Armodafinil: Uses, Mechanism of Action, Drug Interactions, and Disadvantages

Overview:

In an age where sleep deprivation is an all too common byproduct of our fast-paced lives, the quest for enhanced wakefulness and cognitive performance has led to exploring various solutions. Armodafinil, a pharmaceutical marvel, stands at the forefront of this pursuit, offering a promising remedy for those seeking to combat excessive sleepiness and fatigue. Armodafinil gained FDA (Food and Drug Administration) approval on June 15, 2007, as a treatment for narcolepsy, obstructive sleep apnea, and shift work sleep disorder. It is a derivative of Modafinil and is known for its extended duration of action in promoting wakefulness. This article is the gateway to understanding the multifaceted world of Armodafinil.

Drug Group:

Armodafinil belongs to a class of drugs known as wakefulness-promoting agents or eugeroics.

Available Doses and Dosage Forms:

Here are some common doses and dosage forms of Armodafinil:

Tablets:

Armodafinil is commonly available in tablet form, with varying strengths, including:

• A 50 mg (milligram) tablet is a round, white to off-white pill with no markings on one side and "205" imprinted on the other.

• A 150 mg tablet is an oval, white to off-white pill with no markings on one side and "215" imprinted on the other.

• A 200 mg tablet is a rounded, rectangular, white to off-white pill with no markings on one side and "220" imprinted on the other.

• A 250 mg tablet is an oval, white to off-white pill with no markings on one side and "225" imprinted on the other.

Extended-Release Formulations: While Armodafinil itself is primarily available in immediate-release tablet form, there are also some extended-release formulations of modafinil (which is closely related to Armodafinil) available, such as Armodafinil, that provide a more sustained effect over a more extended period. These may come in capsule or tablet form with varying strengths.

For Patients:

What Is Shift Work Disorder?

Shift work sleep disorder (SWSD) is a sleep disorder marked by disturbances in the circadian rhythm, typically observed in individuals with non-traditional work schedules. It occurs when an individual's work schedule conflicts with the natural circadian rhythm, which regulates the sleep-wake cycle in the body.

Symptoms: Common symptoms include excessive daytime sleepiness, difficulty falling asleep or staying asleep during the day, and poor sleep quality.

Circadian Rhythm Disruption: SWSD occurs because the work schedule conflicts with the body's natural circadian rhythm, which regulates the sleep-wake cycle.

Health Implications: Long-term SWSD can lead to increased risks of health problems such as obesity, diabetes, cardiovascular disease, depression, and anxiety.

Management Strategies:

1. Sleep Hygiene: Practicing good sleep habits to optimize daytime sleep quality.

2. Light Management: Regulating exposure to natural and artificial light to help adjust the body's internal clock.

3. Medications: In some cases, doctors may prescribe wakefulness-promoting medications.

4. Shift Scheduling: Adjusting work schedules when possible to create more consistent sleep patterns.

Seeking Medical Advice: Individuals experiencing SWSD symptoms should consult a doctor or sleep specialist for tailored treatment and advice.

Impact on Social Life: SWSD can also affect a person's social and family life due to work-related sleep disruptions and irregular hours.

Recognition: SWSD is a recognized medical condition, and its management is essential for overall well-being, especially for those with irregular work schedules.

How Does Armodafinil Work?

Armodafinil exerts its effects by influencing specific brain neurotransmitters, even though the precise details of its mechanism of action still need to be comprehended. It primarily impacts three key neurotransmitters: dopamine, norepinephrine, and histamine. Here is how it works:

1. Dopamine: Armodafinil increases the release of dopamine, a neurotransmitter associated with reward, motivation, and wakefulness. This boost in dopamine levels contributes to enhanced alertness and a feeling of increased wakefulness.

2. Norepinephrine: The drug also elevates norepinephrine levels, which modulates the body's reaction to stress. Higher norepinephrine levels can lead to increased wakefulness and improved concentration.

3. Histamine: Armodafinil influences histamine levels in the brain, promoting wakefulness and reducing the propensity to fall asleep during inappropriate times.

What Is the Dosage of Armodafinil?

Armodafinil is administered in tablet form via oral ingestion, typically taken once daily. Tablets are available in four different strengths: 50 mg, 150 mg, 200 mg, and 250 mg.

How Effective Is Armodafinil?

Here are some general considerations regarding its effectiveness:

1. Narcolepsy: Armodafinil is typically quite effective in reducing excessive daytime sleepiness and improving wakefulness in individuals with narcolepsy. It is considered a first-line treatment for this condition.

2. Obstructive Sleep Apnea: Armodafinil can effectively manage the excessive daytime sleepiness associated with obstructive sleep apnea. However, it is usually combined with other treatments, like continuous positive airway pressure (CPAP) therapy, for better results.

3. Shift Work Sleep Disorder: Armodafinil can help shift workers stay awake and alert during non-traditional working hours. It is generally considered adequate for this purpose.

4. Off-label Use: Some people use Armodafinil off-label for cognitive enhancement or to combat fatigue. While it may provide a short-term boost in alertness and cognitive function, its long-term effectiveness must be clarified. Additionally, it may have side effects and should only be used under medical supervision.

What Are the Things to Inform the Doctor Before Taking the Drug?

Before Taking Armodafinil:

• Inform the doctor and pharmacist about any allergies to Armodafinil, Modafinil, or other medications.

• Disclose all prescription and over-the-counter drugs, vitamins, supplements, and herbal products the patient uses or plans to use.

• Mention specific medications that one may be taking, such as anticoagulants, Clomipramine, Cyclosporine, Diazepam, Erythromycin, Ketoconazole, Omeprazole, seizure medications, Midazolam, MAO inhibitors, Propranolol, Rifampin, and Triazolam.

• Report a history of excessive alcohol consumption, street drug use, or misuse of prescription medications.

• Notify the doctor of any past experiences of chest pain, irregular heartbeats, or other heart issues after taking stimulants, as well as any history of heart attack, chest pain, high blood pressure, mental illnesses (e.g., depression, mania, psychosis), and heart, liver, or kidney disease.

• Be aware that Armodafinil may reduce the effectiveness of hormonal contraceptives (birth control methods), and discuss alternative contraception options with the doctor.

• Inform the doctor about the pregnancy, planning to become pregnant, or breastfeeding.

• If one anticipates undergoing surgery, including dental procedures, let the healthcare provider or dentist know that the patient uses Armodafinil.

• Understand that Armodafinil may affect the patient’s judgment, cognitive abilities, and coordination. It is better to avoid driving or operating machinery until on Armodafinil.

• Avoid alcohol consumption while taking Armodafinil.

How Is Armodafinil Administered?

Follow these instructions for taking Armodafinil precisely as directed by the healthcare provider:

• Adhere to the doctor's prescription for the appropriate Armodafinil dosage tailored to the needs. Only modify the Armodafinil dose after consulting the doctor.

• The doctor will advise the patient on the optimal time of day to take Armodafinil:

  • Individuals with narcolepsy or obstructive sleep apnea (OSA) typically take Armodafinil once daily in the morning.

  • Those with shift work sleep disorder (SWD) typically take Armodafinil approximately one hour before starting the work shift.

• Only alter the timing of the Armodafinil dose with prior consultation with the doctor. Shifting the time of Armodafinil may interfere with the ability to fall asleep if taken too close to bedtime.

• Armodafinil can be taken with or without food, as preferred.

• If the person accidentally takes more Armodafinil than prescribed or suspects an overdose, promptly contact the doctor or a poison control center.

What Are the Side Effects of Armodafinil?

Armodafinil may result in severe side effects. Stop using Armodafinil and promptly contact the healthcare provider or seek emergency assistance if one encounters any of the following:

1. A severe rash or a severe allergic reaction.

2. Mental (psychiatric) manifestations, including

• Depression (overwhelming sadness and loss of interest in life).

• Anxiety (excessive worry and fear about the future).

• Hallucinations (perceiving things that are not real).

• Intense escalation in activity and speech (mania).

• Suicidal thoughts.

• Aggressive behavior.

• Other mental issues.

3. Symptoms indicative of a heart condition include chest pain, irregular heart rhythms, and breathing difficulties.

Typical side effects that may occur in anyone using Armodafinil comprise:

• Headaches.

• Nausea.

• Dizziness.

• Difficulty falling asleep.

Dietary Considerations:

Consuming grapefruit or grapefruit juice while taking Armodafinil can lead to increased Armodafinil levels in the body, potentially intensifying its effects and side effects. Discussing grapefruit consumption with the healthcare provider and avoiding it to ensure safe medication use is best.

Missed Dose:

Skip the missed dose and adhere to the usual dosing timetable. Avoid taking an extra amount to compensate for the one that is missed.

Overdose:

Signs of an Armodafinil overdose are as follows:

• Difficulty falling asleep.

• Unsettled restlessness.

• State of confusion.

• Sensation of disorientation.

• Heightened excitement.

• Perception of hallucinations (seeing, hearing, feeling, or sensing things that are not real).

• Experiencing nausea and diarrhea.

• Altered heart rate, either accelerated or slowed.

• Chest discomfort.

• Elevated blood pressure.

No particular antidote is available for counteracting the harmful effects of an Armodafinil overdose. In the event of an overdose, the primary approach should focus on providing supportive care, including continuous cardiovascular monitoring.

Storage:

Keep Armodafinil at a room temperature range of 68 to 77 degrees Fahrenheit (20°C to 25°C). Also, ensure that Armodafinil and all medications are stored outside the children's reach.

For Doctors:

Indication:

Armodafinil is prescribed to enhance wakefulness in adult patients experiencing excessive sleepiness linked to obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD).

Usage Restrictions

In cases of OSA, Armodafinil is intended to address excessive sleepiness, and it is not meant to treat the underlying obstruction.

Dose and Dosing Considerations:

1. For Obstructive Sleep Apnea (OSA) or Narcolepsy: The recommended dosage ranges from 150 mg to 250 mg once daily in the morning.

2. For Shift Work Disorder (SWD): Take 150 mg once daily, approximately one hour before the start of the work shift.

3. For Patients with Hepatic Impairment: The doctor may prescribe a reduced dose if the patient has severe hepatic impairment.

4. For Geriatric Patients: For elderly patients, it is advisable to consider a lower dose.

What Are the Pharmacological Aspects of Armodafinil?

Pharmacodynamics:

Here are some key aspects of Armodafinil pharmacodynamics:

• Wakefulness Promotion: Armodafinil enhances wakefulness and reduces excessive sleepiness.

• Dopamine Regulation: It inhibits dopamine reuptake, increasing dopamine levels associated with alertness and mood.

• Indirect Dopaminergic Activity: Armodafinil acts as an indirect dopamine receptor agonist, influencing brain dopamine levels.

• Sympathomimetic-Like Actions: It shares some effects with sympathomimetic agents (e.g., increased alertness).

• Minimal Cardiovascular Effects: Armodafinil does not significantly affect heart rate or blood pressure, unlike stimulants.

• Non-Sleep-Inducing: Armodafinil does not induce sleep but helps individuals stay awake.

• Non-Habit Forming: It has a lower risk of dependence and abuse than other wake-promoting agents.

Mechanism:

• The precise mechanisms by which Armodafinil promotes wakefulness remain unidentified. Armodafinil (R-modafinil) exhibits pharmacological characteristics similar to modafinil, a combination of R- and S-modafinil, as observed in animal and in vitro studies. Both the R- and S-enantiomers display similar pharmacological effects in animals.

• Armodafinil and modafinil share wake-promoting properties akin to sympathomimetic agents such as amphetamine and methylphenidate, although the pharmacological profiles are not identical to those of sympathomimetic amines.

• The alpha1-adrenergic receptor antagonist, Prazosin, can diminish modafinil-induced wakefulness. However, modafinil does not exhibit activity in other in vitro test systems that respond to α-adrenergic agonists, such as the rat vas deferens preparation.

• Armodafinil acts as an indirect dopamine receptor agonist, with both Armodafinil and Modafinil binding to the dopamine transporter and inhibiting dopamine reuptake in vitro. In some animal brain regions, modafinil has been associated with increased extracellular dopamine levels. Modafinil did not induce wakefulness in mice without the dopamine transporter (DAT), suggesting its DAT-dependent nature. However, unlike Amphetamine, the wake-promoting effects of modafinil were not counteracted by the dopamine receptor antagonist haloperidol in rats. Additionally, alpha-methyl-p-tyrosine, a dopamine synthesis inhibitor, blocked Amphetamine's action but did not inhibit locomotor activity induced by Modafinil.

• In addition to promoting wakefulness and increasing locomotor activity in animals, Modafinil induces psychoactive and euphoric effects, altering mood, perception, thinking, and feelings in humans, which are typical of other central nervous system stimulants. Modafinil also exhibits reinforcing properties, as seen in self-administration studies in monkeys trained to self-administer cocaine, and it was partially identified as stimulant-like.

• Based on nonclinical investigations, two major metabolites, acid and sulfone, derived from modafinil or Armodafinil, do not contribute significantly to the central nervous system-activating properties of the parent compounds.

Pharmacokinetics:

• Armodafinil exhibits linear, dose-dependent kinetics.

• Steady-state is achieved within about a week of dosing.

• At a steady state, Armodafinil has higher concentrations than modafinil due to the faster elimination of one component.

• It is well-absorbed when taken orally, with minimal impact from food.

• Armodafinil has moderate distribution in the body and minimal interactions with highly protein-bound drugs.

• Metabolism involves several pathways, resulting in two primary metabolites.

• Elimination primarily occurs through liver metabolism, with a small amount excreted in urine.

Toxicity:

Non-clinical toxicity levels for Armodafinil are:

• Carcinogenesis: Armodafinil (R-modafinil) was administered orally to male mice at doses up to 300 mg/kg/day and to female mice at doses up to 100 mg/kg/day for approximately two years. No tumorigenic effects were observed. In a rat study, modafinil (a mixture of R- and S-modafinil) was given orally at doses up to 60 mg/kg/day for two years, with no tumorigenic effects.

• Plasma Exposure: Even at the highest doses tested in mice and rats, plasma Armodafinil exposures were lower than those observed in humans taking the maximum recommended dose of Armodafinil (250 mg/day).

• Mutagenesis: Armodafinil showed no mutagenic effects in an in vitro bacterial reverse mutation assay and an in vitro chromosomal aberration assay in human lymphocytes. Similarly, Modafinil tested negative in various in vitro and in vivo mutagenicity assays.

• Impairment of Fertility: No specific fertility and early embryonic development study was conducted with Armodafinil alone. However, in studies with modafinil, where male and female rats were given oral doses up to 480 mg/kg/day before and during mating (continuing in females through day 7 of gestation), an increase in the time to mate was observed at the highest dose. No other effects on fertility or reproductive parameters were noted. The no-effect dose was 240 mg/kg/day, which resulted in lower plasma Armodafinil exposure than the maximum recommended dose in humans.

Clinical Studies: The efficacy of Armodafinil in enhancing wakefulness in patients with excessive sleepiness associated with Shift Work Disorder (SWD) was demonstrated in a 12-week, double-blind, placebo-controlled clinical trial conducted across multiple centers. A total of 254 individuals with chronic SWD participated in the study, with random allocation to receive either NUVIGIL at a daily dose of 150 mg or a placebo. All enrolled patients met the established criteria for chronic SWD, which included:

• Either a primary complaint of excessive sleepiness or insomnia linked to a work schedule (typically night shifts) occurring during the regular sleep phase or a polysomnography and the Multiple Sleep Latency Test (MSLT) confirming the disruption of a normal sleep-wake pattern, indicative of disturbed chronobiological rhythmicity.

• No other underlying medical or mental condition accounted for the symptoms.

• The symptoms do not meet the criteria for any other sleep disorder causing insomnia or excessive sleepiness (e.g., jet lag).

It is important to note that not all individuals who complain of sleepiness while engaged in shift work meet the diagnostic criteria for SWD. In this clinical trial, only patients with symptoms persisting for a minimum of three months were included.

Additionally, enrolled patients were required to work at least five-night shifts per month, exhibit excessive sleepiness during the night shifts (with an MSLT score of more than or equal to six minutes), and have daytime insomnia confirmed through daytime polysomnography.

The primary measures of effectiveness included:

• Sleep latency was evaluated using the multiple sleep latency test (MSLT) during a simulated night shift at the final visit.

• Changes in the overall disease status of patients were assessed using the Clinical Global Impression of Change (CGI-C) scale at the final visit.

Patients treated with Armodafinil demonstrated a statistically significant sleep onset delay compared to those receiving the placebo, as measured by the nighttime MSLT at the final visit. Moreover, a statistically significantly higher number of Armodafinil-treated patients showed improvements in the overall clinical condition, as assessed by the CGI-C scale at the final visit.

What Are the Contraindications of Armodafinil?

Armodafinil should not be used in patients with known hypersensitivity or allergy to modafinil or its inactive components.

Warnings and Precautions:

The warnings and precautions associated with Armodafinil are as follows:

• Serious Dermatologic Reactions: Armodafinil and Modafinil can cause severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Discontinue treatment if any skin issues arise.

• DRESS/Multiorgan Hypersensitivity: DRESS (drug reaction with eosinophilia and systemic symptoms), a severe hypersensitivity reaction, has occurred with Armodafinil. Symptoms may include fever, rash, and organ involvement. Discontinue Armodafinil if suspected. Cross-sensitivity with other drugs is possible.

• Angioedema and Anaphylaxis: Armodafinil may lead to angioedema and hypersensitivity reactions. Patients must discontinue the treatment and promptly seek medical attention if any signs of these reactions occur.

• Persistent Sleepiness: Patients should know that Armodafinil might not fully resolve the sleepiness. Regular assessments are necessary, and caution is advised for activities requiring alertness.

• Psychiatric Symptoms: Anxiety, agitation, depression, and suicidal ideation have been reported. Caution is needed, especially in patients with psychiatric histories.

• Effects on Ability to Drive and Use Machinery: Armodafinil may affect judgment and motor skills, so caution is advised when operating vehicles or machinery.

• Cardiovascular Events: Patients with certain heart conditions should avoid Armodafinil. Blood pressure and heart rate monitoring may be necessary.

What Are the Drug Interactions of Armodafinil?

• Effects of Armodafinil on CYP3A4/5 Substrates: Armodafinil may enhance the clearance of drugs metabolized by CYP3A4/5, like steroidal contraceptives, Cyclosporine, Midazolam, and Triazolam. This can lead to reduced drug exposure in the body. Adjusting the dosage of these medications may be necessary when used together with Armodafinil.

• Steroidal Contraceptives: The efficacy of steroidal contraceptives can be compromised when taken with Armodafinil and for a month after discontinuing Armodafinil treatment. Consider alternative or additional forms of contraception when using steroidal contraceptives concurrently with Armodafinil.

• Cyclosporine: Armodafinil may lower circulating levels of Cyclosporine. Monitoring cyclosporine concentrations in the blood and adjusting the dosage when co-administered with Armodafinil is advisable.

• Effects of Armodafinil on CYP2C19 Substrates: Armodafinil may extend the elimination of drugs metabolized by CYP2C19, such as Phenytoin, Diazepam, Propranolol, Omeprazole, and Clomipramine. This can result in higher systemic exposure to these drugs. Consider reducing the dosage of these medications when used alongside Armodafinil.

• Warfarin: When co-administered with Armodafinil, more frequent monitoring of prothrombin times should be considered, especially with warfarin therapy.

• Monoamine Oxidase (MAO) Inhibitors: Be cautious when administering MAO inhibitors and Armodafinil simultaneously.

Specific Considerations:

The particular considerations are as follows:

• Pregnancy Registry: A pregnancy exposure registry monitors outcomes in women exposed to Armodafinil during pregnancy. Healthcare providers should encourage pregnant patients and pregnant women to enroll.

Risk Summary: Limited data on Armodafinil use during pregnancy make it challenging to assess associated risks. Reports have indicated intrauterine growth restriction and spontaneous abortion alongside Armodafinil and Modafinil. Armodafinil shares some properties with sympathomimetics linked to these adverse effects.

Animal Data: Studies in pregnant rats and rabbits exposed to Armodafinil and modafinil during organogenesis revealed developmental toxicity, including fetal growth delay and increased fetal mortality. While the effects occurred at doses exceeding human exposure, the highest no-effect doses were comparable to or lower than the recommended human dose.

• Lactation: No data exist on Armodafinil in human milk or its side effects on breastfed infants or milk production. Modafinil was found in rat milk during lactation. Consider breastfeeding benefits, clinical needs, and potential effects on the breastfed child.

• Reproductive Potential: Hormonal contraceptives may be less effective with Armodafinil, so users should consider additional contraception methods during treatment and one month after stopping Armodafinil.

• Pediatric Use: Safety and effectiveness in pediatric (children) patients have not been established. Serious rash has been observed in pediatric patients taking Modafinil.

• Geriatric Use: Elimination of Armodafinil and its metabolites may decrease with aging in elderly patients. Lower doses and close monitoring may be needed in this population.

• Hepatic Impairment: Patients with severe hepatic (liver) impairment should receive reduced Armodafinil dosages. Consult the dosing recommendations for hepatic impairment in clinical pharmacology.