Armodafinil

Name: Armodafinil

What brand names are available for armodafinil?

Nuvigil

What is the dosage for armodafinil?

The recommended dose is 150 or 250 mg every morning or 150 mg daily one hour prior to the work shift.

Warnings

Included as part of the PRECAUTIONS section.

Uses of Armodafinil

Armodafinil is a prescription medication used to improve wakefulness in adults who are very sleepy due to one of the following diagnosed sleep disorders:

  • narcolepsy
  • obstructive sleep apnea (OSA). Armodafinil tablets are used with other medical treatments for this sleep disorder. Armodafinil tablets do not take the place of using your CPAP machine or other treatments that your doctor has prescribed for this condition. It is important that you continue to use these treatments as prescribed by your doctor.
  • shift work disorder (SWD)

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

 

Armodafinil Drug Class

Armodafinil is part of the drug class:

  • Centrally acting sympathomimetics

Other Requirements

  • Store armodafinil at 20° to 25°C (68° to 77°F).
  • Keep this and all medicines out of the reach of children.
  • Armodafinil is classified as federally controlled substance (C-IV), because it can be abused or lead to dependence. Keep armodafinil in a safe place to prevent misuse and abuse.

Patient Handout

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What is the most important information I should know about armodafinil?

You should not use this medicine if you have ever had a rash or allergic reaction caused by armodafinil or modafinil (Provigil).

Stop taking armodafinil and call your doctor if you have a skin rash, no matter how mild. Other signs of a severe reaction include fever, swelling in your face or tongue, mouth sores, trouble breathing, swelling in your legs, yellowing of your skin or eyes, and skin rash or blistering sores.

Uses of Armodafinil

  • It is used to treat a lot of sleepiness that may happen with sleep apnea, narcolepsy, or shift work problems.
  • It may be given to you for other reasons. Talk with the doctor.

Dosage Forms and Strengths

  • 50 mg - Each white to off-white round tablet is debossed with 'E226' on one side and plain on the other side.
  • 150 mg - Each white to off-white oval-shaped tablet is debossed with 'E227' on one side and plain on the other side.
  • 250 mg - Each white to off-white oval-shaped tablet is debossed with 'NAT375' on one side and plain on the other side.

Armodafinil - Clinical Pharmacology

Mechanism of Action

The mechanism(s) through which Armodafinil promotes wakefulness is unknown. Armodafinil (R-modafinil) has pharmacological properties similar to those of modafinil (a mixture of R- and S-modafinil), to the extent tested in animal and in vitro studies. The R- and S-enantiomers have similar pharmacological actions in animals.

Armodafinil and modafinil have wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although their pharmacologic profile is not identical to that of the sympathomimetic amines.

Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist, prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to α-adrenergic agonists such as the rat vas deferens preparation.

Armodafinil is an indirect dopamine receptor agonist; both Armodafinil and modafinil bind in vitro to the dopamine transporter and inhibit dopamine reuptake. For modafinil, this activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. In genetically engineered mice lacking the dopamine transporter (DAT), 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, a dopamine synthesis inhibitor, 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, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine; modafinil was also partially discriminated as stimulant-like.

Based on nonclinical studies, two major metabolites, acid and sulfone, of modafinil or Armodafinil, do not appear to contribute to the CNS-activating properties of the parent compounds.

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 to 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 administration of a single-dose of 50 mg Armodafinil tablets or 100 mg PROVIGIL (modafinil, a 1:1 mixture of R- and S-enantiomers) are nearly superimposable. However, the Cmax and AUC0-∞, of Armodafinil at steady-state were approximately 37% and 70% higher, respectively, following administration of 200 mg Armodafinil tablets than the corresponding values of modafinil following administration of 200 mg PROVIGIL due to the more rapid clearance of the S-enantiomer (elimination half-life approximately 4 hours) as compared to the R-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 (tmax) may be delayed by approximately 2-4 hours in the fed state. Since the delay in tmax is also associated with elevated plasma concentrations later in time, food can potentially affect the onset and time course of pharmacologic action for Armodafinil tablets.

Distribution

Armodafinil has an apparent volume of distribution of approximately 42 L. Data specific to Armodafinil protein binding are not available. However, modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of Armodafinil tablets with highly protein-bound drugs is considered to be minimal.

Elimination

After oral administration of Armodafinil tablets, Armodafinil exhibits an apparent monoexponential decline from the peak plasma concentration. The apparent terminal t½ is approximately 15 hours. The oral clearance of Armodafinil tablets is approximately 33 mL/min.

Metabolism

In vitro and in vivo data show that Armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the single most prominent metabolic pathway, with sulfone formation by cytochrome P450 (CYP) 3A4/5 being next in importance. The other oxidative products are formed too slowly in vitro to enable identification of the enzyme(s) responsible. Only two metabolites reach appreciable concentrations in plasma (i.e., R-modafinil acid and modafinil sulfone).

Excretion

Data specific to Armodafinil tablets disposition are not available. However, modafinil is mainly eliminated via metabolism, predominantly in the liver, with less than 10% of the parent compound excreted in the urine. A total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1.0% in the feces).

Specific Populations

Age

In a clinical study, systemic exposure of Armodafinil was approximately 15% higher in elderly subjects (≥65 years of age, N=24), corresponding to approximately 12% lower oral clearance (CL/F), as compared to young subjects (18-45 years of age, N=25). Systemic exposure of Armodafinil acid (metabolite) was approximately 61% and 73% greater for Cmax and AUC0-τ, respectively, compared to young subjects. Systemic exposure of the sulfone metabolite was approximately 20% lower for elderly subjects compared with young subjects. A subgroup analysis of elderly subjects demonstrated elderly subjects ≥75 and 65-74 years of age had approximately 21% and 9% lower oral clearance, respectively, compared to young subjects. Systemic exposure was approximately 10% greater in subjects 65-74 years of age (N=17) and 27% greater in subjects ≥75 years of age (N=7), respectively, when compared to young subjects. The change is considered not likely to be clinically significant for elderly patients, however, because some elderly patients have greater exposure to Armodafinil, consideration should be given to the use of lower doses.

Sex

Population pharmacokinetic analysis suggests no gender effect on the pharmacokinetics of Armodafinil.

Ethnicity

The influence of race/ethnicity on the pharmacokinetics of Armodafinil has not been studied.

Hepatic Impairment

The pharmacokinetics and metabolism of modafinil were examined in patients with cirrhosis of the liver (6 men and 3 women). Three patients had stage B or B+ cirrhosis and 6 patients had stage C or C+ cirrhosis (per the Child-Pugh score criteria). Clinically 8 of 9 patients were icteric and all had ascites. In these patients, the oral clearance of modafinil was decreased by about 60% and the steady state concentration was doubled compared to normal patients [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

Renal Impairment

In a single dose 200 mg modafinil study, severe chronic renal failure (creatinine clearance ≤20 mL/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to modafinil acid (metabolite) was increased 9-fold.

Drug Interactions

In vitro data demonstrated that Armodafinil weakly induces CYP1A2 and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by Armodafinil. Other CYP activities did not appear to be affected by Armodafinil. An in vitro study demonstrated that Armodafinil is a substrate of P-glycoprotein.

Potential Interactions with Drugs That Inhibit, Induce, or Are Metabolized by Cytochrome P450 Isoenzymes and Other Hepatic Enzymes

The existence of multiple pathways for Armodafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing Armodafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of Armodafinil tablets due to CYP inhibition by concomitant medications. However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of Armodafinil, coadministration of potent inducers of CYP3A4/5 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4/5 (e.g., ketoconazole, erythromycin) could alter the plasma concentrations of Armodafinil.

The Potential of Armodafinil Tablets to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition

  • Drugs Metabolized by CYP3A4/5
    In vitro data demonstrated that Armodafinil is a weak inducer of CYP3A activity in a concentration-related manner. In a clinical study, concomitant administration of Armodafinil tablets 250 mg resulted in a reduction in systemic exposure to midazolam by 32% after a single oral dose (5 mg) and 17% after a single intravenous dose (2 mg). Therefore, the blood levels and effectiveness of drugs that are substrates for CYP3A enzymes (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be reduced after initiation of concomitant treatment with Armodafinil tablets [see Drug Interactions (7)].
    In a separate clinical study, concomitant administration of Armodafinil tablets 250 mg with quetiapine (300 mg to 600 mg daily doses) resulted in a reduction in the mean systemic exposure of quetiapine by approximately 29%. No dose adjustment is required.
  • Drugs Metabolized by CYP1A2
    In vitro data demonstrated that Armodafinil is a weak inducer of CYP1A2 in a concentration-related manner. However, in a clinical study using caffeine as a probe substrate, no significant effect on CYP1A2 activity was observed.
  • Drugs Metabolized by CYP2C19
    In vitro data demonstrated that Armodafinil is a reversible inhibitor of CYP2C19 activity. In a clinical study, concomitant administration of Armodafinil tablets 400 mg resulted in a 40% increase in exposure to omeprazole after a single oral dose (40 mg), as a result of moderate inhibition of CYP2C19 activity [see Drug Interactions (7)].
  • Interactions with CNS Active Drugs
    Concomitant administration of Armodafinil tablets with quetiapine reduced the systemic exposure of quetiapine.
    Data specific to Armodafinil tablets drug-drug interaction potential with other CNS active drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to Armodafinil tablets.
    Concomitant administration of modafinil with methylphenidate or dextroamphetamine produced no significant alterations on the pharmacokinetic profile of modafinil or either stimulant, even though the absorption of modafinil was delayed for approximately one hour.
    Concomitant modafinil or clomipramine did not alter the pharmacokinetic profile of either drug; however, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine was reported in a patient with narcolepsy during treatment with modafinil.
    Data specific to Armodafinil or modafinil drug-drug interaction potential with monoamine oxidase (MAO) inhibitors are not available [see Drug Interactions (7)].
  • Interaction with P-Glycoprotein
    An in vitro study demonstrated that Armodafinil is a substrate of P-glycoprotein. The impact of inhibition of P-glycoprotein is not known.
  • Interactions with Other Drugs
    Data specific to Armodafinil drug-drug interaction potential for additional other drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to Armodafinil tablets.
    Warfarin: Concomitant administration of modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of R- and S-warfarin. However, since only a single dose of warfarin was tested in this study, an interaction cannot be ruled out [see Drug Interactions (7)].

How Supplied/Storage and Handling

How Supplied

Armodafinil tablets are available as follows:

50 mg: Each white to off-white round tablet is debossed with 'E226' on one side and plain on the other side.

NDC 51991-322-06 Bottles of 60
NDC 51991-322-90 Bottles of 90
NDC 51991-322-10 Bottles of 1000

150 mg: Each white to off-white oval-shaped tablet is debossed with 'E227' on one side and plain on the other side.

NDC 51991-323-06 Bottles of 60
NDC 51991-323-90 Bottles of 90
NDC 51991-323-10 Bottles of 1000

250 mg: Each white to off-white oval-shaped tablet is debossed with 'NAT375' on one side and plain on the other side.

NDC 51991-324-06 Bottles of 60
NDC 51991-324-90 Bottles of 90
NDC 51991-324-05 Bottles of 500

Storage

Store at 20º - 25° C (68º - 77º F).

Use Labeled Indications

Narcolepsy: To improve wakefulness in patients with excessive sleepiness associated with narcolepsy.

Obstructive sleep apnea: To improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea (OSA).

Limitations of use: In OSA, armodafinil is indicated to treat excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating armodafinil for excessive sleepiness.

Shift-work disorder: To improve wakefulness in patients with excessive sleepiness associated with shift-work disorder.

Where can i get more information?

Your pharmacist can provide more information about armodafinil.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Side effects

The following serious adverse reactions are described below and elsewhere in the labeling:

  • Serious Dermatologic Reactions [see WARNINGS AND PRECAUTIONS]
  • Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity [see WARNINGS AND PRECAUTIONS]
  • Angioedema and Anaphylaxis Reactions [see WARNINGS AND PRECAUTIONS]
  • Persistent Sleepiness [see WARNINGS AND PRECAUTIONS]
  • Psychiatric Symptoms [see WARNINGS AND PRECAUTIONS]
  • Effects on Ability to Drive and Use Machinery [see WARNINGS AND PRECAUTIONS]
  • Cardiovascular Events [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

NUVIGIL has been evaluated for safety in over 1,100 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy.

Most Common Adverse Reactions

In the placebo-controlled clinical trials, the most common adverse reactions ( ≥ 5%) associated with the use of NUVIGIL more frequently than in placebo-treated patients were headache, nausea, dizziness, and insomnia. The adverse reaction profile was similar across the studies.

Table 1 presents the adverse reactions that occurred at a rate of 1% or more and were more frequent in NUVIGIL-treated patients than in placebo-treated patients in the placebo-controlled clinical trials.

Table 1: Adverse Reactions in Pooled Placebo-Controlled Clinical Trials* in OSA, Narcolepsy, and SWD with NUVIGIL (150 mg and 250 mg)

  NUVIGIL (%)
N=645
Placebo (%)
N=445
Headache 17 9
Nausea 7 3
Dizziness 5 2
Insomnia 5 1
Anxiety 4 1
Diarrhea 4 2
Dry Mouth 4 1
Depression 2 0
Dyspepsia 2 0
Fatigue 2 1
Palpitations 2 1
Rash 2 0
Upper Abdominal Pain 2 1
Agitation 1 0
Anorexia 1 0
Constipation 1 0
Contact Dermatitis 1 0
Decreased Appetite 1 0
Depressed Mood 1 0
Disturbance In Attention 1 0
Dyspnea 1 0
Hyperhydrosis 1 0
Increased Gamma-Glutamyltransferase 1 0
Increased Heart Rate 1 0
Influenza-Like Illness 1 0
Loose Stools 1 0
Migraine 1 0
Nervousness 1 0
Pain 1 0
Paresthesia 1 0
Polyuria 1 0
Pyrexia 1 0
Seasonal Allergy 1 0
Thirst 1 0
Tremor 1 0
Vomiting 1 0
* Adverse reactions that occurred in ≥ 1% of NUVIGIL-treated patients and greater incidence than that of placebo.

Dose-Dependent Adverse Reactions

In the placebo-controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of NUVIGIL and placebo, the following adverse reactions were dose-related: headache, rash, depression, dry mouth, insomnia, and nausea. See Table 2 for additional information.

Table 2: Dose-Dependent Adverse Reactions in Pooled Placebo-Controlled Clinical Trials in OSA, Narcolepsy and SWD

  NUVIGIL 250 mg (%)
N=198
NUVIGIL 150 mg (%)
N=447
NUVIGIL Combined (%)
N=645
Placebo (%)
N=445
Headache 23 14 17 9
Nausea 9 6 7 3
Insomnia 6 4 5 1
Dry Mouth 7 2 4 < 1
Rash 4 1 2 < 1
Depression 3 1 2 < 1

Adverse Reactions Resulting In Discontinuation Of Treatment

In placebo-controlled clinical trials, 44 of the 645 patients (7%) who received NUVIGIL discontinued due to an adverse reaction compared to 16 of the 445 (4%) of patients that received placebo. The most frequent reason for discontinuation was headache (1%).

Laboratory Abnormalities

Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of NUVIGIL, but not placebo. Few patients, however, had GGT or AP elevations outside of the normal range. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin, although there were rare cases of isolated elevations of AST and/or ALT. A single case of mild pancytopenia was observed after 35 days of treatment and resolved with drug discontinuation. A small mean decrease from baseline in serum uric acid compared to placebo was seen in clinical trials. The clinical significance of this finding is unknown.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of NUVIGIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: Mouth Sores (including mouth blistering and ulceration)

Read the entire FDA prescribing information for Nuvigil (Armodafinil)

Read More »

For Healthcare Professionals

Applies to armodafinil: oral tablet

Dermatologic

Common (1% to 10%): Rash, contact dermatitis, hyperhidrosis[Ref]

Immunologic

Common (1% to 10%): Seasonal allergy
Frequency not reported: Angioedema, anaphylaxis[Ref]

Psychiatric

Common (1% to 10%): Insomnia, anxiety, depression, agitation, depressed mood, disturbance in attention, nervousness
Frequency not reported: Irritability, suicidal ideation[Ref]

Cardiovascular

Common (1% to 10%): Palpitations, increased heart rate, increased blood pressure[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, diarrhea, dry mouth, dyspepsia, upper abdominal pain, constipation, vomiting, loose stools[Ref]

General

The following reactions occurred more frequently with the 250 mg/day dose compared to the 150 mg/day dose: headache, rash, depression, dry mouth, insomnia, nausea.[Ref]

Genitourinary

Common (1% to 10%): Polyuria[Ref]

Hematologic

Frequency not reported: Pancytopenia[Ref]

Hepatic

Common (1% to 10%): Increased gamma-glutamyltransferase, increased alkaline phosphatase
Rare (less than 0.1%): Elevated AST and/or ALT[Ref]

Metabolic

Common (1% to 10%): Anorexia, decreased appetite,
Frequency not reported: Decreased serum uric acid[Ref]

Nervous system

Very common (10% or more): Headache (17%)
Common (1% to 10%): Dizziness, paresthesia, tremor, migraine[Ref]

Other

Common (1% to 10%): Fatigue, influenza-like illness, pain, pyrexia, thirst[Ref]

Respiratory

Common (1% to 10%): Dyspnea[Ref]

Some side effects of armodafinil may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Dialysis

Data not available

Armodafinil Pregnancy Warnings

This drug should be used during pregnancy only if the potential benefit justifies the possible risk to the fetus. US FDA pregnancy category: C Comments: There is a potential increased risk of pregnancy when using steroidal contraceptives (including depot or implantable contraceptives) with this drug and for 1 month after treatment discontinuation.

Intrauterine growth restriction and spontaneous abortion have been reported with this drug and modafinil. In animal studies for this drug, developmental toxicity (increased fetal visceral and skeletal variations, decreased fetal body weight) was observed at clinically relevant plasma exposures and at a dose of 600 mg/kg/day. Animal studies for modafinil have also revealed development toxicity at doses from 20 to 200 mg/kg/day; however, a study with a 480 mg/kg/day dose demonstrated no adverse effects on embryofetal development. Fertility information is not available for this drug, but oral administration of modafinil produced an increase in the time to mate at the 480 mg/kg/day dose; no other fertility effects were observed. There are no controlled data in human pregnancy. To monitor the outcomes of pregnant women exposed to this drug, a pregnancy registry has been established. Healthcare providers are encouraged to register pregnant patients, and pregnant women are encouraged to enroll themselves by calling 1-866-404-4106 (toll free). US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Armodafinil Breastfeeding Warnings

Caution is recommended. Excreted into human milk: Unknown Excreted into animal milk: Data not available Comments: The effects in the nursing infant are unknown.

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