Patient and Event Characteristics
We identified 17,290 case reports meeting the study criteria for all types of serious adverse events, including 13,243 cases in the smoking cessation population and 4,047 in the antibiotic comparison group. In the smoking cessation treatment population, 3,249/13,243 (25%) of the cases reflected either depression, suicidal/self-injurious behavior or both, compared to 48/4,047 (1%) of the cases in the antibiotic group. shows the patient and case report characteristics overall for the three smoking cessation drugs and the antibiotic comparison group. While patient and case report characteristics overall were similar among all four groups, a few differences could be observed. As might be expected, antibiotics were used in a wider range of patient age than were the smoking cessation products, as indicated by a greater standard deviation in the mean age. Reporting sources were evenly divided between consumers and health professionals except for nicotine replacement products, for which 83% of case reports came from consumers.
Characteristics of Adverse Drug Event Reports.
The specific medical terms (MedDRA Preferred Terms) that resulted in the classification of a case in either of the two primary SMQs are shown in . For the suicidal/self-injurious behavior SMQ, suicidal ideation was the most frequent term, appearing in 1,255/2,045 (61%) of cases. However, completed suicide appeared in 298 cases (15%) and suicide attempt in another 388 cases (19%). For the depression SMQ the simple Preferred Term Depression appeared in 1,913/2,210 (87%) of selected cases. Among the smoking cessation drugs, the only marked difference in term frequency was that the varenicline cases were coded to a greater variety of different terms than were the bupropion and nicotine products.
MedDRA terms in suicidal/self-Injurious behavior and depression SMQs.
The odds ratio and 95% confidence intervals for the endpoints in this study are shown in and . shows the results compared to nicotine replacement. Varenicline showed disproportional risks, OR 8.4 (CI 6.8–10.4). The odds ratio for bupropion was smaller than for varenicline, but also elevated, OR 2.9 (CI 2.3–3.7). For varenicline compared to bupropion, the odds ratio was 2.9 (CI 2.5–3.4). The results were similar when depression and suicidal/self-injurious behavior were examined separately. Also, 954/3,249 (29%) of the composite endpoint cases fell into both the depression and suicidal/self injurious behavior SMQs. As seen in , the data show that compared to the antibiotic comparison group, the OR was elevated for all three smoking cessation treatments, although to different degrees: varenicline OR 36.6 (CI 27.5–48.9), bupropion OR 12.5 (CI 9.1–17.2); nicotine replacement products OR 4.3 (CI 3.1–6.2).
Varenicline, bupriopion versus nicotine replacement.
Varenicline, bupropion versus 3 antibiotics.
Concomitant Therapy Drugs
We identified 58 drugs (including bupropion and varenicline) which currently have a Boxed Warning, Warning or Precaution about suicidal behaviors in the prescribing information. Overall, 3,068/17,290 (18%) of all cases included concomitant therapy with another drug with a suicide warning or precaution. The results when these cases were excluded are also shown in and . The statistics were similar to the primary endpoint, which did not exclude these cases.
Headache and Pain
The headache and pain adverse event terms were selected because they are among the most frequent and widely reported, non-specific symptoms both with and without drug therapy, and not clearly associated with any of the study drugs. Headache or pain occurred in 1,032/13,243 (8%) of the smoking cessation cases, but the differences among the three drugs were not statistically significant (χ2
0.28). However, headache and pain were reported more frequently for the smoking cessation treatment patients than for the antibiotic comparison group OR 1.95 (CI 1.7–2.3). While the difference is small, the result is plausible since nicotine withdrawal could cause these symptoms.
Unadjusted Event Totals
Even though varenicline was marketed for approximately 4 years of the nearly 13-year study period, it accounted for a disproportionate share of the overall total serious adverse drug events reported in the smoking cessation population, 9,575/13,243 (72%). For the main outcome measure we identified 3,249 reported events of suicidal/self-injurious behavior or depression, 2,925 (90%) for varenicline, 229 (7%) for bupropion, and 95 (3%) for nicotine replacement. For completed suicides, varenicline was associated with 272/295 (92%) of smoking treatment cases, bupropion for 19 cases (6%) and nicotine products for 4 cases (1%). The results were similar for suicide attempts, with 323/381 (85%) of all reported suicide attempts for varenicline, 56 cases (15%) for bupropion, and 2 cases (<1%) for nicotine replacement products.