Review of Varenicline (CHANTIX) for Smoking Cessation

Cigarette smoking damages practically every organ in the human body and causes an overwhelming number of deadly diseases, from lung cancer and chronic obstructive pulmonary disease to heart attack and stroke.[1]

Medications play a limited role in helping smokers overcome nicotine dependency.[2] Varenicline (CHANTIX) is one such medication. Approved by the Food and Drug Administration (FDA) in 2006, the drug reduces the symptoms of nicotine withdrawal by blocking nicotine from binding to the brain receptors that are involved in reinforcing the effects of nicotine dependency.[3] The drug is available as oral tablets, which are taken twice a day for 12 weeks and can be continued for an additional 12 weeks. With $827 million in sales in 2016, the drug is one of the top 200 most prescribed drugs in the U.S.[4]

Varenicline is effective in helping many people quit smoking. However, it is associated with serious adverse effects, including neuropsychiatric symptoms (such as depression or suicidal thoughts or actions) and cardiovascular disease (including abnormal heart rhythm, heart attack and stroke). The benefit harm balance of varenicline is less favorable than nicotine replacement therapies, which were first approved 30 years ago and are available in various forms, including in gum, inhaled and skin patch versions (HABITROL, NICODERM CQ, NICORETTE, NICOTROL, THRIVE and others). [5]

Therefore, Public Citizen’s Health Research Group has classified varenicline as a drug of last resort: It should not be used unless all other methods of smoking cessation have failed.[6]

Effectiveness of varenicline versus other drugs

Varenicline’s approval was supported by six clinical trials that enrolled a total of nearly 3,700 chronic smokers who were treated with varenicline, bupropion (ZYBAN) — another oral smoking cessation drug that contains the same active ingredient found in the antidepressant drug WELLBUTRIN — or a placebo.[7] In these trials, 40 to 51 percent of varenicline-treated subjects were tobacco-abstinent after three months of therapy, whereas 30 percent of bupropion-treated subjects and 12 to 18 percent of placebo-treated subjects were tobacco-abstinent. However, only 19 to 23 percent of vareniclinetreated subjects, 14 to 16 percent of bupropion-treated subjects and 4 to 10 percent of placebo-treated subjects were tobacco-abstinent nine months after therapy ended, indicating a high rate of smoking relapse. The smoking cessation rates achieved in these trials, which appear to have been conducted in academic centers or specialist clinics, may not translate to routine primary practice for two reasons.[8] First, these trials provided smoking cessation counseling to all subjects, an important level of support that may not be routinely available to many patients in usual clinical practice. Second, the trials excluded smokers with past or current serious medical illnesses.

Adverse effects of varenicline

Clinical trials showed that the most common adverse effects of varenicline are abnormal dreams, constipation, flatulence, headache, nausea and vomiting.[9]

After the drug’s approval, reports of serious neuropsychiatric adverse effects in patients treated with varenicline streamed into the FDA. These adverse effects included changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety and panic attacks, suicidal ideation, suicide attempts and completed suicide. They were reported in patients with or without preexisting psychiatric disease.

In response, the FDA required a black-box warning — the strongest warning that the agency can require — be added to varenicline’s labeling in 2009.[10] The warning alerted health care professionals and patients to the drug’s potential to cause some of the aforementioned neuropsychiatric adverse effects.

In October 2014, Public Citizen, along with four other groups (the Institute for Safe Medication Practices, the National Center for Health Research, Consumers Union and the National Physicians Alliance), petitioned the FDA to strengthen the black-box warning on varenicline by including additional adverse effects, such as psychotic symptoms, blackouts, convulsions and impaired vision, unexplained hostility, and anger and aggression toward others.[11] However, the agency denied our petition[12] and instead decided to remove the blackbox warning altogether in December 2016.[13] The FDA made this decision despite acknowledging that the risk of severe neuropsychiatric adverse effects associated with this drug “is still present.”

The FDA’s action was based on the results of a single trial, known as EAGLES,[14] which was mandated by the agency to determine the neuropsychiatric safety of varenicline. The trial did not find a significant increase in the rates of neuropsychiatric adverse effects that interfered with usual daily functioning with use of either varenicline or bupropion relative to the nicotine patch or placebo in subjects with or without psychiatric disorders.

But the FDA’s own scientists identified several flaws in the trial, including widespread inconsistencies in the detection and classification of what were deemed neuropsychiatric events.[15] They concluded that the trial did not accurately capture the precise number and scope of these adverse events associated with varenicline.[16]

In September 2016, The FDA convened a panel of 19 experts who were asked to give their opinions on whether the agency should remove or retain the 2009 black-box warning in the drug’s labeling.[17] Ten experts supported removal of the black-box warning, four voted to modify this warning and the remaining five members voted to keep it. Several of these experts pointed out variability in how the data in the EAGLES trial were collected and how the adverse effects were classified, which could have affected the trial’s findings. They also were concerned that the trial lacked adequate statistical power to detect rare adverse effects, such as suicide.

Although the first warning on varenicline’s current labeling still pertains to the drug’s neuropsychiatric adverse effects, including suicidal ideation and behavior, it is less likely to be noticed by health care professionals and patients than was the black-box warning that was formerly required by the FDA. The current warning recommends that patients treated with varenicline be monitored for these adverse effects and instructs them to stop taking the drug and to contact a health care professional if they experience these adverse effects.

Importantly, varenicline also has been linked to postmarketing reports of cardiovascular adverse events. A smoking cessation trial in patients with stable cardiovascular disease showed that cardiovascular adverse effects were infrequent overall, although nonfatal heart attack and nonfatal stroke occurred more frequently in patients treated with varenicline than in those treated with a placebo. However, this trial did not find differences in death rates between patients treated with varenicline and those who received a placebo.

Additional adverse effects of varenicline include new or worsening seizures; accidental injuries (such as traffic accidents) likely due to somnolence, dizziness, loss of consciousness or difficulty concentrating; harmful behavior to self, others or property; and hypersensitivity reactions including swelling of the throat and upper respiratory passages.

What You Can Do

If you smoke, you should try to quit. If you have tried to quit in the past and relapsed, do not worry! Most smokers have to make several attempts to stop before finally succeeding (the average number of tries is around four before successfully quitting).[18]

Seeing your doctor or a professional smoking cessation counselor is a good first step to devise a long-term strategy for quitting.

If you decide to use a smoking cessation drug, talk to your doctor about trying the minimum effective dose of one of the currently available nicotine replacement therapies,[19] along with some form of counseling with a health care professional. Not all smokers respond the same way to every nicotine replacement therapy, so you should try several formulations, such as the patch and the inhaled variety, to see which one works best for you.[20] If nicotine replacement therapy is unsuccessful, talk to your doctor about treatment with Zyban (see our August 2018 issue for more details about Zyban).[21]

Because of its safety risks, varenicline should be a last-resort drug for smoking cessation.

References

[1] U.S. Department of Health and Human Services. How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. 2010.

[2] Varenicline: new drug. Smoking cessation: no better than nicotine. Prescrire Int. 2006;15(86):210-212.

[3] Pfizer. Label: Varenicline (CHANTIX). June 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021928s045_046lbl.pdf. Accessed September 7, 2018.

[4] Symphony Health. Top 200 drugs – 2016. https://symphonyhealth.com/wp-content/uploads/2017/04/Top-200-Drug-List-2016.pdf. Accessed September 7, 2018.

[5] Public Citizen joins other groups in requesting additional warnings on CHANTIX label. Worst Pills, Best Pills News. March 2015. /newsletters/view/950. Accessed September 7, 2018.

[6] WorstPills.org. Smoking cessation. /chapters/view/16. Accessed September 7, 2018.

[7] Pfizer. Label: Varenicline (CHANTIX). June 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021928s045_046lbl.pdf. Accessed September 7, 2018.

[8] BMJ Group. Varenicline for smoking cessation. Drug Ther Bull. 2008;46(5):33-36.

[9] Pfizer. Label: Varenicline (CHANTIX). June 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021928s045_046lbl.pdf. Accessed September 7, 2018.

[10] Pfizer. Label: Varenicline (CHANTIX). July 2009. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021928s012s013lbl.pdf. Accessed September 7, 2018.

[11] Public Citizen. Petition to the FDA requesting a stronger boxed warning and new restrictions on the use of varenicline (Chantix). October 8, 2014. http://www.citizen.org/documents/2225.pdf. Accessed September 7, 2018.

[12] Public Citizen. FDA response to Public Citizen’s petition to the FDA requesting a stronger boxed warning and new restrictions on the use of Varenicline (Chantix). December 16, 2016. http://www.citizen.org/documents/Chantix-FDA-Petition-Response.pdf. Accessed September 7, 2018.

[13] Food and Drug Administration. FDA drug safety communication: FDA revises description of mental health side effects of the stop-smoking medicines Chantix (varenicline) and Zyban (bupropion) to reflect clinical trial findings. December 16, 2016. http://www.fda.gov/Drugs/DrugSafety/ucm532221.htm. Accessed September 7, 2018.

[14] Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016;387(10037):2507-2520.

[15] Public Citizen. Testimony before the FDA’s Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee regarding the black box warning on the smoking cessation drug varenicline (Chantix). September 14, 2016. http://www.citizen.org/documents/2340.pdf. Accessed September 7, 2018.

[16] Food and Drug Administration. Briefing document for the September 14, 2016, joint meeting of the Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee: Serious neuropsychiatric adverse events with drugs for smoking cessation. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM520103.pd. Accessed September 7, 2018.

[17] Food and Drug Administration. Summary minutes of the joint meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. September 14, 2016. https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/psychopharmacologicdrugsadvisorycommittee/ucm524402.pdf. Accessed September 7, 2018.

[18] Public Citizen joins other groups in requesting additional warnings on CHANTIX label. Worst Pills, Best Pills News. March 2015. /newsletters/view/950. Accessed September 7, 2018.

[19] Cardiac adverse effects of nicotine replacement therapy. Prescrire Int. 2015;24(166):293.

[20] Public Citizen joins other groups in requesting additional warnings on CHANTIX label. Worst Pills, Best Pills News. March 2015. /newsletters/view/950. Accessed September 7, 2018.

[21] Bupropion (ZYBAN) for Smoking Cessation. Worst Pills, Best Pills News. August 2018. /newsletters/view/1216. Accessed September 10, 2018.