Armodafinil

Last updated

Armodafinil
Armodafinil structure.svg
(R)-modafinil-from-xtal-3D-bs-17.png
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
Legal status
Legal status
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
  • (–)-2-[(R)-(diphenylmethyl)sulfinyl]acetamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.207.833 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H15NO2S
Molar mass 273.35 g·mol−1
3D model (JSmol)
  • C1=CC=C(C=C1)C(C2=CC=CC=C2)[S@](=O)CC(=O)N
  • 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 Yes check.svgY
  • Key:YFGHCGITMMYXAQ-LJQANCHMSA-N Yes check.svgY
   (verify)

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]

Contents

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]

Medical uses

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]

Psychiatry

Bipolar disorder

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]

Schizophrenia

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]

Jet lag

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

Available forms

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]

Adverse effects

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]

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. [24]

Pharmacology

Armodafinil 150mg blister Armodafinil 150mg.jpg
Armodafinil 150mg blister

Pharmacodynamics

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]

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 Cmax 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 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 Tmax 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)-(–)-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]

Society and culture

Brand names

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

  • Acronite (by Consern Pharma): India
  • Armoda: ACI Pharmaceuticals (Symbiota), Bangladesh
  • Armod: India (by Emcure Pharmaceuticals Ltd)
  • Artvigil: India (by HAB Pharma) [27]
  • Neoresotyl: Chile, Colombia
  • Nuvigil: USA, Chile, Ukraine, Israel, Mexico, [28] Australia
  • R-Modawake: India
  • Waklert: India (by Sun Pharma) [29]
  • Modavital: El Salvador (Farmaceutica INHOSPI (by Laboratorios Marceli)
  • Nodement: Syrian Arab republic (by hama pharma)
  • Armowake: Egypt (by EVA Pharma)

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."

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. [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.

Research

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]

Related Research Articles

<span class="mw-page-title-main">Modafinil</span> Eugeroic medication

Modafinil, sold under the brand name Provigil among others, is a wakefulness-promoting medication used primarily to treat narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and sudden sleep attacks. Modafinil is also approved for stimulating wakefulness in people with sleep apnea and shift work sleep disorder. It is taken by mouth. Modafinil is not approved by the US Food and Drug Administration (FDA) for use in people under 17 years old.

A psychiatric or psychotropic medication is a psychoactive drug taken to exert an effect on the chemical makeup of the brain and nervous system. Thus, these medications are used to treat mental illnesses. These medications are typically made of synthetic chemical compounds and are usually prescribed in psychiatric settings, potentially involuntarily during commitment. Since the mid-20th century, such medications have been leading treatments for a broad range of mental disorders and have decreased the need for long-term hospitalization, thereby lowering the cost of mental health care. The recidivism or rehospitalization of the mentally ill is at a high rate in many countries, and the reasons for the relapses are under research.

<span class="mw-page-title-main">Stimulant</span> Drug that increases activity of central nervous system

Stimulants are a class of drugs that increase the activity of the brain. They are used for various purposes, such as enhancing alertness, attention, motivation, cognition, mood, and physical performance. Some of the most common stimulants are caffeine, nicotine, amphetamines, cocaine, methylphenidate, and modafinil.

<span class="mw-page-title-main">Methylphenidate</span> Central nervous system stimulant

Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a primary medication for ADHD ; it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect. For ADHD, the effectiveness of methylphenidate is comparable to atomoxetine but modestly lower than amphetamines, alleviating the executive functioning deficits of sustained attention, inhibition, working memory, reaction time and emotional self-regulation.

<span class="mw-page-title-main">Aripiprazole</span> Atypical antipsychotic

Aripiprazole, sold under the brand names Abilify and Aristada, among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder; other uses include as an add-on treatment in major depressive disorder and obsessive–compulsive disorder (OCD), tic disorders, and irritability associated with autism. Aripiprazole is taken by mouth or via injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.

<span class="mw-page-title-main">Dextroamphetamine</span> CNS stimulant and isomer of amphetamine

Dextroamphetamine (INN:dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine is generally regarded as the prototypical stimulant.

Stimulant psychosis is a mental disorder characterized by psychotic symptoms. It involves and typically occurs following an overdose or several day binge on psychostimulants, though one study reported occurrences at regularly prescribed doses in approximately 0.1% of individuals within the first several weeks after starting amphetamine or methylphenidate therapy. Methamphetamine psychosis, or long-term effects of stimulant use in the brain, depend upon genetics and may persist for some time.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

<span class="mw-page-title-main">Dexmethylphenidate</span> CNS Stimulant

Dexmethylphenidate, sold under the brand name Focalin among others, is a potent central nervous system (CNS) stimulant used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years. It is taken by mouth. The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours. It is the more active enantiomer of methylphenidate.

<span class="mw-page-title-main">Tetrabenazine</span> Medication for hyperkinetic movement disorders

Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the U.S. Food and Drug Administration approved the use of tetrabenazine to treat chorea associated with Huntington's disease. Although other drugs had been used "off label," tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s.

Cephalon, Inc. was an American biopharmaceutical company co-founded in 1987 by pharmacologist Frank Baldino, Jr., neuroscientist Michael Lewis, and organic chemist James C. Kauer—all three former scientists with the DuPont Company. Baldino served as Cephalon's chairman and chief executive officer, until his death in December 2010. The company's name comes from the adjective "cephalic" meaning "related to the head or brain", as it was established primarily to pursue treatments for neurodegenerative diseases.

<span class="mw-page-title-main">Lisdexamfetamine</span> Central nervous system stimulant prodrug

Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours.

Attention deficit hyperactivity disorder management options are evidence-based practices with established treatment efficacy for ADHD. Approaches that have been evaluated in the management of ADHD symptoms include FDA-approved pharmacologic treatment and other pharmaceutical agents, psychological or behavioral approaches, combined pharmacological and behavioral approaches, cognitive training, neurofeedback, neurostimulation, physical exercise, nutrition and supplements, integrative medicine, parent support, and school interventions. Based on two 2024 systematic reviews of the literature, FDA-approved medications and to a lesser extent psychosocial interventions have been shown to improve core ADHD symptoms compared to control groups.

<span class="mw-page-title-main">Levoamphetamine</span> CNS stimulant and isomer of amphetamine

Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination with dextroamphetamine in varying ratios under brand names like Adderall and Evekeo. The drug is known to increase wakefulness and concentration in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries. Levoamphetamine is taken by mouth.

<span class="mw-page-title-main">Eugeroic</span> Drug for wakefulness and alertness

A eugeroic, or eugregoric, also known as a vigilance-promoting agent, is a type of drug that increases vigilance. The term has been used inconsistently and in multiple ways in the scientific literature, either to refer specifically to modafinil-type wakefulness-promoting agents or to refer to wakefulness-promoting agents generally. It was first introduced in the French literature in 1987 as a descriptor for modafinil-like wakefulness-promoting drugs and for purposes of distinguishing such drugs from psychostimulants. However, the term "eugeroic" has not been widely adopted in the literature, and instead the term "wakefulness-promoting agent" has been more widely used, both for modafinil-type drugs and other agents.

<span class="mw-page-title-main">Cariprazine</span> Atypical antipsychotic medicine

Cariprazine, sold under the brand name Vraylar among others, is an atypical antipsychotic developed by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor. It is taken by mouth.

<span class="mw-page-title-main">Brexpiprazole</span> Atypical antipsychotic

Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer's disease.

<span class="mw-page-title-main">Flmodafinil</span> Wakefulness-promoting drug/Dopamine reuptake inhibitor

Flmodafinil, also known as bisfluoromodafinil and lauflumide, is a wakefulness-promoting agent related to modafinil which has been developed for treatment of a variety of different medical conditions. These include chronic fatigue syndrome, idiopathic hypersomnia, narcolepsy, attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease. Aside its development as a potential pharmaceutical drug, flmodafinil is sold online and used non-medically as a nootropic.

<span class="mw-page-title-main">Esmodafinil</span> Unmarketed enantiomer of modafinil

Esmodafinil (also known as (S)-modafinil or (+)-modafinil; developmental code name CRL-40983) is the enantiopure (S)-(+)-enantiomer of modafinil. Unlike armodafinil ((R)-(–)-modafinil), esmodafinil has never been marketed on its own.

References

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  2. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
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  27. ↑ "Artvigil Review [2021 Guide] Uses, Side Effects, & Dosing". modafinil.org. October 2021.
  28. ↑ Lundbeck Mexico, S.A. de C.V.
  29. ↑ "Waklert Review [2021 Guide] Uses, Side Effects, & Dosing". modafinil.org. October 2021.
  30. ↑ "Poisons Standard". Therapeutics Goods Administration, Department of Health. Australian Government. March 2018.
  31. ↑ "LAW no. 219". Romanian Parliament (in Romanian). 26 July 2021.
  32. 1 2 3 4 "Armodafinil - Teva Pharmaceutical Industries". AdisInsight. 4 January 2024. Retrieved 21 September 2024.
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