ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described elsewhere in the labeling:1.Serious Rash, including Stevens-Johnson Syndrome [see Warnings and Precautions (5.1)]2.Angioedema and Anaphylaxis Reactions [see Warnings and Precautions (5.2)]3.Multi-organ Hypersensitivity Reactions [see Warnings and Precautions (5.3)]4.Persistent Sleepiness [see Warnings and Precautions (5.4)]5.Psychiatric Symptoms [see Warnings and Precautions (5.5)]6.Effects on Ability to Drive and Use Machinery [see Warnings and Precautions (5.6)]7.Cardiovascular Events [see Warnings and Precautions (5.7)]. 1.Serious Rash, including Stevens-Johnson Syndrome [see Warnings and Precautions (5.1)]. 2.Angioedema and Anaphylaxis Reactions [see Warnings and Precautions (5.2)]. 3.Multi-organ Hypersensitivity Reactions [see Warnings and Precautions (5.3)]. 4.Persistent Sleepiness [see Warnings and Precautions (5.4)]. 5.Psychiatric Symptoms [see Warnings and Precautions (5.5)]. 6.Effects on Ability to Drive and Use Machinery [see Warnings and Precautions (5.6)]. 7.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 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 ReactionsIn 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 presents the adverse reactions that occurred at 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 SWDModafinil tablets (%) (n 934)Placebo (%) (n 567)Headache3423Nausea113Nervousness73Rhinitis76Back Pain65Diarrhea65Anxiety51Dizziness54Dyspepsia54Insomnia51Anorexia41Dry Mouth42Pharyngitis42Chest Pain31Hypertension31Abnormal Liver Function21Constipation21Depression21Palpitation21Paresthesia20Somnolence21Tachycardia21Vasodilatation20Abnormal Vision10Agitation10Asthma10Chills10Confusion10Dyskinesia10Edema10Emotional Lability10Eosinophilia10Epistaxis10Flatulence10Hyperkinesia10Hypertonia10Mouth Ulceration10Sweating10Taste Perversion10Thirst10Tremor10Urine Abnormality10Vertigo10 Adverse Reactions that occurred in >=1% of modafinil tablets-treated patients (either 200, 300, or 400mg once daily) and greater incidence than placeboDose-Dependent Adverse ReactionsIn 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 TreatmentIn 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 higher rate for modafinil tablets than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain, and nervousness (each <1%).Laboratory AbnormalitiesClinical 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, but not clinically significantly abnormal, GGT and AP values appeared to increase with time in the population treated with modafinil tablets 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 tablets. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hematologic: agranulocytosis Psychiatric disorders: psychomotor hyperactivity.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism(s) through which modafinil promotes wakefulness is unknown. Modafinil has wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although the pharmacologic profile is not identical to that of the sympathomimetic amines.Modafinil-induced wakefulness can be attenuated by the 1-adrenergic receptor antagonist, prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to -adrenergic agonists such as the rat vas deferens preparation.Modafinil is not direct- or indirect-acting dopamine receptor agonist. However, in vitro, modafinil binds to the dopamine transporter and inhibits dopamine reuptake. 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, dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil.In the cat, equal wakefulness-promoting doses of methylphenidate and amphetamine increased neuronal activation throughout the brain. Modafinil at an equivalent wakefulness-promoting dose selectively and prominently increased neuronal activation in more discrete regions of the brain. The relationship of this finding in cats to the effects of modafinil in humans is unknown.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.The optical enantiomers of modafinil have similar pharmacological actions in animals. Two major metabolites of modafinil, modafinil acid and modafinil sulfone, do not appear to contribute to the CNS-activating properties of modafinil.. 12.3 Pharmacokinetics. Modafinil is 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 (Cmin,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 to days of dosing.AbsorptionModafinil tablet is readily absorbed after oral administration, with peak plasma concentrations occurring at to 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 tablets bioavailability; however, time to reach peak concentration (tmax) may be delayed by approximately one hour if taken with food.DistributionModafinil tablets have 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 tablets with highly protein-bound drugs is considered to be minimal.Metabolism and EliminationThe 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 clinical study using radiolabeled modafinil, 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). 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 PopulationsAgeA slight decrease (approximately 20%) in the oral clearance (CL/F) of modafinil was observed in single dose study at 200 mg in 12 subjects with mean age of 63 years (range 53 to 72 years), but the change was considered not likely to be clinically significant. In multiple dose study (300 mg/day) in 12 patients with 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)].GenderThe pharmacokinetics of modafinil are not affected by gender.RaceThe influence of race on the pharmacokinetics of modafinil has not been studied.Renal ImpairmentIn 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 ImpairmentThe pharmacokinetics and metabolism of modafinil were examined in patients with cirrhosis of the liver (6 men and women). Three patients had stage or B+ cirrhosis and patients had stage or C+ cirrhosis (per the Child-Pugh score criteria). Clinically of 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 InteractionsIn vitro data demonstrated that modafinil weakly induces CYP1A2, CYP2B6, and possibly CYP3A activities in 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 EnzymesThe existence of multiple pathways for modafinil metabolism, as well as the fact that non-CYP-related pathway is the most rapid in metabolizing modafinil, suggest that there is low probability of substantive effects on the overall pharmacokinetic profile of modafinil tablets 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 tablets to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition1.Drugs Metabolized by CYP3A4/51.In vitro data demonstrated that modafinil is weak inducer of CYP3A activity in 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 tablets [see Drug Interactions (7)]. 2.Ethinyl Estradiol Administration of modafinil to female volunteers once daily at 200 mg/day for days followed by 400 mg/day for 21 days resulted in mean 11% decrease in mean Cmax and 18% decrease in mean AUC0-24 of ethinyl estradiol (EE2; 0.035 mg; administered orally with norgestimate). There was no apparent change in the elimination rate of ethinyl estradiol.3.Triazolam In the drug interaction study between modafinil tablets and ethinyl estradiol (EE2), on the same days as those for the plasma sampling for EE2 pharmacokinetics, single dose of triazolam (0.125 mg) was also administered. Mean Cmax and AUC0- of triazolam were decreased by 42% and 59%, respectively, and its elimination half-life was decreased by approximately an hour after the modafinil treatment.4.Cyclosporine One case of an interaction between modafinil and cyclosporine, substrate of CYP3A4, has been reported in 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.5.Midazolam In clinical study, concomitant administration of armodafinil 250 mg resulted in reduction in systemic exposure to midazolam by 32% after single oral dose (5 mg) and 17% after single intravenous dose (2 mg).6.Quetiapine In separate clinical study, concomitant administration of armodafinil 250 mg with quetiapine (300 mg to 600 mg daily doses) resulted in reduction in the mean systemic exposure of quetiapine by approximately 29%.1.Drugs Metabolized by CYP1A21.In vitro data demonstrated that modafinil is weak inducer of CYP1A2 in concentration-related manner. However, in clinical study with armodafinil using caffeine as probe substrate, no significant effect on CYP1A2 activity was observed. 1.Drugs Metabolized by CYP2B61.In vitro data demonstrated that modafinil is weak inducer of CYP2B6 activity in concentration-related manner. 1.Drugs Metabolized by CYP2C91.In vitro data demonstrated that modafinil produced an apparent concentration-related suppression of expression of CYP2C9 activity suggesting that there is potential for metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin and phenytoin) [see Drug Interactions (7)]. 2.Warfarin: Concomitant administration of modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of R- and S-warfarin. However, since only single dose of warfarin was tested in this study, an interaction cannot be ruled out [see Drug Interactions (7)].1.Drugs Metabolized by CYP2C191.In vitro data demonstrated that modafinil is reversible inhibitor of CYP2C19 activity. CYP2C19 is also reversibly inhibited, with similar potency, by 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 tablets [see Drug Interactions (7)]. 2.In clinical study, concomitant administration of armodafinil 400 mg resulted in 40% increase in exposure to omeprazole after single oral dose (40 mg), as result of moderate inhibition of CYP2C19 activity.1.Interactions with CNS Active Drugs1.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.2.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 patient with narcolepsy during treatment with modafinil.3.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; to 10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. Modafinil tablets may cause elevation of the levels of the tricyclics in this subset of patients [see Drug Interactions (7)].4.Concomitant administration of armodafinil with quetiapine reduced the systemic exposure of quetiapine.1.Interaction with P-Glycoprotein1.An in vitro study demonstrated that armodafinil is substrate of P-glycoprotein. The impact of inhibition of P-glycoprotein is not known.. 1.Drugs Metabolized by CYP3A4/51.In vitro data demonstrated that modafinil is weak inducer of CYP3A activity in 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 tablets [see Drug Interactions (7)]. 2.Ethinyl Estradiol Administration of modafinil to female volunteers once daily at 200 mg/day for days followed by 400 mg/day for 21 days resulted in mean 11% decrease in mean Cmax and 18% decrease in mean AUC0-24 of ethinyl estradiol (EE2; 0.035 mg; administered orally with norgestimate). There was no apparent change in the elimination rate of ethinyl estradiol.3.Triazolam In the drug interaction study between modafinil tablets and ethinyl estradiol (EE2), on the same days as those for the plasma sampling for EE2 pharmacokinetics, single dose of triazolam (0.125 mg) was also administered. Mean Cmax and AUC0- of triazolam were decreased by 42% and 59%, respectively, and its elimination half-life was decreased by approximately an hour after the modafinil treatment.4.Cyclosporine One case of an interaction between modafinil and cyclosporine, substrate of CYP3A4, has been reported in 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.5.Midazolam In clinical study, concomitant administration of armodafinil 250 mg resulted in reduction in systemic exposure to midazolam by 32% after single oral dose (5 mg) and 17% after single intravenous dose (2 mg).6.Quetiapine In separate clinical study, concomitant administration of armodafinil 250 mg with quetiapine (300 mg to 600 mg daily doses) resulted in reduction in the mean systemic exposure of quetiapine by approximately 29%.. 1.In vitro data demonstrated that modafinil is weak inducer of CYP3A activity in 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 tablets [see Drug Interactions (7)]. 2.Ethinyl Estradiol Administration of modafinil to female volunteers once daily at 200 mg/day for days followed by 400 mg/day for 21 days resulted in mean 11% decrease in mean Cmax and 18% decrease in mean AUC0-24 of ethinyl estradiol (EE2; 0.035 mg; administered orally with norgestimate). There was no apparent change in the elimination rate of ethinyl estradiol.. 3.Triazolam In the drug interaction study between modafinil tablets and ethinyl estradiol (EE2), on the same days as those for the plasma sampling for EE2 pharmacokinetics, single dose of triazolam (0.125 mg) was also administered. Mean Cmax and AUC0- of triazolam were decreased by 42% and 59%, respectively, and its elimination half-life was decreased by approximately an hour after the modafinil treatment.. 4.Cyclosporine One case of an interaction between modafinil and cyclosporine, substrate of CYP3A4, has been reported in 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.. 5.Midazolam In clinical study, concomitant administration of armodafinil 250 mg resulted in reduction in systemic exposure to midazolam by 32% after single oral dose (5 mg) and 17% after single intravenous dose (2 mg).. 6.Quetiapine In separate clinical study, concomitant administration of armodafinil 250 mg with quetiapine (300 mg to 600 mg daily doses) resulted in reduction in the mean systemic exposure of quetiapine by approximately 29%.. 1.Drugs Metabolized by CYP1A21.In vitro data demonstrated that modafinil is weak inducer of CYP1A2 in concentration-related manner. However, in clinical study with armodafinil using caffeine as probe substrate, no significant effect on CYP1A2 activity was observed. 1.In vitro data demonstrated that modafinil is weak inducer of CYP1A2 in concentration-related manner. However, in clinical study with armodafinil using caffeine as probe substrate, no significant effect on CYP1A2 activity was observed. 1.Drugs Metabolized by CYP2B61.In vitro data demonstrated that modafinil is weak inducer of CYP2B6 activity in concentration-related manner. 1.In vitro data demonstrated that modafinil is weak inducer of CYP2B6 activity in concentration-related manner. 1.Drugs Metabolized by CYP2C91.In vitro data demonstrated that modafinil produced an apparent concentration-related suppression of expression of CYP2C9 activity suggesting that there is potential for metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin and phenytoin) [see Drug Interactions (7)]. 2.Warfarin: Concomitant administration of modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of R- and S-warfarin. However, since only single dose of warfarin was tested in this study, an interaction cannot be ruled out [see Drug Interactions (7)].. 1.In vitro data demonstrated that modafinil produced an apparent concentration-related suppression of expression of CYP2C9 activity suggesting that there is potential for metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin and phenytoin) [see Drug Interactions (7)]. 2.Warfarin: Concomitant administration of modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of R- and S-warfarin. However, since only single dose of warfarin was tested in this study, an interaction cannot be ruled out [see Drug Interactions (7)].. 1.Drugs Metabolized by CYP2C191.In vitro data demonstrated that modafinil is reversible inhibitor of CYP2C19 activity. CYP2C19 is also reversibly inhibited, with similar potency, by 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 tablets [see Drug Interactions (7)]. 2.In clinical study, concomitant administration of armodafinil 400 mg resulted in 40% increase in exposure to omeprazole after single oral dose (40 mg), as result of moderate inhibition of CYP2C19 activity.. 1.In vitro data demonstrated that modafinil is reversible inhibitor of CYP2C19 activity. CYP2C19 is also reversibly inhibited, with similar potency, by 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 tablets [see Drug Interactions (7)]. 2.In clinical study, concomitant administration of armodafinil 400 mg resulted in 40% increase in exposure to omeprazole after single oral dose (40 mg), as result of moderate inhibition of CYP2C19 activity.. 1.Interactions with CNS Active Drugs1.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.2.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 patient with narcolepsy during treatment with modafinil.3.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; to 10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. Modafinil tablets may cause elevation of the levels of the tricyclics in this subset of patients [see Drug Interactions (7)].4.Concomitant administration of armodafinil with quetiapine reduced the systemic exposure of quetiapine.. 1.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.. 2.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 patient with narcolepsy during treatment with modafinil.. 3.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; to 10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. Modafinil tablets may cause elevation of the levels of the tricyclics in this subset of patients [see Drug Interactions (7)].. 4.Concomitant administration of armodafinil with quetiapine reduced the systemic exposure of quetiapine.. 1.Interaction with P-Glycoprotein1.An in vitro study demonstrated that armodafinil is substrate of P-glycoprotein. The impact of inhibition of P-glycoprotein is not known.. 1.An in vitro study demonstrated that armodafinil is substrate of P-glycoprotein. The impact of inhibition of P-glycoprotein is not known.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Narcolepsy. The effectiveness of modafinil tablets in improving wakefulness in adult patients with excessive sleepiness associated with narcolepsy was established in two US 9-week, multi-center, placebo-controlled, parallel-group, double-blind studies of outpatients who met the criteria for narcolepsy. total of 558 patients were randomized to receive modafinil tablets 200 or 400 mg/day, or placebo. The criteria for narcolepsy include either: 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least three months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy); or 2) complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes. For entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, via Multiple Sleep Latency Test (MSLT) with two or more sleep onset REM periods and the absence of any other clinically significant active medical or psychiatric disorder. The MSLT, an objective polysomnographic assessment of the patients ability to fall asleep in an unstimulating environment, measured latency (in minutes) to sleep onset averaged over test sessions at 2-hour intervals. For each test session, the subject was told to lie quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep occurred or 15 minutes after sleep onset.In both studies, the primary measures of effectiveness were: 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT); and 2) the change in the patients overall disease status, as measured by the Clinical Global Impression of Change (CGI-C). For successful trial, both measures had to show statistically significant improvement.The MWT measures latency (in minutes) to sleep onset averaged over test sessions at hour intervals following nocturnal polysomnography. For each test session, the subject was asked to attempt to remain awake without using extraordinary measures. Each test session was terminated after 20 minutes if no sleep occurred or 10 minutes after sleep onset. The CGI-C is 7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved. Patients were rated by evaluators who had no access to any data about the patients other than measure of their baseline severity. Evaluators were not given any specific guidance about the criteria they were to apply when rating patients.Both studies demonstrated improvement in objective and subjective measures of excessive daytime sleepiness for both the 200 mg and 400 mg doses compared to placebo. Patients treated with modafinil tablets showed statistically significantly enhanced ability to remain awake on the MWT at each dose compared to placebo at final visit (Table 2). statistically significantly greater number of patients treated with modafinil tablets at each dose showed improvement in overall clinical condition as rated by the CGI-C scale at final visit (Table 3).Nighttime sleep measured with polysomnography was not affected by the use of modafinil tablets.. 14.2 Obstructive Sleep Apnea (OSA). The effectiveness of modafinil tablets in improving wakefulness in patients with excessive sleepiness associated with OSA was established in two multi-center, placebo-controlled clinical studies of patients who met the criteria for OSA. The criteria include either: 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated features such as loud snoring, morning headaches and dry mouth upon awakening; or 2) excessive sleepiness or insomnia and polysomnography demonstrating one of the following: more than five obstructive apneas, each greater than 10 seconds in duration, per hour of sleep and one or more of the following: frequent arousals from sleep associated with the apneas, bradytachycardia, and arterial oxygen desaturation in association with the apneas. In addition, for entry into these studies, all patients were required to have excessive sleepiness as demonstrated by score >=10 on the Epworth Sleepiness Scale (ESS), despite treatment with continuous positive airway pressure (CPAP). Evidence that CPAP was effective in reducing episodes of apnea/hypopnea was required along with documentation of CPAP use.In the first study, 12-week trial, total of 327 patients with OSA were randomized to receive modafinil tablets 200 mg/day, modafinil tablets 400 mg/day, or matching placebo. The majority of patients (80%) were fully compliant with CPAP, defined as CPAP use greater than hours/night on 70% of nights. The remainder were partially CPAP compliant, defined as CPAP use 4 hours/night on >30% of nights. CPAP use continued throughout the study. The primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patients overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit [see Clinical Studies (14.1) for description of these measures].Patients treated with modafinil tablets showed statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT at final visit (Table 2). statistically significant greater number of patients treated with modafinil tablets showed improvement in overall clinical condition as rated by the CGI-C scale at final visit (Table 3). The 200 mg and 400 mg doses of modafinil tablets produced statistically significant effects of similar magnitude on the MWT, and also on the CGI-C.In the second study, 4-week trial, 157 patients with OSA were randomized to receive modafinil tablets 400 mg/day or placebo. Documentation of regular CPAP use (at least hours/night on 70% of nights) was required for all patients. The primary measure of effectiveness was the change from baseline on the ESS at final visit. The baseline ESS scores for the modafinil tablets and placebo groups were 14.2 and 14.4, respectively. At week 4, the ESS was reduced by 4.6 in the modafinil tablets group and by 2.0 in the placebo group, difference that was statistically significant.Nighttime sleep measured with polysomnography was not affected by the use of modafinil tablets.. 14.3 Shift Work Disorder (SWD). The effectiveness of modafinil tablets in improving wakefulness in patients with excessive sleepiness associated with SWD was demonstrated in 12-week placebo-controlled clinical trial. total of 209 patients with chronic SWD were randomized to receive modafinil tablets 200 mg/day or placebo. All patients met the criteria for chronic SWD. The criteria include: 1) either, a) primary complaint of excessive sleepiness or insomnia which is temporally associated with work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms, and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change [jet lag] syndrome).It should be noted that not all patients with complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWD. In the clinical trial, only patients who were symptomatic for at least months were enrolled.Enrolled patients were also required to work minimum of night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score 6 minutes), and have daytime insomnia documented by daytime polysomnogram.The primary measures of effectiveness were 1) sleep latency, as assessed by the MSLT performed during simulated night shift at the final visit and 2) the change in the patients overall disease status, as measured by the CGI-C at the final visit [see Clinical Studies (14.1) for description of these measures].Patients treated with modafinil tablets showed statistically significant prolongation in the time to sleep onset compared to placebo-treated patients, as measured by the nighttime MSLT at final visit (Table 2). statistically significant greater number of patients treated with modafinil tablets showed improvement in overall clinical condition as rated by the CGI-C scale at final visit (Table 3).Daytime sleep measured with polysomnography was not affected by the use of modafinil tablets.Table 2. Average Baseline Sleep Latency and Change from Baseline at Final Visit (MWT and MSLT in minutes)DisorderMeasureModafinil tablets 200 mgModafinil tablets 400 mgPlaceboBaselineChange from BaselineBaselineChange from BaselineBaselineChange from BaselineNarcolepsy IMWT5.82.36.62.35.8-0.7Narcolepsy IIMWT6.12.25.92.06.0-0.7OSAMWT13.11.613.61.513.8-1.1SWDMSLT2.11.7--2.00.3Significantly different than placebo for all trials (p<0.01 for all trials but SWD, which was p<0.05)Table 3. Clinical Global Impression of Change (CGI-C) (Percent of Patients Who Improved at Final Visit)DisorderModafinil tablets 200 mgModafinil tablets 400 mgPlaceboNarcolepsy I64%72%37%Narcolepsy II58%60%38%OSA61%68%37%SWD74%------36%Significantly different than placebo for all trials (p<0.01).

SPL MEDGUIDE SECTION.

Medication Guide. Modafinil Tablets, USP 100 mg and 200 mg(moe daf nil)Rx OnlyRead this Medication Guide before you start taking modafinil tablets and each time you get refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.What is the most important information should know about modafinil tabletsModafinil tablets may cause serious side effects including serious rash or serious allergic reaction that may affect parts of your body such as your liver or blood cells. Any of these may need to be treated in hospital and may be life-threatening.Stop taking modafinil tablets and call your doctor right away or get emergency help if you have any of these symptoms:1.skin rash, hives, sores in your mouth, or your skin blisters and peels2.swelling of your face, eyes, lips, tongue, or throat3.trouble swallowing or breathing4.fever, shortness of breath, swelling of the legs, yellowing of the skin or whites of the eyes, or dark urine.If you have severe rash with modafinil tablets, stopping the medicine may not keep the rash from becoming life-threatening or causing you to be permanently disabled or disfigured.Modafinil tablets are not approved for use in children for any medical condition.It is not known if modafinil tablets are safe or effective in children under 17 years of age.What are modafinil tabletsModafinil tablets are prescription medicine used to improve wakefulness in adults who are very sleepy due to one of the following diagnosed sleep disorders:1.narcolepsy2.obstructive sleep apnea (OSA). Modafinil tablets are used to treat excessive sleepiness, but not the obstruction or medical condition that is causing OSA. You should talk with your doctor about treatments for OSA before you start taking modafinil tablets and during treatment with modafinil tablets. Modafinil tablets do not take the place of treatments that your doctor has prescribed for OSA. It is important that you continue to use these treatments as prescribed by your doctor.3.shift work disorder (SWD)Modafinil tablets will not cure these sleep disorders. Modafinil tablets may help the sleepiness caused by these conditions, but it may not stop all your sleepiness. Modafinil tablets do not take the place of getting enough sleep. Follow your doctors advice about good sleep habits and using other treatments.Modafinil is federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep modafinil tablets in safe place to prevent misuse and abuse. Selling or giving away modafinil tablets may harm others, and is against the law. Tell your doctor if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.Who should not take modafinil tabletsDo not take modafinil tablets if you:1.are allergic or developed rash to modafinil or armodafinil (NUVIGIL(R) or any of the ingredients in modafinil tablets. See the end of this Medication Guide for complete list of ingredients in modafinil tablets.What should tell my doctor before taking modafinil tablets Tell your doctor about all of your medical conditions including, if you:1.have history of mental health problems, including psychosis2.have heart problems or had heart attack3.have high blood pressure. Your blood pressure may need to be checked more often while taking modafinil tablets.4.have liver or kidney problems5.have history of drug or alcohol abuse or addiction6.are pregnant or planning to become pregnant. It is not known if modafinil will harm your unborn baby. Pregnancy Registry: There is registry for women who become pregnant during treatment with PROVIGIL. The purpose of this registry is to collect information about the safety of modafinil during pregnancy. Contact the registry as soon as you learn that you are pregnant, or ask your doctor to contact the registry for you. You or your doctor can get information and enroll you in the registry by calling 1-866-404-4106.7.are breastfeeding. It is not known if modafinil passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take modafinil tablets.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Modafinil tablets and many other medicines can interact with each other, sometimes causing side effects. Modafinil tablets may affect the way other medicines work, and other medicines may affect how modafinil tablets works. Your dose of modafinil tablets or certain other medicines may need to be changed.Especially, tell your doctor if you use or take:1.a hormonal birth control method, such as birth control pills, shots, implants, patches, vaginal rings, and intrauterine devices (IUDs). Hormonal birth control methods may not work while you take modafinil tablets. Women who use one of these methods of birth control may have higher chance for getting pregnant while taking modafinil tablets, and for one month after stopping modafinil tablets. Talk to your doctor about birth control choices that are right for you while taking modafinil tablets.Know the medicines you take. Keep list of them and show it to your doctor and pharmacist when you get new medicine. Your doctor or pharmacist will tell you if it is safe to take modafinil tablets and other medicines together. Do not start any new medicines with modafinil tablets unless your doctor has told you it is okay. How should take modafinil tablets1.Take modafinil tablets exactly as prescribed by your doctor. Your doctor will prescribe the dose of modafinil tablets that is right for you. Do not change your dose of modafinil tablets without talking to your doctor. 2.Your doctor will tell you the right time of day to take modafinil tablets. 1.People with narcolepsy or OSA usually take modafinil tablets one time each day in the morning.2.People with SWD usually take modafinil tablets about hour before their work shift.3.Do not change the time of day you take modafinil tablets unless you have talked to your doctor. If you take modafinil tablets too close to your bedtime, you may find it harder to go to sleep.4.You can take modafinil tablets with or without food.5.If you take more than your prescribed dose or if you take an overdose of modafinil tablets, call your doctor or go to the nearest hospital emergency room right away.Symptoms of an overdose of modafinil tablets may include:1.trouble sleeping 2.restlessness 3.confusion 4.feeling disoriented 5.feeling excited6.hearing, seeing, feeling, or sensing things that are not really there (hallucinations)7.nausea and diarrhea8.a fast or slow heartbeat9.chest pain10.increased blood pressureWhat should avoid while taking modafinil tablets1.Do not drive car or do other dangerous activities until you know how modafinil tablets affect you. People with sleep disorders should always be careful about doing things that could be dangerous. Do not change your daily habits until your doctor tells you it is okay.2.You should avoid drinking alcohol. It is not known how drinking alcohol will affect you when taking modafinil tablets.What are possible side effects of modafinil tabletsModafinil tablets may cause serious side effects. Stop taking modafinil tablets and call your doctor right away or get emergency help if you get any of the following:1.a serious rash or serious allergic reaction. (See What is the most important information should know about modafinil tablets)2.mental (psychiatric) symptoms, including:1.depression2.feeling anxious3.hearing, seeing, feeling, or sensing things that are not really there (hallucinations)4.an extreme increase in activity and talking (mania)5.thoughts of suicide6.aggressive behavior7.other mental problems3.symptoms of heart problem, including chest pain, abnormal heartbeat, and trouble breathing.Common side effects that can happen in anyone who takes modafinil tablets include:1.headache2.back pain3.nausea4.feeling nervous5.stuffy nose6.diarrhea7.feeling anxious8.trouble sleeping 9.dizziness10.upset stomachModafinil tablets are not approved for use in children for any medical condition including Attention Deficit Hyperactivity Disorder (ADHD). In studies of modafinil tablets in children with narcolepsy, side effects included:1.Tourettes syndrome2.hostile behavior3.increase in sudden loss of muscle tone and severe muscle weakness4.increase in seeing and hearing things when falling asleep5.increase in suicidal thoughts6.low white blood count7.painful menstrual periodsTell your doctor if you get any side effect that bothers you or that does not go away while taking modafinil tablets.These are not all the side effects of modafinil tablets. For more information, ask your doctor or pharmacist.Some effects of modafinil tablets on the brain are the same as other medicines called stimulants. These effects may lead to abuse or dependence on modafinil tablets.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store modafinil tablets1.Store modafinil tablets at room temperature between 20 to 25C (68 to 77F); excursions permitted from 15 to 30C (59 to 86F).2.Keep modafinil tablets and all medicines out of the reach of children.General information about the safe and effective use of modafinil tabletsMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use modafinil tablets for condition for which it was not prescribed. Do not give modafinil tablets to other people, even if they have the same symptoms you have. It may harm them and it is against the law.This Medication Guide summarizes the most important information about modafinil tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about modafinil tablets that is written for health professionals. For more information, call Apotex Corp. at 1-800-706-5575.What are the ingredients in modafinil tabletsActive Ingredient: modafinilInactive Ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and methylcellulose.All registered trademarks in this document are the property of their respective owners.This Medication Guide has been approved by the U.S. Food and Drug Administration.APOTEX CORP. MODAFINIL TABLETS, USP 100 mg and 200 mgManufactured byManufactured for Apotex Inc.Apotex Corp.Toronto, OntarioWeston, FloridaCanada M9L 1T933326 Distributed By:MAJOR(R) PHARMACEUTICALS17177 Laurel Park Dr., Suite 233Livonia, MI 48152Refer to package label for Distributors NDC Number Revised: June 2015Rev. 7. 1.skin rash, hives, sores in your mouth, or your skin blisters and peels. 2.swelling of your face, eyes, lips, tongue, or throat. 3.trouble swallowing or breathing. 4.fever, shortness of breath, swelling of the legs, yellowing of the skin or whites of the eyes, or dark urine.. 1.narcolepsy. 2.obstructive sleep apnea (OSA). Modafinil tablets are used to treat excessive sleepiness, but not the obstruction or medical condition that is causing OSA. You should talk with your doctor about treatments for OSA before you start taking modafinil tablets and during treatment with modafinil tablets. Modafinil tablets do not take the place of treatments that your doctor has prescribed for OSA. It is important that you continue to use these treatments as prescribed by your doctor.. 3.shift work disorder (SWD). 1.are allergic or developed rash to modafinil or armodafinil (NUVIGIL(R) or any of the ingredients in modafinil tablets. See the end of this Medication Guide for complete list of ingredients in modafinil tablets.. 1.have history of mental health problems, including psychosis. 2.have heart problems or had heart attack. 3.have high blood pressure. Your blood pressure may need to be checked more often while taking modafinil tablets.. 4.have liver or kidney problems. 5.have history of drug or alcohol abuse or addiction. 6.are pregnant or planning to become pregnant. It is not known if modafinil will harm your unborn baby. Pregnancy Registry: There is registry for women who become pregnant during treatment with PROVIGIL. The purpose of this registry is to collect information about the safety of modafinil during pregnancy. Contact the registry as soon as you learn that you are pregnant, or ask your doctor to contact the registry for you. You or your doctor can get information and enroll you in the registry by calling 1-866-404-4106.. 7.are breastfeeding. It is not known if modafinil passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take modafinil tablets.. 1.a hormonal birth control method, such as birth control pills, shots, implants, patches, vaginal rings, and intrauterine devices (IUDs). Hormonal birth control methods may not work while you take modafinil tablets. Women who use one of these methods of birth control may have higher chance for getting pregnant while taking modafinil tablets, and for one month after stopping modafinil tablets. Talk to your doctor about birth control choices that are right for you while taking modafinil tablets.. 1.Take modafinil tablets exactly as prescribed by your doctor. Your doctor will prescribe the dose of modafinil tablets that is right for you. Do not change your dose of modafinil tablets without talking to your doctor. 2.Your doctor will tell you the right time of day to take modafinil tablets. 1.People with narcolepsy or OSA usually take modafinil tablets one time each day in the morning.2.People with SWD usually take modafinil tablets about hour before their work shift.. 1.People with narcolepsy or OSA usually take modafinil tablets one time each day in the morning.. 2.People with SWD usually take modafinil tablets about hour before their work shift.. 3.Do not change the time of day you take modafinil tablets unless you have talked to your doctor. If you take modafinil tablets too close to your bedtime, you may find it harder to go to sleep.. 4.You can take modafinil tablets with or without food.. 5.If you take more than your prescribed dose or if you take an overdose of modafinil tablets, call your doctor or go to the nearest hospital emergency room right away.. 1.trouble sleeping 2.restlessness 3.confusion 4.feeling disoriented 5.feeling excited. 6.hearing, seeing, feeling, or sensing things that are not really there (hallucinations). 7.nausea and diarrhea. 8.a fast or slow heartbeat. 9.chest pain. 10.increased blood pressure. 1.Do not drive car or do other dangerous activities until you know how modafinil tablets affect you. People with sleep disorders should always be careful about doing things that could be dangerous. Do not change your daily habits until your doctor tells you it is okay.. 2.You should avoid drinking alcohol. It is not known how drinking alcohol will affect you when taking modafinil tablets.. 1.a serious rash or serious allergic reaction. (See What is the most important information should know about modafinil tablets). 2.mental (psychiatric) symptoms, including:1.depression2.feeling anxious3.hearing, seeing, feeling, or sensing things that are not really there (hallucinations)4.an extreme increase in activity and talking (mania)5.thoughts of suicide6.aggressive behavior7.other mental problems. 1.depression. 2.feeling anxious. 3.hearing, seeing, feeling, or sensing things that are not really there (hallucinations). 4.an extreme increase in activity and talking (mania). 5.thoughts of suicide. 6.aggressive behavior. 7.other mental problems. 3.symptoms of heart problem, including chest pain, abnormal heartbeat, and trouble breathing.. 1.headache. 2.back pain. 3.nausea. 4.feeling nervous. 5.stuffy nose. 6.diarrhea. 7.feeling anxious. 8.trouble sleeping 9.dizziness. 10.upset stomach. 1.Tourettes syndrome. 2.hostile behavior. 3.increase in sudden loss of muscle tone and severe muscle weakness. 4.increase in seeing and hearing things when falling asleep. 5.increase in suicidal thoughts. 6.low white blood count. 7.painful menstrual periods. 1.Store modafinil tablets at room temperature between 20 to 25C (68 to 77F); excursions permitted from 15 to 30C (59 to 86F).. 2.Keep modafinil tablets and all medicines out of the reach of children.. modafinil-02.jpg.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1). 8.1 Pregnancy. Pregnancy Category CThere are no adequate and well-controlled studies of modafinil in pregnant women. Intrauterine growth restriction and spontaneous abortion have been reported in association with modafinil (a mixture of R- and S-modafinil) and armodafinil (the R-enantiomer of modafinil). Although the pharmacology of modafinil is not identical to that of the sympathomimetic amines, it does share some pharmacologic properties with this class. Certain of these drugs have been associated with intrauterine growth restriction and spontaneous abortions. Whether the cases reported with modafinil are drug-related is unknown. In studies of modafinil and armodafinil conducted in rats (modafinil, armodafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant plasma exposures. Modafinil tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased incidence of visceral and skeletal variations in the offspring at the highest dose tested. The higher no-effect dose for embryofetal developmental toxicity in rats (100 mg/kg/day) was associated with plasma modafinil AUC less than that in humans at the recommended human dose (RHD) of modafinil tablets (200 mg/day). However, in subsequent study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed. Oral administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in increased incidences of fetal visceral and skeletal variations and decreased fetal body weight at the highest dose tested. The highest no-effect dose for embryofetal developmental toxicity in rats (200 mg/kg/day) was associated with plasma armodafinil AUC less than that in humans at the RHD of modafinil tablets.Modafinil administered orally to pregnant rabbits throughout organogenesis at doses of up to 100 mg/kg/day had no effect on embryofetal development; however, the doses used were too low to adequately assess the effects of modafinil on embryofetal development. In subsequent developmental toxicity study evaluating doses of 45, 90, and 180 mg/kg/day in pregnant rabbits, the incidences of fetal structural alterations and embryofetal death were increased at the highest dose. The highest no-effect dose for developmental toxicity (100 mg/kg/day) was associated with plasma modafinil AUC similar to that in humans at the RHD of modafinil 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, dose resulting in plasma modafinil AUC less than that in humans at the RHD of modafinil tablets. No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring.Pregnancy RegistryA pregnancy registry has been established to collect information on the pregnancy outcomes of women exposed to modafinil tablets. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-866-404-4106 (toll free).. 8.3 Nursing Mothers. It is not known whether modafinil or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when modafinil tablets are administered to nursing woman.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established. Modafinil tablets are not approved in this population for any indication.Serious skin rashes, including erythema multiforme major (EMM) and Stevens-Johnson Syndrome (SJS) have been associated with modafinil use in pediatric patients [see Warnings and Precautions (5.1)].In controlled 6-week study, 165 pediatric patients (aged to 17 years) with narcolepsy were treated with modafinil (n=123), or placebo (n=42). There were no statistically significant differences favoring modafinil over placebo in prolonging sleep latency as measured by MSLT, or in perceptions of sleepiness as determined by the clinical global impression-clinician scale (CGI-C).In the controlled and open-label clinical studies, treatment emergent adverse reactions of the psychiatric and nervous system included Tourettes syndrome, insomnia, hostility, increased cataplexy, increased hypnagogic hallucinations, and suicidal ideation. Transient leukopenia, which resolved without medical intervention, was also observed. In the controlled clinical study, of 38 girls, ages 12 or older, treated with modafinil experienced dysmenorrhea compared to of 10 girls who received placebo.There were three to week, double-blind, placebo-controlled, parallel group studies in children and adolescents (aged to 17 years) with Attention-Deficit Hyperactivity Disorder (ADHD). Two of the studies were flexible-dose studies (up to 425 mg/day), and the third was fixed-dose study (340 mg/day for patients <30 kg and 425 mg/day for patients >=30 kg). Although these studies showed statistically significant differences favoring modafinil over placebo in reducing ADHD symptoms as measured by the ADHD-RS (school version), there were cases of serious rash including one case of possible SJS among 933 patients exposed to modafinil in this program. Modafinil is not approved for use in treating ADHD.. 8.5 Geriatric Use. In clinical trials, experience in limited number of modafinil-treated patients who were greater than 65 years of age showed an incidence of adverse reactions similar to other age groups. In elderly patients, elimination of modafinil and its metabolites may be reduced as consequence of aging. Therefore, consideration should be given to the use of lower doses and close monitoring in this population [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].. 8.6 Hepatic Impairment. In patients with severe hepatic impairment, the dose of modafinil tablets should be reduced to one-half of that recommended for patients with normal hepatic function [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 7.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)8.Angioedema and Anaphylaxis Reactions: If suspected, discontinue modafinil tablets. (5.2)9.Multi-organ Hypersensitivity Reactions: If suspected, discontinue modafinil tablets. (5.3)10.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)11.Psychiatric Symptoms: Use caution in patients with history of psychosis, depression, or mania. Consider discontinuing modafinil tablets if psychiatric symptoms develop. (5.5)12.Known Cardiovascular Disease: Consider increased monitoring. (5.7). 7.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). 8.Angioedema and Anaphylaxis Reactions: If suspected, discontinue modafinil tablets. (5.2). 9.Multi-organ Hypersensitivity Reactions: If suspected, discontinue modafinil tablets. (5.3). 10.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). 11.Psychiatric Symptoms: Use caution in patients with history of psychosis, depression, or mania. Consider discontinuing modafinil tablets if psychiatric symptoms develop. (5.5). 12.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 case of possible Stevens-Johnson Syndrome (SJS) and 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 to 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 to weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., months). Accordingly, duration of therapy cannot be relied upon as means to predict the potential risk heralded by the first appearance of 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 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 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 to 33) to the initiation of modafinil.Although there have been limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur.If multi-organ hypersensitivity reaction is suspected, modafinil tablets should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be possibility.. 5.4 Persistent Sleepiness. Patients with abnormal levels of sleepiness who take modafinil tablets should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking modafinil tablets, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities.. 5.5 Psychiatric Symptoms. Psychiatric adverse reactions have been reported in patients treated with modafinil.In the adult modafinil tablets controlled trials, psychiatric symptoms resulting in treatment discontinuation (at frequency >=0.3%) and reported more often in patients treated with modafinil tablets compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (<1%), confusion (<1%), agitation (<1%), and depression (<1%).Postmarketing adverse reactions associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation, and aggression, some resulting in hospitalization. Many, but not all, patients had prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil tablets (three times the recommended dose) and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation.Caution should be exercised when modafinil tablets are given to patients with history of psychosis, depression, or mania. Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in patients treated with modafinil tablets. If psychiatric symptoms develop in association with modafinil tablets administration, consider discontinuing modafinil tablets. 5.6 Effects on Ability to Drive and Use Machinery. Although modafinil tablets have not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that modafinil tablets therapy will not adversely affect their ability to engage in such activities.. 5.7 Cardiovascular Events. In modafinil clinical studies, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on ECG occurred in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. In Canadian clinical trial, 35 year old obese narcoleptic male with prior history of syncopal episodes experienced 9-second episode of asystole after 27 days of modafinil treatment (300 mg/day in divided doses). Modafinil tablets are not recommended in patients with history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation. Consider increased monitoring in patients with recent history of myocardial infarction or unstable angina.Blood pressure monitoring in short term (<= months) controlled trials showed no clinically significant changes in mean systolic and diastolic blood pressure in patients receiving modafinil tablets as compared to placebo. However, retrospective analysis of the use of antihypertensive medication in these studies showed that greater proportion of patients on modafinil tablets required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential use was slightly larger when only studies in OSA were included, with 3.4% of patients on modafinil tablets and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication. Increased monitoring of heart rate and blood pressure may be appropriate in patients on modafinil tablets. Caution should be exercised when prescribing modafinil tablets to patients with known cardiovascular disease.