Armodafinil (trade name Nuvigil) is the
enantiopure
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...
compound of the
eugeroic modafinil (Provigil).
It consists of only the (''R'')-(−)-
enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
of the
racemic modafinil. Armodafinil is produced by the
pharmaceutical company Cephalon Inc. and was approved by the U.S.
Food and Drug Administration (FDA) in June 2007.
In 2016, the FDA granted
Mylan
Mylan N.V. was a global generic and specialty pharmaceuticals company. In November 2020, Mylan merged with Upjohn, Pfizer's off-patent medicine division, to form Viatris. Previously, the company was domiciled in the Netherlands, with principal ...
rights for the first
generic
Generic or generics may refer to:
In business
* Generic term, a common name used for a range or class of similar things not protected by trademark
* Generic brand, a brand for a product that does not have an associated brand or trademark, other ...
version of Cephalon's Nuvigil to be marketed in the U.S.
Because armodafinil has a longer
half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...
than
modafinil does, it may be more effective at improving wakefulness in patients with
excessive daytime sleepiness
Excessive daytime sleepiness (EDS) is characterized by persistent sleepiness and often a general lack of energy, even during the day after apparently adequate or even prolonged nighttime sleep. EDS can be considered as a broad condition encompass ...
.
Medical uses
Armodafinil is currently FDA-approved to treat
excessive daytime sleepiness
Excessive daytime sleepiness (EDS) is characterized by persistent sleepiness and often a general lack of energy, even during the day after apparently adequate or even prolonged nighttime sleep. EDS can be considered as a broad condition encompass ...
associated with
obstructive sleep apnea,
narcolepsy
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affect ...
, and
shift work disorder
Shift work sleep disorder (SWSD) is a circadian rhythm sleep disorder characterized by insomnia, excessive sleepiness, or both affecting people whose work hours overlap with the typical sleep period. Insomnia can be the difficulty to fall asleep o ...
.
It is commonly used
off-label to treat
attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
,
chronic fatigue syndrome
Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME) or ME/CFS, is a complex, debilitating, long-term medical condition. The causes and mechanisms of the disease are not fully understood. Distinguishing core symptoms are ...
, and
major depressive disorder, and has been repurposed as an adjunctive treatment for
bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
.
It has been shown to improve vigilance in air traffic controllers,
however in the United States, sleep prevention medications such as Provigil (Modafinil) and Nuvigil (Armodafinil) are not approved by the 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
bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated 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.
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.
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
Jet lag is a physiological condition that results from alterations to the body's circadian rhythms caused by rapid long-distance trans-meridian (east–west or west–east) travel. For example, someone flying from New York to London, i.e. from ...
.
Adverse effects
In placebo-controlled studies, the most commonly observed side effects were
headache,
xerostomia
Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause.
This symptom is very common and is often seen as a side eff ...
(dry mouth),
nausea,
dizziness, and
insomnia.
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
Steven's-Johnson Syndrome, or other
hypersensitivities
Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune s ...
to armodafinil.
Pharmacology
Pharmacodynamics
The
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targ ...
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- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
and
methylphenidate, although its pharmacologic profile is not identical to that of the sympathomimetic amines. Armodafinil is an indirect
dopamine receptor agonist
A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the ...
; it binds ''in vitro'' to the
dopamine transporter
The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopami ...
(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
A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have f ...
haloperidol in rats. In addition,
alpha-methyl-p-tyrosine
Alpha-methyl-''p''-tyrosine (AMPT) is a tyrosine hydroxylase enzyme inhibitor and is therefore a drug involved in inhibiting the catecholamine biosynthetic pathway. AMPT inhibits tyrosine hydroxylase whose enzymatic activity is normally regulate ...
, 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
A psychoactive drug, psychopharmaceutical, psychoactive agent or psychotropic drug is a chemical substance, that changes functions of the nervous system, and results in alterations in perception, mood, consciousness, cognition or behavior.
Th ...
and
euphoric
Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danc ...
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 and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
(CNS)
stimulants in humans.
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
ethylphenidate"
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.
Legal status
In Australia, and the United States, Armodafinil is considered to be a Schedule 4 prescription-only medicine or prescription animal remedy.
[Poisons Standard March 2018 https://www.legislation.gov.au/Details/F2018L00168] 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.
Ne
lawsstate 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.
Marketing
Brand names
Armodafinil is sold under a wide variety of brand names worldwide:
See also
References
External links
Nuvigil (armodafinil) Tablets Official Site*
Medication Guide for Patients*
Full Prescribing Information
{{Monoamine reuptake inhibitors
Acetamides
CYP3A4 inducers
Dopamine reuptake inhibitors
Drugs with unknown mechanisms of action
Enantiopure drugs
Stimulants
Sulfoxides
World Anti-Doping Agency prohibited substances