160 mm 01 ® of expression of CYP2C9 activity. Other CYP activities may not appear to be affected 100mg Tablets by modafinil. Dowvigil 200mg Tablets Potential Interactions with Drugs that Inhibit, Induce, or are Metabolized by (Modafinil) Cytochrome P450 Isoenzymes and Other Hepatic Enzymes There may be a low probability of substantive effects on the overall pharmacokinetic profile of modafinil due to CYP inhibition by concomitant medications. Due to the partial DESCRIPTION involvement of CYP3A enzymes in the metabolic elimination of modafinil, coadministration Dowvigil (modafinil) is a wakefulness promoting agent for oral administration. Modafinil of potent inducers of CYP3A4/5 (e.g., carbamazepine, phenobarbital, and rifampin) or is a racemic compound. The chemical name for modafinil is 2-[(diphenylmethyl) inhibitors of CYP3A4/5 (e.g., ketoconazole, erythromycin) may alter the plasma sulfinyl]acetamide. The molecular formula is C15H15NO2S and the molecular weight is concentrations of modafinil. 273.35. The Potential of Modafinil to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition COMPOSITION Drugs Metabolized by CYP3A4/5 Each tablet contains: Modafinil is a weak inducer of CYP3A activity in a concentration-related manner. Modafinil (USP)……………………………… 100mg Therefore, the blood levels and effectiveness of drugs that are substrates for CYP3A enzymes (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may Each tablet contains: be reduced after initiation of concomitant treatment with modafinil. Modafinil (USP)……...……………………… 200mg Ethinyl Estradiol: Administration of modafinil once daily at 200mg/day for 7 days followed by 400mg/day for 21 days may result in a mean 11% decrease in mean Cmax THERAPEUTIC INDICATIONS and 18% decrease in mean AUC0-24 of ethinyl estradiol.There may be no apparent Dowvigil is indicated to improve wakefulness in adult individuals with excessive change in the elimination rate of ethinyl estradiol. sleepiness associated with narcolepsy, obstructive sleep apnea (OSA), or shift work Triazolam: Mean Cmax and AUC0- of triazolam may be decreased by 42% and 59%, disorder (SWD). respectively, and its elimination half-life is known to be decreased by approximately an Limitations of Use hour after the modafinil treatment. In OSA, Dowvigil is indicated to treat excessive sleepiness and not as treatment for Cyclosporine: After one month of administration of 200mg/day of modafinil, the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment cyclosporine blood levels may be decreased by 50%. of choice for the patient, a maximal effort to treat with CPAP for an adequate period Midazolam: Concomitant administration of armodafinil 250mg is known to result in of time should be made prior to initiating and during treatment with Dowvigil for excessive a reduction in systemic exposure to midazolam by 32% after a single oral dose (5mg) sleepiness. and 17% after a single intravenous dose (2mg). Quetiapine: Concomitant administration of armodafinil 250mg with quetiapine (300mg CLINICAL PHARMACOLOGY to 600mg daily doses) is known to result in a reduction in the mean systemic exposure Mechanism of Action of quetiapine by approximately 29%. The mechanism(s) through which modafinil promotes wakefulness is unknown. Modafinil Drugs Metabolized by CYP1A2 has wake-promoting actions similar to sympathomimetic agents including amphetamine Modafinil is a weak inducer of CYP1A2 in a concentration-related manner. However and methylphenidate, although the pharmacologic profile is not identical to that of the no significant effect on CYP1A2 activity is known to be observed when armodafinil, sympathomimetic amines. using caffeine as a probe substrate. Modafinil-induced wakefulness can be attenuated by the 1-adrenergic receptor Drugs Metabolized by CYP2B6 antagonist, prazosin; However, modafinil is inactive in other assay systems known to Modafinil is a weak inducer of CYP2B6 activity in a concentration-related manner. be responsive to -adrenergic agonists. Modafinil is not a direct or indirect acting Drugs Metabolized by CYP2C9 dopamine receptor agonist. However, modafinil binds to the dopamine transporter and Modafinil may produce an apparent concentration-related suppression of expression inhibits dopamine reuptake. This activity has been associated with increased extracellular of CYP2C9 activity suggesting that there is a potential for a metabolic interaction dopamine levels in some brain regions. Alpha-methyl-p- tyrosine, a dopamine synthesis between modafinil and the substrates of this enzyme (e.g., S-warfarin and phenytoin) inhibitor, blocks the action of amphetamine, but does not block locomotor activity Warfarin: Concomitant administration of modafinil with warfarin may not produce induced by modafinil. significant changes in the pharmacokinetic profiles of R- and S-warfarin. Modafinil produces psychoactive and euphoric effects, alterations in mood, perception, Drugs Metabolized by CYP2C19 thinking, and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing Modafinil is a reversible inhibitor of CYP2C19 activity. CYP2C19 is also reversibly properties; and may also partially be discriminated as stimulant-like.Two major metabolites inhibited, with similar potency, by a circulating metabolite, modafinil sulfone. Although of modafinil, modafinil acid and modafinil sulfone, do not appear to contribute to the the maximum plasma concentrations of modafinil sulfone are much lower than those CNS-activating properties of modafinil. of parent modafinil, the combined effect of both compounds may produce sustained Pharmacokinetics partial inhibition of the enzyme. Therefore, exposure to some drugs that are substrates Modafinil is a 1:1 racemic compound, whose enantiomers have different pharmacokinetics for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) (e.g., the half-life of R-modafinil is approximately three times that of S-modafinil in adult may be increased when used concomitantly with modafinil. humans). The enantiomers do not interconvert. At steady state, total exposure to R- Concomitant administration of armodafinil 400mg is known to result in a 40% increase modafinil is approximately three times that for S-modafinil. The trough concentration in exposure to omeprazole after a single oral dose (40mg), as a result of moderate (Cmin.ss) of circulating modafinil after once daily dosing may consist of 90% of R-modafinil inhibition of CYP2C19 activity. and 10% of S-modafinil. The effective elimination half-life of modafinil after multiple Interactions with CNS Active Drugs doses is known to be 15 hours. The enantiomers of modafinil may exhibit linear kinetics Concomitant administration of modafinil with methylphenidate or dextroamphetamine upon multiple dosing of 200- 600mg/day once daily in healthy individuals. Apparent is not known to produce significant alterations on the pharmacokinetic profile of modafinil steady states of total modafinil and R-modafinil may reach after 2-4 days of dosing. or either stimulant, even though the absorption of modafinil may be delayed for Absorption approximately one hour. Modafinil is readily absorbed after oral administration, with peak plasma concentrations Concomitant modafinil or clomipramine is not known to alter the pharmacokinetic known to occur at 2-4 hours. The bioavailability of modafinil tablets is approximately profile of either drug; However, increased levels of clomipramine and its active metabolite equal to that of an aqueous suspension. The absolute oral bioavailability may not be desmethylclomipramine may occur in an individual with narcolepsy during treatment determined due to the aqueous insolubility (<1mg/mL) of modafinil, which precluded with modafinil. intravenous administration. Food is known to have no effect on overall modafinil CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic bioavailability; however, time to reach peak concentration (Tmax) may be delayed by antidepressants (e.g., clomipramine and desipramine) and selective serotonin reuptake approximately one hour if taken with food. inhibitors that are primarily metabolized by CYP2D6. In tricyclic-treated individuals Distribution deficient in CYP2D6, the amount of metabolism by CYP2C19 may be substantially Modafinil has an apparent volume of distribution of approximately 0.9L/kg. In human increased. Modafinil may cause elevation of the levels of the tricyclics in these individuals. plasma, in vitro, modafinil is moderately bound to plasma protein (approximately 60%), Concomitant administration of armodafinil with quetiapine is known to reduce the mainly to albumin. The potential for interactions of modafinil with highly protein bound systemic exposure of quetiapine. drugs is considered to be minimal. Interaction with P-Glycoprotein Metabolism and Elimination Armodafinil is a substrate of P-glycoprotein. The impact of inhibition of P-glycoprotein The major route of elimination is known to be metabolism (approximately 90%), primarily is not known. by the liver, with subsequent renal elimination of the metabolites. Urine alkalinization may have no effect on the elimination of modafinil. DOSAGE AND ADMINISTRATION Metabolism may occur through hydrolytic deamidation, S-oxidation, aromatic ring Dosage in Narcolepsy and Obstructive Sleep Apnea (OSA) hydroxylation, and glucuronide conjugation. Less than 10% of an administered dose The recommended dosage of Dowvigil for