This update is in follow-up to the Drug Safety Communications issued on 6/16/2011 and 7/22/2011

Safety Announcement

Additional Information for Patients

Additional Information for Health Care Professionals

Data Summary

References

Safety Announcement

[12-12-2012] The U.S. Food and Drug Administration (FDA) is informing the public about the results of a large, combined analysis (called a meta-analysis) of clinical trials that compared patients who received the smoking cessation drug Chantix (varenicline) to patients who received a placebo (an inactive treatment). FDA required the manufacturer of Chantix to conduct the meta-analysis to further evaluate the cardiovascular safety of the drug, and believes it is important to let health care professionals and patients know about the results of this study. FDA first notified the public about a possible increased risk of cardiovascular adverse events with Chantix in its June 2011 Drug Safety Communication (DSC).

Facts about Chantix (varenicline) A prescription medicine used to help adults quit smoking that works by blocking the effects of nicotine (from smoking) on the brain 1

Increases the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo

According to sales for the 12-month period ending August 2012, the majority of Chantix® (varenicline) was distributed to outpatient retail pharmacies (88% retail, 8% non-retail, and 4.5% mail-order).2 For the 12-month period ending in September 2012, a total of approximately 2.3 million Chantix® prescriptions were dispensed and approximately 1.26 million patients received Chantix® prescriptions from U.S. outpatient retail pharmacies.3

A higher occurrence of major adverse cardiovascular events (a combined outcome of cardiovascular-related death, nonfatal heart attack, and nonfatal stroke) was observed in patients using Chantix compared to placebo. These events were uncommon in both the Chantix and placebo groups, and the increased risk was not statistically significant, which means it is uncertain whether the excess risk for the Chantix group was due to the drug or due to chance. However, the data were analyzed many different ways and consistently showed a higher occurrence of events in patients using Chantix, which makes it seem more likely that it is related to the drug and not purely a chance finding (see Data Summary below).

The meta-analysis findings of cardiovascular risk are similar to the findings in the smoking cessation clinical trial of patients with stable cardiovascular disease that was described in FDA’s June 16, 2011 DSC. The Warnings and Precautions section of the Chantix label has been updated to include the results of the meta-analysis.

Health care professionals are advised to weigh the risks of Chantix against the benefits of its use. It is important to note that smoking is a major risk factor for cardiovascular disease, and Chantix is effective in helping patients to quit smoking and abstain from it for as long as one year. The health benefits of quitting smoking are immediate and substantial.

Patients taking Chantix should contact their health care professional if they experience new or worsening symptoms of cardiovascular disease, such as chest pain, shortness of breath, calf pain when walking, or sudden onset of weakness, numbness, or difficulty speaking. Patients should also contact their health care professional if they have any questions or concerns about Chantix.



Additional Information for Patients

Smoking is a major risk factor for cardiovascular disease, and Chantix may help you quit smoking. The health benefits of quitting smoking are immediate and substantial, including decreasing the chances of developing lung disease, heart disease, and some cancers.

Contact your health care professional if you experience new or worsening symptoms of cardiovascular disease while taking Chantix, for example: Shortness of breath or trouble breathing New or worsening chest pain New or worse pain in legs when walking Sudden onset of weakness, paralysis, numbness, or difficulty speaking or understanding speech

Read the Medication Guide you get along with your Chantix prescription. It explains the risks associated with the use of Chantix.

Talk to your health care professional if you have questions or concerns about Chantix or about quitting smoking.

Report side effects from the use of Chantix to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of this page.



Additional Information for Health Care Professionals

Smoking is an independent and major risk factor for cardiovascular disease, and Chantix is effective in helping patients quit smoking. The health benefits of quitting smoking are immediate and substantial.

Weigh the risks of Chantix against the benefits of its use.

Counsel patients to seek medical attention if they experience new or worsening symptoms of cardiovascular disease while taking Chantix.

Encourage patients to read the Medication Guide they receive along with their Chantix prescription.

Report adverse events involving Chantix to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of this page.



Data Summary

A meta-analysis was conducted to systematically assess the cardiovascular safety of Chantix. The meta-analysis incorporated data from 7,002 patients (4,190 Chantix and 2,812 placebo) that were enrolled in 15 Pfizer-sponsored, randomized, double-blind, placebo-controlled clinical trials of ≥12 weeks treatment duration. The smoking cessation clinical trial of patients with stable cardiovascular disease that was discussed in the June 16, 2011, Drug Safety Communication was among the studies included in the meta-analysis. The primary cardiovascular safety assessment included an analysis of the occurrence and timing of major adverse cardiovascular events (MACE). The MACE composite outcome included the following endpoints: cardiovascular-related death, nonfatal myocardial infarction, and nonfatal stroke. Cardiovascular events included in this composite outcome were adjudicated by a blinded, independent committee.

Overall, there was a low incidence of MACE occurring within 30 days of treatment discontinuation (Chantix 0.31% [13/4190] vs. placebo 0.21% [6/2812]) in the trials included in the meta-analysis. The meta-analysis showed that exposure to Chantix resulted in an adjusted hazard ratio of MACE of 1.95 (95% confidence interval: 0.79, 4.82), which is based on trials reporting at least one MACE. This is similar to an estimated increase of 6.3 MACE per 1,000 patient-years of exposure (95% confidence interval: -2.40, 15.10). These results are summarized in the table below.

The meta-analysis also showed higher rates of composite outcomes in patients on Chantix relative to placebo across different time frames and pre-specified sensitivity analyses, including various study groupings and cardiovascular endpoints. Although these findings were not statistically significant, they were consistent. Because the number of adverse cardiovascular events was small overall, the power for finding a statistically significant difference in a signal of this magnitude is low.

It should be noted that the incidence of cardiovascular mortality (Chantix 0.05% [2/4190] vs. placebo 0.07% [2/2812]) and all-cause mortality (Chantix 0.14% [6/4190] vs. placebo 0.25% [7/2812]) was lower in the Chantix group compared to the placebo group, although this finding was also not statistically significant.

Adjusted Hazard Ratio and Incidence Rate Differences for MACE

Chantix

N=4190 Placebo

N=2812 Full meta-analysis (15 studies) MACE cases (%) 13 (0.31%) 6 (0.21%) Patient-years of exposure 1316 839 Hazard Ratio (95% CI) 1.95 (0.79, 4.82) Rate Difference

per 1,000 patient-years (95% CI) 6.30 (-2.40, 15.10)

Patients censored at 30 days after treatment.

CI=confidence interval; MACE=major adverse cardiovascular events



References

MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US). Drug & Supplements Monograph: Varenicline. Available from: http://www.nlm.nih.gov/medlineplus/druginfo/meds/a606024.html. Accessed October 18, 2012. IMS Health, IMS National Sales Perspectives™, MAT August 2012. Extracted October 2012. IMS Health, Vector One®: National and Total Patient Tracker. Extracted October 2012.

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