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New Heart-Risk Safety Warning for Varenicline (CHANTIX): Do Not Use Until 2013

Worst Pills, Best Pills Newsletter article September, 2011


FDA Black Box Warning


  • Serious neuropsychiatric events including, but not limited to, depression, suicidal ideation, suicide attempt and completed suicide have been reported in patients taking CHANTIX.
  • All patients being treated with CHANTIX should be observed for neuropsychiatric symptoms, including behavioral changes, hostility, agitation, depressed mood and suicide-related events,...


FDA Black Box Warning


  • Serious neuropsychiatric events including, but not limited to, depression, suicidal ideation, suicide attempt and completed suicide have been reported in patients taking CHANTIX.
  • All patients being treated with CHANTIX should be observed for neuropsychiatric symptoms, including behavioral changes, hostility, agitation, depressed mood and suicide-related events, including ideation, behavior and attempted suicide.
  • The above symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide, have been reported in some patients attempting to quit smoking while taking CHANTIX.
  • Patients with serious psychiatric illness, such as schizophrenia, bipolar disorder and major depressive disorder, did not participate in the premarketing studies of CHANTIX, and the safety and efficacy of CHANTIX in such patients has not been established.
  • Patients should stop taking CHANTIX and contact a health care provider immediately if agitation, hostility, depressed mood or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior.

The Food and Drug Administration (FDA) now requires that the professional product label for the smoking-cessation drug varenicline (CHANTIX) must warn of an increased risk of cardiovascular adverse events in patients with existing cardiovascular disease. The adverse effects of varenicline on the heart must now be added to the list of potentially serious safety problems associated with the drug (see the FDA-required black box warning for information on psychiatric adverse effects and other serious possible adverse effects):

Cardiovascular events: In a trial of patients with stable cardiovascular disease (CVD), certain cardiovascular events were reported more frequently in patients treated with varenicline. Patients with CVD should be instructed to notify their health care providers of new or worsening cardiovascular symptoms and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction.

Shortly after the June 2011 FDA heart warning to the public, the Canadian Medical Association Journal released a meta-analysis bolstering the FDA’s warning. This analysis of 14 gold-standard, randomized clinical trials (13 trials involving smokers and one, smokeless tobacco users) found safety concerns about the potential for an increased risk of serious adverse cardiovascular events associated with the use of varenicline among tobacco users.

The FDA approved varenicline for sale in May 2006, and in the September 2007 Worst Pills, Best Pills News, Public Citizen invoked our Seven Year Rule recommending not using the drug until 2013. This rule is based on a study we co-authored in the May 1, 2002, Journal of the American Medical Association, which found that half of the combined number of drug safety withdrawals and black box warnings, the strongest type of safety warning the FDA can request, occurred or were issued within seven years of new drug approvals — so we created the Seven Year Rule.

Despite the growing list of safety problems with varenicline, there were almost 3 million prescriptions for the drug in 2010. This represents a more than 20 percent decrease from 2009 prescriptions. However, 2010 sales amounted to almost $400 million.

What is the therapeutic value of varenicline?

The decision to use a medication hinges on a balance between the drug’s potential harms and documented benefits, and the possible consequences of having no treatment or taking other available treatments. The potential harms of varenicline are not trivial, but what are the drug’s documented benefits?

We evaluated the harms and benefits of the drug in a September 2007 Worst Pills, Best Pills News article analyzing data from a trial involving 1,023 subjects followed for up to one year. Using that data, Table 3 summarizes varenicline’s effectiveness compared to a placebo and bupropion (ZYBAN), a drug also approved by the FDA for smoking cessation. Bupropion is also an antidepressant that is sold as WELLBUTRIN. Do not take ZYBAN and WELLBUTRIN together; they are the same drug.

The boldfaced bottom row of Table 3 shows that the percentage of subjects abstinent from smoking at 52 weeks was 12 percent greater with varenicline and 4 percent greater with bupropion compared to a placebo.

Some additional context provides the necessary perspective to interpret these results. In all the study’s test groups, subjects were provided an educational booklet on smoking cessation and received up to 10 minutes of smoking-cessation counseling at each weekly treatment visit. This level of resources (educational material and counseling) may not be possible outside of a clinical-trial setting, because of the cost. Therefore, the results of these clinical trials may overestimate the therapeutic benefit of varenicline compared to its effect in the real world.

It is also important to examine how varenicline compares to over-the-counter nicotine patches. To assess this, we searched the U.S. National Library of Medicine’s database for published randomized clinical trials comparing varenicline to nicotine patches and located two such trials.

The first trial comparing treatment with varenicline to treatment with nicotine patches was sponsored by varenicline’s manufacturer, Pfizer Inc., and published in the respiratory medicine journal Thorax in 2008. The investigators measured the self-reported continuous abstinence rate (CAR), which was confirmed using a chemical test during the last four weeks of treatment. There was a statistically significant 12.7 percent difference in favor of varenicline.

The second trial was funded using public money and was published in Circulation Journal in 2010. These researchers measured 12- and 24-week smoking abstinence rates. No significant difference in abstinence rates was observed between the varenicline and nicotine patch groups. At 12 weeks, there was a 7.2 percent difference in favor of nicotine patches, and at 24 weeks, the difference was 7.1 percent in favor of nicotine patches.

A major criticism of both of these trials is that both the investigators and the subjects knew who was receiving the varenicline and the nicotine patches. This is a sure recipe for bias.

The results of these two trials leave in doubt absolute conclusions about the relative effectiveness of varenicline and nicotine patches. At this time, no clear, consistent evidence from randomized clinical trials proves that varenicline is a better choice than nicotine patches.

Varenicline Medication Guide

Varenicline is among a growing list of drugs required to be dispensed with an FDA-approved Medication Guide, written in nontechnical language specifically for consumers. The FDA has the authority to require Medication Guides for drugs that present serious public health concerns.

The Medication Guide for varenicline can be obtained on the FDA’s website at http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm or by asking a pharmacist.

What You Can Do

An argument can be made that varenicline should come off the market. There are safer alternatives available, such as nonpharmacological methods and nicotine-replacement products that include nicotine patches.

There is no question that smoking involves a physical addiction to nicotine as well as psychological “addiction” to the patterns of smoking in certain circumstances or situations. Unless attention is paid to both kinds of addictions, the chance of success in smoking cessation will not be as good as it could be.

Studies have shown that you have a better chance of breaking an addiction to smoking if you have help. You can get support in many ways: Tell your family, friends and coworkers that you are going to quit and want their support. Ask them not to smoke around you or leave cigarettes out. Talk to your health care provider (for example, doctor, dentist, nurse, pharmacist, psychologist or smoking counselor).

Get individual, group or telephone counseling. The more counseling you have, the better your chances are of quitting. Programs are given at local hospitals and health centers. Call your local health department for information about programs.

Consumers should report serious adverse events with drugs or product quality problems to the FDA’s MedWatch Adverse Event Reporting program online or by regular mail, fax or phone.

(in addition to the new heart warning at the beginning of this article)

  • Angioedema [allergic reaction that can involve mucous membranes] and hypersensitivity reactions: Such reactions, including angioedema, infrequently life-threatening, have been reported. Instruct patients to discontinue CHANTIX and immediately seek medical care if symptoms occur.
  • Serious skin reactions: Rare, potentially life-threatening skin reactions have been reported. Instruct patients to discontinue CHANTIX and contact a health care provider immediately at first appearance of skin rash with mucosal lesions [or any other signs of hypersensitivity].
  • Accidental injury: Accidental injuries (e.g., traffic accidents) have been reported. Instruct patients to use caution driving or operating machinery until they know how CHANTIX may affect them.
  • Nausea: Nausea is the most common adverse reaction (up to 30 percent incidence rate). Dose reduction may be helpful.

* CHANTIX product label

Symptoms of angioedema that could occur with varenicline*

  • Peeling of the skin
  • Rash
  • Redness
  • Swelling
  • Swelling of the face, mouth and throat that can cause trouble breathing

*Some of these reactions can be life-threatening.

 Table 3: Smoking-Cessation Drug Effectiveness


Weeks of Treatment

Varenicline Subjects (# and % Not Smoking)

Bupropion Subjects (# and % Not Smoking)

Placebo Subjects (# and % Not Smoking)

Difference Between Varenicline and Placebo at 52 Weeks

Difference Between Bupropion and Placebo at 52 Weeks

9 to 12

151 (43%)

102 (30%)

60 (18%)



9 to 24

102 (29%)

69 (20%)

45 (14%)



9 to 52

79 (23%)

51 (15%)

35 (11%)