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Pemoline hepatotoxicity and postmarketing surveillance
D J Safer1, J M Zito, J E Gardner
1Division of Child Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. dsafer@jhmi.edu
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.
Method:
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.
Conclusion:
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.
Insights
Delayed awareness of pemoline
Area of Science:
- Pharmacovigilance
- Hepatotoxicity
- Drug Safety Surveillance
Background:
- Pemoline, a stimulant medication, was associated with significant hepatotoxic adverse drug reactions (ADRs).
- Reports of pemoline-induced liver injury and fatalities were submitted to the U.S. Food and Drug Administration (FDA) over two decades.
Purpose of the Study:
- To review FDA reports of pemoline-associated hepatotoxicity from 1975 to 1996.
- To assess the medical community's awareness of these serious drug safety issues.
Main Methods:
- Analysis of all Adverse Drug Reaction (ADR) reports involving pemoline submitted to the FDA between 1975 and 1996.
- Review of published medical literature and direct FDA data on pemoline-related deaths.
Main Results:
- Premarketing trials indicated hepatic abnormalities with pemoline use.
- Between 1975 and 1989, the FDA received reports of 12 cases of jaundice and 6 deaths in youths linked to pemoline hepatotoxicity.
- Widespread physician awareness of serious pemoline hepatotoxicity did not occur until December 1996, despite earlier reports.
Conclusions:
- Deficiencies in postmarketing surveillance and public reporting systems in the U.S. contributed to significant delays in addressing pemoline hepatotoxicity.
- These systemic limitations hindered a timely and appropriate response to the drug's liver toxicity.
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