Zofran is a dangerous drug whenever it is used to treat conditions for which it is not indicated, such as the off-label suppression of nausea and vomit in pregnant women. Zofran is the brand name of the drug Ondansetron, an antiemetic drug marketed by the pharmaceutical company GlaxoSmithKline (GSK) since the Food and Drugs Administration (FDA) approved its use in the US in 1991 1. This drug was one of the highest-selling medications in America: almost 80% of the $1.3 billion sales in the first nine months of 2006 came from the US market 2. Ondansetron is a 5-HT3 antagonist from the family of the so-called “sertrons”, that acts by blocking the action of the neurotransmitter serotonin within the human brain. Serotonin binds to the 5-HT3 receptors of the vagal afferents and solitary tract nucleus (STN), initiating the vomiting reflex. This drug inhibits serotonin binding to these receptors, effectively suppressing nausea and vomiting triggered by several chemotherapy agents, including radiations 3. Other than to prevent nausea and vomiting consequent to cancer treatments such as chemotherapy and radiotherapy, this drug is also indicated to control postoperative nausea and vomiting 4.
The risky off-label use of Zofran for morning sickness
The FDA never approved ondansetron for any indication other than those stated on the label. However, at some point, this drug started being marketed as a treatment for morning sickness even though the American College of Obstetricians and Gynecologists never recommended it 5. Nausea and vomiting are quite common during pregnancy, so many women resort to any kind of remedy to treat it especially in the most severe instances (called hyperemesis gravidarum). From 2008 to 2013, the number of monthly prescriptions of this antiemetic for nausea and vomiting in pregnancy (NVP) has increased from 50,000 to over 110,000. It was estimated that 97.7% of the US prescriptions for the treatment of NVP are with off-label medications that are not safe enough to be classified as safe in pregnancy (FDA category A) 6. The off-label use of this medication as a treatment for morning sickness, however, is not devoid of significant risks for both the mother and the fetus as well. Zofran safety in pregnant women has been classified by FDA as “category B”, meaning that there are no adequate human studies that can neither demonstrate its dangerousness nor disprove it 1.
Zofran Birth Defects
Several recent studies have thoroughly shown that ondansetron can cross the placenta and reach the fetus in a significant amount, actually questioning the safety and tolerability of this antiemetic drug during pregnancy. The longer elimination half-life of this medication in fetuses means that the medication actually keeps being active in the infant’s body for a longer time than in the mother’s one, further increasing this drug’s dangerousness during pregnancy 7, 8. A controversial Danish study that initially ruled out the potentially teratogenic effect of this medication showed opposite results after a second analysis 9. A deeper analysis of the same registry used in the first study showed that using Zofran during pregnancy was associated with a 2-fold increased risk of cardiac malformations in fetuses, and a 30% increased risk of major congenital malformations and birth defects 10. Another Swedish study published in the medical journal Reproductive Toxicology showed that the off-label use of this medication during pregnancy was associated with a significantly increased risk for a cardiac septum defect 11. Other birth defects include cleft palate, cleft lip, renal malformations and neural tube defects, as showed by the results of a study from the Center for Birth Defects Research and Prevention that included almost 10,000 pregnant women 12.
Several pregnant women suffer from depression and are thus prescribed other drugs that help them cope with this condition. These drugs include selective serotonin reuptake inhibitors (SSRIs): a group of medications that affect the metabolism of a brain neurotransmitter called serotonin. In May 2013 the FDA issued a warning on 5-HT3 receptor antagonists such as ondansetron, indicating that they identified a “potential safety issue” with these drugs are co-administered together with SSRIs 13. The interaction between SSRIs and 5-HT3 receptor antagonists can, in fact, cause the dangerous serotonin syndrome, a life-threatening condition that is often difficult to recognize and which can lead a patient to death if not properly treated1 4. Symptoms of serotonin syndrome include agitation, confusion or lethargy, tremor, hyperthermia, tachycardia, dilated pupils, diarrhea, nausea, and vomiting.
Cardiovascular accidents and Abnormal heart rhythm (Arrhythmia)
In June 2012, the FDA issued another warning of possible serious cardiac output (QT) prolongation and Torsade the Pointe after administration of the antiemetic. This medication may, in fact, affect the electrical activity of the heart, resulting in potentially fatal arrhythmias. FDA thus recommended against the use of this drug in patients with congestive heart failure or congenital long-QT syndrome, taking concomitant medications that prolong the QT interval, or suffering from electrolyte abnormalities such as hypokalemia or hypomagnesemia 15. The risk for serious cardiovascular accidents including sudden death linked to this medication was so high that, in December 2012, FDA decided to recall the 32 mg intravenous (IV) dose from the market 16. Again, as it has never been approved for use in pregnant women, FDA did not address the particular dangers associated with this drug during pregnancy. However, severe nausea and vomiting associated with hyperemesis gravidarum can cause dehydration and electrolyte imbalances, making ondansetron an extremely dangerous and unsafe medication in pregnant women.