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® 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 individuals with narcolepsy or OSA is 200mg may be excreted as the parent compound. A total of 81% of the administered radioactivity taken orally once a day as a single dose in the morning. known to be recovered in 11 days post-dose, predominantly in the urine (80% vs. 1.0% Doses up to 400mg/day, given as a single dose, are known to be well tolerated, but in the feces). The largest fraction of the drug in urine is known to be modafinil acid, there is no consistent evidence that this dose confers additional benefit beyond that but at least six other metabolites may be present in lower concentrations. Only two of the 200mg/day dose. metabolites may reach appreciable concentrations in plasma, i.e., modafinil acid and Dosage in Shift Work Disorder (SWD) modafinil sulfone. Modafinil acid, modafinil sulfone, 2- (diphenylmethyl)sulfonyl]acetic The recommended dosage of Dowvigil for individuals with SWD is 200mg taken orally acid and 4-hydroxy modafinil, may be inactive or may not appear to mediate the arousal once a day as a single dose approximately 1 hour prior to the start of their work shift. effects of modafinil. Dosage Modifications in Individuals with Severe Hepatic Impairment In adults, decrease in trough levels of modafinil sometimes may be observed after In individuals with severe hepatic impairment, the dosage of Dowvigil should be reduced multiple weeks of dosing, suggesting auto-induction, but the magnitude of the decreases to one-half of that recommended for individuals with normal hepatic function. and the inconsistency of their occurrence may suggest that their clinical significance Use in Geriatric Individuals is minimal. Significant accumulation of modafinil sulfone is known to be observed after Consideration should be given to the use of lower doses and close monitoring in geriatric multiple doses due to its long elimination half-life of 40 hours. Auto-induction of individuals. metabolizing enzymes, most importantly cytochrome P-450 CYP3A4, may be observed after incubation of primary cultures of human hepatocytes with modafinil and after CONTRAINDICATIONS extended administration of modafinil at 400mg/day. Modafinil is contraindicated in individuals with known hypersensitivity to modafinil or Special Populations armodafinil or its inactive ingredients Age Clearance of modafinil may be reduced in the elderly. DRUG INTERACTIONS Gender Effects of Modafinil on CYP3A4/5 Substrates The pharmacokinetics of modafinil may not be affected by gender. The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, Race cyclosporine, midazolam, and triazolam) may be increased by modafinil via induction The influence of race on the pharmacokinetics of modafinil is not known. of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment Renal Impairment of these drugs should be considered when these drugs are used concomitantly with Severe chronic renal failure (creatinine clearance 20mL/min) is not known to significantly modafinil. influence the pharmacokinetics of modafinil 200mg single dose, but exposure to The effectiveness of steroidal contraceptives may be reduced when used with modafinil modafinil acid (an inactive metabolite) may be increased 9-fold. and for one month after discontinuation of therapy. Alternative or concomitant methods Hepatic Impairment of contraception are recommended for individuals taking steroidal contraceptives (e.g., In individuals which may have stage B or B+ cirrhosis and individuals with stage C or ethinyl estradiol) when treated concomitantly with modafinil and for one month after C+ cirrhosis (per the Child-Pugh score criteria), the oral clearance of modafinil may discontinuation of modafinil treatment. be decreased by about 60% and the steady state concentration may be doubled Blood levels of cyclosporine may be reduced when used with modafinil. Monitoring compared to normal individuals. of circulating cyclosporine concentrations and appropriate dosage adjustment for Pharmacokinetic Drug Interactions cyclosporine should be considered when used concomitantly with modafinil. Modafinil weakly induces CYP1A2, CYP2B6, and possibly CYP3A activities in a Effects of Modafinil on CYP2C19 Substrates concentration-related manner and that CYP2C19 activity is reversibly inhibited by Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, modafinil. Modafinil is known to produce an apparent concentration-related suppression propranolol, omeprazole, and clomipramine) may be prolonged by modafinil via inhibition of metabolic enzymes, with resultant higher systemic exposure. In individuals deficient Adverse Reactions occurring in ( 1%) in the CYP2D6 enzyme, the levels of CYP2D6 substrates which have ancillary routes Headache, nausea, nervousness, rhinitis, back pain, diarrhea, anxiety, dizziness, of elimination through CYP2C19, such as tricyclic antidepressants and selective dyspepsia, insomnia, anorexia, dry mouth, pharyngitis, chest pain, hypertension, serotonin reuptake inhibitors, may be increased by co-administration of modafinil. Dose abnormal liver function, constipation, depression, palpitation, paresthesia, somnolence, adjustments of these drugs and other drugs that are substrates for CYP2C19 may be tachycardia, vasodilatation, abnormal vision, agitation, asthma, chills, confusion, necessary when used concomitantly with modafinil. dyskinesia, edema, emotional lability, eosinophilia, epistaxis, flatulence, hyperkinesia, Warfarin hypertonia, mouth ulceration, sweating, taste perversion, thirst, tremor, urine abnormality, More frequent monitoring of prothrombin times/INR should be considered whenever and vertigo modafinil is co-administered with warfarin. Adverse Reactions Resulting in Discontinuation of Treatment Monoamine Oxidase (MAO) Inhibitors Headache, nausea, anxiety, dizziness, insomnia, chest pain, and nervousness Caution should be used when concomitantly administering MAO inhibitors and modafinil. Laboratory Abnormalities Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase WARNINGS AND PRECAUTIONS (AP) are known to be higher following administration of modafinil. Few patients, however, Drug Abuse and Dependence may show GGT or AP elevations outside of the normal range. Shifts to higher, but not Modafinil may produce psychoactive and euphoric effects, alterations in mood, perception, clinically significantly abnormal, GGT and AP values may appear to increase with time thinking, and feelings typical of other CNS stimulants. Patients should be observed for in the population treated with modafinil. No differences are known to occur in alanine signs of misuse or abuse. No withdrawal symptoms are known to occur with modafinil aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or during 14 days of observation following 9 week of use, although sleepiness returned total bilirubin. in narcoleptic patients. Other Adverse Reaction Serious Rash, including Stevens - Johnson syndrome Hematologic: Agranulocytosis Serious rash requiring hospitalization and discontinuation of treatment is known to Psychiatric Disorders: Psychomotor hyperactivity occur in association with the use of modafinil. Serious or life-threatening rash, including SJS, toxic epidermal necrolysis (TEN), and USE IN SPECIAL POPULATION drug rash with eosinophilia and systemic symptoms (DRESS) are known to occur in Pregnancy adults and children. Estimates of the background incidence rate for these serious skin Pregnancy Category C. Sufficient data is not available for the use of modafinil in reactions in the general population are known to range between 1 to 2 cases per pregnant women. Intrauterine growth restriction and spontaneous abortion are known million-person years. to occur in association with modafinil (a mixture of R- and S-modafinil) and armodafinil There are no factors that are known to predict the risk of occurrence or the severity (the R-enantiomer of modafinil). Modafinil should be used during pregnancy only if the of rash associated with modafinil. Nearly all cases of serious rash associated with potential benefit justifies the potential risk to the fetus. modafinil are known to occur within 1 to 5 weeks after treatment initiation. However, Lactation isolated cases are known to occur after prolonged treatment (e.g., 3 months). Accordingly, It is not known whether modafinil or its metabolites are excreted in human milk. Because duration of therapy cannot be relied upon as a means to predict the potential risk many drugs are excreted in human milk, caution should be exercised when modafinil heralded by the first appearance of a rash. is administered to a nursing woman Although benign rashes also occur with modafinil, it is not possible to reliably predict Pediatrics which rashes will prove to be serious. Accordingly, modafinil should be discontinued Use in individuals under 18 years of age is not recommended. Safety and effectiveness at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of in pediatric individuals below the age of 18 years is not known. treatment may not prevent a rash from becoming life-threatening or permanently Geriatrics disabling or disfiguring. In elderly patients, elimination of modafinil and its metabolites may be reduced as a Angioedema and Anaphylaxis Reactions consequence of aging. Therefore, consideration should be given to the use of lower Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), may doses and close monitoring in this population occur in treatment with armodafinil, the R enantiomer of modafinil. However, angioedema Hepatic impairment may occur with modafinil. Individuals should be advised to discontinue therapy and In patients with severe hepatic impairment, the dose of modafinil should be reduced immediately report to their physician for any signs or symptoms. to one-half of that recommended for patients with normal hepatic function. Multi-organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions are known to occur in close temporal association OVERDOSAGE (median time to detection 13 days: range 4-33) to the initiation of modafinil. No specific antidote exists for the toxic effects of a modafinil overdose. Such overdoses Multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. should be managed with primarily supportive care, including cardiovascular monitoring. 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 are STABILITY diverse; However, individuals typically, although not exclusively, presented with fever See expiry on the pack. and rash associated with other organ system involvement. Other associated manifestations include myocarditis, hepatitis, liver function test abnormalities, PACKS hematological abnormalities (e.g., eosinophilia, leukopenia, and thrombocytopenia), Dowvigil is supplied in the following dosage form, strengths and pack size: pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, Tablets 100mg 20’s other organ system symptoms and signs may occur. Tablets 200mg 20’s If a multi-organ hypersensitivity reaction is suspected, modafinil should be discontinued. Although there is no data available to indicate cross-sensitivity with other drugs that INSTRUCTIONS produce this syndrome, the experience with drugs associated with multi-organ Keep all medicines out of the reach of children. hypersensitivity would indicate this to be a possibility. Protect from light, heat and moisture. Persistent Sleepiness Store below 30 OC. Individuals with abnormal levels of sleepiness who take modafinil should be advised that their level of wakefulness may not return to normal. Individuals with excessive To be sold on prescription of a registered sleepiness, including those taking modafinil, should be frequently reassessed for their medical practitioner only. degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that individuals may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities. Psychiatric Symptoms Psychiatric adverse reactions may occur in individuals treated with modafinil. Psychiatric symptoms may include anxiety (1%), nervousness (1%), insomnia (<1%), confusion (<1%), agitation (<1%), and depression (<1%). Other adverse reactions associated with the use of modafinil may include mania, delusions, hallucinations, suicidal ideation, and aggression, some resulting in hospitalization. Ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600mg doses of modafinil (three times the recommended dose) and sleep deprivation may occur. No known evidence of psychosis 36 hours after drug discontinuation. Caution should be exercised when modafinil is given, to individuals with a history of psychosis, depression or mania. Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in individuals treated with modafinil. If psychiatric symptoms develop in association with modafinil administration, consider discontinuing modafinil. Effects on Ability to Drive and Use Machinery Although modafinil is not known to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Individuals should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that modafinil therapy will not adversely affect their ability to engage in such activities. Cardiovascular Events Cardiovascular adverse reactions, including chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on ECG may occur in individuals in association with mitral valve prolapse or left ventricular hypertrophy. Modafinil is not recommended in individuals with a history of left ventricular hypertrophy or in individuals 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 individuals with a recent history of myocardial infarction or unstable angina. Blood pressure monitoring showed no clinically significant changes in mean systolic and diastolic blood pressure in individuals receiving modafinil as compared to placebo. However, retrospective analysis of the use of antihypertensive medication may show a greater proportion of individuals on modafinil requiring new or increased use of antihypertensive medications. Increased monitoring of heart rate and blood pressure may be appropriate in individuals on modafinil. Caution should be exercised when prescribing modafinil to individuals with known cardiovascular disease. ADVERSE REACTION Serious Adverse Reactions Serious rash including Stevens-Johnson Syndrome, angioedema and anaphylaxis reactions, multi-organ hypersensitivity reactions, persistent sleepiness, psychiatric Manufactured by: symptoms, effects on ability to drive and use machinery and cardiovascular events Most Common Adverse Reactions ( 5%) Martin Dow Limited Headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, Plot 37, Sector 19, Korangi Industrial Area, dizziness, and dyspepsia. Karachi-74900, Pakistan.