What is Zofran?
Zofran (ondansetron) and its spinoff Zuplenz are prescription medications approved to prevent nausea and vomiting associated with surgery and cancer chemotherapy and radiation therapy.
Increasingly, doctors prescribe Zofran for off-label — or unapproved — uses such as treating stomach problems in children and morning sickness in expectant mothers.
First in Class to Go to Market
In 1991, the U.S. Food and Drug Administration (FDA) approved Zofran, making it the first in its class to hit the market.
GlaxoSmithKline developed, manufactured and sold the drug. The company’s patent for Zofran expired at the end of 2006, and the FDA approved generic versions of ondansetron from several vendors soon after. In 2015, GlaxoSmithKline sold the rights to Zofran, along with the rest of its oncology portfolio of medications, to Novartis.
MonoSol Rx developed a closely related drug, Zuplenz, and first sold it in October 2010. Today, several vendors market Zuplenz in the U.S. The medication comes in 8 mg soluble film doses that dissolve without water.
How Zofran Works
Cancer treatments induce nausea and vomiting because they cause specialized cells in the lining of the intestines to release a neurotransmitter called serotonin.
Zofran is an antiemetic medication — medication used to relieve symptoms of nausea and vomiting — and belongs to a class called 5HT3 receptor antagonists. It works by blocking serotonin in the areas of the brain that trigger nausea and vomiting.
Types of Zofran
When it first gained FDA approval in 1991, Zofran came in the form of an injection for intravenous (IV) use. Over the years, the FDA has approved various oral forms of the drug.
Zofran Injection, 2mg/L (approved 1991)
Zofran Injection is a clear, colorless solution for intravenous use. It is available as a 2 mL single dose and a 20 mL multi-dose vial.
Zofran Tablets, 4 mg and 8 mg (approved 1992)
Zofran tablets are oval-shaped, film-coated tablets engraved with “Zofran” on one side. They are available in 4 mg and 8mg doses. The 4 mg tablets are white with “4” engraved on one side. The 8 mg tablets are yellow with “8” engraved on one side.
Zofran Premixed Injection, 32 mg (approved 1995; recalled 2012)
In 2012, the 32 mg Zofran Premixed Injection was pulled from the market because of the potential for serious cardiac risks, according to the FDA. The drug was sold pre-mixed in solutions of either dextrose or sodium chloride in plastic containers.
Zofran Oral Solution, 4mg/5mL (approved 1997; discontinued 2016)
In 2016, Novartis discontinued Zofran Oral Solution without providing a reason but stating it was not due to manufacturing, product quality, safety or efficacy concerns. The drug, which comes in a 50-mL bottle, is a clear, colorless to light yellow liquid with a strawberry odor.
Zofran Orally Disintegrating Tablets 4mg, 8mg (approved 1999)
Zofran ODT Orally Disintegrating Tablets are white, round tablets. Like the Zofran regular tablets, the disintegrating tablets are available in 4 mg and 8 mg doses. The 4 mg tablets feature “Z4” on one side; the 8 mg feature “Z8.”
How to Take Zofran
Zofran’s label recommends adult patients take the first dose of ondansetron 30 minutes before they start chemotherapy, one to two hours before they start radiation therapy, or one hour before undergoing surgery. Patients sometimes take additional doses one to three times a day during chemotherapy or radiation therapy and for 1 to 2 days after they finish their treatment.
- Zofran Tablet: Zofran in the regular tablet form should be swallowed with a full glass of water. Zofran can be taken with or without food.
- Zofran ODT: To take Zofran ODT tablets, peel back the foil backing of one blister and gently remove the tablet using dry hands. Do not try to push the tablet through the foil backing. Once the tablet is out of the packaging, immediately place it on top of the tongue. The tablet will dissolve in seconds. Do not try to chew it or swallow it whole. Once the tablet has dissolved, swallow several times with saliva. You do not need to take the drug with liquid.
- Zofran Oral Solution: Patients should measure the liquid medicine with the dosing syringe provided or with a dose-measuring spoon or medicine cup. They should not take amounts of the medicine larger or smaller than what’s prescribed by a doctor.
Storing and Disposing of Zofran
Zofran users should store this medication in its original container, tightly closed and away from children. The tablets and the rapidly disintegrating tablets should be kept in the refrigerator or at room temperature away from light. Patients should not store Zofran Oral Solution in the bathroom. It should be kept in the bottle, upright, at room temperature and away from light, excess heat and moisture.
To ensure pets, children and other people cannot consume unneeded medication, dispose of Zofran carefully. This can be done through a medicine take-back program. Do not flush the medication down the toilet.
Certain drugs may increase the risk of serious side effects when used with Zofran, Zuplenz or generic ondansetron. These drugs include:
- Phenytoin, carbamazepine and rifampin
- Selective serotonin reuptake inhibitors (SSRI) and serotonin and noradrenaline reuptake inhibitors (SNRI)
- Alfentanil and atracurium
- Drugs affecting the cytochrome P-450 drug-metabolizing enzyme
Zofran is linked to possible side effects, some of which are serious, including serotonin syndrome and QT interval prolongation.
Serotonin Syndrome occurs when too much serotonin is present in the body. It is a serious condition that can be life-threatening. Symptoms include high fever, irregular heartbeat, agitation, dizziness, tremor, seizures and unconsciousness.
QT Interval Prolongation
Zofran can affect the electricity in the heart, causing erratic heartbeats that can be fatal. According to the drug’s label, electrocardiogram (ECG) monitoring is recommended in patients with conditions such as congestive heart failure.
|Other Serious Side Effects Include:|
|Blurred vision||Vision loss||Shortness of breath|
|Seizures||Loss of consciousness||Chest pain|
|Hives or rash||Swelling|
|More Common Side Effects Include:|
FDA Drug Safety Communications & Zofran Recall
In 2012, the 32 mg intravenous dose of Zofran was pulled from the market due to concerns that it could trigger QT interval prolongation, a heart rhythm disorder that could lead to an abnormal and potentially fatal heart rhythm called Torsades de Pointes. Prior to the recall, the FDA released Drug Safety Communications alerting the public to the cardiovascular safety concerns.
Abnormal Heart Rhythms
In September 2011, the FDA announced it made changes to Zofran’s label and required the manufacturer of Zofran to conduct “a thorough QT study to assess the potential for the drug to prolong the QT interval.”
The FDA had previously noted that ondansetron could increase the risk of developing QT interval prolongation. The agency also pointed to articles published in the medical literature that describe QT interval prolongation with ondansetron.
Previous versions of the ondansetron labels included a warning about QT interval prolongation. The FDA added a new warning to avoid the use of ondansetron in patients with congenital long QT syndrome because these patients are at particular risk for developing Torsade.
According to the safety communication, patients at particular risk for developing Torsade include:
- Patients with underlying heart conditions, such as congenital long QT syndrome
- Patient who are predisposed to low levels of potassium and magnesium in the blood
- Patients taking other medications that lead to QT prolongation
The agency also added recommendations for ECG monitoring in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure or bradyarrhythmias (slow heart rate) and in patients taking other medications that can lead to QT prolongation.
Clinical Study Results
The FDA released another Drug Safety Communication in June 2012, informing health care professionals and the public that preliminary results from a clinical study suggested that a 32 mg, single intravenous dose of Zofran may cause QT interval prolongation. As a result, GlaxoSmithKline removed the 32 mg, single intravenous dose from the drug’s label.
The updated label said the drug could be used in adults and children with chemotherapy-induced nausea and vomiting at a dose of 0.15 mg/kg administered every four hours for three doses; however, no single intravenous dose should exceed 16 mg.
In December 2012, the FDA notified health care professionals that the 32 mg, single intravenous dose of Zofran would no longer be marketed because of the potential for serious cardiac risks. The FDA said in its Drug Safety Communication that it was working with the manufacturers of all 32 mg dose ondansetron injectable products (brand and generic) to recall them from the market. The drugs were sold pre-mixed in solutions of either dextrose or sodium chloride in plastic containers.
List of ondansetron products voluntarily withdrawn from the U.S. market
|Ondansetron Hydrochloride Injection, USP premix in Intravia Plastic Container||Baxter Healthcare Corporation|
|Ondansetron Hydrochloride and Dextrose in Plastic Container||Hospira|
|Ondansetron Hydrochloride and Dextrose in Plastic Container||Teva|
|Ondansetron Hydrochloride and Dextrose in Plastic Container||Bedford Labs|
|Ondansetron Hydrochloride and Dextrose in Plastic Container||Claris Lifesciences|
Zofran Use in Expectant Mothers
Although Zofran, Zuplenz and the generic ondansetron are FDA-approved only for use in treating nausea and vomiting after chemotherapy or radiotherapy or after surgery, many doctors prescribe them for off-label uses, including treatment of morning sickness in expectant mothers.
Many pregnant women experience nausea and vomiting during pregnancy (NVP), commonly referred to as morning sickness. The most serious form of NVP, called hyperemesis gravidarum (HG), can lead to malnutrition and dehydration — health reactions dangerous for both the mother and the baby. NVP is most serious during the first trimester when the baby is developing. Many mothers rely on anti-nausea drugs to get them through the first few weeks.
Recognizing a new market of patients for its drug, GlaxoSmithKline advertised to doctors and mothers-to-be looking for relief from these symptoms.
‘Escalating Use of Ondansetron’ Among Pregnant Women
Ondansetron use increased from less than 1 percent of pregnancies in 2001 to 22.2 percent in 2014, according to an FDA article published in February 2017. The agency attributed much of the increase to oral ondansetron beginning in 2006.
FDA staff assessed ondansetron and other antiemetic use among pregnant women delivering live births between 2001 and 2015. In over 2.3 million pregnancies, the prevalence of ondansetron was 15.2 percent, according to the FDA. Use was highest in the first trimester.
“We observed a marked increase in ondansetron use by study year, prescribed to nearly one-quarter of insured pregnant women in 2014,”the agency said. “Given the widespread use of ondansetron in pregnancy, data establishing product efficacy and methodologically rigorous evaluation of post-marketing safety are needed.”
Zofran and Birth Defect Studies
Studies have given conflicting results about the potential for Zofran to cause birth defects. Until the FDA changed its letter rating system in 2015, Zofran, Zuplenz and the generic ondansetron were labeled as Pregnancy Risk Category B, meaning there is no evidence of risk to humans.
Still, experts say the possibility exists for Zofran to have an effect on a developing fetus because it easily crosses the placental barrier. It has also been found to take longer to leave neonatal bodies immediately after birth than it does the mother’s body.
In studies and lawsuits filed by mothers and families of injured babies, a number of birth defects are linked to the medication. These include:
In 2011, a large study by Boston University’s Slone Epidemiology Center and the Centers for Disease Control and Prevention found “possible risks” of ondansetron, particularly for cleft palate. The researchers looked at data from the National Birth Defects Prevention Study (NBDPS), a multi-site population-based case-control study, and found statistical evidence that they said “could be chance findings, [but] warrant further investigation.”
Cardiac Septum Defect
The following year, researchers led by Bengt Danielsson reviewed data from the Swedish Medical Birth Register and the Swedish Register of Prescribed Drugs to identify more than a thousand infants delivered to women who had taken ondansetron in early pregnancy between 1998 and 2012. They then performed statistical analysis on the incidence of congenital malformations and found a “low but increased risk” associated with ondansetron for “a cardiac septum defect,” but “no statistically significantly increased risk for a major malformation.”
Congenital Heart Defects
Two 2013 studies that both used data from the Medical Birth Registry and National Patient Register in Denmark yielded conflicting results regarding ondansetron and birth defects. The first study published in the New England Journal of Medicine looked at data collected between 2004 and 2011. The average age of the fetus at exposure was 10 weeks, by which time most of the danger of malformations was past. The study concluded, “Ondansetron taken during pregnancy was not associated with a significantly increased risk of adverse fetal outcomes.”
The second study, using data from the same sources but from 1997 to 2010, “found a doubling in the prevalence of major congenital heart defects in children whose mothers redeemed a prescription of ondansetron in the first trimester of pregnancy.” The study cited in particular failures of the heart to form properly called atrial septal defects, ventricular septal defects and atrioventricular septal defects
A different 2013 study, which looked at birth records in Western Australia between 2002 and 2005, “did not detect any adverse outcomes from the use of ondansetron in pregnancy but could not conclude that ondansetron is safe to use in pregnancy.” While “the study was too small to assess risks of individual birth defects” (only 251 births associated with the drug out of almost 97,000 births total) the researchers found a seven-fold increase in the risk for kidney malformations associated with ondansetron.
Ondansetron Use for Hyperemesis Gravidarum
Results of the latest study of ondansetron use for hyperemesis gravidarum (HG), published in 2016, contradicted many of the earlier studies. Researchers led by Marlena Fejzo of the UCLA Department of Medicine collected information on more than a thousand women exposed to ondansetron during pregnancy and compared to control groups of women with a history of HG but no ondansetron exposure and women with neither a history of HG nor ondansetron exposure. Not only did they not find an association between the drug and birth defects, they found evidence suggesting that women who took Zofran were less likely to have a miscarriage or a stillbirth.
Studies also link the following birth defects to Zofran:
- Mental problems
- Physical deformities
- Hearing Loss
- Vision problems
- Abnormal blood pressure
- Stomach problems
- Cleft lip
- Club foot
- Webbed toes
- Skull deformities
Review of Eight Studies
A review of eight previous studies in 2016 noted that the three largest studies showed no increased risk for birth defects, while two studies “demonstrated a slightly increased risk of cardiac defects specifically … a finding that was not replicated in other studies.”
“The most consistent association (if any) appears to be a small increase in the incidence of cardiac abnormalities, the bulk of which are septal defects,” the study’s author Shaun Carstairs wrote.
Carstairs concluded “the overall risk of birth defects associated with ondansetron exposure appears to be low.”
Alternatives to Zofran
A 2014 study in the American Journal of Obstetrics & Gynecology says 97.7 percent of prescriptions for the treatment of nausea and vomiting in pregnancy in the U.S. “are with medications not labeled for use in pregnancy, not indicated for nausea and vomiting in pregnancy, and not classified as safe in pregnancy by the Food and Drug Administration. “ That group includes Zofran, Zuplenz and ondansetron.
As an alternative, morning sickness sufferers can turn to a combination of doxylamine and pyridoxine, which the FDA approved in 2013 specifically to treat nausea and vomiting in pregnancy. It’s available under brand names such as Bonjesta and Diclegis in the U.S. and Diclectin in Canada.
While doxylamine/pyridoxine is the only FDA-approved medication for morning sickness, doctors continue to write off-label prescriptions for other medications. First-line alternatives include antihistamines diphenhydramine and meclizine, which were deemed Pregnancy Risk Category B, like Zofran.
Second-line alternatives include anti-emetic medications such as dopamine antagonists Reglan (metoclopramide), Compazine (prochlorperazine), Phenergan (promethazine), and Inapsine (droperidol). However, unlike Zofran, all of those medications were in the FDA’s Pregnancy Risk Category C, a higher-risk classification that designates drugs for which animal studies have shown adverse effects on the fetus, but there are no adequate studies of use on pregnant women.
Some doctors also suggest dimenhydrinate, the over-the-counter medication found in Dramamine, to treat morning sickness, which also falls in Pregnancy Risk Category B.
- Taylot, L.G. et al. (2017, February 21). Antiemetic use among pregnant women in the United States: the escalating use of ondansetron. Retrieved from https://www.accessdata.fda.gov/scripts/publications/search_result_record.cfm?id=56835
- U.S. National Library of Medicine. (2015, December 15). Ondansetron. Retrieved from https://medlineplus.gov/druginfo/meds/a601209.html
- What you need to know about morning sickness and NVP. Morning Sickness USA. Retrieved from http://www.morningsicknessusa.com/morningsicknessandnvp
- Horsager-Boehrer, Robyn, M.D. (2015, July 14). Zofran for morning sickness: The risks are minimal. UT Southwestern Medical Center. Retrieved from http://www.utswmedicine.org/stories/articles/year-2015/zofran-pregnancy.html
- Zofran Prescribing Information. (2016). Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020103s035_020605s019_020781s019lbl.pdf
- Einarson, A. et al. (2004, September). The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. BJOG: An International Journal of Obstetrics & Gynaecology. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15327608
- Anderka, M. et al. (2012, January). Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Research Part A: Clinical and Molecular Teratology. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299087/
- Danielsson, B. et al. (2014, December). Use of ondansetron during pregnancy and congenital malformations in the infant. Reproductive Toxicology. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25450422
- Pasternak, B. et al. (2013, February). Ondansetron in pregnancy and risk of adverse fetal outcomes. New England Journal of Medicine. New England Journal of Medicine. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23445092
- Andersen, JT et al. (2013). Ondansetron Use in Early Pregnancy and the Risk of Congenital Malformations—A Register Based Nationwide Control Study. International Society of Pharmaco-epidemiology. Retrieved from http://www.acphd.org/media/410526/ondansetron%20with%20increased%20risk%20of%20congenital%20malformations.pdf
- Colvi, Lin et al. (2013). Off-Label Use of Ondansetron in Pregnancy in Western Australia. BioMed Research International. Retrieved from https://www.hindawi.com/journals/bmri/2013/909860/
- Fejzo, Marlena S. et al. (2016, April 29). Ondansetron in pregnancy and risk of adverse fetal outcomes in the United States. Reproductive Toxicology. Retrieved from https://www.sciencedirect.com/
- Carstairs, Shaun D. (2016, May). Ondansetron Use in Pregnancy and Birth Defects: A Systematic Review. Obstetrics & Gynecology. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27054939
- Koren, G. (2014, December). Treating morning sickness in the United States—changes in prescribing are needed. American Journal of Obstetrics & Gynecology. Retrieved from http://www.ajog.org/
- LeClair v. GlaxoSmithKline. (2015, February 16). United States District Court of the District of Massachusetts. Complaint and Jury Demand. Case No. 1:15-cv-10429. Retrieved from http://zofranresourcecenter.com/wp-content/uploads/2015/02/LeClair-2.pdf
- U.S. National Library of Medicine. (2014). Zofran – ondansetron hydrochloride injection. Daily Med. Retrieved from http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d9a71b42-ddfc-49d5-7280-0fc0041dba41section-1
- Smith, Judith A. et al. (2017, January 3). Treatment and outcome of nausea and vomiting of pregnancy. UpToDate. Retrieved from http://www.uptodate.com/contents/treatment-and-outcome-of-nausea-and-vomiting-of-pregnancy
- Walker, Molly. (2016, April 14). No Clear Evidence Linking Nausea Drug to Serious Birth Defects. MedPage Today. Retrieved from http://www.medpagetoday.com/
- Siu, SS et al. (2006). Placental transfer of ondansetron during early human pregnancy. Clinical Pharmacokinetics. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16584287
- Elkomy, Mohanned H. et al. (2017, February). Ondansetron Pharmacokinetics in Pregnant Women and Neonates: Towards a New Treatment for Neonatal Abstinence Syndrome. Clinical Pharmacology & Therapeutics. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325425/
- Smith, Juditn et al. (2017, January 3). Treatment and outcome of nausea and vomiting of pregnancy. UpToDate. Retrieved from http://www.uptodate.com/contents/treatment-and-outcome-of-nausea-and-vomiting-of-pregnancy
- FDA.gov. (2016, November 11). FDA Drug Shortages. Retrieved from https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Zofran+Oral+Solution&st=d&tab=tabs-2
- Drugs.com. (2016, November 3). Zofran. Retrieved from https://www.drugs.com/zofran.html
- FDA.gov. (2011, September 15). FDA Drug Safety Communication: Abnormal heart rhythms may be associated with use of Zofran (ondansetron). Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm271913.htm
- FDA.gov. (2012, June 29). FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran). Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm310190.htm