Modafinil

1 INDICATIONS AND USAGE Modafinil tablets are indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea (OSA), or shift work disorder (SWD). Limitations of Use In OSA, modafinil 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 and during treatment with modafinil tablets for excessive sleepiness. Modafinil tablets are indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea (OSA), or shift work disorder (SWD). ( 1 ) Limitations of Use In OSA, modafinil tablets are indicated to treat excessive sleepiness and not as treatment for the underlying obstruction.

2 DOSAGE AND ADMINISTRATION The recommended dosage of modafinil tablets for each indication is as follows: Narcolepsy or OSA: 200 mg once a day in the morning. ( 2.1 ) SWD: 200 mg once a day, taken approximately one hour prior to start of the work shift. ( 2.2 ) Severe Hepatic Impairment: reduce dose to half the recommended dose. ( 2.3 , 12.3 ) Geriatric Patients: consider lower dose. ( 2.4 , 12.3 ) 2.1 Dosage in Narcolepsy and Obstructive Sleep Apnea (OSA) The recommended dosage of modafinil tablets for patients with narcolepsy or OSA is 200 mg taken orally once a day as a single dose in the morning. Doses up to 400 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that this dose confers additional benefit beyond that of the 200 mg/day dose [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.1 , 14.2 )] . 2.2 Dosage in Shift Work Disorder (SWD) The recommended dosage of modafinil tablets for patients with SWD is 200 mg taken orally once a day as a single dose approximately 1 hour prior to the start of their work shift. 2.3 Dosage Modifications in Patients with Severe Hepatic Impairment In patients with severe hepatic impairment, the dosage of modafinil tablets should be reduced to one-half of that recommended for patients with normal hepatic function [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . 2.4 Use in Geriatric Patients Consideration should be given to the use of lower doses and close monitoring in geriatric patients [see Use in Specific Populations ( 8.5 )] .

5 WARNINGS AND PRECAUTIONS Serious Rash, including Stevens-Johnson Syndrome: Discontinue modafinil tablets at the first sign of rash, unless the rash is clearly not drug-related. ( 5.1 ) Angioedema and Anaphylaxis Reactions: If suspected, discontinue modafinil tablets. ( 5.2 ) Multi-organ Hypersensitivity Reactions: If suspected, discontinue modafinil 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 caution in patients with a history of psychosis, depression, or mania. Consider discontinuing modafinil tablets if psychiatric symptoms develop. ( 5.5 ) Known Cardiovascular Disease: Consider increased monitoring. ( 5.7 ) 5.1 Serious Rash, including Stevens-Johnson Syndrome Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of modafinil. 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. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo. Modafinil tablets are not approved for use in pediatric patients for any indication [see Use in Specific Populations ( 8.4 )] . Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide postmarketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years. There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil tablets. Nearly all cases of serious rash associated with modafinil occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes also occur with modafinil tablets, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, modafinil tablets should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring. 5.2 Angioedema and Anaphylaxis Reactions Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed in patients treated with armodafinil, the R enantiomer of modafinil (which is the racemic mixture). No such cases were observed in modafinil clinical trials. However, angioedema has been reported in postmarketing experience with modafinil. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness). 5.3 Multi-organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions, including at least one fatality in postmarketing experience, have occurred in close temporal association (median time to detection 13 days: range 4 to 33) to the initiation of modafinil. …

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

7 DRUG INTERACTIONS Effects of Modafinil 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 modafinil 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 modafinil tablets [see Clinical Pharmacology ( 12.3 )] . The effectiveness of steroidal contraceptives may be reduced when used with modafinil 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 modafinil tablets and for one month after discontinuation of modafinil tablets treatment. Blood levels of cyclosporine may be reduced when used with modafinil tablets. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with modafinil tablets. Effects of Modafinil Tablets on CYP2C19 Substrates Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by modafinil tablets via inhibition of metabolic enzymes, with resultant higher systemic exposure. In individuals deficient in the CYP2D6 enzyme, the levels of CYP2D6 substrates which have ancillary routes of elimination through CYP2C19, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, may be increased by co-administration of modafinil tablets. Dose adjustments of these drugs and other drugs that are substrates for CYP2C19 may be necessary when used concomitantly with modafinil tablets [see Clinical Pharmacology ( 12.3 )] . Warfarin More frequent monitoring of prothrombin times/INR should be considered whenever modafinil tablets are coadministered with warfarin [see Clinical Pharmacology ( 12.3 )] . Monoamine Oxidase (MAO) Inhibitors Caution should be used when concomitantly administering MAO inhibitors and modafinil tablets. Steroidal contraceptives (e.g., ethinyl estradiol): Use alternative or concomitant methods of contraception while taking modafinil tablets and for one month after discontinuation of modafinil tablets 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 )

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Serious Rash, including Stevens-Johnson Syndrome [see Warnings and Precautions ( 5.1 )] Angioedema and Anaphylaxis Reactions [see Warnings and Precautions ( 5.2 )] Multi-organ Hypersensitivity 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, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp., Drug Safety at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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. Modafinil tablets have been evaluated for safety in over 3,500 patients, of whom more than 2,000 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy. Most Common Adverse Reactions In placebo-controlled clinical trials, the most common adverse reactions (≥ 5%) associated with the use of modafinil tablets more frequently than placebo-treated patients were headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. The adverse reaction profile was similar across these studies. Table 1 presents the adverse reactions that occurred at a rate of 1% or more and were more frequent in modafinil tablets-treated patients than in placebo-treated patients in the placebo-controlled clinical trials. Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials* in Narcolepsy, OSA, and SWD Modafinil tablets (%) (n = 934) Placebo (%) (n = 567) Headache 34 23 Nausea 11 3 Nervousness 7 3 Rhinitis 7 6 Back Pain 6 5 Diarrhea 6 5 Anxiety 5 1 Dizziness 5 4 Dyspepsia 5 4 Insomnia 5 1 Anorexia 4 1 Dry Mouth 4 2 Pharyngitis 4 2 Chest Pain 3 1 Hypertension 3 1 Abnormal Liver Function 2 1 Constipation 2 1 Depression 2 1 Palpitation 2 1 Paresthesia 2 0 Somnolence 2 1 Tachycardia 2 1 Vasodilatation 2 0 Abnormal Vision 1 0 Agitation 1 0 Asthma 1 0 Chills 1 0 Confusion 1 0 Dyskinesia 1 0 Edema 1 0 Emotional Lability 1 0 Eosinophilia 1 0 Epistaxis 1 0 Flatulence 1 0 Hyperkinesia 1 0 Hypertonia 1 0 Mouth Ulceration 1 0 Sweating 1 0 Taste Perversion 1 0 Thirst 1 0 Tremor 1 0 Urine Abnormality 1 0 Vertigo 1 0 * Adverse Reactions that occurred in ≥1% of modafinil tablets-treated patients (either 200, 300, or 400 mg once daily) and greater incidence than placebo Dose-Dependent Adverse Reactions In the placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of modafinil tablets and placebo, the following adverse reactions were dose related: headache and anxiety. Adverse Reactions Resulting in Discontinuation of Treatment In placebo-controlled clinical trials, 74 of the 934 patients (8%) who received modafinil tablets discontinued due to an adverse reaction compared to 3% of patients that received placebo. The most frequent reasons for discontinuation that occurred at a higher rate for modafinil tablets than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain, and nervousness (each <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 modafinil tablets, but not placebo. Few patients, however, had GGT or AP elevations outside of the normal range. Shifts to higher, …