FDA Smokes Black Box Warning on Chantix

Megan Brooks

December 19, 2016

The US Food and Drug Administration (FDA) has approved dropping the black box warning regarding possible serious neuropsychiatric side effects with Pfizer's smoking cessation drug varenicline (Chantix, Champix), Pfizer said on December 16.

The FDA first put a black box warning on varenicline in 2009 after receiving reports linking the drug to psychiatric side effects, including suicidal thoughts, hostility, and agitation.

Earlier this year, a joint FDA advisory committee voted to remove a box warning about possible neuropsychiatric side effects. As reported by Medscape Medical News, members of the Psychopharmacologic Drug Advisory Committee and the Drug Safety and Risk Management Advisory Committee concluded that in light of results of a large postmarketing randomized clinical trial, the box warning on varenicline is not warranted. The FDA agreed.

The removal of the box warning is based on the outcomes of EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study), which involved patients with and without a history of psychiatric disorder, Pfizer said in a news release.

EAGLES compared the safety and efficacy of varenicline, bupropion (multiple brands), nicotine replacement patch, and placebo in approximately 8000 smokers without and with a history of psychiatric disorder.

In the cohort of patients without a history of psychiatric disorder, varenicline was not found to be associated with an increased incidence of clinically significant neuropsychiatric adverse events in a composite endpoint comprising anxiety, depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, and irritability.

In the cohort of patients with a history of psychiatric illness, there were more events reported in each treatment group compared to the nonpsychiatric cohort, and the incidence of events in the composite endpoint was higher for each of the active treatments compared to placebo.

Serious neuropsychiatric events were reported in 0.6% of varenicline-treated patients, with 0.5% involving psychiatric hospitalization. In placebo-treated patients, serious neuropsychiatric events occurred in 0.6%, with 0.2% requiring hospitalization.

Although the FDA approved removal of the black box warning on varenicline, the labeling states that postmarketing studies have reported serious or clinically significant neuropsychiatric adverse events in patients treated with the drug.

These included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide.

The label advises prescribers to "observe patients attempting to quit smoking with varenicline for the occurrence of such symptoms and instruct them to discontinue the drug and contact a healthcare provider if they experience such adverse events."

European regulators lifted the warning regarding neuropsychiatric side effects with varenicline in May 2016.

"We are pleased with the FDA's decision to update the Chantix labeling based on EAGLES – the largest clinical trial of smoking cessation medications – and we expect this new information may further facilitate an informed discussion about quitting with Chantix between smokers and healthcare providers," Freda Lewis-Hall, MD, Pfizer's chief medical officer and executive vice president, said in the release.

"While the benefits of quitting are immediate and substantial, few smokers are able to quit on their own and need the help of counseling and smoking cessation therapy," added Anne Eden Evins, MD, MPH, director, Massachusetts General Hospital Center for Addiction Medicine, in Boston.

"As healthcare providers work on the front lines to help people who are struggling to quit smoking, this new labeling provides clinically relevant information on the safety and efficacy of Chantix to help them and their patients make informed decisions about smoking cessation treatment."

Pfizer also said additional labeling revisions will include information on the superior efficacy of varenicline compared to bupropion or the nicotine patch.

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