Side Effects of Zofran (ondansetron)

Zofran (ondansetron) is an anti-nausea medication used to prevent and treat nausea and vomiting caused by cancer chemotherapy and to prevent vomiting and nausea after surgery.

Chemotherapy agents cause increased secretion of serotonin, which stimulates serotonin (5-HT3) receptors in the brain, resulting in nausea and vomiting. Zofran works by selectively blocking serotonin (5-HT3) receptors, thereby reducing the effect of increased serotonin due to chemotherapy. 

Common side effects of Zofran include

• headache,
• feeling unwell (malaise),
• fatigue,
• drowsiness,
• constipation,
• dizziness, and
• diarrhea.

Serious side effects of Zofran include

• abnormal heart rate and rhythm.

Drug interactions of Zofran include apomorphine, due to sudden lowering in blood pressure and loss of consciousness.

• Phenytoin, carbamazepine, and rifampin can increase Zofran elimination and decrease blood levels, possibly lowering the effects of Zofran.
• Dronedarone can increase blood levels of Zofran by reducing its breakdown in the liver. This may increase side effects Zofran. This combination may also increase the risk of abnormal heartbeats.

There are no adequate studies of Zofran in pregnant women to determine its safe and effective use during pregnancy.

It is unknown if Zofran enters breast milk; therefore, it is best for breastfeeding mothers to be cautious before using it.

Side effects of ondansetron are

• headache,
• malaise,
• fatigue,
• drowsiness,
• constipation,
• dizziness, and
• diarrhea.

Some individuals may develop abnormal heart rate and rhythm.

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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions have been reported in clinical trials of patients treated with ondansetron, the active ingredient of Zofran. A causal relationship to therapy with Zofran was unclear in many cases.

Prevention Of Chemotherapy-Induced Nausea And Vomiting

The most common adverse reactions reported in greater than or equal to 4% of 300 adults receiving a single 24mg dose of Zofran orally in 2 trials for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (cisplatin greater than or equal to 50 mg/m²) were:

• headache (11%) and
• diarrhea (4%).

The most common adverse reactions reported in 4 trials in adults for the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (primarily cyclophosphamide-based regimens) are shown in Table 3.

Table 3: Most Common Adverse Reactions in Adults^a for the Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Chemotherapy [Primarily Cyclophosphamide-based Regimens]

Less Common Adverse Reactions

Central Nervous System: Extrapyramidal reactions (less than 1% of patients).

Hepatic: Aspartate transaminase (AST) and/or alanine transaminase (ALT) values exceeded twice the upper limit of normal in approximately 1% to 2% of 723 patients receiving Zofran and cyclophosphamide-based chemotherapy in US clinical trials. 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 is unclear.

Liver failure and death has been reported in cancer patients receiving concurrent medications, including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.

Integumentary: Rash (approximately 1% of patients).

Other (less than 2%): Anaphylaxis, bronchospasm, tachycardia, angina, hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures. Except for bronchospasm and anaphylaxis, the relationship to Zofran is unclear.

Prevention Of Radiation-Induced Nausea And Vomiting

The most common adverse reactions (greater than or equal to 2%) reported in patients receiving Zofran and concurrent radiotherapy were similar to those reported in patients receiving Zofran and concurrent chemotherapy and were headache, constipation, and diarrhea.

Prevention Of Postoperative Nausea And Vomiting

The most common adverse reactions reported in adults in trial(s) of prevention of postoperative nausea and vomiting are shown in Table 4. In these trial(s), patients were receiving multiple concomitant perioperative and postoperative medications in both treatment groups.

Table 4: Most Common Adverse Reactions in Adults^a for the Prevention of Postoperative Nausea and Vomiting

In a crossover study with 25 subjects, headache was reported in 6 subjects administered Zofran ODT with water (24%) as compared with 2 subjects administered Zofran ODT without water (8%).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ondansetron. Because these reactions 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.

Cardiovascular

Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart block, QT/QTc interval prolongation, and ST segment depression), palpitations, and syncope. 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., anaphylactic 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, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

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.

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 inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue Zofran 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 Zofran is recommended for patients on these drugs.

Tramadol

Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small trials indicate that when used together, Zofran may increase patient-controlled administration of tramadol. Monitor patients to ensure adequate pain control when ondansetron is administered with tramadol.

Chemotherapy

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

In a crossover trial in 76 pediatric patients, intravenous ondansetron did not increase systemic concentrations of high-dose methotrexate.

Alfentanil And Atracurium

Zofran 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.

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.