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 )] .

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 Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 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 has 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 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-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 (%) (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-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 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 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 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, but not placebo. Few patients, however, had GGT or AP elevations outside of the normal range. Shifts to higher, but not clinically significantly abnormal, GGT and AP values appeared to increase with time in the population treated with modafinil in the placebo-controlled clinical trials. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of modafinil. 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. Hematologic: agranulocytosis Psychiatric disorders: psychomotor hyperactivity

12.3 Pharmacokinetics Modafinil is a 1:1 racemic compound, whose enantiomers have different pharmacokinetics (e.g., the half-life of R-modafinil is approximately three times that of S-modafinil in adult humans). The enantiomers do not interconvert. At steady state, total exposure to R-modafinil is approximately three times that for S-modafinil. The trough concentration (C min,ss ) of circulating modafinil after once daily dosing consists of 90% of R-modafinil and 10% of S-modafinil. The effective elimination half-life of modafinil after multiple doses is about 15 hours. The enantiomers of modafinil exhibit linear kinetics upon multiple dosing of 200 to 600 mg/day once daily in healthy volunteers. Apparent steady states of total modafinil and R-modafinil are reached after 2 to 4 days of dosing. Absorption Modafinil is readily absorbed after oral administration, with peak plasma concentrations occurring at 2 to 4 hours. The bioavailability of modafinil tablets is approximately equal to that of an aqueous suspension. The absolute oral bioavailability was not determined due to the aqueous insolubility (<1 mg/mL) of modafinil, which precluded intravenous administration. Food has no effect on overall modafinil bioavailability; however, time to reach peak concentration (t max ) may be delayed by approximately one hour if taken with food. Distribution Modafinil has an apparent volume of distribution of approximately 0.9 L/kg. In human plasma, in vitro , modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of modafinil with highly protein-bound drugs is considered to be minimal. Metabolism and Elimination The major route of elimination is metabolism (approximately 90%), primarily by the liver, with subsequent renal elimination of the metabolites. Urine alkalinization has no effect on the elimination of modafinil. Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent compound. In a clinical study using radiolabeled modafinil, a total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1% in the feces). The largest fraction of the drug in urine was modafinil acid, but at least six other metabolites were present in lower concentrations. Only two metabolites reach appreciable concentrations in plasma, i.e., modafinil acid and modafinil sulfone. In preclinical models, modafinil acid, modafinil sulfone, 2-[(diphenylmethyl)sulfonyl]acetic acid and 4-hydroxy modafinil, were inactive or did not appear to mediate the arousal effects of modafinil. In adults, decreases in trough levels of modafinil have sometimes been observed after multiple weeks of dosing, suggesting auto-induction, but the magnitude of the decreases and the inconsistency of their occurrence suggest that their clinical significance is minimal. Significant accumulation of modafinil sulfone has been observed after multiple doses due to its long elimination half-life of 40 hours. Auto-induction of metabolizing enzymes, most importantly cytochrome P-450 CYP3A4, has also been observed in vitro after incubation of primary cultures of human hepatocytes with modafinil and in vivo after extended administration of modafinil at 400 mg/day. Specific Populations Age A slight decrease (approximately 20%) in the oral clearance (CL/F) of modafinil was observed in a single dose study at 200 mg in 12 subjects with a mean age of 63 years (range 53 to 72 years), but the change was considered not likely to be clinically significant. In a multiple dose study (300 mg/day) in 12 patients with a mean age of 82 years (range 67 to 87 years), the mean levels of modafinil in plasma were approximately two times those historically obtained in matched younger subjects. Due to potential effects from the multiple concomitant medications with which most of the patients were being treated, the apparent difference in modafinil pharmacokinetics may not be attributable solely to the effects of aging. However, the results suggest that the clearance of modafinil may be reduced in the elderly [see Dosage and Administration ( 2.4 ) and Use in Specific Populations ( 8.5 )] . Gender The pharmacokinetics of modafinil are not affected by gender. Race The influence of race on the pharmacokinetics of modafinil has not been studied. 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 (an inactive metabolite) was increased 9 fold. 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 )] . Drug Interactions In vitro data demonstrated that modafinil weakly induces CYP1A2, CYP2B6, and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by modafinil. In vitro data also demonstrated that modafinil produced an apparent concentration-related suppression of expression of CYP2C9 activity. Other CYP activities did not appear to be affected by modafinil. Potential Interactions with Drugs That Inhibit, Induce, or Are Metabolized by Cytochrome P450 Isoenzymes and Other Hepatic Enzymes The existence of multiple pathways for modafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing modafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of modafinil due to CYP inhibition by concomitant medications. However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of modafinil, 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 modafinil. The Potential of Modafinil to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition • Drugs Metabolized by CYP3A4/5 • In vitro data demonstrated that modafinil is a weak inducer of CYP3A activity in a concentration-related manner. 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 modafinil [see Drug Interactions ( 7 )] . • Ethinyl Estradiol - Administration of modafinil to female volunteers once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days resulted in a mean 11% decrease in mean C max and 18% decrease in mean AUC 0-24 of ethinyl estradiol (EE2; 0.035 mg; administered orally with norgestimate). There was no apparent change in the elimination rate of ethinyl estradiol. • Triazolam - In the drug interaction study between modafinil and ethinyl estradiol (EE 2 ), on the same days as those for the plasma sampling for EE 2 pharmacokinetics, a single dose of triazolam (0.125 mg) was also administered. Mean C max and AUC 0-∞ of triazolam were decreased by 42% and 59%, respectively, and its elimination half-life was decreased by approximately an hour after the modafinil treatment. • Cyclosporine - One case of an interaction between modafinil and cyclosporine, a substrate of CYP3A4, has been reported in a 41 year old woman who had undergone an organ transplant. After one month of administration of 200 mg/day of modafinil, cyclosporine blood levels were decreased by 50%. The interaction was postulated to be due to the increased metabolism of cyclosporine, since no other factor expected to affect the disposition of the drug had changed. • Midazolam - In a clinical study, concomitant administration of armodafinil 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). • Quetiapine - In a separate clinical study, concomitant administration of armodafinil 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%. • Drugs Metabolized by CYP1A2 • In vitro data demonstrated that modafinil is a weak inducer of CYP1A2 in a concentration-related manner. However, in a clinical study with armodafinil using caffeine as a probe substrate, no significant effect on CYP1A2 activity was observed. • Drugs Metabolized by CYP2B6 • In vitro data demonstrated that modafinil is a weak inducer of CYP2B6 activity in a concentration-related manner. • Drugs Metabolized by CYP2C9 • In vitro data demonstrated that modafinil produced an apparent concentration-related suppression of expression of CYP2C9 activity suggesting that there is a potential for a metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin and phenytoin) [see Drug Interactions ( 7 )] . • 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 )] . • Drugs Metabolized by CYP2C19 • In vitro data demonstrated that modafinil is a reversible inhibitor of CYP2C19 activity. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone. Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Therefore, exposure to some drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be increased when used concomitantly with modafinil [see Drug Interactions ( 7 )] . • In a clinical study, concomitant administration of armodafinil 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. • Interactions with CNS Active Drugs • 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. • CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) and selective serotonin reuptake inhibitors that are primarily metabolized by CYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor metabolizers of debrisoquine; 7 to 10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. Modafinil may cause elevation of the levels of the tricyclics in this subset of patients [see Drug Interactions ( 7 )] . • Concomitant administration of armodafinil with quetiapine reduced the systemic exposure of quetiapine. • 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.