Armodafinil, sold under the brand nameNuvigil, is awakefulness-promotingmedication which is used to treatexcessive daytime sleepiness associated withobstructive sleep apnea,narcolepsy, andshift work disorder.[1] It is also usedoff-label for certain other indications.[10] The drug is takenby mouth.[1]
Side effects of armodafinil includeheadache,nausea,dizziness, andinsomnia.[1] Armodafinil acts as aselective atypicaldopamine reuptake inhibitor (DRI) and hence as an indirectdopamine receptor agonist.[1][5][11] However, othermechanisms might also be involved in its effects.[1][5][11] Chemically, armodafinil is theenantiopure (R)-(–)-enantiomer of theracemic mixturemodafinil (brand name Provigil).[1][4][5] Both enantiomers of modafinil areactive as DRIs and wakefulness-promoting agents, but armodafinil is morepotent and longer-acting.[4][5]
Armodafinil is produced by thepharmaceutical companyCephalon[12] and was approved by theUnited StatesFood and Drug Administration (FDA) in 2007.[13][14] In 2016, the FDA grantedMylan rights for the firstgeneric version of armodafinil to be marketed in the United States.[15]
Armodafinil is currently FDA-approved to treatexcessive daytime sleepiness (EDS) associated withobstructive sleep apnea (OSA),narcolepsy, andshift work sleep disorder (SWSD).[12] It is commonly usedoff-label to treatattention deficit hyperactivity disorder (ADHD),chronic fatigue syndrome (CFS), andmajor depressive disorder (MDD), and has been repurposed as anadjunctive treatment forbipolar disorder.[10] It has been shown to improvevigilance inair traffic controllers;[16] however, in the United States,wakefulness-promoting medications such asmodafinil (Provigil) and armodafinil (Nuvigil) are not approved by theFederal Aviation Administration (FAA) for civilian controllers or pilots.[17]
Armodafinil, along with racemic modafinil, has been repurposed as an adjunctive treatment for acute depression in people withbipolar disorder.[10] Meta-analytic evidence showed that add-on modafinil and armodafinil were more effective than placebo on response to treatment, clinical remission, and reduction in depressive symptoms, with only minor side effects, but the effect sizes are small and the quality of evidence has to be considered low, limiting the clinical relevance of current evidence. However current dosage for bipolar disorder is 150 mg once daily. Paradoxical tiredness and sleeping is observed in some cases.[10]
In June 2010, it was revealed that a phase II study of armodafinil as an adjunctive therapy in adults withschizophrenia had failed to meet the primary endpoints, and the clinical program was subsequently terminated.[18] However, a study published later that year showed that patients with schizophrenia treated with armodafinil showed fewer of thenegative symptoms of schizophrenia.[19]
On March 30, 2010, the FDA declined to approve use of Nuvigil to treatjet lag.[20][21]
Armodafinil is available in the form of 50, 150, 200, and 250 mgoraltablets.[1]
A 50 mg dose of armodafinil is essentially equivalent to at 100 mg dose ofmodafinil in terms of drug levels.[8]
In placebo-controlled studies, the most commonly observed side effects wereheadache,xerostomia (dry mouth),nausea,dizziness, andinsomnia.[10] Possible side effects also include depression, anxiety, hallucinations, euphoria, extreme increase in activity and talking, anorexia, tremor, thirst, rash, suicidal thoughts, and aggression. Symptoms of an overdose on armodafinil include trouble sleeping, restlessness, confusion, disorientation, feeling excited, mania, hallucinations, nausea, diarrhea, severely increased or decreased heart beat, chest pain, and increased blood pressure.[12][22][23] Serious rashes can develop in rare cases, and require immediate medical attention due to the possibility ofStevens–Johnson syndrome, or otherhypersensitivities to armodafinil.[12]
Armodafinil has a lowmisuse potential similar tomodafinil.
Hypertensive crises have been reported when armodafinil has been taken withmonoamine oxidase inhibitors (MAOIs) liketranylcypromine.[24]
Themechanism of action of armodafinil is unknown. Armodafinil (R-(−)-modafinil) has pharmacological properties almost identical to those ofmodafinil (a mixture ofR-(−)- and (S)-(+)-modafinil). The (R)- and (S)-enantiomers have similar pharmacological action in animals. Armodafinil has wake-promoting actions similar tosympathomimetic agents includingamphetamine andmethylphenidate, although its pharmacologic profile is not identical to that of the sympathomimetic amines. Armodafinil bindsin vitro to thedopamine transporter (DAT) and inhibits dopamine reuptake. For modafinil, this activity has been associatedin vivo with increased extracellular dopamine levels. In genetically engineered mice lacking the dopamine transporter, modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent.[25] However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by thedopamine receptor antagonisthaloperidol in rats. In addition,alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis, blocks the action of amphetamine but does not blocklocomotor activity induced by modafinil.
In addition to its wake-promoting effects and ability toincrease locomotor activity in animals, according to Nuvigil prescribing information from manufacturer Cephalon, armodafinil producespsychoactive andeuphoric effects, alterations in mood, perception, thinking, and feelings typical of othercentral nervous system (CNS)stimulants in humans.[12] Armodafinil, like racemic modafinil, may also possess reinforcing properties, as evidenced by its self-administration in monkeys previously trained to administercocaine; armodafinil was also partially discriminated as stimulant-like. A Cephalon-founded study in which patients were administered modafinil, methylphenidate, and a placebo found that modafinil produces "psychoactive and euphoric effects and feelings consistent with [methylphenidate]."[12]
Like modafinil, armodafinil is aninhibitor and/orinducer of certaincytochrome P450enzymes.[7][26] It moderately inducesCYP3A4 and moderately inhibitsCYP2C19.[7][26] In contrast to modafinil however, armodafinil does not induceCYP1A2.[7][26]
Armodafinil exhibits linear time-independent kinetics following single and multiple oral dose administration. Increase in systemic exposure is proportional over the dose range of 50–400 mg. No time-dependent change in kinetics was observed through 12 weeks of dosing. Apparent steady state for armodafinil was reached within 7 days of dosing. At steady state, the systemic exposure for armodafinil is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the (R)-(−)-enantiomer following a single dose of 50 mg Nuvigil or 100 mg Provigil (modafinil being a 1:1 mixture of (R)-(−)- and (S)-(−)- enantiomers) are nearly superimposable. However, theCmax of armodafinil at steady state was 37% higher following administration of 200 mg Nuvigil than the corresponding value of modafinil following administration of 200 mg Provigil due to the more rapid clearance of the (S)-(+)-enantiomer.
Armodafinil is readily absorbed after oral administration. The absolute oralbioavailability was not determined due to the aqueous insolubility of armodafinil, which precludedintravenous administration. Peak plasma concentrations are attained at approximately 2 hours in the fasted state. Food effect on the overall bioavailability of armodafinil is considered minimal; however, time to reach peak concentration may be delayed 2–4 hours in the fed state. Since the delay inTmax is also associated with elevated plasma concentration later in time, food can potentially affect the onset and time course of pharmacologic action of armodafinil.
Armodafinil, or (R)-(–)-modafinil, is theenantiopure (R)-(–)-enantiomer of theracemic mixturemodafinil, whileesmodafinil is the (S)-(+)-enantiomer.[4]
A number ofanalogues of armodafinil are known, includingadrafinil,flmodafinil,fladrafinil, and others.[4]
Armodafinil is sold under a wide variety of brand names worldwide:
In Australia, and the United States, Armodafinil is considered to be a Schedule 4 prescription-only medicine or prescription animal remedy.[30] Schedule 4 is defined as "Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."
As of 2021, new laws do not directly include Armodafinil as a doping agent, but they do include Modafinil, as Armodafinil is an enantiomer of Modafinil it will show up on lab tests, but it can be debated if it is or not the same substance.
New laws state that simple possession is not a criminal offence and is punished with a fine and confiscation.[31] Importing into Romania and exporting from Romania of the substance, without a valid medical prescription, is a criminal offence and is punished with jail time between two and seven years.
Besideshypersomnia, armodafinil was under development for the treatment offatigue,bipolar depression, andschizophrenia.[32] However, development for these indications was discontinued.[32] The drug reachedphase 3clinical trials for treatment of fatigue prior to the discontinuation of its development for this use in January 2024.[32] Aside from the preceding indications, armodafinil is currently under development for the treatment ofeating disorders and, as of January 2024, is in phase 3 trials for this use.[32]
Stimulants, sometimes used for narcolepsy and attention deficit hyperactivity disorder, are not acceptable. Included are amphetamines (Adderall), pemoline (Cylert), methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and modafinil (Provigil).
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