Pemoline, once known by brand names like Cylert, functioned as a central nervous system (CNS) stimulant. It was formerly used for certain neurological conditions. However, due to significant safety concerns, it was withdrawn from most markets.
Historical Uses
Pemoline was primarily prescribed for two main medical conditions: Attention-Deficit/Hyperactivity Disorder (ADHD) and narcolepsy. For individuals with ADHD, it was utilized to manage symptoms such as distractibility, hyperactivity, and impulsivity. The drug aimed to improve focus and reduce restlessness.
In the context of narcolepsy, a chronic neurological disorder characterized by excessive daytime sleepiness, pemoline was used for its alerting effects. Its stimulant properties helped to counteract the overwhelming drowsiness. The typical dosage for ADHD ranged from 18.75 to 112.5 mg once daily, with most patients finding effectiveness between 56.25 and 75 mg.
How Pemoline Worked
The precise mechanism of action for pemoline was not entirely understood, but it operated as a central nervous system stimulant. The medication was thought to affect neurotransmitters in the brain, the brain’s chemical messengers. By influencing these neurotransmitters, pemoline aimed to enhance alertness, improve focus, and modify behavior.
Research suggested that pemoline acted as a selective dopamine reuptake inhibitor and a dopamine releasing agent. This led to increased levels of dopamine in the brain, functioning as an indirect agonist of dopamine receptors. Unlike some other stimulants, it had minimal effects on norepinephrine, resulting in fewer cardiovascular side effects.
Reasons for Market Withdrawal
The primary reason for pemoline’s withdrawal was its association with severe and potentially fatal liver toxicity, including hepatic failure. Reports of liver abnormalities emerged even before the drug’s approval in 1975, with hepatic enzyme level elevations noted in 1% to 3% of youths in premarketing clinical trials. Between 1975 and 1996, the U.S. Food and Drug Administration (FDA) received 193 reports of liver-related adverse drug reactions in patients under 20, including 13 cases of acute liver failure, 11 of which resulted in death or liver transplantation.
The FDA estimated that the risk of acute liver failure from pemoline was 10 to 25 times greater than in the general population. In response to these concerns, the FDA issued a boxed warning in 1999, highlighting the risk of liver failure and recommending periodic liver tests. Despite these warnings, studies indicated that physicians were often not performing the recommended liver function monitoring.
The drug was withdrawn in the United Kingdom in September 1997 and in Canada in September 1999, due to liver toxicity. In the United States, Abbott Laboratories voluntarily ceased sales in May 2005. The FDA officially withdrew approval for generic pemoline products in November 2005, concluding that the risks of liver toxicity outweighed the benefits.
Current Status and Implications
Pemoline is no longer available by prescription in most major global markets, including the United States, Canada, and the United Kingdom, due to its documented liver toxicity. While it remains available in Japan for narcolepsy, its use there is rare due to ongoing concerns about liver damage.
The withdrawal of pemoline highlights the ongoing importance of pharmacovigilance, the process of monitoring the safety of marketed drugs. The discontinuation of pemoline led to a shift towards alternative treatments for conditions like ADHD and narcolepsy. This emphasizes the continuous evaluation of drug safety post-market approval, as unforeseen adverse effects can emerge. Understanding the history of pemoline underscores the need for robust drug development processes and vigilant patient safety protocols.