Greater Suicide Risk With Varenicline vs Other Cessation Meds

No Place for Agent as First-Line Treatment, Researchers Say

Deborah Brauser

November 02, 2011

November 2, 2011 — Varenicline (Chantix, Pfizer), is associated with a significantly increased risk for suicidal behavior and depression, according to new research.

In a study of more than 13,000 cases of adverse events involving smoking cessation products over the course of 13 years, investigators found that 90% of the reports of self-injurious behavior or depression were associated with the use of varenicline. Bupropion and nicotine replacement products were responsible for the remaining 7% and 3%, respectively.

"This should not be a first-line drug. If you start with the others, [and] they don't work, and you have to use a drug, then you use Chantix. But you must monitor the mental status of patients who use it," coinvestigator Curt D. Furberg, MD, PhD, professor of public health sciences at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, told Medscape Medical News.

"Ideally, I think it should come off the market, but that is not realistic. So a more realistic recommendation is to restrict its use."

Dr. Curt D. Furberg

The study was published online November 2 in PLoS One.

Stricter Warnings Needed?

Dr. Furberg said in a release that these findings contradict the implications of a recent review conducted by the US Food and Drug Administration (FDA), and reported by Medscape Medical News, which found no differences in psychiatric hospitalizations between varenicline and nicotine replacement therapy.

"The FDA hospitalization studies were flawed because they could not capture most of the serious psychiatric side effects, including suicide, depression, aggression, and assaults. These can be catastrophic events but do not normally result in hospitalization," he said.

"We found that Chantix is associated with more suicidal behavior reports than any other smoking-cessation drug on the U.S. market. The risks simply outweigh the benefits."

Although the medication currently carries an FDA boxed warning about the risk for these behaviors, Dr. Furberg said the warning should be revised to say that varenicline has the highest risk compared with other cessation treatments.

In a statement to Medscape Medical News, the FDA said that this study's "overall conclusion that there is a postmarketing signal" for adverse events with varenicline is not new, and that they have requested that Pfizer conduct a clinical study "to characterize the neuropsychiatric safety profile of varenicline versus placebo, bupropion, and nicotine replacement therapies in subjects with and without a previous history of a psychiatric disorder, with results expected in 2017."

They also note that 2 recent studies comparing varenicline with bupropion and placebo found that quit rates were higher in patients treated with varenicline than in patients treated with bupropion.

"We continue to believe that when used as directed in the currently approved labeling, Chantix is a safe and effective treatment to help patients stop smoking," said the FDA.

A statement released by Pfizer notes that, "based upon the limited data we have seen," the study's conclusions are inconsistent with other clinical studies and with the FDA's recent statements that the current label warnings for varenicline are appropriate.

"The analysis does not appear to contain any new information with respect to Chantix," they add.

Serious Adverse Effects

According to the investigators, 1 in 5 deaths in the United States is caused by tobacco use each year. In addition, the use of this substance adds $193 billion to healthcare costs.

However, 2 of the most used medications for smoking cessation, varenicline and bupropion, have both FDA boxed warnings and a mandatory medication guide for patients regarding possible serious psychiatric adverse events.

"While suicidal behavior or depression appears to be prominent side effects of varenicline, they are by no means the only safety issues," lead author Thomas J. Moore, senior scientist at the Institute for Safe Medication Practices in Horsham, Pennsylvania, said in a release.

"It has been associated with aggression and unprovoked violence in past studies[, and] its effects on vision, cognition, and motor control and other risks have led to its being banned for airline pilots, air traffic controllers, and military pilots, and restricted for truck drivers."

Dr. Furberg said that soon after the drug was first approved, its most alarming adverse effect was "blackouts," or the sudden loss of consciousness.

In addition, Dr. Furberg was the lead investigator of a meta-analysis published online in July in the Canadian Medical Journal, and reported by Medscape Medical News' sister publication heartwire, that found that varenicline was also associated with increased risk for cardiovascular events.

In the current study, the researchers sought to compare suicide and depression rates in patients who took various smoking cessation products.

They examined serious injury case reports between 1998 and September 2010 from the FDA's Adverse Event Reporting System database involving varenicline (n = 9575), bupropion (n = 1751), or nicotine replacement products (n = 1917).

Significant Suicide Risk

Of the 3249 cases of self-injurious behavior or depression found, 2925 were associated with use of varenicline, 229 with bupropion, and 95 with nicotine replacement products.

Compared with nicotine replacement, the odds ratio for these behaviors was 8.4 for varenicline (95% confidence interval [CI], 6.8 - 10.4) and 2.9 for bupropion (95% CI, 2.3 - 3.7).

"The disproportionality persisted after excluding reports indicating concomitant therapy with any of 58 drugs with suicidal behavior warnings or precautions in the prescribing information," report the investigators.

Compared with bupropion, the odds ratio for varenicline was 2.9 (95% CI, 2.5 - 3.4).

"The manufacturer has said that cases of suicide are not because of the drug, but because people who try quitting are different from the general population," said Dr. Furberg.

"And we did confirm that people who want to quit and are taking smoking cessation therapy are at the high risk of committing suicide and being depressed. But among the drugs used, Chantix was worse."

He said that the researchers agree with policy recommendations from the US Veterans Administration (VA) that state that varenicline should be prescribed only after bupropion, nicotine replacement, or a combination of both, fail.

"The VA also recommends a mental status exam to assess risk of suicidal or violent behavior prior to prescribing varenicline," Dr. Furberg added.

"My background is as a cardiovascular person, and I devoted my whole life to developing treatments to prevent heart attacks and so on. So I'm all for smoking cessation. But across the board, this is one of the worst drugs on the US market."

Conclusion Misleading, Says FDA

The FDA said that study limitations include "the fact that spontaneous reporting of psychiatric events with varenicline has been stimulated by media publicity and FDA communications, but this potential source of disproportionate reporting was not accounted for in the analysis."

"This report reviewed AERS data from 1998-Sept 2010, but stimulated reporting has been observed as early as 2007. In addition, the full-text narratives of individual case reports were not available for this analysis," they added.

Another limitation cited was that the study measured the proportion of reports in the database, rather than observing the frequency of adverse event with the use of the medications examined. In addition, instead of odds ratios, the FDA said that proportional reporting ratios (PRRs) would be the more appropriate term.

"Moore et al's conclusion that 'varenicline shows a substantial, statistically significant increased risk of reported depression and suicidal/self-injurious behavior' is misleading, as PRRs are measures of association and not measures of risk," said the FDA.

Pfizer adds in their statement that "it is not appropriate to draw conclusions" based on comparisons between different medications and reporting rates.

"Post-marketing reports can come from any source ranging from patients to healthcare providers, and from phone calls to internet postings and lawyers. Often these reports lack sufficient medical information to enable meaningful assessment," they write.

"Given the significant public health risks of smoking, Pfizer stands by Chantix as an important treatment option for adult smokers who want to quit."

Questions Remain

"I don't think this study moves us any further along in determining whether or not varenicline causes these events or if there is some other confounding factor that is associated with these events," J. Taylor Hays, MD, professor of medicine and associate director of the Mayo Nicotine Dependence Center in Rochester, Minnesota, told Medscape Medical News.

Dr. J. Taylor Hays

Dr. Hays, who was not involved with the study, said he also does not think the findings establish that varenicline is associated with a higher risk compared with other smoking cessation medications and cited the FDA's recent review.

"Depending on the methods used, you can often see different results. And when you do retrospective studies that have all of these inherent biases and confounders, I just don't think you can reasonably establish whether or not the drug is truly harmful. Or are there other things going on?"

He recommended that clinicians tell their patients that all of these medications are efficacious, and when used in conjunction with behavior treatments, "they work even better."

"That can more than double the chance of successful quitting among patients who are motivated to quit. And I think varenicline should be a first-line drug as it's been proven to be among the most effective."

Dr. Hays added that patients should also be told about the possible risks that have been reported and that if they experience any adverse effects, they need to stop using the medication and call their clinician.

However, he noted that the FDA's current boxed warnings are appropriate.

"The FDA has done their due diligence. There are some reports that these associations are out there. But what we need to know is whether or not it's associated in a causal way with use of this drug or with other things," said Dr. Hays.

"Dr. Furberg's assertion is that there is this mountain of data that this is a terribly harmful drug but there are many, many other studies that have shown no harm. Overall, I think it's important that people who want to quit should receive the best treatment."

"As they say, it's important to not throw out the baby with the bathwater," he concluded.

Three of the 5 study authors have disclosed no relevant financial relationships. The other 2 study authors report having served as expert witnesses and consulting experts in military and legal cases in which varenicline had been taken. Dr. Hays reported having received past research funding from Pfizer.

PLoS One. Published online November 2, 2011.

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