Pemoline hepatotoxicity and postmarketing surveillance.
OBJECTIVE
To review the numerous reports of hepatotoxic adverse drug reactions (ADRs) ascribed to pemoline that were sent to the U.S. Food and Drug Administration (FDA) between 1975 and 1996 and to describe the medical community's lack of awareness of these reports.


METHODS
All ADR reports from 1975 through 1996 wherein pemoline was the suspect agent were obtained from the FDA MedWatch Internet site, and some details of nine pemoline-related deaths in youths were obtained directly from the FDA. The published literature on this subject was fully reviewed.


RESULTS
(1) In premarketing clinical trials with pemoline in the early 1970s, hepatic abnormalities were noted in enzyme levels (1%-3% of youths receiving maintenance treatment), during rechallenges (6 of 6), and in biopsies (2 of 2). (2) Between 1975 and 1989, 12 cases of jaundice and 6 deaths in youths ascribed to pemoline hepatotoxicity were reported to the FDA. (3) The first medical literature report of a serious ADR ascribed to pemoline was in a 1989 letter to the editor. (4) Physicians generally only became aware of serious pemoline hepatotoxicity in December 1996. (5) Pemoline use increased until 1997.


CONCLUSIONS
Limitations in postmarketing surveillance and public reporting in the United States, particularly in the 1980s, largely accounted for delays in an appropriate response to pemoline hepatotoxicity.
Safer
D J
DJ
Division of Child Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. dsafer@jhmi.edu
Zito
J M
JM
Gardner
J E
JE
D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000175:diagnosis / Q000401:mortality; D008111:Liver Function Tests; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy*; D008875:Middle Aged; D010389:Pemoline / Q000008:administration & dosage / Q000009:adverse effects*; D011358:Product Surveillance, Postmarketing / Q000706:statistics & numerical data*; D014481:United States / Q000453:epidemiology; D014486:United States Food and Drug Administration
D000697:Central Nervous System Stimulants; D010389:Pemoline