The most common side effect of Zofran (ondansetron) is headache, which affects up to 24% of people taking it for chemotherapy-related nausea. Constipation and diarrhea are the next most frequent complaints. Most side effects are mild and resolve on their own, but there are a few less common reactions worth knowing about.
Headache, Constipation, and Diarrhea
Headache is by far the most reported side effect across every use of Zofran. In clinical trials for moderately emetogenic chemotherapy, 24% of patients on Zofran reported headaches compared to 13% on placebo. For people using it after surgery, the rate drops to about 9%, versus 5% on placebo. Even at its lowest reported rate, headache is still roughly twice as common with Zofran as without it.
Constipation shows up in about 9% of people taking Zofran for chemotherapy-related nausea, compared to less than 1% on placebo. That’s a significant jump, and it makes sense given how the drug works: Zofran blocks certain receptors in the gut that help regulate how quickly food moves through your digestive tract. Slowing things down is a predictable trade-off for stopping nausea. Diarrhea, somewhat paradoxically, also appears in about 4% of patients receiving higher doses for highly emetogenic chemotherapy.
Dizziness and Vision Changes
Some people experience transient dizziness during or shortly after receiving Zofran, particularly when it’s given intravenously. Blurred vision has also been reported, sometimes with difficulty focusing. These effects are typically brief. In rare cases with IV administration, temporary vision loss has occurred, resolving anywhere from a few minutes to 48 hours later.
Liver Enzyme Elevations
Zofran can cause temporary increases in liver enzymes, the blood markers that indicate liver stress. In clinical trials, 6% to 8% of patients on Zofran showed significant elevations, compared to about 2% on an older anti-nausea drug. One study found that 17% of patients with normal baseline levels saw a temporary spike in one liver enzyme (ALT) to twice the upper limit of normal.
These increases are generally transient and don’t appear to be related to dose or how long you take the drug. They typically don’t cause symptoms you’d notice, and they resolve after stopping Zofran. But if you’re on the medication for an extended period, your provider may check liver function through routine blood work.
Heart Rhythm Changes
Zofran can affect the electrical timing of your heartbeat, a change called QT prolongation. This happens in a dose-dependent way, meaning higher doses carry more risk. At an 8 mg IV dose, the effect on heart rhythm is small (about 6 milliseconds longer than placebo). At 32 mg IV, it jumps to 20 milliseconds, which is why the FDA pulled the 32 mg IV dose from the market and capped single IV doses at 16 mg.
For most people taking standard oral doses, this isn’t a practical concern. The risk increases substantially if you have a pre-existing heart rhythm condition, heart failure, low potassium, or low magnesium. It also rises if you’re taking other medications that affect heart rhythm. In rare cases, a dangerous arrhythmia called Torsade de Pointes has been reported.
Serotonin Syndrome Risk
Zofran works by blocking serotonin receptors, which means it interacts with the same brain signaling system targeted by many antidepressants. If you take Zofran alongside an SSRI, SNRI, or other serotonin-boosting medication, there’s a potential for serotonin syndrome, a condition where serotonin levels climb too high. The interaction is classified as moderate to major in clinical significance.
Signs of serotonin syndrome include high body temperature, elevated blood pressure, and muscle rigidity. It can also cause agitation, rapid heart rate, and loss of coordination. This is uncommon, but it’s worth flagging if you’re on antidepressants and your provider prescribes Zofran for nausea.
Zofran During Pregnancy
Many people encounter Zofran for the first time when it’s prescribed for severe morning sickness, so questions about pregnancy safety come up often. Some studies have suggested a possible doubling in risk of cleft palate and heart defects in babies exposed to ondansetron during pregnancy, but other studies using similar data did not replicate those findings.
Even if the increased risk is real, the absolute numbers remain very small. Cleft palate occurs in roughly 1 in 1,000 births normally, so a doubling would mean approximately 2 in 1,000. UT Southwestern Medical Center has characterized the risk as “very, very small.” The decision to use Zofran during pregnancy typically comes down to weighing that small potential risk against the severity of nausea and dehydration.
How Long Side Effects Last
Zofran is a relatively short-acting drug. After an oral dose, it reaches peak levels in the bloodstream within one to two hours. Most side effects track with the drug’s presence in your body, so they tend to fade as the medication is cleared. The FDA label repeatedly describes side effects like dizziness, vision changes, liver enzyme elevations, and heart rhythm effects as “transient,” meaning they resolve once the drug wears off or is discontinued. Headache and constipation may linger slightly longer if you’ve been taking multiple doses over several days, but they generally clear within a day or two of your last dose.