A Review of Varenicline (CHANTIX) To Quit Smoking

Editor’s note: The following article is based on publicly available documents prepared by Food and Drug Administration (FDA) scientific and medical staff. The documents are available  here. These FDA documents are the most complete and objective information available at the time a new drug is approved.

What is varenicline?
Varenicline, sold by Pfizer Inc. of New York, was approved by the FDA in May 2006 for use as an aid in smoking cessation treatment. It belongs to a new family of drugs, not containing nicotine, but thought to work by stimulating nicotine receptors in the brain, just as nicotine does. The drug thus appears to act in a manner pharmacologically similar to nicotine.

The drug’s popularity is growing. According to Pfizer, more than 100,000 new prescriptions a week were written for CHANTIX in March of this year. The company plans to step up its advertising this summer.

What is known about the safety of varenicline?
As is unfortunately true for many new drugs, not much is known right now about the drug’s long-term safety – most people involved in the clinical trials have taken the drug for less than one year. Of the 4,690 people who took varenicline in pre-approval clinical trials, 456 subjects were treated for at least 24 weeks, but only 112 subjects had received varenicline for one year or more at the time of the drug’s approval. However, in these studies, the most common side effect appeared to be nausea – uncomfortable, not life-threatening, but occurring in more than one-third of patients using the drug and often causing patients to discontinue the drug.

Varenicline is the first in a new family of drugs and works differently than other smoking cessation drugs (see Table 3). Because of that, it is possible that unknown and unpredictable side effects may occur after the drug is used in large numbers of patients.

What evidence did the FDA use to approve varenicline?
The FDA relied on six controlled clinical trials submitted by manufacturer Pfizer to approve varenicline.  These six trials involved 6,743 subjects (including patients given a placebo) and lasted between six and 12 weeks.

The FDA approval standard for smoking-cessation drugs is that the drug must be shown effective in two independent clinical trials. In these trials, more smokers in the treated group must quit and not relapse.

How effective was varenicline in these clinical trials?
Table 1 outlines varenicline’s effectiveness compared to placebo and bupropion (ZYBAN), a drug also approved by the FDA for smoking cessation, in a clinical trial. The trial involved 1,023 subjects who were followed for up to one year. The FDA has allowed Pfizer to make claims comparing the effectiveness of varenicline and bupropion, based on this trial. As is evident in Table 1, there is some difference in abstinence rates between varenicline and bupropion after one year.

Overall, at the end of one year, 23 percent of the subjects using varenicline had quit smoking without relapse at least until that point.

It is questionable whether such results would be obtained in the real world as smokers participating in the trials received free varenicline, free individual 10-minute long counseling sessions with physicians and as many as 10 clinic visits during the duration of the trials. Outside of such a clinical setting, however, many physicians will simply prescribe the drug and provide little and/or infrequent counseling.

What are the most common side effects seen with varenicline in the clinical trails submitted to the FDA?
The most common side effect was nausea, which was reported by 40 percent of those receiving varenicline in one clinical trial. Of those subjects who reported nausea in that trial, 19 percent ultimately discontinued the drug. Other side effects increased by the drug compared to a placebo included insomnia, abnormal dreams and depression.

The FDA medical officer reviewing varenicline commented that these side effects “suggest that tolerability issues may limit the chronic use of varenicline.”

The side effects that most often contributed to the discontinuation of varenicline in one of the pre-approval clinical trials are summarized in Table 2.

Has the FDA approved other treatments to help people quit smoking?
Yes, there are many other drug treatments approved by the FDA to help people quit smoking. These are primarily nicotine-replacement products and are listed in Table 3. Bupropion is the only other non-nicotine smoking cessation product currently available on the market in the US. 

What You Can Do
Wait to use varenicline until 2014 – seven years after the date of FDA approval. 

In general, people should wait at least seven years from the date of FDA approval to take any new drug unless it is one of those rare “breakthrough” drugs that offers a documented therapeutic advantage over older, proven drugs. This is because new drugs are tested in a relatively small number of people before being released, and serious adverse effects or life-threatening drug interactions may not be detected until the new drug has been taken by hundreds of thousands of people.

We call this our Seven-Year Rule. It is based on a study we co-authored in the May 1, 2002 Journal of the American Medical Association. This study found that half of all new drug safety withdrawals occurred within the first two years of FDA approval. Half of the combined number of drug safety withdrawals and black box warnings, the strongest type of safety warning the FDA can request, occurred within seven years of new drug approvals – thus the Seven Year Rule.

Table 1. Comparison of abstinence rates between varenicline, bupropion and placebo in a clinical trial

Table 2. Side effects most frequently causing patients to permanently discontinue use of varenicline and placebo

Table 3. FDA-approved products to quit smoking