Zofran (Ondansetron) adverse reactions include a life-threatening condition called serotonin syndrome when it interacts with other medications. When GlaxoSmithKline (GSK) started marketing this drug as an off-label medication to treat morning sickness and nausea and vomiting in pregnancy (NVP), they never suspected that this drug could be so dangerous. Or maybe they did, as in 2012 the U.S. Department of Justice (DOJ) found them guilty of criminal behavior and misrepresenting animal studies to hide the possible toxicity of this drug (1). Zofran is an antiemetic serotonin 5-HT3 receptor antagonist approved by Food and Drugs Administration (FDA) for the treatment and control of nausea and vomiting consequent to cancer treatments and surgical interventions (2). However, its widespread use as an off-label medication during pregnancy exposed millions of pregnant women and their babies to serious risks such as birth defects, arrhythmias, and serotonin syndrome.
What is Serotonin Syndrome?
Serotonin (also known as 5-hydroxytryptamine; 5-HT) is a neurotransmitter produced by the human body that serves various roles such as transmitting nervous signals between the gastrointestinal tract (GI tract) and the central nervous system (CNS). Serotonin is very well known for its effects on mood, as it contributes to the subjective sensation of well-being as well as regulating sleep and appetite (3). Serotonin, however, is also responsible for chemotherapy-induced nausea and vomiting, and, for this reason, all the “sertron” drugs such as ondansetron act by blocking the 5-HT3 receptor in the brain and suppressing these symptoms (4).
As reduced levels of serotonin are often associated with depression, several drugs such as Selective serotonin reuptake inhibitors (SSRIs) act by increasing the amount of serotonin in the blood. However, interactions and combinations between drugs that exert a similar serotonin-increasing effect such as Zofran or some antibiotics may become dangerous if the levels of this neurotransmitters reach a certain point. Serotonin syndrome is, in fact, a consequence of serotonin poisoning, and it is a serious condition that can cause a patient’s death if it is not quickly treated.
Serotonin syndrome symptoms include (5):
- Agitation or restlessness
- Rapid heart rate and high blood pressure
- Dilated pupils
- Loss of muscle coordination or twitching muscles
- Muscle rigidity
- Heavy sweating
However, when the severity of the syndrome reaches a certain point, other symptoms such as high fever, seizures, irregular heartbeat and unconsciousness may appear. In this case, the patient’s life is at risk, and emergency treatment should be sought immediately.
Zofran serotonin syndrome during pregnancy
Ondansetron can cause a serotonin syndrome when used in combination with other drugs such as SSRIs and monoamine oxidase inhibitors (MAOIs). Two years ago the FDA issued a warning on 5-HT3 receptor antagonists including Zofran, stating that they can pose a “potential safety issue” for serotonin syndrome when they are co-administered together with SSRIs or other similar serotonin-blocking drugs (6). The studies that have been published showed that these medications can increase serotonergic activity to abnormally high levels when used in combination with fentanyl (an opioid analgesic often used to treat pain during labor and delivery) and mirtazapine (a new antidepressant drug) (7).
Depression, however, is a very common condition in pregnant women, which are thus prescribed antidepressant medications to help to cope with this disorder. About 20% of women suffer from depression during their lifetime, with pregnancy being one of the most vulnerable periods of their lives (8). As depression during pregnancy is a matter of great importance mostly because it leads to negative maternal and fetal outcomes, this condition is often treated with antidepressant medication such as SSRIs or MAOIs. The off-label use of Zofran to treat morning sickness and NVP can thus lead to dangerous drug interactions. However, as FDA never approved this drug for use during pregnancy, no recommendations against its use have ever been issued. It should also be noted how depression seems to be more frequent during the earliest period of gestation, which is also the time when women are more at risk of birth defects (9).
Article written by: Dr. Claudio Butticè, Pharm.D.
Last Updated: 2016/05/31