Abstracts

To review reports of rash from clinical trials of zonisamide (ZNS) and to determine the proportion of cases attributable to the drug.
[italic]Background[/italic]: ZNS is a structurally novel anticonvulsant drug that is chemically classified as a sulfonamide due to the presence of an SO[sub]2[/sub]NH[sub]2[/sub] (sulfonamide) moiety. It is not a member of the arylamine family of sulfonamide antibiotics (ie, the [ldquo]sulfa drugs[rdquo]) and does not contain the structural features of arylamine sulfonamides that are thought to induce allergic reactions. In clinical trials, all occurrences of an adverse event are used to calculate the event[rsquo]s incidence, regardless of whether or not it was attributable to the study drug. We hope to elucidate from reports of rash in clinical trials how many cases are likely related to ZNS treatment.
Thirty-five cases of rash were analyzed: 28 nonfatal cases in the United States (US) from the Food and Drug Administration[rsquo]s MedWatch database and 7 rash-related deaths in Japanese post-marketing studies of ZNS. Each case was independently reviewed by 3 physicians, who judged whether the rash was likely caused by ZNS ([gt]50% likelihood of a causal relationship), likely not caused by ZNS ([lt]50% likelihood), or ambiguous (50% likelihood).
Mean age of patients in the US was 21.8 yrs (n=21) and mean ZNS dosage was 179 mg/d (n=21). Mean age of patients in Japan was 64 yrs (n=7) and mean ZNS dosage was 222 mg/d (n=7). Of the 28 instances of rash in the US, 9 cases (32.1%) were judged by all 3 reviewers as likely related to ZNS. An additional 4 cases (14.3%) were judged as likely related to ZNS by 2 of the 3 reviewers. At least 2 of 3 reviewers determined that ZNS was not likely to be the cause of rash in 13 cases (46.4%). In 2 cases (7.1%), the reviewers agreed that causality was ambiguous. Of the 7 rash-related deaths in Japan, the reviewers agreed that 3 cases (42.9%) were ZNS related. One case (14.3%) was assessed by all 3 reviewers as unrelated to ZNS. The other 3 cases (42.9%) were ambiguous because the relationship between rash and ZNS was confounded by the presence of multiple drugs in all 3 cases and possible sepsis in 1 case.
In this series of cases, less than half of the cases of rash in the US patients (46.4%) were attributed to ZNS by a majority of the reviewers. Only 9 of these cases (32.1%) were judged as likely ZNS related by all 3 physicians. The majority of the rash related deaths in Japan (57.1%) were unrelated to ZNS or ambiguous. This analysis indicates that the incidence of ZNS-related rash is actually much lower than the total incidence of rash reported in clinical trials.
[Supported by: In part by Elan Pharmaceuticals.]