Chantix: 36,342 adverse events, 595 suicide attempts

Chantix: 36,342 adverse events, 595 suicide attempts

John (Gold)
Joined: 18 Dec 2008, 23:57

22 May 2008, 09:08 #1

Strong Safety Signal Seen
for New Varenicline Risks
May 21, 2008

A strong signal of multiple safety problems with Chantix (varenicline), a drug to help people stop smoking, has been seen in a pilot program to identify new drug risks in adverse drug events reported to the U.S. Food and Drug Administration.
Varenicline is suspected in various adverse drug event reports of causing a wide spectrum of injuries, including serious accidents and falls, potentially lethal cardiac rhythm disturbances, severe skin reactions, acute myocardial infarction, seizures, diabetes, psychosis, aggression and suicide. The cases were analyzed and classified using computerized excerpts of adverse event reports which the FDA publishes for research use.

The FDA approved varenicline in May 2006 after granting it a priority review. Varenicline is a partial agonist of one of the nicotinic acetylcholine receptors in the brain and nervous system,1 and currently the only marketed and approved drug with this mechanism of action.

In the 4th quarter of 2007 varenicline accounted for 988 serious injuries in the U.S. reported to the FDA, more than any other individual drug in this time period. By comparison the FDA received a median of 5 reports of serious injury for 769 different drugs in the 4th quarter. Only 35 drugs accounted for 100 or more reports. This large volume of reports prompted us to conduct an analysis of all adverse events for varenicline since marketing approval in 2006.

The FDA has recently issued a Public Health Advisory about one of the most marked adverse effects of varenicline, psychiatric symptoms that included "changes in behavior, agitation, suicidal ideation, attempted and completed suicide." 2 However, the FDA alert provided no information about the numbers of reported neuropsychiatric events among treated smokers.

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. These totals included 28 cases of suicide and 41 mentions of homicidal ideation, 60 cases of paranoia and 55 cases of hallucination. The categories were not mutually exclusive.

However, the adverse drug event reports for varenicline describe other kinds of serious harm for which no warnings now exist, either from the FDA or from the manufacturer, Pfizer Inc. The cases (including those with psychiatric effects) were classified using standardized medical queries developed by the pharmaceutical industry to identify potential adverse events in clinical studies and postmarket surveillance. Adverse event reports in themselves do not establish a causal link to the drug, only that an observer suspected a relationship. Depending on the features of the specific event, it could be counted in multiple categories, and classifications are not definitive. Among the most prominent were:
  • Accidents and injuries. A total of 173 serious events described accidental injury, including 28 road traffic accidents and 77 falls, some leading to fractures of rib, facial bones, hand, ankle, spine, and lower limbs. In these cases a variety of potential causes were identified, including loss of consciousness, mental confusion, dizziness and muscle spasms.
  • Vision disturbance. At least 148 reports contained medical terms indicating vision disturbances, including 68 cases described as blurred vision and 26 terms indicating transient or other forms of blindness. This reported effect could also describe a mechanism that could or did contribute to accidents and injuries.
  • Heart rhythm disturbances. The FDA received 224 domestic reports classified as potential cardiac rhythm disturbances. This category, however, was dominated by reports of sudden loss of consciousness, an event that could also have non-cardiac causes. However, this category also included smaller numbers of cardiac arrests and identifiable abnormal cardiac rhythms
  • Seizures and abnormal muscle spasms or movements. Serious reported events included 86 cases of convulsions (seizures), 372 reports of a wide variety of movement disorders, including tremors, muscle spasms, twitching, tics, drooling, and motor hyperactivity. The extent to which these problems resolved with a reduced dose or by halting treatment could not be determined from these data.
  • Moderate and severe skin reactions. Reported serious events included 338 cases of hives or swelling of the tongue, face, eyes, lips or other areas. In addition, 65 cases were classified as severe and included blisters, exfoliation of the skin and lips, and Stevens-Johnson Syndrome.
  • Diabetes. The FDA has received 544 reports suggesting varenicline may be related to a loss of glycemic control. This category included many cases of weight loss or gain that could have alternative causes, but also identified numerous cases of symptoms and laboratory tests consistent with new onset diabetes.

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 pilots3 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. We promptly notified the FDA of our findings.

This report was written by:

Thomas J. Moore, Senior Scientist, Drug Safety and Policy, ISMP
Michael R. Cohen RPh, MS, ScD, President, ISMP
Curt D. Furberg, MD, PhD, Professor of Public Health Sciences, Wake Forest University School of Medicine.

Institute for Safe Medication Practices
200 Lakeside Drive, Suite 200
Horsham, PA 19044

Corresponding Author
Thomas J. Moore

Full report available at the above link
Last edited by John (Gold) on 07 Jul 2011, 16:26, edited 1 time in total.

John (Gold)
Joined: 18 Dec 2008, 23:57

22 May 2008, 09:09 #2

Chantix blamed for 3,063
serious injuries and 78 deaths
May 21, 2008[/size]
A study released today examined 6,363 U.S. Food and Drug Administration (FDA) adverse drug reaction reports implicating Pfizer's quit smoking pill Chantix (varenicline) and found that 3,063 involved serious injuries. Its recommendation? "We recommend that patients and doctors exercise caution in the use of varenicline and consider the use of alternative approaches to smoking cessation."

Authored by The Institute for Safe Medication Practices (ISMP), a non-profit medication watchdog, ISMP looks for safety flags while monitoring all adverse events reported to the FDA for all medications.

ISMP monitoring noted that "by the 3rd quarter of 2007 varenicline produced a signal not previously seen for any other drug. It produced more serious reports than any other drug for multiple types of events: more potential cases of angioedema, cardiac arrhythmia, diabetes and severe cutaneous injury. By the 4th quarter of 2007 varenicline accounted for more reports of serious drug adverse events in the United States than any other drug."

During the 4th quarter of 2007 the FDA received 998 reports of serious varenicline adverse events compared to only 372 for the addictive troublemaker oxycodone, a potent medication for relief of moderate to severe pain. While ISMP estimates that a total of 3.5 million Chantix (varenicline) prescriptions were written in the U.S. since FDA approval in May 2006, government estimates place annual oxycodone prescriptions written at more than 7 million.

The study found that while the FDA has issued warnings regarding Chantix's link to suicidal acts, thoughts or behaviors, psychosis, hostility and aggression, it has ignored "other kinds of serious harm for which no warnings now exist, either from the FDA or from the manufacturer, Pfizer Inc."

While the FDA received 78 death reports in which "varenicline was the principal suspect drug," only 28 resulted from suicide. There were "numerous reports suggesting cardiac causes, both thromboembolic and arrhythmic," writes ISMP.

Among reports of serious events were 173 accidents and injuries, 338 angioedemas, 224 cardiac arrhythmias, 86 convulsions, 139 embolic and thrombotic events, 372 extrapyramidal syndromes, 544 cases of hyperglycemia/new onset diabetes mellitus, 525 reports of hostility/aggression, 397 psychosis and psychotic disorders, 227 reports of suicide/self-injury, 65 severe cutaneous adverse reactions, and 148 vision disturbances.

Could there possibly be a common thread among such a diverse group of disorders? Yes, says the ISMP study. A subtype of acetylcholine receptor known as alpha 4 beta 2 plays "numerous roles in the brain and body and is central to muscle contractions -- both voluntary movement and heart muscle contractions, as well as the tone of the smooth muscles that line the blood vessels."

According to the study, Pfizer researchers found that varenicline was most active against alpha 4 beta 2 type acetylcholine receptors. They focused on the fact that it caused the release of dopamine within the brain while blocking nicotine from occupying alpha 4 beta 2 receptors. It notes that "many antipsychotic drugs block dopamine receptors, but they also cause movement disorders. The loss of muscle control seen in Parkinson's disease is the result of the destruction of dopamine-producing cells in the brain."

The gravity and number of serious injuries attributed to Chantix caused the report to lightly touch on an equally pressing risk analysis concern, the value of Chantix in helping smokers quit. While noting that counseling rich varenicline clinical trials produced 52-week quit rates of approximately 22 percent, it cites two early nicotine gum studies while noting that they achieved comparable rates.

In fact, a 1976 nicotine gum study headed by Russell found that 23% of nicotine gum users were still not smoking at 1 year. The 1980 nicotine gum study by Raw produced a whopping 38% rate, in 1982 Jarvis found a 31% rate, in 1983 Schneider 30%, in 1984 Hialmarson 29%, in 1986 Daughton 31%, in 1987 Kornitzer 32%, and in 1989 Tonnesen boasted a 44% one year quit smoking rate.

What wasn't mentioned in the ISMP study was that in real-world competition, outside of clinical trials that were rich in support and counseling, nearly all quitting method surveys to date show that, long-term, cold turkey quitters actually perform better than users of nicotine gum, patch, lozenge and Zyban.

A 2006 National Cancer Institute quitting method survey of 8,200 smokers found that at 9 months 16% of "on your own" quitters were still not smoking compared to just 14% among quitters relying upon the nicotine patch, gum, lozenge or Zyban.

While ISMP faults the FDA for neglect in warning Chantix users about risks other than mental and emotional, just as culpable is its approval of Pfizer's clinical trial design when: (1) they involved a record number of provider counseling/support contacts (twenty-five), contacts the FDA knows could account for nearly all effectiveness seen; (2) no assessments to test study blinding was requested or conducted, when the FDA knows that it is probably impossible to blind drug addiction studies, as smokers with any quitting history recognize the onset of full-blown nicotine withdrawal; (3) excluded 28% of study applicants, including nearly all having any significant medical condition, and then permitted Pfizer to market Chantix to groups intentionally excluded; and (4) allowed NRT use between the end of treatment and week 52, and then certified ongoing NRT users as having been successful Chantix quitters.

If Pfizer knows, via real-world quitting data gathered through its website, that Chantix's real-world effectiveness is substantially less than shown in clinical trials, with Chantix injuries so numerous and serious, does Pfizer have both legal and ethical duties to immediately share that data with both the FDA and smokers considering using Chantix?

If Chantix isn't living up to Pfizer marketing hype, do reports like this ISMP study obligate Pfizer to be more forthright, honest and clear about both varenicline's safety and effectiveness?

"These data provide a strong signal that the risks of varenicline treatment have been underestimated, and show that a wide spectrum of serious injuries are being reported in large numbers," ISMP warns.

"Table 1 shows that in the 4th quarter of 2007, the other highest ranked drugs (e.g. fentanyl, interferon beta, etanercept) are all high alert drugs with black box warnings, are intended for serious illness in patients and have benefits that are accompanied by substantial risks. In comparison, varenicline is intended for use in healthy people to help stop smoking."

Does it make sense, if inside a very slow burning building, to pay money for the right to use the most dangerous exist path out?

Never in the history of smoking cessation has any quitting product harmed so many. It makes one wonder whether instead of helping smokers the FDA and Pfizer have declared war upon them.
No Copyright - This Article is Public Domain
John R. Polito is solely responsible for the content of this article.
Any factual error will be immediately corrected upon receipt of credible authority
in support of the writer's contention. E-mail comments to [][/url]

Joined: 19 Dec 2008, 00:00

22 May 2008, 09:17 #3

I for one don't want my pilot on chantix. Just too much at stake. Think about it.

John (Gold)
Joined: 18 Dec 2008, 23:57

22 May 2008, 18:50 #4

May 22, 2008 - New York Times
F.A.A. Bans Antismoking Drug, Citing Side Effects By STEPHANIE SAUL
The Federal Aviation Administration said Wednesday it would no longer permit pilots or air traffic controllers to use the smoking cessation drug Chantix, citing potential side effects that could pose a threat to the safe operation of aircraft.

The Food and Drug Administration issued a public health advisory in February, saying that some Chantix users had developed a variety of serious psychiatric symptoms, and that some had committed suicide.

An F.A.A. spokeswoman, Laura Brown, said the agency had approved the use of Chantix for airline pilots and flight controllers last year, but was notifying 150 pilots and 30 air traffic controllers known to be using it that the drug was no longer acceptable and should be discontinued.

Ms. Brown said the decision was based on emerging data on the drug, including a report from a watchdog group, the Institute for Safe Medication Practices, linking Chantix to a wide array of health and safety problems. They include accidents and falls, potentially lethal heart rhythm disturbances, heart attacks, seizures, diabetes and various psychiatric disturbances.

The institute's findings, which were based on an analysis of adverse events reported to the F.D.A., said that from May 2006 through December 2007, there were 227 reports of suicide attempts or suicides, 397 cases of possible psychosis and 525 reports of hostility or aggression. Those reports included 28 suicides and 41 mentions of homicidal thoughts, 60 cases of paranoia and 55 cases of hallucinations.

The data, the report said, "provide a strong signal" that the risks of treatment with varenicline, the active chemical in Chantix, have been underestimated. This year, Public Citizen's Health Research Group, another consumer watchdog organization, had called for a black-box warning - F.D.A.'s strongest drug alert - on Chantix.

Chantix, made by Pfizer, was approved in 2006 for sale in this country and the European Union. Worldwide sales of the drug were $883 million last year, and an estimated 6.5 million people have used it.

Pfizer issued a statement Wednesday saying that the current labeling for Chantix reflected the product's safety profile, including warnings that it had the potential to cause psychiatric problems and might impair driving.

"There are few things that provide greater health benefits than quitting smoking," said the Pfizer statement, issued by a company spokesman, Francisco Gebauer. "When considering the use of Chantix for their patients, health care providers should discuss the risks of smoking, the health benefits of quitting smoking, and the product's efficacy and safety profile."

In after-hours trading Wednesday, Pfizer's shares fell 22 cents, to $19.79, a 1.1 percent decline.

Dr. Timothy Anderson, a pharmaceutical analyst for Sanford C. Bernstein & Company, responded to Wednesday's report by downgrading estimates for Chantix sales in 2012, to $700 million, from $1.6 billion.

Chantix, taken in pill form, partly blocks and partly stimulates a nicotine receptor in the brain and in clinical studies was shown to help smokers quit. Potential problems associated with Chantix were first publicized last September when a Dallas musician, Jeffrey Carter Albrecht, was shot to death after he began behaving bizarrely while taking Chantix.

The Institute for Safe Medication Practices study noted that some of the reports of adverse events it analyzed could have been spurred by that publicity and by a November 2007 early warning about the drug from the F.D.A.

An F.D.A. spokeswoman, Susan Cruzan, said the agency was also conducting a special safety review of Chantix and was requiring pharmacists to distribute a medication guide to patients, warning of the potential side effects.

The F.A.A. was also planning to notify associations representing both commercial and private pilots that Chantix was no longer permitted, Ms. Brown said.

Online story source link

Joined: 18 Dec 2008, 23:57

23 May 2008, 20:18 #5

Thanks for the update, John

Good for the FAA! They are protecting their employees, even if they are probably just trying to avoid a law suit due to the possibility of planes crashing when managed by people on Chantix...

This whole Chantix affair is scandalous. Even if the FDA will now distribute a "medication guide" that warns patients of the side effects of Chantix, the prescription itslef is construed by patients as a medical endorsement of the product...

Shame on the pharmacological industry.


John (Gold)
Joined: 18 Dec 2008, 23:57

28 Sep 2008, 21:49 #6

Freedom's No Debate Policy
We ask members to remain mindful that here inside Freedom our mission truly is single minded: nicotine cessation. Whether your family is into tobacco farming or you are an executive at a tobacco company or work for Pfizer or are a health care provider who has recommended Chantix or Champix, you are as welcome here as any. This forum cannot permit posts that attack or vilify any profession or occupation or that have potential to promote debate that could divide or weaken the forum's support efforts and damage its mission.

Chantix is once again being actively marketed by Pfizer here in the U.S. and it won't be long before it's back in the headlines. So far, 5 of 6 varenicline sales worldwide have been in the United States. I'm told that reports of serious adverse reactions continue to pour into the FDA. Product liability lawsuits are now being filed across the nation on behalf of hundreds of users who have committed or attempted suicide, or sustained other serious injury or death.

Over the next two years Pfizer will be compelled to produce risk-benefit documentation showing what it knew both in regard to risks and effectiveness and when it knew it. This is the first time ever that nationwide civil litigation has focused upon a cessation product. We can expect lots of finger-pointing and headlines.

We will continue to share risk and effectiveness news here at Freedom for the the benefit of visitors looking in who may be considering varenicline. We may even share judicial findings. What we will not do is share allegations and arguments that will be traded during litigation, or permit attack upon any lawful occupation. There are plenty of forums that invite such discussions. If our objective is operation of a forum where all who are dependent upon nicotine are made to feel comfortable being here then this cannot be one of them.

Our sincere thanks to all members for helping keep Freedom united, strong and focused upon the forum's mission, staying nicotine-free today.

Breathe deep, hug hard, live long,

John (Gold x9)

John (Gold)
Joined: 18 Dec 2008, 23:57

23 Oct 2008, 04:16 #7

Pfizer's Chantix
Continues Killing Quitters
October 22, 2008[/size]
ImageMarketed in the U.S. as Chantix and other nations as Champix, another bomb just fell on Pfizer's quit smoking pill varenicline. According to a just released report by The Institute for Safe Medication Practices (ISMP), a non-profit medication watchdog, "In the first quarter of 2008, varenicline accounted for more reports of serious injury than the 10 best selling brand name prescription drugs combined."

The report indicates that the U.S. Food and Drug Administration (FDA) received serious adverse event reports on 773 different drugs during the 1st quarter of 2008. Chantix topped the list. During that period there were 1,001 new reports of serious injuries among varenicline users, including 50 additional deaths. By comparison, varenicline users accounted for 998 serious injury reports and 78 deaths during the 4th quarter of 2007.

The ISMP report notes that there were only 17 reports of serious injury among all forms of nicotine replacement therapy combined (the nicotine patch, gum, lozenge, spray, and inhaler). This quitting method risk data, when combined with results from the only head-to-head study pitting varenicline against NRT, should allow FDA officials to engaged in informed risk-benefit analysis.

A Pfizer smoking cessation study published in February 2008 compared 10 weeks of nicotine patch use to 12 weeks of varenicline use. Even after Pfizer gifted varenicline a two-week treatment advantage, varenicline failed to prove superior in 7-day point prevalence findings. Participants were asked at both 6 months and 1 year whether or not they had smoked a cigarette in the past 7 days. Pfizer's researchers, which included four Pfizer employees, were forced to report that there "were no significant differences" between nicotine patch and Chantix smoking abstinence rates at either 6 months or a year.

According to the ISMP report, varenicline again recorded the highest number of suicide/self-harm events of any medication with 226. The combined total for the next two closest drugs reporting suicide attempts was 22% less (oxycodone with 89 reports and acetaminophen with 87).

The ISMP report asserts that broader warnings are needed. It encourages the FDA and Pfizer to add a prominent warning about accident risks to both the patient Medication Guide and prescribing information sheet for doctors, a warning similar to the new warnings about psychiatric side effects.

The ISMP report also flags additional kinds of side effects, including serious accidental injuries. It highlights traffic accidents and concerns that varenicline induced seizures, disturbances in vision, panic attacks or impaired judgment may be playing a role.

It encourages further investigation of possible varenicline links to diabetes, potentially life-threatening interruption of the heart rhythm, heart attacks, strokes, and moderate to severe allergic reactions.

The ISMP's May 2008 report raised concerns about potential alertness and motor control related accidents among transportation industry workers using varenicline. In response, the Federal Aviation Administration banned the use of Chantix by airline pilots, the Department of Transportation limited its use among truck drivers, and the Department of Defense prohibited its use by aircraft and missile crews.

This time the bomb dropped on varenicline may prove fatal. If varenicline is not more effective than NRT, while causing nearly 5,800% greater harm than NRT, then why is it sill on the market? If the FDA has difficulty answering this question, it may well be that our nation's medication system has far greater concerns than just varenicline.
No Copyright - This Article is Public Domain

Joined: 11 Nov 2008, 19:22

02 Jul 2009, 03:19 #8

As shown by the below articles, today the U.S. Food & Drug Administration (FDA) required that both Chantix, whose chemical name is varenicline and that's marketed outside the US as Champix, and Zyban (bupropion) to carry the highest warning of all, a "Black Box," warning users of the risk of suicide among other serious risks.

Chantix and Zyban Get Boxed Warnings

The FDA announced yesterday afternoon that the smoking cessation drugs Chantix (varenicline) and Zyban (bupropion) must bear black box warnings for serious mental health symptoms, including changes in behavior, hostility, depression, and attempted suicide.

In addition to being used in smoking cessation, buproprion is also marketed as an atypical antidepressant under the brand name Wellbutrin, as well as in a generic form. All these products will receive increased warnings highlighting the risks for mental health events. (The drugs already carry black box warnings for suicidality.)

According to FDA, symptoms have occurred in patients with and without histories of psychiatric illness, and tend to occur shortly after medication starts and end when treatment is stopped. But there have been instances reported where side effects continue even after the patient stops taking the drug.

According to raw FDA numbers, 98 people taking Pfizer's Chantix committed suicide, while 14 people took their lives while on GlaxoSmithKline's Zyban. One hundred eighty-eight people attempted suicide on Chantix, and 17 tried while taking Zyban.

"It has been difficult to evaluate some of these cases, as we are working off adverse event reports," said Bob Rappaport, director, Division of Anesthesia, Analgesia and Rheumatology Products, CDER. "People who stopped smoking without using medication may also report similar symptoms in nicotine withdrawal. However, we examined some cases where people were using the products under discussion and also had the adverse events while smoking."
Rappaport admitted in a teleconference that both smoking cessation aids are effective, and possible risks should be weighed against the health benefits of quitting smoking.

Both companies can continue to advertise the drugs, but additional warnings must be added to the risk statements. However, they will no longer be allowed to run reminder ads.

About Time or Too Late?

Chantix came under fire last year in the blogosphere and media as hundreds of consumers began posting on Web forums that they had become increasingly depressed while on the smoking cessation drug.

Minutes after FDA announced the call for increased warnings, Pfizer released a statement saying that it would update its labeling to add the black box warning and adjust the current warning. Pfizer wouldn't comment whether recent public scrutiny has affected sales, or whether the company will retool its sales force in light of the new warnings.

Zyban, Really?

The black box for Zyban, however, is a bit of a surprise.

"We looked at three products [including nicotine replacement treatments] to get some sort of idea if Chantix would stick out," Rappaport said. "We were surprised to find that Zyban seemed out to have the same characteristic of [adverse] reporting and the same reporting rates. So this is a new thing for Zyban."

Pfizer and GSK are being required to conduct clinical trials to determine incidents of mental health symptoms in people trying to quit smoking, including people with and without pre-existing mental conditions.
FDA said that it doesn't expect the results of the trials to be revealed for several years.

Source Link
© 2009 Advanstar Communications, Inc. All rights reserved.

Joined: 06 Dec 2008, 16:58

27 Jul 2010, 18:17 #9

Thoughts and Acts of Aggression/Violence Toward Others Reported in Association with Varenicline

Annals of Pharmacotherapy

Published Online, 20 July 2010, /">http://www.theannal ..., DOI 10.1345/aph.1P172.
Thomas J Moore AB, Joseph Glenmullen MD, Curt D Furberg MD PhD Abstract

BACKGROUND: Thoughts and acts of aggression/violence toward others have been reported in postmarketing surveillance of varenicline, an aid to smoking cessation.

OBJECTIVE: To identify the common characteristics of these thoughts and acts of aggression/violence toward others and assess the likely relationship to varenicline treatment.

METHODS: We obtained 78 adverse event reports from the Food and Drug Administration MedWatch database containing medical terms describing possible acts or thoughts of aggression/violence; 4 additional cases were reported in clinical trials, and 3 others came from the published literature. We used psychiatric diagnostic criteria and an adverse event causality assessment tool to identify 26 case reports for study.

RESULTS: The selected cases described 10 events with assault, 9 cases of homicidal ideation, and 7 cases of other thoughts or acts of aggression/violence. The most frequent common characteristics were (1) inexplicable and unprovoked event, (2) the victim was anyone nearby, (3) no indication of a prior history of similar behavior in the patient, and (4) early onset of psychiatric adverse effects, often before stopping smoking. Where dechallenge/rechallenge information was available, psychiatric adverse effects resolved in 13/14 (93%) cases after discontinuation.

CONCLUSIONS: The clear temporal relationship, lack of prior history of this behavior, and unusual nature of these events strengthens the accumulating scientific evidence that varenicline is associated with thoughts and acts of aggression/violence. We recommend that physicians and pharmacists ensure that all patients are informed of possible psychiatric symptoms of varenicline, including violent and aggressive thoughts. All patients should be advised to contact a health-care provider immediately if these symptoms occur and varenicline should be discontinued without delay. ... ph.1P172v1
Note: Full text PDF freely available from link immediately above.

Joined: 11 Nov 2008, 19:22

15 Dec 2010, 16:02 #10

With Pfizer, FDA Shunning Tests on Mentally Ill, Promise of Smoking Remedy Chantix Turns to Ashes for Some

By Lilly Fowler on December 15, 2010

[omitted photo of: "Linda Ware with her granddaughter, two days before she committed suicide in 2008."]

Late one morning in June 2008, 57-year-old Southern California real estate agent Linda Ware was driving with her cousin along a desert highway when she began hallucinating. Envisioning in the distance a sign that read “God Is in the Realm,” she pulled over suddenly and ordered her cousin out of the car. Then, just as abruptly, Ware burst out laughing and pulled back onto the road again.

Although Ware suffered from depression, as her daughter Cary Ussery related, she’d never acted like this. A few days earlier, however, she had started taking Chantix, a pill meant to help her quit smoking by suppressing the effects of nicotine on the brain.

The day after the driving incident, a family friend found Linda Ware slumped by her bed, dead from a fatal cocktail of prescription drugs, a suicide note at her side.

Tragedy has plagued Chantix ever since it was approved in May, 2006, even as the drug has helped some smokers kick the habit. By mid-2009,  the U.S. Food and Drug Administration had received reports of nearly 100 suicides, 200 attempted suicides and close to 5,000 serious psychiatric events overall. Hundreds of reports of side effects have continued to stream in this year.

A review of the drug’s history shows that Pfizer Inc., the giant pharmaceutical company that makes Chantix, failed in its years of clinical trials to test the product on the mentally ill or those with a recent history of depression — even though millions of smokers suffer from psychiatric problems. Moreover, FDA regulators approved Chantix after a speeded-up “priority review” process, and did not request a follow-up study on mentally ill patients using the medication, even though the agency’s own safety reviewer reported that the exclusion of such smokers may have undermined the clinical trials.

It wasn’t until three years later, after thousands of reports of serious side effects, that the FDA told Pfizer to conduct trials including people with a history of mental illness. The agency then also slapped a so-called black box warning, the FDA’s strongest alert, on the medication.

The controversy over Chantix’s side effects, particularly for smokers with mental health issues, has triggered a torrent of lawsuits. About 1,000 such cases have been filed in federal court, and plaintiffs lawyers say they anticipate bringing forward more than 1,000 additional suits. There also are scattered cases in state courts in New York, Illinois and elsewhere. Plaintiffs in more than half of the cases claim the drug led to suicides or suicide attempts, and many say they suffered psychosis, blackouts, aggression, diabetes or other problems. No cases have yet been tried or settled.

The plaintiffs lawyers argue that Pfizer, the world’s largest pharmaceutical company with sales this year of more than $60 billion, neglected to test Chantix adequately before its release, deliberately hid evidence of serious side effects and failed to sufficiently warn consumers about its risks. Pfizer has turned over to plaintiffs lawyers more than six million pages of documents under a protective order that bars their public release.

Pfizer, for its part, defends Chantix and says it “acted responsibly and appropriately at all times in connection with the development, approval, and marketing” of the drug. The FDA, likewise, says it acted properly in approving the drug, despite the problems that emerged after it went on the market.

“The agency does not feel any mistakes were made,” said FDA spokeswoman Sandy Walsh.“We can never speculate as to what may happen with a drug once it goes into widespread use after approval.”

The FDA’s failure at the outset to require Pfizer to include the mentally ill in its research, however, points to a potentially serious flaw in the agency’s regulation of drug safety for these particularly vulnerable consumers. Although the mentally ill commonly are excluded from drug clinical trials, they account for a disproportionate number of smokers and are a key part of the target market for smoking cessation treatments.

Their exclusion baffles experts such as Dr. Karen Lasser, a Boston University researcher who has studied the link between mental illness and smoking. “You need to think about who is going to be taking the drug,” she said.

Paul Thacker, a former Senate Finance Committee investigator who has written about FDA decision-making, agreed. “If you’re not thinking in that way,” he said, “then you’re not doing your job.”

Back when Chantix was approved, Pfizer officials figured they had a potential major new star in their portfolio. With nearly 70 percent of the estimated 45 million smokers in the U.S. hoping to quit, the market appeared to be vast. Sales quickly zoomed to $883 million in 2007, which turned out to be the drug’s peak year. (During the first nine months of this year, sales totaled $522 million.)

Chantix, which is sold as a pill, works by taking the pleasure out of smoking by interfering with the way nicotine ordinarily affects the brain. At the same time, it spurs the release of dopamine, which helps control the brain’s pleasure centers the way smoking usually does.

Pfizer launched Chantix with a news release spotlighting the dire statistics on quitting smoking: less than 7 percent of smokers who try to quit on their own make it past the one-year mark. In contrast, clinical trials showed that about 22 percent of Chantix users who took the drug for three months were able to abstain from smoking for a year or more.

The company early on promoted its product through a series of TV, print and online ads that, without mentioning Chantix or its side effects, sought to sell people on the idea of quitting smoking. The “My Time to Quit” campaign was intended to draw smokers to a website that, after providing quick facts about kicking the habit, tiptoed to information about the drug. Overall, Pfizer has spent about $300 million on advertising for Chantix, according to the Nielsen Co., a media information business.

Pfizer also spread its influence by paying doctors to give talks to other physicians on smoking cessation techniques while also giving funds to universities. The University of Wisconsin-Madison said the company has given it more than $3 million, mainly for continuing medical education courses it offers on smoking cessation.

The multi-pronged promotional effort by Pfizer eventually addressed rising concerns about the drug. In 2008, Joseph Feczko, then Pfizer’s chief medical officer, wrote an opinion piece in the Wall Street Journal. Headlined “Smoking Has Side Effects Too,” the piece tried to offset the negative publicity about Chantix with a reminder on the hazards of smoking. It also explained how regulators and drug companies conduct follow-up research, and alert the public, after they receive reports of serious side effects.

Along the way, a controversial tack Pfizer took to push its product was a study written by a team of employees headed by Kathryn E. Williams, then part of the company’s Global Research and Development unit. The study, which was published in 2007 in the journal Current Medical Research and Opinion, deemed Chantix safe for long-term use. (Labeling on the drug prescribes a 12-week course of treatment, but the study looked at consumers who used Chantix for a year.)

The article, however, was flawed in that failed to provide statistical analysis to back up the claim, according to Dr. John Spangler, a smoking cessation expert at Wake Forest University’s School of Medicine. He wrote to the journal to complain, noting that the numbers actually indicated Chantix patients were 2.5 times more likely to suffer a serious adverse event than those on a placebo.

“I don’t know what they were trying to accomplish,” Spangler said in a recent interview. “A faulty study has been included into the world’s medical literature.” Pfizer declined to comment on the study.  The journal, for its part, said via email that the article “underwent rigorous and independent peer review, and full disclosure of the authors’ employment and funding was made.”

Other studies have demonstrated that Chantix has helped some smokers, but often is no better than other options for quitting. For instance, a study published in in the journal “Thorax” in 2008 showed that Chantix works better than the nicotine patch for some people, but not for others. Other researchers have concluded that nicotine gum is just as effective as Chantix.

What’s more, most people who give up smoking quit cold turkey, without medication. A 2006 survey of more than 8,000 smokers by the National Cancer Institute found similar success rates among those who used medication in trying to quit and those who didn’t. The figures showed that 16 percent of the non-medicated group abstained from smoking after nine months, versus 14 percent for the group using medications.

Still, experts such as Lirio Covey, a professor of clinical psychology at Columbia University who worked on early studies of Chantix, say the FDA’s approval of Chantix made sense. “Some people really have a hard time stopping smoking. Chantix does have some utility,” Covey said. “I would say that it’s a pretty good drug, but it’s not the first resort” for treatment.

For Covey, who said she has received close to $80,000 from Pfizer this year to study the effects on mood of smoking cessation, the key facts are these: millions have taken Chantix to stop smoking, and the number of people who suffered severe side effects is relatively small. In her estimation, the benefits of the drug outweigh the risks. She also believes it’s still not clear if the side effects are the result of the drug or nicotine withdrawal.

But questions about why Chantix’s safety wasn’t fully evaluated extend back at least to May, 2006, when the FDA’s safety reviewer for the drug, Dr. Howard Josefberg, submitted his report to the agency. He endorsed approving Chantix, but found that Pfizer’s clinical trials may have been “too carefully screened.” He noted that the studies excluded people treated for depression over the previous 12 months as well as “those with histories of panic disorder, psychosis or bipolar disorder.”

“The patient population studied, then, may not represent the true target population should varenicline be approved,” added Josefberg, using the generic name for Chantix.

The report by Josefberg, who declined to be interviewed for this story, indicated that three or four people died out of the roughly 5,000 smokers treated with Chantix in clinical trials. FDA researchers, however, said all of the fatalities appeared to be unrelated to the drug.

Still, one death in particular piqued the interest of scientists. A white male in his 60s who took the drug for close to six months took his own life. “Patient 103510121069 represents the most potentially concerning case,” Josefberg wrote. He “committed suicide by hanging 27-days after completing the 24-week varenicline treatment.” The patient had a history of severe depression but neglected to share his troubled past with those screening patients, according to FDA documents.

More than 80 other Chantix patients in the trials reported serious side effects. In one case, a 46-year-old white female, who stopped taking the drug after a week, arrived at work speaking incoherently, confronting colleagues, and overturning furniture, according to FDA documents. She was hospitalized for acute psychosis. Later reports indicated the patient had some history of psychotic behavior, but had failed to tell investigators, according to FDA documents.

All told, Josefberg concluded that there was no clear connection between Chantix and any deaths or serious adverse events, psychiatric or otherwise. He recommended the FDA approve the drug with a warning that alerted users to side effects such as potential heart problems, nausea, insomnia and abnormal dreams, while adding that the trial data was far from conclusive on the drug’s cardiovascular effects.

The routine exclusion of mentally ill subjects from clinical trials, researchers say, is justified in certain cases. Sometimes the subjects are too sick to consent to participate. Mentally ill patients may also fail to follow the proper dose regimens or other instructions. In addition, including people with mental or other health problems in drug research can complicate evaluating the results of a medication.

Yet many experts argue that excluding the vast numbers of Americans who are mentally ill from the trials leaves in doubt the real world effects of drugs on many people who may be vulnerable. According to the National Institute of Mental Health, 26 percent of Americans 18 and older, or close to 60 million people, suffer from a diagnosable mental disorder in a given year. About 6 percent suffer from a serious mental illness.

Beyond that, the mentally ill account for a big proportion of American smokers. A report this spring from the U.S. Centers for Disease Control and Prevention found that 43 percent of adults with depression smoke, versus 22 percent of other adults.

Boston University’s Lasser, in a recent analysis relying on the broader definition of mental illness, concluded that people with such disorders represent about 40 percent of all smokers.

Raymond Lorenz, the author of a recent paper on Chantix and the mentally ill and a faculty member at Auburn University’s pharmacy school, said more research is needed to gauge the risks that psychiatric patients face when they take the medication. Still, he wrote that excluding the mentally ill “seems to be a glaring oversight” in Pfizer’s trials before the FDA approved Chantix.

The FDA could have, but didn’t, ask Pfizer to conduct additional research — in this case, research including mentally ill smokers — immediately after Chantix was approved. The agency sometimes does that as a compromise, to ensure that medications reach patients without extra years of delays, while keeping an eye on a drug’s side effects after it comes into widespread use.

By late 2007, however, the parade of Chantix warnings and restrictions by federal authorities had begun. That November the FDA issued a warning that some patients taking Chantix reported having suicidal thoughts. Two months later, the agency ordered revised labeling indicating that Chantix’s safety for mentally ill patients was not established. Other federal agencies also took action, including the Federal Aviation Administration, which banned pilots and air traffic controllers from using Chantix.

Finally, in July, 2009, the FDA came around to fully embracing testing Chantix on the mentally ill. “We are going to require that they study folks that have mental health disorders,” said  Dr. Curtis Rosebraugh, an FDA drug evaluation official, in a telephone conference call media briefing. “There is a disproportionate amount [of them] that smoke and they would be potentially exposed to this drug. We have no idea if that subgroup population is at higher risk or not and so we do want to get some sense of that.”

Chantix users like Brandon Campbell already have a sense of that.

In July 2007, Campbell, a 33-year-old IT technician at Duke University Hospital, gave the drug a try after enrolling in an employee wellness program to quit smoking. Although Campbell, like Ware, had a history of depression, there was no indication as yet that the safety of the drug had not been established in people like him. Soon after finishing the recommended 12-week course of treatment, Campbell recalls, he started experiencing severe symptoms. He felt disconnected from reality, had trouble remembering things, and became emotionally unstable—breaking down over trifles. He also contemplated suicide. He’d been depressed before, sure, but had never felt, as he put it, like driving over a cliff.

The problems persisted. This past summer, Campbell said, he sat in his garage in Durham, North Carolina, with the doors shut tight and the car running, hoping to die. Then the police started beating on the door, and he was rushed to the hospital. Campbell still smokes and says he still wants to quit, but he's exceedingly wary of trying any more pharmaceuticals. “It's like playing Russian roulette,” he says.

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