FDA

Armodafinil

Approved 9 May 2019OralTablet

The FDA lists this product in 32 strengths and forms.

Indications

Armodafinil tablets are indicated to improve wakefulness in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD). Limitations of Use In OSA, armodafinil tablets are 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 tablets for excessive sleepiness.

Contraindications

Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil or their inactive ingredients [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil. ( 4 )

Warnings and precautions

Serious Rash, including Stevens-Johnson Syndrome: discontinue armodafinil tablets at the first sign of rash, unless the rash is clearly not drug-related. ( 5.1 )
DRESS/Multi-organ Hypersensitivity Reactions: if suspected, discontinue armodafinil tablets. (5.2)
Angioedema and Anaphylaxis Reactions: if suspected, discontinue armodafinil tablets. (5.3)
Persistent Sleepiness: assess patients frequently for degree of sleepiness and, if appropriate, advise patients to avoid driving or engaging in any other potentially dangerous activity. ( 5.4 )
Psychiatric Symptoms: use particular caution in treating patients with a history of psychosis, depression, or mania. Consider discontinuing armodafinil tablets if psychiatric symptoms develop. ( 5.5 )
Known Cardiovascular Disease: consider increased monitoring. ( 5.7 )

5.1Serious Dermatologic Reactions, Including Stevens-Johnson Syndrome and Toxic Epidermal Necrosis

Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of armodafinil tablets or modafinil (the racemic mixture of S- and R-enantiomers). Armodafinil tablets have not been studied in pediatric patients in any setting and are not approved for use in pediatric patients for any indication. In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age < 17 years); these rashes included 1 case of possible Stevens-Johnson syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction/Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.2) ] .

At a glance

Brand name: Armodafinil
Route: Oral
Dosage form: Tablet
Applicant: Mylan Pharms Inc
Status: Prescription
FDA approval: 9 May 2019
Application: ANDA200043-001

Indications

Contraindications

Warnings and precautions

Serious Rash, including Stevens-Johnson Syndrome: discontinue armodafinil tablets at the first sign of rash, unless the rash is clearly not drug-related. ( 5.1 )
DRESS/Multi-organ Hypersensitivity Reactions: if suspected, discontinue armodafinil tablets. (5.2)
Angioedema and Anaphylaxis Reactions: if suspected, discontinue armodafinil tablets. (5.3)
Persistent Sleepiness: assess patients frequently for degree of sleepiness and, if appropriate, advise patients to avoid driving or engaging in any other potentially dangerous activity. ( 5.4 )
Psychiatric Symptoms: use particular caution in treating patients with a history of psychosis, depression, or mania. Consider discontinuing armodafinil tablets if psychiatric symptoms develop. ( 5.5 )
Known Cardiovascular Disease: consider increased monitoring. ( 5.7 )

5.1Serious Dermatologic Reactions, Including Stevens-Johnson Syndrome and Toxic Epidermal Necrosis

Interactions

Effects of Armodafinil Tablets on CYP3A4/5 Substrates: The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by armodafinil tablets via induction of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment of these drugs should be considered when these drugs are used concomitantly with armodafinil tablets [see Clinical Pharmacology (12.3) ] .

The effectiveness of steroidal contraceptives may be reduced when used with armodafinil tablets and for one month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with armodafinil tablets and for one month after discontinuation of armodafinil tablet treatment. Blood levels of cyclosporine may be reduced when used with armodafinil tablets.

Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with armodafinil tablets. Effects of Armodafinil Tablets on CYP2C19 Substrates: Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by armodafinil tablets via inhibition of metabolic enzymes, with resultant higher systemic exposure.

Dose reduction of these drugs may be required when these drugs are used concomitantly with armodafinil tablets. Warfarin: More frequent monitoring of prothrombin times/INR should be considered whenever armodafinil tablets are coadministered with warfarin [see Clinical Pharmacology (12.3) ] . Monoamine Oxidase (MAO) Inhibitors: Caution should be used when concomitantly administering MAO inhibitors and armodafinil tablets.

Steroidal contraceptives (e.g., ethinyl estradiol): use alternative or concomitant methods of contraception while taking armodafinil tablets and for one month after discontinuation of armodafinil tablet treatment. ( 7 )
Cyclosporine: blood concentrations of cyclosporine may be reduced. ( 7 )
CYP2C19 substrates, such as omeprazole, phenytoin, and diazepam: exposure of these medications may be increased. ( 7 ) 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 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) ] .

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Limited available data on armodafinil use in pregnant women are insufficient to inform a drug associated risk of adverse pregnancy outcomes. Intrauterine growth restriction and spontaneous abortion have been reported in association with armodafinil and modafinil. Although the pharmacology of armodafinil is not identical to that of the sympathomimetic amines, armodafinil shares some pharmacologic properties with this class [see Clinical Pharmacology (12.1) ].

Some sympathomimetics have been associated with intrauterine growth restriction and spontaneous abortions. In animal reproduction studies of armodafinil (R-modafinil) and modafinil (a mixture of R- and S-modafinil) conducted in pregnant rats (armodafinil, modafinil) and rabbits (modafinil) during organogenesis, evidence of developmental toxicity (increased embryofetal and offspring mortality, decreased fetal growth) was observed at clinically relevant plasma exposures.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Oral administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in decreased fetal body weight and increased incidences of fetal variations indicative of growth delay at the highest dose, which was also maternally toxic.

The highest no-effect dose for embryofetal developmental toxicity in rat (200 mg/kg/day) was associated with a plasma armodafinil exposure (AUC) less than that in humans at the maximum recommended human dose (MRHD) of armodafinil tablets (250 mg/day). Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout organogenesis produced an increase in resorptions and an increased incidence of fetal variations at the highest dose tested.

The higher no-effect dose for embryofetal developmental toxicity (100 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the MRHD of armodafinil tablets. However, in a subsequent rat study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed. In a study in which modafinil (45, 90, or 180 mg/kg/day was orally administered to pregnant rabbits during organogenesis, embryofetal death was increased at the highest dose.

The highest no-effect dose for developmental toxicity (100 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the MRHD of armodafinil tablets. Modafinil administration to rats throughout gestation and lactation at oral doses of up to 200 mg/kg/day resulted in decreased viability in the offspring at doses greater than 20 mg/kg/day, a dose resulting in a plasma armodafinil AUC less than that in humans at the MRHD of armodafinil tablets.

No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring.

Adverse reactions

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

Serious Dermatologic Reactions [see Warnings and Precautions (5.1) ]
Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.2) ]
Angioedema and Anaphylaxis Reactions [see Warnings and Precautions (5.3) ]
Persistent Sleepiness [see Warnings and Precautions (5.4) ]
Psychiatric Symptoms [see Warnings and Precautions (5.5) ]
Effects on Ability to Drive and Use Machinery [see Warnings and Precautions (5.6) ]
Cardiovascular Events [see Warnings and Precautions (5.7) ] Most common adverse reactions (≥ 5%): headache, nausea, dizziness, and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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. Armodafinil tablets have 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 armodafinil tablets 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 armodafinil tablet-treated patients than in placebo-treated patients in the placebo-controlled clinical trials. Table 1: Adverse Reactions in Pooled Placebo-Controlled Clinical Trials Adverse reactions that occurred in ≥ 1% of armodafinil tablet-treated patients and greater incidence than that of placebo. in OSA, Narcolepsy, and SWD with Armodafinil Tablets (150 mg and 250 mg) Armodafinil Tablets (%) 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 Dose-Dependent Adverse Reactions In the placebo-controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of armodafinil tablets 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 Armodafinil Tablets 250 mg (%) N = 198 Armodafinil Tablets 150 mg (%) N = 447 Armodafinil Tablets 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 armodafinil tablets 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 armodafinil tablets, 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.

6.2Postmarketing Experience

The following adverse reactions have been identified during post approval use of armodafinil tablets. 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)

Armodafinil

Indications

Contraindications

Warnings and precautions

5.1Serious Dermatologic Reactions, Including Stevens-Johnson Syndrome and Toxic Epidermal Necrosis

At a glance

Two medicines in one question?

Armodafinil

Indications

Contraindications

Warnings and precautions

5.1Serious Dermatologic Reactions, Including Stevens-Johnson Syndrome and Toxic Epidermal Necrosis

At a glance

Two medicines in one question?

5.2Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity

5.3Angioedema and Anaphylaxis Reactions Angioedema

5.4Persistent Sleepiness Patients

5.5Psychiatric Symptoms

5.6Effects on Ability to Drive and Use Machinery

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information