Provigil Cardiovascular Impact Long-Term: What the Evidence Actually Shows

What the label reports about blood pressure and heart rate

In pooled placebo-controlled trials of Provigil for narcolepsy, obstructive sleep apnea and shift work disorder, patients received 200, 300 or 400 mg once daily; 934 received modafinil and 567 received placebo [1].

Reactions reported more often on modafinil than placebo in that pooled set: hypertension 3% versus 1%, chest pain 3% versus 1%, palpitation 2% versus 1%, tachycardia 2% versus 1% and vasodilatation 2% versus 0% [1].

The label also reports a treatment change: a larger share of modafinil patients needed new or increased antihypertensive medicine, 2.4% versus 0.7% on placebo across the pooled trials and 3.4% versus 1.1% in the obstructive sleep apnea studies [1]. These figures describe how often patients started or increased antihypertensive treatment during the trials; they do not establish why each prescription changed or that blood pressure rose across everyone taking modafinil [1].

The label also reports chest pain, palpitations, dyspnea and transient ischemic T-wave changes in three subjects with mitral valve prolapse or left ventricular hypertrophy [1].

What the label says about how modafinil works

The Provigil label says the mechanism by which modafinil promotes wakefulness is unknown [1]. It says modafinil has wake-promoting actions similar to sympathomimetics such as amphetamine and methylphenidate, though the pharmacologic profile is not identical to that of the sympathomimetic amines [1]. In vitro, modafinil binds the dopamine transporter and inhibits dopamine reuptake, and the label states it is not a direct- or indirect-acting dopamine receptor agonist [1].

How long the trials actually ran

The 1998 narcolepsy trial randomised 283 people at 18 centers to modafinil 200 mg, 400 mg or placebo for 9 weeks, followed by an open-label treatment period. Modafinil reduced sleepiness on the Epworth Sleepiness Scale, the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test. Adverse experiences were few, dose-dependent and mostly mild to moderate, and efficacy was maintained through up to 40 weeks of open-label treatment [2]. The 40 weeks was an open-label extension, not a long controlled comparison.

The 2005 shift work trial randomized 209 patients for three months to modafinil 200 mg before each shift or placebo. Nighttime sleep latency improved by 1.7 versus 0.3 minutes (P=0.002), 74% versus 36% improved clinically, and fewer modafinil-treated patients reported accidents or near-accidents on the commute home [3]. Headache was the most common adverse event [3].

The armodafinil shift work study ran 12 weeks in 254 night-shift workers at 42 North American sites, with 150 mg before each shift; sleep latency rose from 2.3 to 5.3 minutes versus 2.4 to 2.8 minutes on placebo (P<.001), and armodafinil was well tolerated [4].

A 2016 systematic review of 8 randomised trials in CPAP-treated obstructive sleep apnea found that modafinil and armodafinil improved daytime sleepiness, attention and alertness and clinician-rated condition, but not quality of life or other cognitive domains. No severe adverse effects were reported, but dropout was significantly higher than with placebo [5].

The outcomes summarized from these trials were sleepiness, alertness and clinical condition [2][3][4][5].

What about atrial fibrillation or other arrhythmias?

The label's pooled reaction table lists palpitation and tachycardia at the rates above; it does not break out atrial fibrillation [1].

Spontaneous reports to the FDA cannot fill that gap. The agency's adverse event dashboard states that a report does not mean the drug caused the event, that the information has not been verified, and that occurrence rates cannot be established from such reports [6].

Who the label singles out

The Provigil label says use is not recommended in patients with left ventricular hypertrophy or in patients with mitral valve prolapse syndrome who have previously had CNS-stimulant-triggered symptoms [1]. For patients with known cardiovascular disease, the label says to consider increased monitoring [1].

Heart disease is not a contraindication. The only contraindication on the Provigil label is known hypersensitivity to modafinil, armodafinil or their inactive ingredients [1]. The Provigil label has no boxed warning [1].

Interactions with heart and blood-pressure drugs

Modafinil induces CYP3A4/5, which can lower exposure to steroidal contraceptives, cyclosporine, midazolam and triazolam; the label says to consider dose adjustment of these drugs and to monitor cyclosporine concentrations [1].

Modafinil inhibits CYP2C19, so elimination of phenytoin, diazepam, propranolol, omeprazole and clomipramine may be prolonged, with higher exposure and a possible need for dose adjustment. Propranolol, a beta-blocker, is one of the label's own examples [1].

With warfarin, the label says more frequent prothrombin time and INR monitoring should be considered [1]. With MAO inhibitors, it says to use caution [1].