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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. ( 5.1 ) Avoid ZUPLENZ in patients with congenital long QT syndrome. Monitor ECG in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation. ( 5.2 ) The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension. ( 5.4 ) Serotonin syndrome has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. ( 5.3 ) 5.1 Hypersensitivity Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT 3 receptor antagonists. ZUPLENZ (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 ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ZUPLENZ in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), 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 ondansetron 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 Zuplenz and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Zuplenz and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Zuplenz 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 ZUPLENZ 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 ZUPLENZ is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction.
6 ADVERSE REACTIONS The most common adverse drug events (≥5%) in chemotherapy-induced nausea and vomiting and radiotherapy-induced nausea and vomiting were: headache, malaise/fatigue, constipation, and diarrhea. ( 6.1 ) The most common adverse event (≥5%) in postoperative nausea and vomiting was headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fortovia Therapeutics Inc. at 1-855-273-0468 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 ondansetron, the active ingredient of ZUPLENZ. A causal relationship to therapy with ondansetron was unclear in many cases. Chemotherapy-Induced Nausea and Vomiting Table 1: Adverse Events Reported in ≥5% of Adult Patients After Single Day Therapy Ondansetron HCl Tablets [Highly Emetogenic Chemotherapy (cisplatin dose ≥50 mg/m 2 )] Adverse Event Ondansetron 24 mg once daily N=300 Ondansetron 8 mg twice daily N=124 Ondansetron 32 mg once daily N=117 Headache 33 (11%) 16 (13%) 17 (15%) Diarrhea 13 (4%) 9 (7%) 3 (3%) Table 2: Adverse Events Reported in ≥5% of Adult Patients After Three Days of Therapy With Ondansetron HCl Tablets [Moderately Emetogenic Chemotherapy (primarily cyclophosphamide-based regimens)] Adverse Event Ondansetron 8 mg twice daily N=242 Ondansetron 8 mg three times daily 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 Table 3: Adverse Events Reported in ≥5% of Adult Patients After Single Dose Therapy With Ondansetron HCl Tablets Ondansetron 16 mg Placebo Adverse Event Adverse Events: With the exception of headache, rates of these events were not significantly different in the ondansetron and placebo groups. , Patients were receiving multiple concomitant perioperative and postoperative medications. 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 ondansetron. 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 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 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.