Zofran (ondansetron) is manufactured by the pharmaceutical giant, GlaxoSmithKline (GSK), the 6th largest pharmaceutical company in the world. It was approved by the U.S. Food and Drug Administration in 1991 as an IV injection for the treatment of nausea and vomiting caused by chemotherapy treatments. Within the next decade, Zofran approvals had expanded to include nausea caused by radiotherapy and surgery, availability as an oral tablet, oral solution, quick-dissolving tablet, and IM injections, and was approved for use in both children and adults.
By 2006, when Zofran’s U.S. patent expired, it was in the top-20 for drug sales with revenue of $1.5 billion per year. Though it was approved only for cancer and surgery-related nausea, it also achieved popularity as an off-label treatment for pregnancy-related nausea or morning sickness. After patent expiration, a number of generic formulations of ondansetron were approved for marketing in the U.S.
In 2011, the FDA issued a safety alert regarding Zofran and other ondansetron products, which warned about cardiac effects associated with its use and in 2012, another warning was issued over potential adverse events caused by the 32mg IV dose. After the 2012 notification, all 32mg IV dosage formulations were withdrawn from the market.
In 2013, a number of concerns were raised over potential birth defects but no warnings were issued by the FDA. In 2015, GSK sold the rights to manufacture Zofran and a number of other drugs to Swiss drug maker, Novartis, however, in March of 2018, GSK re-acquired the same drugs including Zofran. GSK has faced a number of lawsuits due to birth defects that plaintiffs claim were caused by Zofran use during pregnancy.
How does Zofran work?
Zofran is a 5-HT3 receptor antagonist which works to prevent nausea by blocking certain receptors in the gastrointestinal tract. It works differently than most other medications used to prevent nausea such as antihistamines Dramamine (dimenhydrinate), Bonine (meclizine), and Phenergan (promethazine) or stomach remedies Pepto-Bismol (bismuth salicylate) and Kaopectate (kaolin).
Antihistamines like Dramamine and Phenergan prevent nausea by blocking histamine messaging from the inner ear to the brain. Stomach remedies like Kaopectate and Pepto-Bismol work by coating the stomach lining. 5HT-3 antagonists like Zofran and another medication, Gantril, work by blocking the 5-HT3 serotonin receptor to prevent nausea.
Serotonin is a neurotransmitter used in the brain but also produced in the lining of the stomach which stimulates digestion and produces a feeling of “fullness” after eating. When a patient is treated with certain medications used in cancer treatment or surgery or when undergoing radiation therapy, a massive release of serotonin from the cells of the intestines may be triggered. The large amount serotonin released in the GI tract often results in nausea and vomiting associated with cancer treatments or while recovering from anesthesia used in surgery.
Zofran as a 5-HT3 inhibitor can prevent or reduce nausea by blocking the serotonin from interacting with the receptor. Because it acts on the 5-HT3 serotonin receptor, it has a number of side effects related to the activity and blockade of the neurotransmitter serotonin.
Zofran Side Effects
All medications have side effects, including Zofran. Most side effects of Zofran are mild or moderate, but some may be severe or life-threatening. The most concerning side effects of Zofran include effects on the heart rhythm, a potential for birth defects and a condition known as serotonin syndrome.
Common Zofran side effects include:
- Diarrhea or constipation
- A headache
- Lightheadedness or dizziness
- Drowsiness or fatigue
- Muscle spasms
- Blurred vision
Some side effects will go away with time but side effects that are bothersome or become more severe should be reported to a healthcare provider.
Serious Zofran Side Effects
Zofran may cause side effects that are more severe or may indicate a serious medical issue. Side effects or symptoms that become severe, worsen over time, affect the heart rate or muscle tone or involve changes in consciousness or behavior should be reported right away.
More serious conditions that may be related to Zofran use include:
Serotonin syndrome is a medical condition that is caused by interfering with the action of serotonin in the brain. Symptoms of serotonin syndrome caused by Zofran can include:
- Muscle rigidity
- High body temperature
- Rapid heart rate
- Changes in blood pressure
- Delirium or mental status change
Certain medications, particularly those affecting serotonin levels may increase the chance for developing these symptoms. Any symptoms of serotonin syndrome should be reported immediately and if severe, should be treated as an emergency.
Abnormal Heart Rhythm
Zofran can change the way the heartbeat is regulated or timed. In 2011, the FDA issued a safety alert regarding Zofran and its potential to affect heart rhythm. Zofran can increase the QT interval in the heart rhythm which may lead to a life-threatening cardiac condition called “torsades des pointes”. This causes a rapid rise in heart rate and may lead to heart attack and sudden death.
Though it can occur with any dosage amount, torsades des pointes has mainly occurred in patients who were given an IV infusion of 32mg with chemo or radiation therapy. After the FDA warning was issued, 32mg dosage formulations were voluntarily withdrawn from the market and are no longer available and prescribing recommendations were changed to reduce initial dosage amounts.
People with underlying heart conditions may still be at risk however and may require additional monitoring. Patients with heart conditions or a history of fainting spells should tell their physician before taking Zofran. Patients with known conditions such as congestive heart failure are recommended to have an electrocardiogram (ECG or EKG) monitoring during Zofran administration.
Though no clear link has been established, some studies have concluded that Zofran use may cause birth defects when given during pregnancy. Zofran is not approved for use during pregnancy or for nausea related to pregnancy but it has been used as an “off-label” treatment. Between 2011 and 2016, multiple studies have been performed regarding Zofran and birth defects, with mixed results.
Birth defects that have been linked to Zofran use include:
- Cleft Palate – In 2011, a Boston University study found “possible risks” linking Zofran and cleft palate. Researchers concluded that a statistical increase showed that further investigation was warranted.
- Cardiac Septum Defect – In 2012, an analysis of data of 1,000 births in Sweden showed a small but statistically significant increase in risk for cardiac septum defect.
- Congenital Heart Defects – In 2013, two studies using data from birth registries in Denmark were conducted. One of the studies showed a 30% increase in risk but the other study showed no increase in risk
- Kidney Malformations – Also in 2013, examination of birth records in Australia found a 7-fold increase in kidney malformations but noted no major adverse outcomes. The researchers believed that the study was too small to reach a conclusion but did not say the medication was safe to use during pregnancy.
The FDA has not confirmed a link and experts have stated that some of the studies may have had problems with their methodologies or the way the studies were conducted. In 2014, an article published in the American Journal of Obstetrics and Gynecology highlighted the risks of Zofran use in pregnant women and stated that conflicting study results could not rule out dangers to a developing fetus.
GlaxoSmithKline and Novartis have faced numerous lawsuits regarding birth defects that may have been caused by Zofran use.
Zofran Drug Interactions
Zofran may interact with other medications and in some cases, should not be taken with other drugs.
Drugs that interact with Zofran may include:
- Beta-blockers (atenolol, acebutolol, metoprolol) used for heart rhythm or high blood pressure
- Antiarrhythmics (amiodarone, disopyramide) used for irregular heart rhythm
- Antiseizure medications (phenytoin)
- Erythromycin antibiotics (erythromycin, clarithromycin)
- Antipsychotics (haloperidol, Mellaril and others)
- Antidepressants (venlafaxine, amitriptyline, and others)
- Pain reliever (tramadol)
Patients should discuss all of their medications with a physician or pharmacist, including over-the-counter drugs, herbs or supplements.
GlaxoSmithKline has been the subject of hundreds of lawsuits due to side effects and birth defects that may have been related to Zofran use. Novartis Pharmaceuticals purchase of GSK’s oncology division has resulted in their naming named as a co-defendant for any injuries that occurred between March 23, 2015, and March 2018. In 2018, GSK’s reacquisition of Zofran was completed.
Notwithstanding claims relating to this product, the drug/medical device remains approved by the U.S. FDA.