Chantix safety at the US Veterans Affairs Health Service

The US Department of Veterans Affairs (which provides healthcare for people who have served in the US armed forces) yesterday issues a bulletin on safety issues with varenicline. In addition to covering some of the safety issues that have been discussed previously on this blog, it provided some data on adverse events within the VA.

The report stated that between September 2006 and April 30, 2008 there were a total of 147,718 prescriptions for varenicline (69,765 unique patients) within the VA. As of May 26 2008 , VA healthcare providers had submitted 417 reports on possible adverse events associated with varenicline. The most common type of adverse event was vomiting (95), followed by nightmares/abnormal dreams (82), depression (68), agitation (33), suicidal ideation (31) and hallucinations (25). Other adverse events were reported much less frequently.

So the overall rate of adverse event reports appears to be around 6 per thousand, of which almost half consist of vomiting, abnormal dreams and other non-life threatening symptoms that are recognized as rarely occurring side effects of the drug. Interpretation of the rates of the other (primarily psychological) symptoms needs to bare in mind that the VA healthcare system provides fairly comprehensive and accessible mental health services and the rates of mental health problems in VA patients is therefore known to be higher than in the general population. For example, one recent study found that 40% of male VA patients were suffering from a current mental health disorder.
http://ajp.psychiatryonline.org/cgi/content/full/156/12/1924

With this background, and an annual rate of suicide attempts of 1% among adult smokers, the numbers of patient being reported as suffering these adverse events in the VA system does not appear to be particularly high. One patient was known to have committed suicide in association with varenicline use, and although every case of suicide is tragic, one case in almost 70,000 patients in the VA system is almost certainly less than the background rate of suicide in the VA system among patients not using Chantix. I am not saying that Chantix may prevent these symptoms or behaviors. However, even after allowing for under-reporting of adverse events (which is normal), the frequency with which these events are being reported among Chantix users does not appear to be above the frequency that we would expect these types of events to be occurring in patients not using Chantix (in fact its much lower). What this means to me is that there is nothing in this new data that stands out as a clear signal that Chantix likely caused these events (other than perhaps vomiting and abnormal dreams, which are known to be increased by Chantix).

Of course it is very difficult to interpret adverse event reports, which are not necessarily recorded in a very systematic manner. The data we have so far suggest the following:

1. Prescribers should continue to use varenicline as one of the first-line medicines shown to help treat nicotine dependence.
2. Prescribers should make patients aware of the potential side effects, including the relatively frequent effects that have been shown to be caused by the drug (e.g. mild nausea in around 30% of patients), as well as the much less frequent symptoms that have not been proven to be caused by the drug (e.g. depression).
3. Providers should follow the US Public Health Service Guideline that recommends not only assisting smokers to quit by prescribing an effective medicine, but also arranging follow-up with patients to monitor progress and side-effects etc. Patients should also be told to notify their doctor immediately if they experience any serious side-effects between appointments.
4. Patients should continue to consider varenicline as a safe and effective treatment for nicotine dependence, but should be prepared to keep in contact with their healthcare provider and to report onset of unpleasant/serious symptoms to that provider if they occur.
5. Additional placebo-controlled trials in more typical patient samples should be carried out, to provide further high-quality data on efficacy and safety.

Labels: champix, Chantix, cigarette smoking, jonathan foulds, safety, varenicline

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Chantix (varenicline) Safety

Last week a report was released by an organization called the “Institute for Safe Medication Practices” (ISMP) which claimed to have safety concerns about Chantix (varenicline, also marketed as Champix outside the United States). The Executive Summary of the report made two main recommendations:

1. Chantix should be avoided or used with caution by persons operating aircraft, motor vehicles or other machines (e.g. power stations) where a lapse in alertness or motor control could have serious consequences.
2. Patients and doctors should excercise caution in the use of Chantix (generally) and “consider the use of alternative approaches to smoking cessation.”

Given that most of us drive a vehicle, the report is basically suggesting that varenicline is such an unsafe drug that it should be avoided. These are strong recommendations, and have immediately resulted in the Federal Aviation Authority (FAA) and Federal Motor Carrier Safety Administration (FMCSA) adding varenicline to their list of drugs that should not be used by pilots or truck drivers. The report itself has not been published in a peer-reviewed journal and so it is reasonable to assess the quality of the data on which it was based, and to evaluate whether the recommendations are warranted on the basis of that data.

The ISMP report was based on an analysis of the frequency and type of serious adverse events that have been reported to the US Food and Drug Administration (FDA) about Chantix, in comparison to other drugs. In particular, the report noted that by the 4th quarter of 2007 Chantix “accounted for more reports of serious adverse events in the United States than any other drug.” This amounted to 988 reports about Chantix in the 4th quarter, as compared with 372 (Oxycodone) to 640 (Interferon Beta) reports about the next 5 most reported drugs.

The report then selected a sample (3063) of the total reports (excluding foreign or unclear reports) for slightly more detailed analysis. It noted that a much larger proportion of the reports about Chantix came from consumers (57%) than is typical of other drugs (26%) for which health professionals are the predominant source. The report also noted that a lower proportion of the reports about Chantix (2.5%) reported deaths, as compared with 17% of reports about other drugs.

The report summarized the most frequent medical terms included in the reports about Chantix. By far the most common term used was nausea (593), which was more than twice as common as any other reported symptom. It was also noteable that among the most commonly reported medical symptoms mentioned in the adverse event reports, many are also recognized nicotine withdrawal symptoms (i.e symptoms known to increase when smokers quit smoking, particularly without any treatment medication), such as depression (287), insomnia (242), anxiety (217), and weight increase (141).

Problems with the ISMP report and its conclusions

There are a number of fundamental problems with the quality of the data, analysis and interpretation in the ISMP report. Before discussing some of these, it is worth discussing the way that reports of serious adverse events are delivered to the FDA. There are 4 main sources of reports.

1. Members of the public can send reports directly to FDA, either by mail or via an on-line reporting system (and I have provided the link on previous posts on this blog about Chantix to ensure that reports reach FDA).
2. Health professionals can report adverse events to FDA.
3. Lawyers sometimes report adverse events to FDA.
4. The manufacturer is required to report to FDA any reports that are brought to its attention directly. Those adverse events that are already mentioned on the product labeling are reported on a quarterly basis, and novel symptoms must be reported within 15 days (expedited).

Reports from the first 3 of these sources are entirely voluntary and are made in a rather haphazard way. The ISMP report estimated that typically between 1 and 10% of serious adverse events are actually reported to FDA. It is commonly found that AE reports peak around two years after the launch of a drug, even if the drug becomes used more often thereafter. The purpose of the FDA’s reporting and monitoring system is to facilitate post-marketing surveillance and enable detection of patterns of adverse events that could potentially be caused by a medicine but were not detected in the initial placebo-controlled trials leading to drug approval. The main point here is that these reports are not made in a systematic way, and the frequency of reports can be influenced by factors such as (a) the frequency of use of the drug (b) the novelty of the drug (c) media coverage of the drug and (d) efforts by the company to interact with users in a manner that will lead to them hearing of and therefore being required to report on AEs.

With these factors in mind, here are some of the problems with the ISMP report:

1. The report fails to consider the frequency of the use of the drug when considering the number of adverse events being reported. Since its launch in August 2006 (i.e. less than 2 years), Chantix has been used by an estimated 5.5 million smokers in the United States. In 2007 alone it was used by 3.8 million new patients in the U.S. (6.2 million prescriptions). This is many times more than the other drugs listed in the ISMP report. For example, Etanercept (Enbrel, the drug with the 3rd largest number of adverse event reports to FDA) was launched in 1998, and has been used by a total of 450,000 patients WORLDWIDE in those 10 years. Comparing frequency of adverse events without adjusting for the frequency of drug use is so obviously inappropriate as to cast doubt on the reliability of the report as a whole.
As mentioned briefly in the ISMP report, many factors can affect the frequency of reporting of adverse events to FDA. In the case of Chantix, the widely publicized death of a rock musician (who was tragically shot by a neighbor in Texas) which his partner felt could have been related to Chantix, sparked off widespread media speculation about potential side effects. The manufacturer also offers a number of direct to consumer quit smoking services, including a free telephone hotline called “Get Quit”. Because this hotline is run by the manufacturer, whenever a caller mentions a symptom, they are immediately transferred to the medical department, the details are noted and the information reported to FDA. These events and procedures can have a large effect of increasing the number of serious adverse events reported and this was not adequately considered in the ISMP report. It is noteworthy that 92% of the events analyzed in the ISMP report came via the manufacturer.

2. The report fails to adequately consider the possibility that some of the reported adverse events may have been caused by nicotine withdrawal. The vast majority of those using Chantix were attempting to quit smoking, which itself is known to cause a range of nicotine withdrawal symptoms, including many of the symptoms most commonly reported to FDA and mentioned in the ISMP report (depression, insomnia, anxiety, weight increase). It is entirely plausible that many of these reported symptoms were caused by nicotine withdrawal rather than Chantix. In fact in the placebo-controlled trials of Chantix, withdrawal symptoms were REDUCED in those using Chantix.

3. The report doesn't adequately consider the serious health effects of tobacco dependence. The ISMP report characterizes the other comparison drugs as being “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.” Unfortunately this statement indicates a misunderstanding of the nature of tobacco dependence as a serious illness causing the premature death of 50% of continuing smokers, and of the fact that a high proportion of patients using smoking cessation medications are already suffering from or at very high risk for smoking-caused illnesses, including some mentioned as adverse events in the report (e.g. cardiac arrhythmias).

4. The report inaccuratley characterizes the relative efficacy of varenicline versus other treatments. The ISMP report states that Chantix has similar long term quit rates to nicotine gum. This statement contradicts the findings of the new US Public Health Service Clinical Practice Guideline on Treating Tobacco Use and Dependence, which found a mean quit rate of 13.8% with placebo, 19% with nicotine gum and 33.2% with varenicline (p109) and that quit rates with varenicline are significantly greater than with the nicotine patch (p121). This Guideline, written after the recent labeling changes for varenicline, concluded that, “Varenicline is an effective smoking cessation treatment that patients should be encouraged to use.” (p113).

Probably the most basic problem with the ISMP report is its failure to consider the frequency of use of the medicines as a factor influencing the interpretation of the frequency of adverse events reported. It therefore remains unclear whether any of these serious adverse events were caused by varenicline. When added to the other problems of interpretation mentioned above, I prefer to rely on the recommendation of the US Clinical Practice Guideline, which resulted from a very thorough review of the available scientific evidence.

So what does this mean for patients considering quitting smoking? As always, rely on the advice of your own doctor rather than on reports in the media or the internet (including this one!).

The complete ISMP report can be found at:
Strong Safety Signal Seen for New Varenicline Risks
http://www.ismp.org/docs/vareniclineStudy.asp

Previous posts on this blog that are relevant to this issue are:
What is nicotine withdrawal syndrome? 3/6/07http://www.healthline.com/blogs/smoking_cessation/2007/03/what-is-nicotine-withdrawal-syndrome.html
Ten tips for coping with nicotine withdrawal. 3/7/07http://www.healthline.com/blogs/smoking_cessation/2007/03/ten-tips-on-coping-with-tobacco.html
Chantix: how does this new stop smoking medicine work? 4/15/07http://www.healthline.com/blogs/smoking_cessation/2007/04/chantix-how-does-this-new-quit-smoking.html
Can quitting smoking trigger depression? 6/16/07http://www.healthline.com/blogs/smoking_cessation/2007/06/can-quitting-smoking-trigger-depression.html
Chantix and mental illness. 08/12/07http://www.healthline.com/blogs/smoking_cessation/2007/08/chantix-and-mental-illness.html
Two new studies of Chantix (varenicline). 08/19/07http://www.healthline.com/blogs/smoking_cessation/2007/08/two-new-studies-of-chantix-varenicline.html
Does Chantix cause mental health problems? 9/20/07http://www.healthline.com/blogs/smoking_cessation/2007/09/does-chantix-cause-mental-health.html
Chantix (varenicline) safety being reviewed by FDA. 11/21/07http://www.healthline.com/blogs/smoking_cessation/2007/11/chantix-varenicline-safety-being.html
New study of Chantix in comparison with NRT. 11/28/07http://www.healthline.com/blogs/smoking_cessation/2007/11/new-study-of-chantix-in-comparison-with.html
Smoking and suicide. 4/22/08 http://www.healthline.com/blogs/smoking_cessation/2008/04/smoking-and-suicide.html

Full reports on the largest placebo-controlled trials of varenicline can be found via:
http://jama.ama-assn.org/cgi/content/full/296/1/47

Labels: cessation, champix, Chantix, cigarette smoking, jonathan foulds, Nicotine Replacement, safety, varenicline

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Thanks to the Dinosaur for Grand Rounds

Thank you to Musings of a Dinosaur for including my post about “Why Comprehensive Tobacco Control” in this week's edition of Grand Rounds. Grand Rounds is a weekly compilation of posts related to health care compiled by a host, who makes a great effort to compile an interesting collection for readers.

Labels: comprehensice tobacco control, dinosaur, grand rounds, jonathan foulds

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Why comprehensive tobacco control?

In my post of May 9th I described some of the reasons why it is unwise to cut funding for comprehensive tobacco control. But what exactly is it and why does it need to be “comprehensive”?

The main reason for trying to reduce tobacco consumption within a population is of course because tobacco (primarily cigarette) smoke is extremely harmful to health. The main goals are:
Reduce initiation of tobacco use (primarily in teenagers)
Reduce exposure to tobacco smoke pollution (in the whole population)
Encourage and help existing tobacco users to quit.

There are lots of different ways of achieving a reduction in use and exposure. Some of the main ones include:
(a) use of mass media to inform the public about the harms from tobacco
(b) pass legislation to protect the public from exposure to tobacco smoke pollution in public places
(c) increase taxes on tobacco products
(d) provide community based activities to educate local communities and organizations about the harms from tobacco and ways of avoiding these
(e) provide services designed to help existing tobacco users to quit. These include brief interventions by health professionals, intensive treatment at special clinics, telephone quitlines, websites to encourage cessation, and free/reduced cost medications
All of these activities need to be organized and evaluated to ensure that they are producing the desired effects.

Evaluations of previous state-wide comprehensive tobacco control programs have found that although each of the components mentioned above have an effect on their own, they work best when combined. If the population is unaware of how harmful tobacco smoke is, they will be less likely to support legislation to ban smoking in workplaces (remembering that bars and restaurants are workplaces). Similarly, if smokers are not aware of the cessation services being provided, they won’t use them. So mass media helps with the other components. Similarly if smoke-free legislation and high cigarette taxes encourages more smokers to try to quit, but there are no treatment services, then the more addicted smokers will be unlikely to succeed in quitting, no-matter how much they want to. So each of these components has a positive influence on and supports the other components, to produce a measurable decrease in the social acceptability of tobacco use, and a decrease in tobacco use in the population. This decrease in tobacco use then translates into a healthier population, with lower rates of smoking caused disease.

CDC has calculated the appropriate level of funding for each State, corresponding to $15 to $20 per capita, depending on the State’s population, demography and the current level of tobacco use. If all states funded tobacco control as recommended by CDC, in 5 years there would be around 5 million fewer smokers in the United States and hundreds of thousands of premature tobacco-caused deaths would be prevented each year. A more detailed review of the evidence supporting this is provided in the Introduction (particularly pages 8-12) of the CDC “Best Practices 2007” document.

Unfortunately, when a state funds tobacco control at too low a level, it becomes impossible to deliver “comprehensive” tobacco control. Unfortunately my own state, New Jersey, is one of 17 states that have committed minimal funds to tobacco control over recent years (less than 10% of CDC recommended funding). That’s why it is so short sighted of legislators to be even considering a cut to the current budget.

Comprehensive tobacco control is the most cost-effective way to improve health and prevent premature deaths from cancer and heart disease and chronic illnesses caused by respiratory diseases and exposing the unborn child to tobacco smoke. With the tobacco industry spending around $13 BILLION per year on promotions and advertising, underfunding tobacco control is a recipe for hooking another generation on these deadly addictive products.

For the CDC’s best practices for Comprehensive Tobacco Control (2007), click on:
http://www.cdc.gov/tobacco/tobacco_control_programs/stateandcommunity/best_practices/

For evidence of a direct effect on health in one of the first states to implement tobacco control see:
http://www.cdc.gov/MMWR/preview/mmwrhtml/mm4947a4.htm

Labels: comprehensice tobacco control, jonathan foulds

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Thanks to Grand Rounds 4.34 at Health Business Blog

Thank you to David E. Williams of Health Business Blog for including my post on why its “Unwise to cut tobacco control funding in tough times” in this week's edition of Grand Rounds. Grand Rounds is a weekly compilation of posts related to health care compiled by a host, who makes a great effort to compile an interesting collection for readers. Check out Health Business Blog as it has lots of interesting articles.
http://www.healthline.com/blogs/smoking_cessation/2008/05/unwise-to-cut-tobacco-control-funding.html

Labels: grand rounds, Health Business, jonathan foulds

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Unwise to cut tobacco control funding in tough times

The U.S. and many other economies across the globe are going through tough financial times just now. In these tough times, legislators and policy makers have to make tough choices about how to spend limited budgets. In recent times in the United States, one of the targets for cuts has been tobacco control funding.

Using my home state as an example, I’d like to summarize some of the reasons why cutting tobacco control funding is not a wise policy, even in tough financial times.

Here in New Jersey, our Comprehensive Tobacco Control Program (CTCP) started in 2000, with funding of $32.5 million via the Master Settlement Agreement. At that time the Centers for Disease Control (CDC) recommended a minimum of $45 million annual expenditure on tobacco control. The program was set up to follow CDC guidelines to have components for media, evaluation, community activities, youth prevention, and smoking cessation. With the post 9/11 recession causing severe budget problems for the state, funding was drastically cut by 66% to $11 million in 2004 and has remained at that level. The state brings in approximately $1 billion per year from tobacco sources (MSA plus tobacco taxes) and so is currently spending around 1% of tobacco revenues on tobacco control. In 2007 the CDC updated its funding recommendations for New Jersey to $120 million ($13.75 per person per year, and 12% of total tobacco-related revenue to the state).

Despite being drastically underfunded, the New Jersey CTCP has had many noteable achievements. Just a few of these are:

- Over the years 2000 to 2007, cigarette taxes were increased from 80 cents per pack to $2.575 per pack (highest state tax in the country).
- Legislation was passed to ban smoking in all workplaces and indoor public places, and implemented in 2006, adding casinos in 2008.
- The number of cigarettes being smoked by New Jersey youth was cut by 50% from 1999 to 2006.
- Adults cigarette smoking fell from 21% during the mid 1990s to 17.1% in 2007, the lowest level recorded.

Some may ask for early signs of a health impact. One early response to reduced smoking is a reduced rate of heart attacks. The number of acute myocardial infarctions causing reported inpatient hospitalizations in New Jersey was above 22,000 every year from 1995 to 2003 (24278 in 2000), but dipped below 22,000 in 2004 and has continued to fall to below 20,000 in 2006. This reduction from the year 2000 to 2006 was evident for every age group over age 15. Clearly all of this reduction cannot be entirely attributed to the CTCP, but it is highly likely that many heart attacks were prevented by the reduced smoking in the state. In tough financial times, one has to consider the cost savings to the healthcare system from reduced hospital admissions for MIs, lung cancer, premature babies, respiratory disease and all the other diseases caused by smoking.

Some point to the successes in reducing smoking and seem to be under the misguided impression that smoking is so rare nowadays that there is no longer a need for robust tobacco control programs. The reality is that according to our latest data (2006), New Jersey’s 7th through 12th graders smoke 90 million cigarettes a year. This does not include the significant proportions smoking cigars and bidis, or chewing tobacco.

Per capita cigarette consumption is currently 43 packs per year (down from 69 packs in 1999), and lower than the average for the country (69 packs).

To put New Jersey’s investment in tobacco control into perspective, on an annual basis it is less than the amount of revenue the state receives in excise taxes from illegal cigarette sales to kids ($11.5 million)!

Yet in that scenario of incredible success despite serious underfunding, New Jersey’s Comprehensive Tobacco Control Program is currently threatened with further cuts. I don’t think we can really say that with New Jersey’s youth smoking 90 million cigarettes per year, and with 43 packs being consumed annually for every person in the state, that the work for tobacco control is done. We are only beginning to see the return on investment in terms of reduced health effects from tobacco. To cut the program now would result in a reversal of the progress, and directly cause more heart attacks, more cases of lung cancer and emphysema, and more premature babies.

Tobacco control spending provides an excellent return on investment, and it is for this reason that CDC recommends that New Jersey should spend $120 million, rather than be considering cutting from $11m. Even in tough financial times, a dollar spent on tobacco control is a dollar well spent on improving health and reducing healthcare costs.

So when times are tough, and money is needed for other important causes (like healthcare for uninsured smokers), a far better way to fund these is to increase the excise tax on cigarettes. http://www.tobaccofreekids.org/reports/prices/



Full details and evaluation of New Jersey’s Comprehensive Tobacco Control Program can be found at: http://www.nj.gov/health/as/ctcp/research.htm

For more details on the toll of tobacco in New Jersey, click on:
http://www.tobaccofreekids.org/reports/settlements/toll.php?StateID=NJ

For the CDC’s best practices for Comprehensive Tobacco Control (2007), click on:
http://www.cdc.gov/tobacco/tobacco_control_programs/stateandcommunity/best_practices/

Labels: cigarette tax, comprehensive tobacco control, funding, jonathan foulds, New Jersey

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Which kids in the US are most likely to use tobacco?

The tobacco industry has a problem. Its products kill the consumers when used as intended. Given the high rate of people ceasing tobacco use due to premature death or success in beating the addiction, the industry has its work cut out in replacing these consumers with new users. Each company is aware that smokers quickly develop brand loyalty, and so the race is on to hook kids before other companies can get their hands on them. Youth are also a major target for tobacco companies because the younger they get them, the more years of tobacco sales will be achieved before the consumer dies.

In the United States, tobacco use by high school kids is defined as either current use (any use in past 30 days) or frequent use (use on 20 out of the last 30 days). The proportion of high school kids who were current (frequent) cigarette smokers in the US increased from 1991 when it was 27.5% (12.5%) to peak in 1997 at 36.4% (16.7%), before falling to 23% (9.7%) in 2005. It is unlikely to be a coincidence that the increase in youth cigarette smoking throughout the 1990s was reversed from the same year the Master Settlement Agreement was signed (law suit in which states sued tobacco companies for tobacco-caused Medicaid costs). The MSA triggered significant publicity about the harmfulness of tobacco, resulted in a marked increase in tobacco control funding, and also resulted in price increases (which was how the companies easily recouped the money they paid in the settlement).

In 2005 white (non-Hispanic) girls had the highest current cigarette use (27%), followed by white boys (24.9%) and Hispanic boys (24.8%). These rates are much higher than among African American high school kids, of whom only 11.8% of girls and 14% of boys were cigarette smokers.

African American youth have consistently had much lower smoking rates than white youth over the past 25 years, although in the early 1970 their smoking rates were similar to whites. No-one knows what caused such a marked decline in African American youth smoking from the early 70s through to the 1980s and beyond. If you have any idea I’d like to hear it (and note that African American youth were also less likely to use alcohol or illicit drugs than white youth during that same time period).

You can read a full report on the latest data on youth cigarette smoking in the US at:
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5526a2.htm

Labels: cigarette smoking, jonathan foulds, USA, youth

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