To the Editor: Modafinil’s package insert cautions about using modafinil in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. No mention is made of premature ventricular contractions (PVCs), also called ventricular ectopic beats, in patients without heart disease. Also, a search of the literature did not reveal any citations about PVCs and modafinil. No treatment-emergent pattern of ECG abnormalities was found in placebo-controlled clinical trials after administration of modafinil, according to its package insert.
Written communication with Cephalon Inc. also revealed the following. First, in open-label studies for up to 52 weeks, no adverse cardiac effects were noted. Second, the nature of postmarketing cardiovascular-related events with modafinil has been similar to those observed during the clinical trials. Third, a post hoc analysis of data from seven studies demonstrated that modafinil did not produce clinically relevant changes in ECG intervals and had no adverse effect on cardiac repolarization in any of the studies evaluated.
Mr. A, a 54-year-old Caucasian man in very good health, was administered modafinil, 100 mg every morning, which was soon increased to 200 mg in the morning and then 100 mg b.i.d. to combat fatigue and lack of concentration. Mr. A was not taking any medications; was free of alcohol, tobacco, and substance use; and consumed little caffeine. Modafinil worked rather well for him in that regard, but after 2.5 months, he developed PVCs, which he felt as a sinking feeling in his chest and associated skipped beats when his pulse was taken. No other symptoms, such as dizziness, sweating, chest pain, and shortness of breath, were present. Mr. A was very conscious of the PVCs and disturbed after experiencing them. The results of a physical examination were normal, and a 24-hour Holter monitor showed 1,695 PVCs.
Mr. A’s diagnosis was unifocal PVCs and a normal sinus rhythm with symptoms. Modafinil was discontinued, but it took 20 days for the PVCs to remit. After a PVC-free interval of a week, Mr. A was rechallenged with the same dose of modafinil. The PVCs returned after only 10 days of taking modafinil. It was again discontinued, and the PVCs subsided in a matter of 2 weeks. Mr. A has been PVC-free since (more than 1 year).
The exact mechanism of action for modafinil is not known. Modafinil has wake-promoting actions, such as sympathomimetic agents, including amphetamine and methylphenidate, but the pharmacological profile is not identical. Modafinil has been reported to be associated with a positive effect in attention deficit hyperactivity symptoms, as well as providing increased energy. Modafinil has not been evaluated in patients with a recent history of myocardial infarction or unstable angina (package insert). Further careful case reports and controlled studies are needed to more precisely correlate modafinil with cardiac arrhythmias, such as PVCs, and to elucidate the causal mechanism responsible.