Drugs, pregnancy, and lactation: ondansetron--troubling data.

For some time, the potent antiemetic ondansetron, a 5-H[T.sub.3]receptor antagonist approved for preventing nausea and vomiting relatedto cancer chemotherapy and surgery, has been used to treat morningsickness, mostly for severe cases of nausea and vomiting in pregnancy(NVP). Ondansetron, which blocks the action of serotonin, is marketed asZofran in the United States and Canada, and is also available in genericformulations.Like most drugs, ondansetron is not labeled for use in pregnancy.
But until recently, the limited reproductive safety data available on
ondansetron have been somewhat reassuring. The first published report
was a Motherisk study comparing pregnancy outcomes of three groups of
women who called a teratogen information service. My colleagues and I
found no increase in the major malformation rate among http://zofranrecallcenter.com/zofran-birth-defects/ - zofran lawsuit utah - the 176
pregnancies of women exposed to ondansetron (a 3.6% rate of major
malformations), compared with the rates among women exposed to other
antiemetics and those exposed to drugs known not be teratogenic (BJOG 2004;111:940-3). However, this sample size could not rule out less than
a threefold increase in malformation rates.

More reassuring data became available earlier this year with the
publication of a study using data from Danish pregnancy birth, and
prescription registries. The study 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
(N. Engl. J. Med. 2013;368:814-23).

However, the mean gestational age of exposure was 10 weeks, so halfthe women who took ondansetron started treatment after that time, pastthe window of risk for malformations, which may have diluted the risk,if it existed. Still, this limitation did not deter from the strength ofthe condusions of the study.But new and troubling evidence suggesting that the drug may be
associated with increased risks during pregnancy--both maternal and
fetal--has recently become available in the medical literature and
elsewhere.

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 (1997-2010), detected a twofold
increase in congenital heart defects associated with ondansetron during
the first trimester of pregnancy.

Of the 1,248 women who filled a prescription for ondansetron during
the first trimester, 4.7% (58) had a baby with a congenital
malformation, compared with 3.5% (31,357) of those who were not exposed
to ondansetron; this represented a 30% increased risk (adjusted odds
ratio, 1.3).

The increased risk was mostly due to the increased prevalence of
heart defects. There was no association with congenital malformations
and first-trimester prescriptions for metoclopramide, another drug used
to treat hyperemesis gravidarum.

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 NVP in the first
trimester. There were over 9,000 pregnant women in the study overall,
both cases and controls; 67% reported NVP and 15% used some kind of
agent to treat NVP. 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 (Birth
Defects Res. A Clin. Mol. Teratol. 2012;94:22-30).

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.

Importantly, potential risks of ondansetron, namely, cardiac
arrhythmias and serotonin syndrome--which can be harmful to both the
mother and fetus--also should be considered. In June 2012, the Food and
Drug Administration (FDA) issued an updated warning about the possible
increased risk of prolongation of the QT interval, which can result in
the potentially fatal arrhythmia Torsade de pointes, associated with
ondansetron. The warning advised against using ondansetron in patients
with congenital long-QT syndrome, and recommended ECG monitoring for
certain patients on ondansetron, including those with electrolyte
abnormalities.

Based on what we hear from women who have been treated withondansetron during pregnancy and contact Motherisk, most clinicians arenot following these recommendations in pregnant women. But monitoringpregnant women taking ondansetron for NVP for these adverse effects isjust as important--particularly because they are prone to electrolyteimbalances, including hypokalemia and hypomagnesemia, specified in theFDA warning.Another recent development is the FDA's announcement in May
2013 that an increased risk for serotonin syndrome in patients taking
5-H[T.sub.3] receptor antagonists, including Zofran, has been identified
as a tential safety issue" in the FDA's adverse event
reporting database during the first quarter of 2013, and that the agency
was investigating this possible association further.

Typically, serotonin http://www.empr.com/zofran-injection/drug/1499/ - http://www.empr.com/zofran-injection/drug/1499/ - syndrome occurs with the coadministration of
two or more dugs that affect serotonin, usually selective serotonin
reuptake inhibitors (SSRIs) or monoamine oxidase (MAO) inhibitors. Cases
of possible or probable serotonin syndrome have been reported with the
use of ondansetron, and because many pregnant women are treated with
SSRIs during pregnancy, the potential for serotonin syndrome with an
SSRI and ondansetron should be considered. Therefore, life-threatening
serotonin syndrome--characterized by a triad of cognitive or behavioral
changes, such as confusion or agitation; autonomic instability; and
neuromuscular changes--should be kept in mind as another potential risk
for pregnant women taking ondansetron.

Based on the available data, one therefore needs to be cautious
with ondansetron, considering the potential risks of cardiac
malformations and oral clefts with first-trimester exposure, which needs
to be studied further, and the maternal risks of serotonin syndrome and
cardiac arrhythmias.

For about 30 years, there was no drug labeled in the United States
for morning sickness, after the unjustified removal of Bendectin
(doxylamine-pyridoxine). Hence, ondansetron has been increasingly used
off-label for this indication. But now that the FDA has approved
Di-clegis (doxylamine succinate and pyridoxine hydrochloride) for
morning sickness--the doxylamine-pyridoxine combination that has been
studied in hundreds of thousands of pregnant women and is a pregnancy
category A drug--there is now a safer option for women with NW.
Therefore, ondansetron should be used cautiously in pregnant women, and
only after drugs with a more established safety record--particularly
doxylamine-pyridoxine--have been prescribed.

E-mail him at obnews@frontlinemedcom.com. Scan the code for more at
obgynnews.com.

Caption: DR. KOREN

BY GIDEON KOREN, M.D.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy,
medicine, and medical genetics at the University of Toronto. He heads
the Research Leadership for Better Pharmacotherapy During Pregnancy and
Lactation at the Hospital for Sick Children, Toronto, where he is
director of the Motherisk Program. He also holds the Ivey Chair in
Molecular Toxicology at the department of medicine, University of
Western Ontario, London. Dr. Koren was a principal investigator in the
U.S. study that resulted in the approval of Didegis, marketed by
Duchesnay USA, and he has served as a consultant to Duchesnay.

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