FDA Requires Boxed Warning on Serious Neuropsychiatric Events for Chantix and Zyban. Is a Ban Next?

The U.S. Food and Drug Administration (FDA) announced on July 1, 2009, that it is requiring manufacturers to put a Boxed Warning on the prescribing information for the smoking cessation drugs Chantix (varenicline) and Zyban (bupropion) and to update the Medication Guides for patients that further discuss the risk of mental health events when using these products. The warning will highlight the risk of serious mental health events including changes in behavior, depressed mood, hostility, and suicidal ideation and behaviors when taking these drugs.

The FDA has received additional information bolstering the suggestion of a possible association between both varenicline and bupropion and serious neuropsychiatric symptoms, in both patients with and those without previous history of psychiatric illness. The FDA first informed the public about the possibility of serious neuropsychiatric symptoms with Chantix on November 20, 2007. The FDA reviewed the agency’s Adverse Event Reporting System (AERS) cases describing suicidal ideation and behavior reported for these compounds from the date of each compounds approval (from approval of the smoking cessation indication for bupropion) to November 27, 2007. The FDA identified 153 reports of suicidal adverse events for varenicline (suicidal ideation-116, suicide-37) and 75 reports for bupropion (suicidal ideation-46, suicide-29).

The FDA states that it believes that these cases likely represent a fraction of those that occurred during this time period due to under reporting to FDA AERS. The total yearly prescriptions and units sold for these products is estimated in the millions. The analyses revealed that some who have taken Chantix and Zyban have reported experiencing unusual changes in behavior, become depressed, or had their depression worsen, and had thoughts of suicide or dying. In many cases, the problems began shortly after starting the medication and ended when the medication was stopped.

However, some people continued to have symptoms after stopping the medication. Also, in a few cases, the problems began after the medication was stopped. Similar information on mental health events will be required for bupropion marketed as the antidepressant Wellbutrin and for generic versions of bupropion. These drugs already carry a Boxed Warning for suicidal behavior in treating psychiatric disorders. Manufacturers also will be required to conduct a clinical trial to determine how often serious neuropsychiatric symptoms occur in patients using various smoking cessation therapies, including patients who currently have psychiatric disorders.

The FDA’s review of adverse events for patients using nicotine patches did not identify a clear link between those medications and suicidal events. The FDA has, over time, progressively increased the seriousness of its concerns and warnings concerning Chantix. Following the FDA’s initial information to the public in November of 2007, on February 1, 2008, the FDA issued an alert as its review of the issue has shown it to be increasingly likely that there is an association between Chantix and serious neuropsychiatric symptoms. As a result, FDA requested that Pfizer, the manufacturer of Chantix, elevate the prominence of this safety information to the WARNINGS and PRECAUTIONS sections of the Chantix prescribing information.

Now that a Boxed Warning has been required, what’s next? A ban?

Last fall, the FDA also began looking into scores of patient reports about blackouts and injuries while taking Chantix. The Federal Aviation Administration later banned use of Chantix by pilots and air traffic controllers. The drug’s label also warns that patients may be too impaired to drive or operate heavy machinery.

Healthcare professionals are being requested to discuss with patients, family members, and caregivers the following:
1. Discuss the possibility of serious neuropsychiatric symptoms in the context of the benefits of quitting smoking with patients before prescribing these medications. Varenicline and bupropion are both effective smoking cessation aids and the health benefits of smoking cessation are immediate and substantial.
2. Worsening or recurrence of serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder, even when the illness was under control. Some patients have experienced a recurrence of a previous psychiatric illness when taking these drugs for smoking cessation.
3. Patients should be instructed to contact their healthcare provider immediately if they observe or develop thoughts about suicide or attempting suicide, feel agitated, aggressive or violent and other unusual changes in mood or behavior.
4. Some symptoms are to be expected when quitting smoking such as irritability, feeling anxious, depressed mood and trouble sleeping when they are withdrawing from nicotine, independent of whether they are taking varenicline or bupropion and that vivid, unusual, or strange dreams may occur while taking Chantix and are not a cause for alarm.
5. Patients who discontinue treatment because of neuropsychiatric events should continue to be monitored until symptoms resolve.
6. Discuss other methods of quitting smoking if it is decided that varenicline or bupropion are not the best treatment option.

Chantix is manufactured by New York-based Pfizer Inc. Zyban is manufactured by GlaxoSmithKline, Brentford, Middlesex, United Kingdom. Chantix was approved in 2006. Saleswere $846 million in 2008, 4 percent less than the prior year due to concerns over side effects.

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