January 4, 1991: The FDA approved Zofran (ondansetron) for chemotherapy-related nausea and vomiting (pdf).
January 5, 1993: The New York Times reported that the FDA approved a pill form of Zofran (pdf).
June 22, 1995: GlaxoWellcome submited a New Drug Application to the FDA for a 4mg/5mL dose of Zofran (ondansetron hydrochloride) (pdf @ p.10).
June 24, 1997: The FDA approved GlaxoWellcome's New Drug Application (see June 22, 1995, entry).
March 9, 1999: The FDA issued a warning letter (pdf) to GlaxoWellcome regarding its marketing of anti-nausea drug Zofran.
According to that letter, Glaxo failed to warn consumers about Zofran's adverse side effects while touting its effectiveness with statements such as:
- "Zofran can,"
- "24-hour control," and
- "Prevention of emesis I to 2 days after chemotherapy."
December 27, 2006: The FDA approved generic versions of Zofran (pdf).
August 2011: To test Zofran's cardiac risks, GlaxoSmithKline began a study titled "A Randomized, Double-blind, Four-period Crossover Study to Investigate the Effect of Intravenous Ondansetron, a 5-HT3 Antagonist, on Cardiac Conduction as Compared to Placebo and Moxifloxacin in Healthy Adult Subjects (pdf)."
September 15, 2011: The FDA issued a Drug Safety Communication regarding Zofran (pdf). That alert stated that:
- Zofran may change the heart's electrical activity and that change could cause an abnormal heart rhythm such as Torsade de Pointes; and
- Zofran's labels would therefore be revised. Per the FDA:
The labels are being revised to include a warning to avoid use in patients with congenital long QT syndrome because these patients are at particular risk for Torsade. Additionally, recommendations for ECG monitoring in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or in patients taking other medications that can lead to QT prolongation.
The FDA also ordered Zofran maker GlaxoSmithKline to conduct QT prolongation studies.
September 2011: GlaxoSmithKline revised Zofran labels (pdf) to include the following, per the FDA:
- "Information regarding post-marketing case reports of Torsade de Pointes;
- Recommendation to avoid use in patients with known congenital long QT syndrome;
- ECG monitoring recommendation in patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation."
January 2012: GlaxoSmithKline completed its study of Zofran's cardiac risks (pdf).
June 29, 2012: The FDA issued a Drug Safety Communication (pdf) in which it stated that the 32 mg dose of Zofran "may affect the electrical activity of the heart (QT interval prolongation)." This could cause some patients to develop Torsades de Pointes, a potentially fatal heart rhythm.
This alert also stated that GlaxoSmithKline was removing this dosage from Zofran labels and that "no single intravenous dose should exceed 16 mg."
July 2, 2012: The U.S. Department of Justice issued a press release (pdf) stating that GlaxoSmithKline would pay a $3 billion settlement after pleading guilty to, among other claims:
- promoting Zofran for off-label uses such as morning sickness treatment (since the FDA only approved the drug for chemotherapy-related and post-operative nausea); and
- paying doctors to prescribe the drug.
July 5, 2012: The FDA released a podcast (transcript) stating preliminary results of GlaxoSmithKline's study (see September 15, 2011, entry) showed that the 32 mg dose of Zofran could cause QT interval prolongation, which could in turn cause a fatal heart rhythm known as Torsades de Pointes.
"Patients who may be at particular risk for QT prolongation with ondansentron are those with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking concomitant medications that prolong the QT interval," the podcast stated.
December 4, 2012: The FDA issued a Drug Safety Communication in which it stated that brand name and generic versions of Zofran were being recalled in the 32 mg dose (pdf).
Per the alert, the 32 mg IV solution increased a patient's risk of developing QT interval prolongation, or irregular heart rhythm. This abnormal heart rhythm could cause Torsades de Pointes, a potentially fatal heart rhythm.
The alert also reiterated the June 2012 warning that a single IV dose should not exceed 16 mg.
The FDA noted that the 32 mg solution "accounted for less than 1 percent of ondansetron IV sales," so the recall should be completed by early 2013.