Armodafinil Drug Information

Dosage in Obstructive Sleep Apnea (OSA) and Narcolepsy

The recommended dosage of armodafinil tablets for patients with OSA or narcolepsy is 150 mg to 250 mg taken orally once a day as a single dose in the morning. In patients with OSA, doses up to 250 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that these doses confer additional benefit beyond that of the 150 mg/day dose .

Dosage in Shift Work Disorder (SWD)

The recommended dosage of armodafinil tablets for patients with SWD is 150 mg taken orally once a day as a single dose approximately 1 hour prior to the start of their work shift.

Dosage Modification in Patients with Severe Hepatic Impairment

In patients with severe hepatic impairment, the dosage of armodafinil tablets should be reduced.

Use in Geriatric Patients Consideration should be given to the use of

lower doses and close monitoring in geriatric patients.

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. Armodafinil 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 armodafinil 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-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 Armodafinil (150 mg and 250 mg) * Adverse reactions that occurred in ≥ 1% of armodafinil-treated patients and greater incidence than that of placebo.

Armodafinil (%) 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 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 250 mg (%) N=198 Armodafinil 150 mg (%) N=447 Armodafinil 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 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, 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 armodafinil. 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)

Effects of Armodafinil 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 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 . The effectiveness of steroidal contraceptives may be reduced when used with armodafinil 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 and for one month after discontinuation of armodafinil treatment.

Blood levels of cyclosporine may be reduced when used with armodafinil. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with armodafinil. Effects of Armodafinil on CYP2C19 Substrates Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by armodafinil 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. Warfarin More frequent monitoring of prothrombin times/INR should be considered whenever armodafinil is coadministered with warfarin . Monoamine Oxidase (MAO) Inhibitors Caution should be used when concomitantly administering MAO inhibitors and armodafinil. Steroidal contraceptives (e.g., ethinyl estradiol): use alternative or concomitant methods of contraception while taking armodafinil and for one month after discontinuation of armodafinil treatment.

Cyclosporine: blood concentrations of cyclosporine may be reduced. CYP2C19 substrates, such as omeprazole, phenytoin, and diazepam: exposure of these medications may be increased.

Pregnancy 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 . 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 to 4% and 15 to 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 (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. 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. 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. No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Serious rash has been seen in pediatric patients receiving modafinil .

Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil or its inactive ingredients . Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil.

Fatal overdoses involving modafinil alone or involving armodafinil or modafinil in combination with other drugs have been reported in the postmarketing setting. Symptoms most often accompanying armodafinil or modafinil overdose, alone or in combination with other drugs, have included anxiety, dyspnea, insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, excitation and hallucination; digestive changes such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension, and chest pain. No specific antidote exists for the toxic effects of a armodafinil overdose.

Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring.