Chantix: Why the Rush?

Armand Rossetti

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In May 2006, the Food and Drug Administration (FDA) approved Pfizer’s Chantix (varenicline tartrate), a smoking cessation drug. Reportedly under priority review, the FDA had cut the usual review period from 10 to six months. Reportedly, the FDA abbreviated its usual review period, because it had received preliminary efficacy studies showing that Chantix was superior to another approved smoking cessation drug, Zyban (bupropion).

The FDA’s Motivation to Reduce the Review Period:

At first blush, the FDA was impressed with evidence that Chantix acted in two ways to help individuals give up smoking: 1) it mimicked the effects of nicotine and eased withdrawal symptoms; and 2) Chantix actually blocked the effects of nicotine in case users resumed smoking. As a result for those on the Chantix cessation program, smoking would be futile because it would not provide a nicotine high.

Before reducing the review period, the FDA analyzed six Chantix clinical trials (five were controlled and randomized), which included 3,659 chronic cigarette smokers averaging 21 cigarettes a day for over 25 years, and those studies revealed that Chantix was superior to placebo in helping people to quit smoking. Two of the five controlled and randomized studies showed that Chantix was superior to Zyban.

At the end of 12 weeks, the two studies provided evidence that 44 percent of the subjects taking Chantix stopped smoking, compared to 30 percent of subjects taking Zyban and only 17 percent of those given a placebo. A one year follow up revealed that 22 percent of those taking Chantix, 16 percent of those taking Zyban and 10 percent given a placebo remained smoke-free.

At the time of FDA approval, the most commonly observed adverse effects in order of declining occurrence were nausea, changes in dreaming, constipation, gas and vomiting.

Developments since FDA the Approved Chantix:

September 24, 2007:

CBS11, Dallas Fort Worth ran a story about a local musician named Carter Albrecht who took a few drinks and then swallowed his first 1 milligram Chantix tablet. Carter’s girlfriend, Ryann drove him home from a local bar and noticed and noticed that Carter didn’t seem himself, and later became abusive and delusional. By the time the couple arrived home, Carter became aggressive and hit Ryann several times, and she remembers being curled up in a fetal position for self protection when Carter asked…"Who did this to you and why are you crying?"

Later that night, Carter ran from the house and apparently broke into a neighbor’s house. Thereafter, a gun fired and Carter subsequently died from a gunshot wound. Family and friends said that Carter was never violent, and both Ryann and Carter’s father felt that Chantix had played a role in this tragedy.

The CBS11 report provided several examples of individuals all over the country who had used Chantix and had felt suicidal, become aggressive, had bad dreams accompanied by horrible suicidal ideations. This prompted CBS11 to access the FDA’s database of adverse side effects (the Manufacturer and User Facility Device Experience Database [MAUDE]) where CBS reporters found thousands of similar and very serious reactions to Chantix.

CBS11 noted that Pfizer had provided one package insert for consumers that listed only five “common” side effects, and another for doctors, listing frightening side effects printed in tiny, 1 millimeter size print. That second list included suicidal thoughts, aggression, and neurological and psychiatric disorders.

According to CBS11’s report, a Dallas addiction psychiatrist, Byron Adinoff said that taking Chantix with alcohol could lead to unpredictable results. However, Chantix contained no warning about possible dangers of taking the drug while consuming alcohol.

What the FDA (and Pfizer) Knew or Should Have Known before the FDA Abbreviated its Chantix Review:

Scientific American posted a November 24, 1997 story on the Internet, showing that people who are addicted to one substance are more likely to be addicted to others. For example, Alcohol and nicotine become habit forming in like ways. In fact, the strongest connection is evident between nicotine and alcohol, because smokers drink twice as much alcohol as non-smokers.

According to the Scientific American story, one study found that alcoholism is 10 to 14 times more prevalent among smokers than non-smokers. And while smoking has dropped 30% among American adults, it remains unchanged among alcoholics.

November 20, 2007:

After receiving thousands of adverse event reports, the FDA issued a release entitled, Early Communication About and Ongoing Safety Review Varenicline (marketed as Chantix). The Early Communication confirmed that there were increased reports of suicidal thoughts, aggressive erratic behavior, and drowsiness among a significant numbers of consumers who had been using Chantix. As a result, the FDA recommended that healthcare professionals monitor patients taking Chantix for behavior and mood changes; that patients contact their doctors if they experience such, and that patients should use caution while driving or operating heavy equipment until they knew how Chantix affected them.

January 18, 2008:

Pfizer released, Pfizer Statement on CHANTIX (varenicline) Labeling Update in the United States that reiterated the FDA’s November 20, 2007 Early Communication. However, Pfizer stated that a causal relationship between Chantix and the reported symptoms had not been established. Nevertheless, Pfizer cited complications, such as nicotine withdrawal, and worsened conditions in patients with pre-existing psychiatric illnesses.

Pfizer continued its Statement by indicating that Chantix was "a real breakthrough medicine" and that its Chantix clinical trial program with more than 5000 patients had shown no incidents of suicidal ideation, depressed mood or suicidal behavior different than placebo-treated patients. Moreover, clinical trials attributed no connection between suicides and Chantix consumption. However, it is important to note that Pfizer admittedly did not include patients with serious psychiatric illnesses such as schizophrenia, bipolar disorder and major depressive disorder in the controlled clinical program. One might want to question why this was the case.

February 1, 2008:

The "FDA News" posted the story: FDA Issues Public Health Advisory on Chantix. That story contained a request that Pfizer add new safety warnings for Chantix. The FDA reported that it had been continuously reviewing adverse event reports (AERs) and had concluded that an association between Chantix and serious neuropsychiatric symptoms was increasing likely. Therefore, the FDA suggested that Pfizer “elevate the prominence of its safety information to the warnings and precautions section of the Chantix prescribing information.” You may

.

May 21, 2008:

The Institute for Safe Medication Practices (ISMP) published a paper entitled, Strong Safety Signal Seen for New Varenicline Risks. The paper provided information that in the fourth quarter of 2007 alone, Chantix accounted for 988 FDA reported serious injuries in the US, more than any other individual drug in that time period. To compare, in the same period, the FDA received a median of 5 reports each for 769 different drugs. After seeing such a large number of Chantix reports, the ISMP conducted a further investigation.

In its February 2008 health advisory, The ISMP report pointed out that the FDA had not provided the numbers of reported neuropsychiatric events. The ISMP report showed that from May 2006 through December 2007, the FDA had received 227 domestic reports of suicidal acts, thoughts or behaviors, 397 cases of possible psychosis and 525 reports of hostility or aggression. Among those events reported, there were 28 cases of suicide, 41 mentions of homicidal ideation, 60 cases of paranoia and 55 cases of hallucination, categories not being mutually exclusive.

In addition, the ISMP saw evidence that reports of other kinds of serious harm suspected as being Chantix related that had no current manufacturer’s warnings. Among the most prominent were: accidents and injuries (123 reports); vision disturbances (148 reports); heart rhythm disturbances (224 reports); seizures and abnormal muscle spasms (372 reports); moderate and severe skin reactions (338 cases); and diabetes (544 reports).

The ISMP then offered the following recommendations and promptly notified the FDA:

“We have immediate safety concerns about the use of varenicline among persons operating aircraft, trains, buses and other vehicles, or in other settings where a lapse in alertness or motor control could lead to massive, serious injury. Other examples include persons operating nuclear power reactors, high-rise construction cranes or life-sustaining medical devices. Based on reports of sudden loss of consciousness, seizures, muscle spasms, vision disturbances, hallucinations, paranoia and psychosis, we believe varenicline may not be safe to use in these settings. The extent to which varenicline has already contributed to accidental death and injury has not yet been investigated because these adverse effects had not been previously reported. The Federal Aviation Administration approved varenicline for use by airline pilots before most of these reports were available.

In addition, we recommend that patients and doctors exercise caution in the use of varenicline and consider the use of alternative approaches to smoking cessation.

Finally, we urge the FDA and the manufacturer to provide warnings to doctors and patients for those adverse effects that can be adequately documented through existing data, and to undertake on a priority basis epidemiological studies or other research to assess other potential risks.”

May 23, 2008:

Less than 48 hours after the Federal Aviation Administration (FAA) learned from reviewing the ISMP report that Chantix might lead to safety problems, it ordered pilots and air traffic controllers to stop taking it immediately. Perhaps the following statement from the FAA underscores the caution that the air travel safety agency takes to assure public safety:

“In November 2007, the FDA began to receive reports of psychiatric problems associated with the medication. The FAA’s Federal Air Surgeon Fred Tilton said he was aware of the anecdotal information circulating about Chantix, but chose to rely on hard data as it became available. “There were indications, but no clear data,” he said. “We don't just act indiscriminately.”

When more conclusive data was published this week, Tilton's Office of Aerospace Medicine moved quickly in response.

Medications approved for pilot and controller use must undergo a rigorous review process before being considered acceptable. When a new class of drug comes on the market, members of FAA’s Office of Aerospace Medicine require at least a year for data to emerge regarding its effects, at which point a review board can then be convened. If any red flags are detected by the board during evaluation, the medication will be prohibited.”

October 23, 2008:

The Los Angeles Times ran a story entitled; Prescription drug injuries and deaths reach record levels, which pointed out that Chantix (varenicline) was the most dangerous medication in the first quarter of 2008. During that period ending in March 2008, Chantix was linked to 1,001 injuries and 50 deaths, followed by heparin, associated with 779 injuries and 102 deaths. In addition, The Times reported that during the first quarter of 2008, Chantix accounted for more reports of serious injury than the 10 bestselling prescription drugs combined.

It is important to note that these statistics were the result of reviewing voluntary adverse event reports that the FDA receives and posts in its Manufacturer and User Facility Device Experience Database (MAUDE). The Los Angeles Times reported that because adverse event reporting is voluntary, researchers have speculated that fewer than 10% of adverse events actually make it into MAUDE.

Although Chantix may have caused the most injuries of any drugi in the first quarter of 2008, it did not cause the most deaths, because 10 other drugs each caused more than 100 deaths. That statistic compared with an average of one to three drugs in previous quarters.

Conclusion:

We live in an era of esoteric drug manufacturing.

Since the rates of injuries and deaths seem to be speeding up, maybe the FDA should not be abbreviating review periods. Perhaps the FDA should review all manufacturer’s literature for one millimeter high typing that contains further, important information about possibilities of serious side effects.

If the FDA finds evidence of suspected danger, perhaps it should recommend a two year period of extreme caution when prescribing medications suspect of those dangers.

If the FAA can wait a year to review postmarketing reports before allowing pilots and air traffic controllers to take certain medications, the FDA should be able to demand that manufacturers that suspect certain dangers connected with the use of a new drug might manifest issue an immediate transitional boxed warning. The transitional boxed warning might also contain an explanation that the early warning is temporary until the two-year postmarketing period ends, and that the manufacturer may either withdraw the transitional warning, if the suspected dangers do not manifest, or make the warning permanent if the suspected dangers persist.

There are benefits that manufacturers, the FDA, health care personnel and consumers must weigh against the risk of taking a drug. However, while everyone reviews those risks that hurt and benefits that help, during the postmarket review, warnings will never hurt anyone.