Since 2008, the Institute for Safe Medication Practices (ISMP) has published QuarterWatch, a program that allows us to look at medication errors and serious side effects reported to the US Food and Drug Administration (FDA) during specific 3-month periods each year. The primary goal of the program is to improve patient safety through the identification of signals that may represent serious safety issues with medications. The term signal means evidence that, in our judgment, is substantial enough to warrant further investigation to determine frequency of occurrence and establish a causal relationship to the suspect drug. We report these potential safety problems to FDA and the companies that make the medicines and we also let your doctors, nurses, and pharmacists know about them by getting the word out to the public through professional media and news reports.
Last week we published QuarterWatch for the third quarter of 2010. Of note, one of the drugs that stood out was Chantix (varenicline), the stop-smoking drug which is heavily advertised on TV. Since 2009, Chantix has carried a boxed warning in its labeling about a possible association of Chantix with suicidal thoughts and aggressive behavior. Before the third quarter last year, FDA's adverse-event database had shown 37 suicides reported to the agency by the manufacturer, Pfizer, and an additional 85 reported by consumers and doctors. During third quarter 2010, we found that hundreds of older serious psychiatric adverse event reports regarding Chantix were not initially entered into the FDA Adverse Event Reporting System (AERS) by Pfizer per usual procedure. Most notable were 150 cases of completed suicides, some dating back to 2007.
In brief, when a drug company learns of a patient’s death, an “expedited” report is normally submitted to FDA within 15 days and flows automatically into AERS. But for unknown reasons, Pfizer classified these suicides among less serious injuries and submitted them amid hundreds of other less serious reports as an appendix to a quarterly text report intended for page-by-page reading. So the reports were not entered into the FDA Adverse Event Reporting System (AERS) as FDA expected.
Thus, until July 2010, when FDA asked the manufacturer to resubmit "thousands" of reports that were reported in periodic summary reports to the agency's AERS system, safety analysts were not aware of more than half of the reported suicide cases in which Chantix was the primary suspect drug, and did not have available hundreds of other reported cases of serious psychiatric side effects. So much missing data could have led to an underestimation of the risks of Chantix.
In response to our QuarterWatch publication last Thursday, FDA posted a statement acknowledging that the reports were initially sent to the Agency in a way that did not allow for comprehensive evaluation. They also noted that a few other manufacturers were also submitting some adverse-event reports through "improper" channels.
FDA said that the reports about Chantix confirmed what they already knew about Chantix and would not have changed the Agency's position on the drug's risks and benefits, given that the data in these reports were consistent with those that led to the 2009 labeling change. They are continuing to monitor the drug’s safety. FDA said they also initiated additional post-market safety activities such as requiring Pfizer to conduct a large, comparative, post-market clinical trial assessing the safety of Chantix among other smoking cessation aids. FDA has also initiated two observational safety studies on Chantix, one with the Veterans Administration and one with the Department of Defense.
When we first examined varenicline data in 2008, reports for this drug outnumbered reports for all other US prescription drugs, although dispensed prescriptions and reported events later declined. Now, with a spike of 1,055 serious ADEs reported in the third quarter of 2010, varenicline again surpassed all other drugs we regularly monitor and also ranked first in reported deaths—more than twice as many as any other drug.
Two other drugs also presented safety signals during Q3 2010. One of these was the new diabetes drug Victoza which was associated with reports of pancreatitis. FDA approval of this drug was controversial because of uncertainty about its cardiovascular risks, and because animal studies showed an increased risk of thyroid cancer. Early adverse event reporting did not speak to these still unresolved issues, but did reveal a marked signal for pancreatitis. Evidence accumulates that similar drugs like Januvia and Byetta may all share an elevated risk of pancreatitis, although possibly to differing degrees.
Signals were also seen with Seroquel (quetiapine). The drug shares with other antipsychotic drugs the risk that some of its most common side effects can be irreversible, notably some cases of diabetes and certain movement disorders. In the third quarter of 2010 we noted hundreds of new reported cases of diabetes associated with Quetiapine, together with a smaller number of reports of dyskinesia (involuntary muscle movements), dystonia (spasms or prolonged contractions), and parkinsonism (tremors or muscle rigidity). You can find our full report here.
Most of the time medicines provide much needed benefits to consumers when used safely. However, there is a great need for better communication and management of risks associated with medicines. The best recommendation we can give to consumers is to be informed. Discuss all your options with your doctors and pharmacist, and ask about the serious side effects of medicines. I highly recommend that you sign up for customized safety alerts for the medications you take). In this way you can help make the most informed decisions about your healthcare.