Diarrhea (2—16%) and constipation (6—11%) were among the most frequently reported adverse events in patients receiving ondansetron during clinical trials for chemotherapy-induced nausea and vomiting (CINV) with moderate-high emetogenic agents. Hiccups have been reported during post-marketing experience with ondansetron.
Urinary retention (5%) and gynecological disorder (7%) have been reported in patients receiving oral ondansetron for postoperative nausea and vomiting (PONV) during clinical trials.
Headache (9—27%) was the most frequently reported adverse event during clinical trials of ondansetron and appeared to be more common in patients receiving the drug for chemotherapy-induced nausea and vomiting (CINV). Preliminary observations in a small number of subjects suggest a higher incidence of headache when ondansetron orally disintegrating tablets are taken with water, when compared to without water. Other neurologic side effects reported include drowsiness (8—20%), malaise and fatigue (9—13%), anxiety or agitation (<= 6%), paresthesias (2%), and dizziness (4—7%). Transient dizziness associated with intravenous infusion has been reported post-marketing. Rarely, extrapyramidal reactions, including oculogyric crisis appearing alone or with other types of dystonic reaction, have been reported with ondansetron use. In one case, extrapyramidal reactions were confirmed by rechallenge. In addition, there have been rare reports of grand mal seizures in patients receiving ondansetron, although a casual relationship has not been established.
Elevated hepatic enzymes were reported in patients receiving either cisplatin- or cyclophosphamide-based chemotherapy during clinical trials. The elevation did not appear to be related to ondansetron dose or duration of therapy. The enzyme levels exceeded twice the upper limit of normal (ULN) in approximately 5% of chemotherapy patients receiving injection dosing, and 1—2% of patients receiving oral therapy, but the increases were transient in nature and did not cause symptomatic hepatic disease. Repeat exposure showed similar elevations in some instances. In addition, hepatic failure and death have been reported in patients with cancer receiving concomitant medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics; the etiology of the hepatic failure is unclear.
Rare cases of hypokalemia have been reported following treatment with ondansetron in oncology patients; the relationship to ondansetron is unclear. It may be prudent to monitor serum electrolytes in select patients, as hypokalemia is a risk factor for electrocardiogram (ECG) changes.
Ondansetron has been associated with QT prolongation and torsade de pointes. Patients at risk for developing torsade de pointes include those with underlying heart conditions, such as congenital long QT syndrome (avoid use), those who are predisposed to hypokalemia and hypomagnesemia, and those taking other medications that lead to QT prolongation. Other cardiovascular adverse events reported during clinical trials with ondansetron include angina, chest pain (unspecified), ECG alterations (including second-degree AV block, QT prolongation, and ST-T wave changes), hypotension (5%), and sinus tachycardia. Bradycardia (6% vs. 6% placebo) was reported in patients receiving oral ondansetron for postoperative nausea and vomiting (PONV). Syncope, palpitations, and arrhythmias, including ventricular tachycardia and supraventricular tachycardia (SVT), bradycardia, premature ventricular contractions (PVCs), atrial fibrillation, and acute myocardial ischemia have been reported during postmarketing use of ondansetron. In some cases, predominantly during intravenous administration, the symptoms of myocardial ischemia appeared immediately after administration but resolved with prompt treatment. Coronary vasospasm (coronary artery spasm) appears to be the most common cause of the ischemia. To minimize the risk of these adverse events in patients receiving intravenous treatment, do not exceed the recommended ondansetron infusion rate and monitor patients for signs and symptoms of myocardial ischemia during and after administration. In patients receiving oral therapy, monitor or advise patients of these symptoms. Intravenous (IV) ondansetron given as a single 32 mg dose causes QT prolongation in a dose-dependent manner; therefore, single IV doses should not exceed 16 mg/dose IV; the 32 mg IV single-dose regimen is no longer indicated for chemotherapy-induced nausea and vomiting (CINV). Oral dosing recommendations have not changed. ECG monitoring is recommended in patients with electrolyte imbalance (e.g., hypokalemia or hypomagnesemia), congestive heart failure, significant bradycardia, or in patients taking other medications that can lead to QT prolongation.
Several reports of anaphylactoid reactions have been associated with serotonin (5-HT3) receptor antagonists, such as ondansetron. Manifestations of anaphylactoid reactions have included angioedema, bronchospasm, dyspnea, hypotension, laryngeal edema, stridor, and/or urticaria. Laryngospasm, shock, cardiac arrest, and respiratory arrest have been reported during allergic reactions in patients receiving injectable ondansetron. Rash (unspecified) (1%), pruritus (2—5%), and flushing have been reported in clinical trials with both oral and injectable formulations. Stevens-Johnson syndrome and toxic epidermal necrolysis (TENS) have been reported with post-marketing use of ondansetron.
An injection site reaction (4%) was reported in patients receiving ondansetron injection intravenously over 2 to 5 minutes during clinical trials for post-operative nausea/vomiting (PONV); symptoms included pain, erythema, and burning at the site.
Visual impairment has occurred with ondansetron use. Cases of transient blindness, predominantly during intravenous (IV) administration, have been reported; resolution occurred within minutes up to 48 hours. Sudden blindness (amaurosis) of 2—3 minute duration occurred in one patient who was administered ondansetron 72 mg IV as a single dose. In another case, transient blindness was reported in a patient who received ondansetron 4mg as a post-operative rapid IV bolus dose. The mechanism by which ondansetron may cause visual impairment is not well understood. Clinicians in the latter case suggest that it may be related to the rate of administration. Transient blurred vision, in some cases associated with accommodation disorder, has also been reported during post-marketing experience.
Fever (2—8%) and shivers or chills (2—5%) were reported in patients receiving ondansetron during clinical trials. Wound problems (28% vs. 31% placebo) were reported in patients receiving oral ondansetron for postoperative nausea and vomiting (PONV).
Serotonin syndrome has been reported with 5-HT3 receptor antagonists, such as ondansetron, during concurrent use of other medications known to increase CNS or peripheral serotonin levels or during overdose. Some of the reported cases were fatal; most occurred in a post-anesthesia care unit or infusion center. If serotonin syndrome becomes evident during treatment, discontinue ondansetron and any other serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is a range of signs and symptoms that can include mental status changes (e.g., agitation, hallucinations, delirium, coma), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and/or seizures. Cases consistent with serotonin syndrome have been reported in pediatric patients after inadvertent overdose of oral ondansetron (estimated ingestion > 5 mg/kg). Symptoms reported in these cases included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizures. Patients required supportive care, including intubation in some cases, with complete recovery in 1—2 days.