking of progressive ileus and/or gastric distension following abdominal surgery or chemotherapy-induced nausea and vomiting: Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction

Adverse reactions

The most common adverse reactions in adults for:

  • prevention of chemotherapy-induced nausea and vomiting (≥5%) are: headache, malaise/fatigue, constipation, and diarrhea.
  • prevention of radiation-induced nausea and vomiting (≥2%) are: headache, constipation, diarrhea.
  • prevention of postoperative nausea and vomiting (≥9%) are: headache and hypoxia.

Drug interactions

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

Serotonergic Drugs: Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitor (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue ZUPLENZ and initiate supportive treatment.

Drugs Affecting Cytochrome P-450 Enzymes: Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ZUPLENZ is recommended for patients on these drugs.

Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from two small trials indicate that when used together, ondansetron may increase patient-controlled administration of tramadol. Monitor patients to ensure adequate pain control when ZUPLENZ is administered with tramadol.

Chemotherapy: Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.

Temazepam: The co-administration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam.

Alfentanil and Atracurium: 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.

Use in special populations

Pregnancy: Published epidemiological studies on the association between ondansetron use and major birth defects have reported inconsistent findings and have important methodological limitations that preclude conclusion about the safety of ondansetron use in pregnancy. Available postmarketing data have not identified a drug-associated risk of miscarriage or adverse maternal outcomes. Reproductive studies in rats and rabbits did not show evidence of harm to the fetus when ondansetron was administered during organogenesis at approximately 6 and 24 times the maximum recommended human oral dose of 24 mg/day, based on body surface area, respectively

Lactation: It is not known whether ondansetron is present in human milk. There are no data on the effects of ZUPLENZ on the breastfed infant or the effects on milk production. However, it has been demonstrated that ondansetron is present in the milk of rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZUPLENZ and any potential adverse effects on the breast fed infant from ZUPLENZ or from the underlying maternal condition

Pediatric Use: The safety and effectiveness of ZUPLENZ have been established in pediatric patients 4 years of age and older for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. Use of ZUPLENZ in these age-groups is supported by evidence from adequate and well-controlled studies of ondansetron HCl in adults with additional data from 3 open-label, uncontrolled, non-US trials in 182 pediatric patients aged 4 to 18 years with cancer who were given a variety of cisplatin or noncisplatin regimens.

The safety and effectiveness of ZUPLENZ have not been established in pediatric patients for:

  • prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy
  • prevention of nausea and vomiting associated with radiotherapy
  • 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 non-UScontrolled clinical trials of oral ondansetron, for which there were subgroup analyses, 938 (19%) were 65 years of age and over.

Renal Impairment: No dosage adjustment is recommended for patients with any degree of renal impairment (mild, moderate, or severe. There is no experience beyond first-day administration of ondansetron.

Overdosage

There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy.

Storage

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.

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