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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 dechaltenge/rechalfenge 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 heafth-care provider immediately if these symptoms occur and varenicline should be discontinued without delay.

Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia.To analyze serious adverse drug event reports about these impulse control disorders received by the US Food and Drug Administration (FDA) and to assess the relationship of these case reports with the 6 FDA-approved dopamine receptor agonist drugs.We conducted a retrospective disproportionality analysis based on the 2.7 million serious domestic and foreign adverse drug event reports from 2003 to 2012 extracted from the FDA Adverse Event Reporting System.Cases were selected if they contained any of 10 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) that described the abnormal behaviors. We used the proportional reporting ratio (PRR) to compare the proportion of target events to all serious events for the study drugs with a similar proportion for all other drugs.We identified 1580 events indicating impulse control disorders from the United States and 21 other countries:710 fordopamine receptor agonist drugs and 870 for other drugs. The dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR = 277.6, P .001). The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P .001) and ropinirole (n = 188; PRR = 152.5, P .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P .001).Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with these specific impulse control disorders. At present, none of the dopamine receptor agonist drugs approved by the FDA have boxed warnings as part of their prescribing information. Our data, and data from prior studies, show the need for more prominent warnings.

BACKGROUND: Two treatments for smoking cessation-varenicline and bupropion-carry Boxed Warnings from the U.S. Food and Drug Administration (FDA) about suicidal/self-injurious behavior and depression. However, some epidemiological studies report an increased risk in smoking or smoking cessation independent of treatment, and differences between drugs are unknown. METHODOLOGY: From the FDA's Adverse Event Reporting System (AERS) database from 1998 through September 2010 we selected domestic, serious case reports for varenicline (n = 9,575), bupropion for smoking cessation (n = 1,751), and nicotine replacement products (n = 1,917). A composite endpoint of suicidal/self-injurious behavior or depression was defined as a case with one or more Preferred Terms in Standardized MedDRA Query (SMQ) for those adverse effects. The main outcome measure was the ratio of reported suicide/self-injury or depression cases for each drug compared to all other serious events for that drug. RESULTS: Overall we identified 3,249 reported cases of suicidal/self-injurious behavior or depression, 2,925 (90%) for varenicline, 229 (7%) for bupropion, and 95 (3%) for nicotine replacement. Compared to nicotine replacement, the disproportionality results (OR (95% CI)) were varenicline 8.4 (6.8-10.4), and bupropion 2.9 (2.3-3.7). The disproportionality persisted after excluding reports indicating concomitant therapy with any of 58 drugs with suicidal behavior warnings or precautions in the prescribing information. An additional antibiotic comparison group showed that adverse event reports of suicidal/self-injurious behavior or depression were otherwise rare in a healthy population receiving short-term drug treatment. CONCLUSIONS: Varenicline shows a substantial, statistically significant increased risk of reported depression and suicidal/self-injurious behavior. Bupropion for smoking cessation had smaller increased risks. The findings for varenicline, combined with other problems with its safety profile, render it unsuitable for first-line use in smoking cessation. Language: en