Armodafinil (Nuvigil, Waklert)

Armodafinil is the R-enantiomer of modafinil. Modafinil is a racemate, a 1:1 mix of two mirror-image molecules that the body clears at different speeds: the S-enantiomer leaves plasma roughly three times faster than the R-enantiomer. Armodafinil keeps only the slower-clearing half, so it is not a new substance but one half of a familiar one.

Clinically, armodafinil (brand name Nuvigil, sold in India among others as Waklert) is approved for excessive daytime sleepiness in narcolepsy, obstructive sleep apnea and shift work disorder. Like modafinil it belongs to the eugeroics, the wakefulness promoters. It is not an amphetamine derivative. The pharmacokinetic rule of thumb: 150mg armodafinil corresponds roughly to 200mg modafinil in total exposure.

This information is for research and educational purposes only. No medical advice.

The mechanism is the same as for the racemate and still not resolved in every detail. At its core sits inhibition of the dopamine transporter (DAT): armodafinil blocks dopamine reuptake into the neuron and thereby raises extracellular dopamine. Unlike amphetamines it does not push dopamine out of the storage vesicles, which is what gives it the calmer character. In the transporter work by Loland and colleagues (Biological Psychiatry 2012) the R-enantiomer bound DAT with roughly three times the affinity of the S-enantiomer, inhibited dopamine uptake far less potently than cocaine and raised dopamine in the nucleus accumbens more modestly but for longer.

On top of that come indirect effects on the hypothalamic wake systems: orexinergic and histaminergic pathways are activated, cortical catecholamines rise, GABA falls. Those are the circuits that run the sleep-wake cycle rather than general drive. Subjectively the result is closer to "not tired" than to "wired".

The most common misconception is that armodafinil is the stronger version of modafinil. It is not, at least not at the peak. Darwish and colleagues (Clinical Drug Investigation 2009) pooled three single-dose studies in healthy adults and normalized everything to 200mg. Both drugs had a single-dose terminal half-life of about 13 hours (the prescribing information puts armodafinil at about 15 hours), similar peak concentrations and a similar time to peak.

The difference appears after the peak. Modafinil declines in two phases because its S-enantiomer disappears quickly in the first hours. Armodafinil declines in a single, flatter phase. Milligram for milligram, exposure (AUC) was 33 to 40 percent higher with armodafinil. Plasma levels late in the day sat clearly above those of modafinil. In practice: same peak, longer afternoon. That is why armodafinil was the compound of choice in shift work research. It is also exactly where its risk to sleep comes from.

Taken on an empty stomach, armodafinil peaks after about 2 hours. A high-fat meal pushes the peak back by 2 to 4 hours without changing total absorption. The mean elimination half-life is around 15 hours. Steady state is reached within about 7 days of daily dosing, with exposure then about 1.8 times above a single dose. Kinetics are linear from 50 to 400mg, so double the dose means double the exposure (prescribing information).

From this follows the single most important rule: dose early or not at all. A dose at noon still carries well over half its peak level at midnight. Unlike modafinil there is no fast-clearing half that eases the evening a little. Taking it with a meal shifts the peak further into the afternoon on top of that.

Exposure is higher in older adults, where the prescribing information advises lower doses. In severe hepatic impairment the dose should be reduced, because elimination runs through the liver.

The strongest evidence is in shift work. Czeisler and colleagues (Mayo Clinic Proceedings 2009) randomized 254 night shift workers with shift work disorder to 150mg armodafinil or placebo, taken 30 to 60 minutes before each shift for 12 weeks. Mean sleep latency during the night shift rose from 2.3 to 5.3 minutes on armodafinil versus 2.4 to 2.8 minutes on placebo. Standardized memory and attention tests improved. Daytime sleep was not disturbed on polysomnography.

In narcolepsy, Harsh and colleagues (Current Medical Research and Opinion 2006) compared 150mg, 250mg and placebo in 196 patients over 12 weeks. Both doses significantly lengthened sleep latency on the Maintenance of Wakefulness Test and improved memory, attention and fatigue. The gap between 150 and 250mg was small: plus 1.3 versus plus 2.6 minutes, against a drop of 1.9 minutes on placebo.

Long-term data come from the open-label extension by Black and colleagues (Journal of Clinical Sleep Medicine 2010): 743 patients for at least 12 months at 50 to 250mg per day, with the effect maintained, 13 percent discontinuing for adverse events and moderate rises in blood pressure and heart rate. What is missing is evidence for cognitive enhancement in rested healthy people. The healthy-volunteer studies of armodafinil were almost all run under sleep deprivation. For the racemate, meta-analyses show only a small effect, as described in the modafinil entry.

Armodafinil induces CYP3A4 and inhibits CYP2C19. Darwish and colleagues (Clinical Pharmacokinetics 2008) measured this in three probe studies in 77 healthy adults: after at least 22 days on 250mg armodafinil, midazolam exposure fell by about 17 percent after intravenous and 32 percent after oral dosing, while caffeine (CYP1A2) was unchanged. Omeprazole was tested separately, with a single 400mg dose of armodafinil given 2 hours before the omeprazole. Omeprazole exposure rose by about 38 percent.

In practice: substances cleared through CYP3A4 become weaker. Hormonal contraceptives are among them. The prescribing information states that hormonal contraception is less reliable during use and for about one month afterwards. In the other direction, levels of CYP2C19 substrates such as omeprazole, diazepam or phenytoin rise. Anyone using such a substance should take that question to a doctor.

• Serious skin reactions: rare but serious. Rash requiring hospitalization, up to Stevens-Johnson syndrome and toxic epidermal necrolysis, is documented for armodafinil and modafinil, along with multi-organ hypersensitivity (DRESS) and angioedema. Any new rash, any blistering and any involvement of mouth, eyes or mucous membranes is a reason to stop and a case for medical assessment. In the pooled registration trials rash occurred in 4 percent on 250mg and 1 percent on 150mg.
• Headache: by far the most common, 17 percent versus 9 on placebo. It is also dose-dependent (23 percent on 250mg, 14 on 150mg).
• Insomnia: 5 percent in the trials, almost always a question of timing. With armodafinil the flatter decline makes this weigh heavier than with modafinil.
• Nausea, dizziness, dry mouth, anxiety, diarrhea: regularly reported, mostly mild to moderate.
• Circulation: in the long-term study blood pressure rose by an average of 3.6/2.3 mmHg and heart rate by 6.7 beats per minute, mostly within the first three months. Anyone with blood pressure issues should keep measuring.
• Mental state: anxiety, agitation, nervousness and depressed mood led to discontinuation more often than on placebo. With a history of psychosis, depression or mania the prescribing information calls for particular caution.
• Abuse potential: lower than with amphetamines, but not zero. Armodafinil is a Schedule IV controlled substance in the US. Cases of abuse are documented.

Store dry, at room temperature and protected from light. Leave tablets in the blister until you need them and keep them out of reach of children. Use split tablets promptly rather than keeping halves around for weeks.