Tuesday, December 8, 2015

Ondansetron Revisited: New and troubling data


Ondansetron is a 5-HT3 receptor antagonist manufactured by GlaxoSmithKline in US and is also available in its generic form, ondansetron.

The drug was approved by The U.S. Food and Drug Administration in 1991 for treating nausea and vomiting caused by cancer treatments such as chemotherapy.

However, doctors began using the drug off-label to treat women with morning sickness.

Presently, 97.7% of prescriptions for the treatment of nausea and vomiting in pregnancy in the United States 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.

The use of ondansetron for nausea and vomiting in pregnancy has increased from 50,000 monthly prescriptions in 2008 to 110,000 at the end of 2013, despite unresolved issues regarding fetal safety and Food and Drug Administration warnings about serious dysrhythmias.

Sales of antiemetics for NVP in the US, 2008-2014
IMS National Prescription Audit from 2008 to 2014.

Estimates suggest one out of every four pregnant women receive a prescription for ondansetron.

In January 2012, a study from the Center for Birth Defects Research and Prevention identified a twofold increased risk for cleft palate associated with ondansetron exposure used for Nausea Vomiting in Pregnancy (NVP) in the first trimester. The study used data from the National Birth Defects Prevention Study, looking at the association between NVP and treatments for NVP and cleft palate, and other noncardiac birth detects.

In 2013, a Danish study by Pasternak B et al compared pregnancy outcomes among almost 2,000 women exposed to ondansetron in pregnancy, and women not exposed to the drug between 2004 and 2011. Exposure to ondansetron was not associated with an increased rate of major malformations (at about 3%), or other adverse fetal outcomes, including stillbirth, preterm delivery, and low birth weight, compared with the unexposed pregnancies

Following this in August 2013, at the International Society of Pharmacoepidemiology meeting in Montreal, the results of a different group of Danish researchers using data from the same national registries employed in the study published in February, but with more pregnancies (almost 900,000) over a longer period (1997 to 2010), detected a twofold increase in congenital heart defects associated with ondansetron during the first trimester of pregnancy.

Overall, the risks associated with ondansetron exposure during the first trimester of pregnancy remain unclear. Most observational research suggests that ondansetron is unlikely to increase the risk for miscarriage, stillbirth, or major birth defects. The few studies evaluating the effect of ondansetron on specific birth defects associate ondansetron exposure early in pregnancy with a small but significant risk for cleft palate and heart defects.

There are also potential maternal risks associated with taking Ondansetron  especially in pregnant women with electrolyte imbalance due to severe nausea and vomiting. These risks include the Serotonin Syndrome which is a triad of cognitive or behavioral changes including confusion, agitation, autonomic instability, and neuromuscular changes.

With these recent studies, we are left with contradictory results regarding the risk of birth defects associated with ondansetron exposure in the first trimester, and more studies may be needed.

Prescribing ondansetron as a first line option is not consistent with American Professors in Gynecology and Obstetrics and American College of Obstetricians and Gynecologists evidence-based recommendations for the management of NVP.

Ondansetron is not recommended by current guidelines as a first-line option for nausea and vomiting in pregnancy. Initial treatments are lifestyle and dietary modifications. If drug therapy is required, doxylamine/pyridoxine is FDA-approved and guideline-endorsed for the treatment of nausea and vomiting in pregnancy. 

In conclusion, with the availability of a safe and effective FDA-approved drug for NVP, there is no reason for women to be exposed to a drug of unproven maternal and fetal safety, which has not been labeled for NVP. 

Given the current evidence, ondansetron should be avoided in the first trimester of pregnancy unless other treatments are ineffective.

Several families filed lawsuits after their children suffered a number of defects, including: mental problems, vision issues, heart defects, cleft palate and lip, clubbed foot and skull deformities.

One of the suits, filed in July 2015 by Angela and Brian Kutzer, claims Glaxo paid doctors to promote and prescribe Zofran and made “false representations about the safety and efficacy” of the drug.

As of October 2015, these lawsuits were consolidated into a multidistrict legislation in the Eastern District of Pennsylvania.


·        Einarson A, Maltepe C, Navioz Y, Kennedy D, Tan MP, Koren G. The safety of ondansetron for nausea and vomiting of pregnancy: A prospective comparative study. BJOG. 2004;111:940-943. Abstract
·        Colvin L, Gill AW, Slack-Smith L, Stanley FJ, Bower C. Off-label use of ondansetron in pregnancy in Western Australia. Biomed Res Int. 2013;2013:909860.
·        Pasternak B, Svanstrom H, Hviid A. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med. 2013;368:814-823. Abstract

1 comment:

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