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zofranWhen Zofran (ondansetron) first received FDA approval in 1991, it was the first in its class to hit the market as a new treatment for nausea and vomiting. The drug was intended to treat sickness following surgery, chemotherapy or radiation, but doctors have been prescribing it for off-label purposes such as morning sickness in pregnant women.

About 1 million pregnant women are exposed to Zofran or its generic equivalent each year, according to Dr. Gideon Koren who published a review of research on Zofran use in pregnant women in the December 2014 issue of American Journal of Obstetrics and Gynecology. He concluded that, given the conflicting studies, “ondansetron use cannot be assumed to be safe during pregnancy.”

Manufacturer GlaxoSmithKline faces serious allegations in more than a dozen Zofran lawsuits that claim the company “aggressively marketed the drug for morning sickness” to doctors and their patients, though they were allegedly aware of “known risks.” Given the similarities in many of the lawsuits filed, it is expected they will be consolidated as part of multidistrict litigation in the very near future, which will streamline court proceedings.

What is Zofran?

Zofran is an anti-emetic belonging to the 5-HT3 antagonist class of drugs, which increases gastric emptying by blocking serotonin in the areas of the brain that trigger nausea and vomiting. Researchers are also looking into other off-label uses for ondansetron like its ability to inhibit advanced Parkinson’s disease related psychosis, reduce cravings in alcoholics and drug addicts, and prevent post-anesthetic shivering.

Common Zofran side effects

The most common Zofran side effects include:

  • Headache
  • Fatigue
  • Diarrhea
  • Constipation
  • Dizziness
  • Wound healing problems
  • Drowsiness

More serious side effects reported to the FDA include:

  • Drug interactions: Ondansetron use along with drugs like Apomorphine, Phenytoin, Carbamazepine, Cisplatin, and Rifampicin has allegedly caused “profound hypotension and loss of consciousness.” Zofran should also be avoided by patients on tricyclic or serotonin reuptake inhibitor anti-depressants due to concerns about potentially fatal Serotonin Syndrome.
  • Hypersensitivity: Patients with a hypersensitivity to 5-HT3 receptor antagonists may suffer shortness of breath, edema, ECG changes, low thyroid functioning, and potentially fatal heart rhythm abnormalities.
  • Masked health problems: Gastric distension may be masked in surgical and chemotherapy patients taking ondansetron.

Zofran is labeled as “Pregnancy Category B,” which means that animal studies show no risks, but there have been “no adequate and well-controlled studies” demonstrate its safety in pregnant women. The label specifically indicates that ondansetron should “be used during pregnancy only if clearly needed.” Further caution is urged for nursing women, as it is “not known whether ondansetron is excreted in human milk.”

Ondansetron and birth defect risks

Initially, a report published in the February 2013 issue of the New England Journal of Medicine examined a Danish registry of 608,385 pregnancies and found no link between Zofran, stillbirth incidences, low birth weight, preterm delivery, or any major birth defects. Critics argued that the risk was not thoroughly assessed because the sample size was too small, the study period (from 2004 to 2011) was too brief, and researchers had primarily looked at mothers given ondansetron past the first 10 weeks (the critical period) of pregnancy.

Another group of researchers looked at the same Danish registry, expanding the scope of the investigation to include 903,207 births between 1997 and 2010, including only women exposed to ondansetron during the first trimester. They found that Zofran use in the first trimester doubled the risk of heart defects and increased the risk of general birth defects by 30 percent.

Birth defects identified in the study included:

  • Heart defects
  • Cleft lip and palate
  • Club feet
  • Craniosynostosis
  • Kidney defects
  • Growth restriction
  • Jaundice
  • Fetal death

On June 25, 2014, the Toronto Star published a scathing review of Zofran as an unapproved morning sickness treatment. Their examination of the FDA’s public side-effect report database from 2012 uncovered two infant deaths, multiple cases of heart defects and kidney malformations, birth weights as low as 4.5 pounds, and musculoskeletal anomalies among babies born to mothers taking ondansetron.

Plaintiffs have since filed suit against GSK, alleging a causal link between Zofran and birth defects, arguing that consumers were not properly warned about the potential dangers posed to pregnant women and their unborn children.

FDA safety announcements

The US Food & Drug Administration has published three safety announcements regarding Zofran use:

  • Abnormal heart rhythms (9/15/2011) – The FDA announced a new warning for patients with congenital long QT syndrome to avoid the medication due to risk of developing Torsades des Pointes, reporting: “Ondansetron may increase the risk of developing abnormal changes in the electrical activity of the heart, which can result in a potentially fatal abnormal heart rhythm.” Additional recommendations for ECG monitoring for patients with electrolyte abnormalities, congestive heart failure and patients taking medications that lead to QT prolongation were also added.
  • Abnormal heart rhythms (6/29/2012) – The FDA alerted health care professionals of a clinical study suggesting that a single 32 mg intravenous dose of ondansetron “may affect the electrical activity of the heart,” which could “pre-dispose patients to develop an abnormal and potentially fatal heart rhythm known as Torsades de Pointes.” GlaxoSmithKline would be removing the 32 mg dose from their labeling, the FDA added.
  • Serotonin syndrome (9/19/2014) –The FDA announced that they had “identified a potential safety issue” regarding 5-HT3 receptor drugs like Zofran, Aloxi, Kytril, and Zuplenz based on information from the FDA Adverse Event Reporting System taken from January to March 2013. The FDA said they are “continuing to evaluate” a possible risk of Seratonin Syndrome with these drugs’ use. Symptoms of Seratonin Syndrome may include agitation, confusion, fever, muscle spasms, headache, diarrhea, high blood pressure, seizures, heartbeat irregularities and even death.

  1. Int Soc Pharmacoepidemiol – “Ondansetron use in early pregnancy and the risk of congenital malformations”

  2. National Law Review – GlaxoSmithKline Seeks Consolidation of Zofran Lawsuits in Federal Court

  3. New England Journal of Medicine - Ondansetron in pregnancy and risk of adverse fetal outcomes.

  4. FDA Drug Safety Communication - New information regarding QT prolongation with ondansetron (Zofran)

  5. FDA - Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS) between January– March 2013

  6. NIH - “Medications Used to Treat Nausea and Vomiting of Pregnancy and the Risk of Selected Birth Defects”

  7. Toronto Star – Birth Defects Blamed On Unapproved Morning Sickness Treatment