Armodafinil, sold under the brand name Nuvigil, is a wakefulness-promoting

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

which is used to treat excessive daytime sleepiness associated with

obstructive sleep apnea Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder and is characterized by recurrent episodes of complete or partial airway obstruction, obstruction of the respiratory tract#Upper respiratory tract, upper airway lea ...

, narcolepsy, and shift work disorder. It is also used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ca ...

for certain other indications. The drug is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of armodafinil include

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, dizziness, and

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

. Armodafinil acts as a selective atypical dopamine reuptake inhibitor (DRI) and hence as an indirect dopamine receptor agonist. However, other mechanisms might also be involved in its effects. Chemically, armodafinil is the enantiopure (''R'')-(–)-

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

of the racemic mixture modafinil (brand name Provigil). Both enantiomers of modafinil are active as DRIs and wakefulness-promoting agents, but armodafinil is more potent and longer-acting. Armodafinil is produced by the pharmaceutical company Cephalon and was approved by the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) in 2007. In 2016, the FDA granted Mylan rights for the first generic version of armodafinil to be marketed in the United States.

Medical uses

Armodafinil is currently FDA-approved to treat excessive daytime sleepiness (EDS) associated with

(OSA), narcolepsy, and shift work sleep disorder (SWSD). It is commonly used

to treat

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD), chronic fatigue syndrome (CFS), and

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

(MDD), and has been repurposed as an adjunctive treatment for

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

. It has been shown to improve vigilance in air traffic controllers, however in the United States, wakefulness-promoting medications such as modafinil (Provigil) and armodafinil (Nuvigil) are not approved by the

Federal Aviation Administration The Federal Aviation Administration (FAA) is a Federal government of the United States, U.S. federal government agency within the United States Department of Transportation, U.S. Department of Transportation that regulates civil aviation in t ...

(FAA) for civilian controllers or pilots.

Psychiatry

Bipolar disorder

Armodafinil, along with racemic modafinil, has been repurposed as an adjunctive treatment for acute depression in people with

. 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.

Schizophrenia

In June 2010, it was revealed that a phase II study of armodafinil as an adjunctive therapy in adults with

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

had failed to meet the primary endpoints, and the clinical program was subsequently terminated. However, a study published later that year showed that patients with schizophrenia treated with armodafinil showed fewer of the negative symptoms of schizophrenia.

Jet lag

On March 30, 2010, the FDA declined to approve use of Nuvigil to treat jet lag.

Available forms

Armodafinil is available in the form of 50, 150, 200, and 250mg oral tablets. A 50mg dose of armodafinil is essentially equivalent to at 100mg dose of modafinil in terms of drug levels.

Adverse effects

In placebo-controlled studies, the most commonly observed side effects were

, xerostomia (dry mouth),

, dizziness, and

. 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. Serious rashes can develop in rare cases, and require immediate medical attention due to the possibility of Stevens–Johnson syndrome, or other hypersensitivities to armodafinil.

Misuse potential

Armodafinil has a low misuse potential similar to modafinil.

Interactions

Hypertensive crises have been reported when armodafinil has been taken with monoamine oxidase inhibitors (MAOIs) like tranylcypromine.

Pharmacology

Pharmacodynamics

The

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

of armodafinil is unknown. Armodafinil (''R''-(−)-modafinil) has pharmacological properties almost identical to those of modafinil (a mixture of ''R''-(−)- and (''S'')-(+)-modafinil). The (''R'')- and (''S'')-enantiomers have similar pharmacological action in animals. Armodafinil has wake-promoting actions similar to sympathomimetic agents including

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

and

methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...

, although its pharmacologic profile is not identical to that of the sympathomimetic amines. Armodafinil binds ''in vitro'' to the

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

(DAT) and inhibits dopamine reuptake. For modafinil, this activity has been associated ''in 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. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis, blocks the action of amphetamine but does not block locomotor activity induced by modafinil. In addition to its wake-promoting effects and ability to increase locomotor activity in animals, according to Nuvigil prescribing information from manufacturer Cephalon, armodafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

(CNS)

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

s in humans. Armodafinil, like racemic modafinil, may also possess reinforcing properties, as evidenced by its self-administration in monkeys previously trained to administer

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

; 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 ethylphenidate" Like modafinil, armodafinil is an inhibitor and/or inducer of certain

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s. It moderately induces

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

and moderately inhibits CYP2C19. In contrast to modafinil however, armodafinil does not induce CYP1A2.

Pharmacokinetics

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, the C_max 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.

Absorption

Armodafinil is readily absorbed after oral administration. The absolute oral bioavailability was not determined due to the aqueous insolubility of armodafinil, which precluded

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

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 in T_max is also associated with elevated plasma concentration later in time, food can potentially affect the onset and time course of pharmacologic action of armodafinil.

Chemistry

Armodafinil, or (''R'')-(–)-modafinil, is the enantiopure (''R'')-(–)-

of the racemic mixture modafinil, while esmodafinil is the (''S'')-(+)-enantiomer. A number of analogues of armodafinil are known, including adrafinil, flmodafinil, fladrafinil, and others.

Society and culture

Brand names

Armodafinil is sold under a wide variety of brand names worldwide:

Legal status

In Australia, and the United States, Armodafinil is considered to be a Schedule 4 prescription-only medicine or prescription animal remedy. 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."

Romania

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. 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.

Research

Besides hypersomnia, armodafinil was under development for the treatment of

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

, bipolar depression, and

. However, development for these indications was discontinued. The drug reached phase 3

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s for treatment of fatigue prior to the discontinuation of its development for this use in January 2024. Aside from the preceding indications, armodafinil is currently under development for the treatment of

eating disorder An eating disorder is a mental disorder defined by abnormal eating behaviors that adversely affect a person's health, physical or mental health, mental health. These behaviors may include eating too much food or too little food. Types of eatin ...

s and, as of January 2024, is in phase 3 trials for this use.

References

External links

Nuvigil (armodafinil) Tablets Official Site
*
Medication Guide for Patients
*
Full Prescribing Information
{{Monoamine reuptake inhibitors Acetamides CYP3A4 inducers Cytochrome P450 inhibitors Dopamine reuptake inhibitors Drugs with unknown mechanisms of action Enantiopure drugs Pro-motivational agents Stimulants Sulfoxides Wakefulness-promoting agents World Anti-Doping Agency prohibited substances Modafinil analogues Attention deficit hyperactivity disorder management Narcolepsy