Armodafinil

Armodafinil

Clinical data
Trade names	Nuvigil, others
Other names	(R)-Modafinil; R-Modafinil; (R)-(–)-Modafinil; (–)-Modafinil; CRL-40982; CEP-10952
AHFS/Drugs.com	Monograph
MedlinePlus	a602016
Pregnancy category	C
Dependence liability	Low
Routes of administration	Oral (tablets)[1]
Drug class	Atypical dopamine reuptake inhibitor; wakefulness-promoting agent
ATC code	N06BA13 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[2] BR: Class B1 (Psychoactive drugs)[3] US: Schedule IV
Pharmacokinetic data
Bioavailability	Unknown (due to poor aqueous solubility;[1] but modafinil is 40–65% based on urinary excretion)[4][5]
Protein binding	Unknown (but for modafinil is moderate, primarily to albumin)[6][7][1]
Metabolism	Liver, including CYP3A4 and other enzymes (hydrolytic amidation, sulfoxidation, aromatic ring hydroxylation, and glucuronide conjugation)[6][8][7]
Metabolites	• Armodafinil acid[6][7] • Modafinil sulfone[6][7]
Onset of action	1.5–6.5 h (range 0.5–11 h) (peak)[7][8]
Elimination half-life	10–17 hours[6][7][5]
Duration of action	Up to 13.5 hours[9]
Excretion	Unknown (but modafinil is excreted 80% in urine and 1.0% in feces)[1]
Identifiers
IUPAC name (–)-2-[(R)-(diphenylmethyl)sulfinyl]acetamide
CAS Number	112111-43-0 Y
PubChem CID	9690109
ChemSpider	7962943 Y
UNII	V63XWA605I
KEGG	D03215 Y
ChEBI	CHEBI:77590 Y
ChEMBL	ChEMBL1201192 Y
CompTox Dashboard (EPA)	DTXSID90920667
ECHA InfoCard	100.207.833
Chemical and physical data
Formula	C15H15NO2S
Molar mass	273.35 g·mol−1
3D model (JSmol)	Interactive image
SMILES C1=CC=C(C=C1)C(C2=CC=CC=C2)[S@](=O)CC(=O)N
InChI InChI=1S/C15H15NO2S/c16-14(17)11-19(18)15(12-7-3-1-4-8-12)13-9-5-2-6-10-13/h1-10,15H,11H2,(H2,16,17)/t19-/m1/s1 Y Key:YFGHCGITMMYXAQ-LJQANCHMSA-N Y
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Armodafinil, sold under the brand name Nuvigil, is a wakefulness-promoting medication which is used to treat excessive daytime sleepiness associated with obstructive sleep apnea, narcolepsy, and shift work disorder.^[1] It is also used off-label for certain other indications.^[10] The drug is taken by mouth.^[1]

Side effects of armodafinil include headache, nausea, dizziness, and insomnia.^[1] Armodafinil acts as a selective atypical dopamine reuptake inhibitor (DRI) and hence as an indirect dopamine receptor agonist.^[1][5][11] However, other mechanisms might also be involved in its effects.^[1][5][11] Chemically, armodafinil is the enantiopure (R)-(–)-enantiomer of the racemic mixture modafinil (brand name Provigil).^[1][4][5] Both enantiomers of modafinil are active as DRIs and wakefulness-promoting agents, but armodafinil is more potent and longer-acting.^[4][5]

Armodafinil is produced by the pharmaceutical company Cephalon^[12] and was approved by the United States Food and Drug Administration (FDA) in 2007.^[13][14] In 2016, the FDA granted Mylan rights for the first generic version of armodafinil to be marketed in the United States.^[15]

Armodafinil is currently FDA-approved to treat excessive daytime sleepiness (EDS) associated with obstructive sleep apnea (OSA), narcolepsy, and shift work sleep disorder (SWSD).^[12] It is commonly used off-label to treat attention deficit hyperactivity disorder (ADHD), chronic fatigue syndrome (CFS), and major depressive disorder (MDD), and has been repurposed as an adjunctive treatment for bipolar disorder.^[10] It has been shown to improve vigilance in air traffic controllers,^[16] however in the United States, wakefulness-promoting medications such as modafinil (Provigil) and armodafinil (Nuvigil) are not approved by the Federal 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 with bipolar 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 with schizophrenia 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 the negative symptoms of schizophrenia.^[19]

On March 30, 2010, the FDA declined to approve use of Nuvigil to treat jet lag.^[20][21]

Armodafinil is available in the form of 50, 150, 200, and 250 mg oral tablets.^[1]

A 50 mg dose of armodafinil is essentially equivalent to at 100 mg dose of modafinil in terms of drug levels.^[8]

In placebo-controlled studies, the most commonly observed side effects were headache, xerostomia (dry mouth), nausea, dizziness, and insomnia.^[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 of Stevens–Johnson syndrome, or other hypersensitivities to armodafinil.^[12]

Armodafinil has a low misuse potential similar to modafinil.

Hypertensive crises have been reported when armodafinil has been taken with monoamine oxidase inhibitors (MAOIs) like tranylcypromine.^[24]

The mechanism of action 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 and methylphenidate, although its pharmacologic profile is not identical to that of the sympathomimetic amines. Armodafinil binds in vitro to the dopamine transporter (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.^[25] 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 (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 administer cocaine; 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 an inhibitor and/or inducer of certain cytochrome P450 enzymes.^[7][26] It moderately induces CYP3A4 and moderately inhibits CYP2C19.^[7][26] In contrast to modafinil however, armodafinil does not induce CYP1A2.^[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, 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.

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

Armodafinil, or (R)-(–)-modafinil, is the enantiopure (R)-(–)-enantiomer of the racemic mixture modafinil, while esmodafinil is the (S)-(+)-enantiomer.^[4]

A number of analogues of armodafinil are known, including adrafinil, 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.

Besides hypersomnia, armodafinil was under development for the treatment of fatigue, bipolar depression, and schizophrenia.^[32] However, development for these indications was discontinued.^[32] The drug reached phase 3 clinical 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 of eating disorders and, as of January 2024, is in phase 3 trials for this use.^[32]

• Nuvigil (armodafinil) Tablets Official Site
  • Medication Guide for Patients
  • Full Prescribing Information