chargeable for [17:<1 Rash 4 1 2> <1 Depression 3 1 2> <1 Adverse Reactions Resulting in Discontinuation of Treatment In placebo-controlled clinical trials, 44 of the 645 patients (7%) who received Armodafinil tablets discontinued due to an adverse reaction compared to 16 of the 445 (4%) of patients that received placebo. The most frequent reason for discontinuation was headache (1%). Laboratory Abnormalities Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of Armodafinil tablets, but not placebo. Few patients, however, had GGT or AP elevations outside of the normal range. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin, although there were rare cases of isolated elevations of AST and/or ALT. A single case of mild pancytopenia was observed after 35 days of treatment and resolved with drug discontinuation. A small mean decrease from baseline in serum uric acid compared to placebo was seen in clinical trials. The clinical significance of this finding is unknown. Postmarketing Experience The following adverse reactions have been identified during post approval use of Armodafinil tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Mouth Sores (including mouth blistering and ulceration). Drug Interactions Effects of Armodafinil Tablets on CYP3A4/5 Substrates The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by Armodafinil tablets via induction of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment of these drugs should be considered when these drugs are used concomitantly with Armodafinil tablets [see Clinical Pharmacology (12.3) ]. The effectiveness of steroidal contraceptives may be reduced when used with Armodafinil tablets and for one month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with Armodafinil tablets and for one month after discontinuation of Armodafinil tablets treatment. Blood levels of cyclosporine may be reduced when used with Armodafinil tablets. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with Armodafinil tablets. Effects of Armodafinil Tablets on CYP2C19 Substrates Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by Armodafinil tablets via inhibition of metabolic enzymes, with resultant higher systemic exposure. Dose reduction of these drugs may be required when these drugs are used concomitantly with Armodafinil tablets. Warfarin More frequent monitoring of prothrombin times/INR should be considered whenever Armodafinil tablets are coadministered with warfarin [see Clinical Pharmacology (12.3) ]. Monoamine Oxidase (MAO) Inhibitors Caution should be used when concomitantly administering MAO inhibitors and Armodafinil tablets. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Limited available data on Armodafinil use in pregnant women are insufficient to inform a drug associated risk of adverse pregnancy outcomes. Intrauterine growth restriction and spontaneous abortion have been reported in association with Armodafinil and modafinil. Although the pharmacology of Armodafinil is not identical to that of the sympathomimetic amines, Armodafinil shares some pharmacologic properties with this class [see Clinical Pharmacology (12.1) ] . Some sympathomimetics have been associated with intrauterine growth restriction and spontaneous abortions. In animal reproduction studies of Armodafinil (R-modafinil) and modafinil (a mixture of R-and S-modafinil) conducted in pregnant rats (Armodafinil, modafinil) and rabbits (modafinil) during organogenesis, evidence of developmental toxicity (increased embryofetal and offspring mortality, decreased fetal growth) was observed at clinically relevant plasma exposures. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Oral administration of Armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in decreased fetal body weight and increased incidences of fetal variations indicative of growth delay at the highest dose, which was also maternally toxic. The highest no-effect dose for embryofetal developmental toxicity in rat (200 mg/kg/day) was associated with a plasma Armodafinil exposure (AUC) less than that in humans at the maximum recommended human dose (MRHD) of Armodafinil tablets (250 mg/day). Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout organogenesis produced an increase in resorptions and an increased incidence of fetal variations at the highest dose tested. The higher no-effect dose for embryofetal developmental toxicity (100 mg/kg/day) was associated with a plasma Armodafinil AUC less than that in humans at the MRHD of Armodafinil tablets. However, in a subsequent rat study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed. In a study in which modafinil (45, 90, or 180 mg/kg/day) was orally administered to pregnant rabbits during organogenesis, embryofetal death was increased at the highest dose. The highest no-effect dose for developmental toxicity (100 mg/kg/day) was associated with a plasma Armodafinil AUC less than that in humans at the MRHD of Armodafinil 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, a dose resulting in a plasma Armodafinil AUC less than that in humans at the MRHD of Armodafinil tablets. No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring. Lactation Risk Summary There are no data on the presence of Armodafinil or its metabolites in human milk, the effects on the breastfed infant, or the effect of this drug on milk production. Modafinil was present in rat milk when animals were dosed during the lactation period. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Armodafinil and any potential adverse effects on the breastfed child from Armodafinil or from the underlying maternal condition. Females and Males of Reproductive Potential The effectiveness of hormonal contraceptives may be reduced when used with Armodafinil tablets and for one month after discontinuation of therapy. Advise women who are using a hormonal method of contraception to use an additional barrier method or an alternative non-hormonal method of contraception during treatment with Armodafinil tablets and for one month after discontinuation of Armodafinil tablets treatment [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Pediatric Use Safety and effectiveness in pediatric patients have not been established. Serious rash has been seen in pediatric patients receiving modafinil [see Warnings and Precautions (5.1) ]. Geriatric Use In elderly patients, elimination of Armodafinil and its metabolites may be reduced as a 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) ]. Hepatic Impairment The dosage of Armodafinil tablets should be reduced in patients with severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ]. Drug Abuse and Dependence Controlled Substance Armodafinil tablets contain Armodafinil, a Schedule IV controlled substance. Abuse Abuse of Armodafinil tablets have been reported in patients treated with Armodafinil tablets. Patterns of abuse have included euphoric mood and use of increasingly large doses or recurrent use of Armodafinil tablets for a desired effect. Drug diversion has also been noted. During the postmarketing period, misuse of Armodafinil tablets has been observed (e.g., taking Armodafinil tablets against a physician's advice, and obtaining Armodafinil tablets from multiple physicians). Abuse of Armodafinil, the active ingredient of Armodafinil tablets, poses a risk of overdosage similar to that seen for modafinil, which may lead to tachycardia, insomnia, agitation, dizziness, anxiety, nausea, headache, dystonia, tremor, chest pain, hypertension, seizures, delirium, or hallucinations. Other signs and symptoms of CNS stimulant abuse include tachypnea, sweating, dilated pupils, hyperactivity, restlessness, decreased appetite, loss of coordination, flushed skin, vomiting, and abdominal pain. In humans, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings, typical of other CNS stimulants. In in vitro binding studies, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. In some studies, modafinil was also partially discriminated as stimulant-like. Physicians should follow patients closely, especially those with a history of drug and/or stimulant (e.g., methylphenidate, amphetamine, or cocaine) abuse. Patients should be observed for signs of misuse or abuse (e.g., incrementation of doses or drug-seeking behavior). The abuse potential of modafinil (200, 400, and 800 mg) was assessed relative to methylphenidate (45 and 90 mg) in an inpatient study in individuals experienced with drugs of abuse. Results from this clinical study demonstrated that modafinil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate). Dependence Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Physical dependence can occur in patients treated with Armodafinil tablets. Abrupt cessation or dose reduction following chronic use can result in withdrawal symptoms, including shaking, sweating, chills, nausea, vomiting, confusion, aggression, and atrial fibrillation. Drug withdrawal convulsions, suicidality, fatigue, insomnia, aches, depression and headache have also been observed during the postmarketing period. Also, abrupt withdrawal has caused deterioration of psychiatric symptoms such as depression. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Multiple cases of development of tolerance to Armodafinil tablets have been reported during the postmarketing period. Overdosage Fatal overdoses involving modafinil alone or involving Armodafinil tablets or modafinil in combination with other drugs have been reported in the postmarketing setting. Symptoms most often accompanying Armodafinil tablets or modafinil overdose, alone or in combination with other drugs, have included anxiety, dyspnea, insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, excitation and hallucination; digestive changes such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension, and chest pain. No specific antidote exists for the toxic effects of an Armodafinil tablets overdose. Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring. Armodafinil Description Armodafinil is a wakefulness-promoting agent for oral administration. Armodafinil is the R-enantiomer of modafinil which is a 1:1 mixture of the R- and S-enantiomers. The chemical name for Armodafinil is 2-[(R)-(diphenylmethyl)sulfinyl] acetamide. The molecular formula is C 15 H 15 NO 2 S and the molecular weight is 273.35. The chemical structure is: Armodafinil is a white to off-white, crystalline powder that is freely soluble in dimethyl formamide, soluble in methanol, insoluble in water. Armodafinil tablets contain 50, 150 or 250 mg of Armodafinil and the following inactive ingredients: anhydrous lactose, croscarmellose sodium, magnesium stearate, povidone and pregelatinized starch. Armodafinil - Clinical Pharmacology Mechanism of Action The mechanism(s) through which Armodafinil promotes wakefulness is unknown. Armodafinil (R-modafinil) has pharmacological properties similar to those of modafinil (a mixture of R- and S-modafinil), to the extent tested in animal and in vitro studies. The R- and S-enantiomers have similar pharmacological actions in animals. Armodafinil and modafinil have wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although their pharmacologic profile is not identical to that of the sympathomimetic amines. Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist, prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to α-adrenergic agonists such as the rat vas deferens preparation. Armodafinil is an indirect dopamine receptor agonist; both Armodafinil and modafinil bind in vitro to the dopamine transporter and inhibit dopamine reuptake. For modafinil, 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, a dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil. 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. Based on nonclinical studies, two major metabolites, acid and sulfone, of modafinil or Armodafinil, do not appear to contribute to the CNS-activating properties of the parent compounds. Pharmacokinetics Armodafinil exhibits linear time-independent kinetics following single and multiple oral dose administration. Increase in systemic exposure is proportional over the dose range of 50 to 400 mg. No time-dependent change in kinetics was observed through 12 weeks of dosing. Apparent steady state for Armodafinil was reached within 7 days of dosing. At steady state, the systemic exposure for Armodafinil is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the R-enantiomer following administration of a single-dose of 50 mg Armodafinil tablets or 100 mg PROVIGIL (modafinil, a 1:1 mixture of R- and S-enantiomers) are nearly superimposable. However, the C max and AUC 0- , of Armodafinil at steady-state were approximately 37% and 70% higher, respectively, following administration of 200 mg Armodafinil tablets than the corresponding values of modafinil following administration of 200 mg PROVIGIL due to the more rapid clearance of the S-enantiomer (elimination half-life approximately 4 hours) as compared to the R-enantiomer. Absorption Armodafinil is readily absorbed after oral administration. The absolute oral bioavailability was not determined due to the aqueous insolubility of Armodafinil, which precluded intravenous administration. Peak plasma concentrations are attained at approximately 2 hours in the fasted state. Food effect on the overall bioavailability of Armodafinil is considered minimal; however, time to reach peak concentration (t max ) may be delayed by approximately 2-4 hours in the fed state. Since the delay in t max is also associated with elevated plasma concentrations later in time, food can potentially affect the onset and time course of pharmacologic action for Armodafinil tablets. Distribution Armodafinil has an apparent volume of distribution of approximately 42 L. Data specific to Armodafinil protein binding are not available. However, modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of Armodafinil tablets with highly protein-bound drugs is considered to be minimal. Elimination After oral administration of Armodafinil tablets, Armodafinil exhibits an apparent monoexponential decline from the peak plasma concentration. The apparent terminal t is approximately 15 hours. The oral clearance of Armodafinil tablets is approximately 33 mL/min. Metabolism In vitro and in vivo data show that Armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the single most prominent metabolic pathway, with sulfone formation by cytochrome P450 (CYP) 3A4/5 being next in importance. The other oxidative products are formed too slowly in vitro to enable identification of the enzyme(s) responsible. Only two metabolites reach appreciable concentrations in plasma (i.e., R-modafinil acid and modafinil sulfone). Excretion Data specific to Armodafinil tablets disposition are not available. However, modafinil is mainly eliminated via metabolism, predominantly in the liver, with less than 10% of the parent compound excreted in the urine. A 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). Specific Populations Age In a clinical study, systemic exposure of Armodafinil was approximately 15% higher in elderly subjects ( 65 years of age, N=24), corresponding to approximately 12% lower oral clearance (CL/F), as compared to young subjects (18-45 years of age, N=25). Systemic exposure of Armodafinil acid (metabolite) was approximately 61% and 73% greater for C max and AUC 0-τ , respectively, compared to young subjects. Systemic exposure of the sulfone metabolite was approximately 20% lower for elderly subjects compared with young subjects. A subgroup analysis of elderly subjects demonstrated elderly subjects 75 and 65-74 years of age had approximately 21% and 9% lower oral clearance, respectively, compared to young subjects. Systemic exposure was approximately 10% greater in subjects 65-74 years of age (N=17) and 27% greater in subjects 75 years of age (N=7), respectively, when compared to young subjects. The change is considered not likely to be clinically significant for elderly patients, however, because some elderly patients have greater exposure to Armodafinil, consideration should be given to the use of lower doses. Sex Population pharmacokinetic analysis suggests no gender effect on the pharmacokinetics of Armodafinil. Ethnicity The influence of race/ethnicity on the pharmacokinetics of Armodafinil has not been studied. Hepatic Impairment The pharmacokinetics and metabolism of modafinil were examined in patients with cirrhosis of the liver (6 men and 3 women). Three patients had stage B or B+ cirrhosis and 6 patients had stage C or C+ cirrhosis (per the Child-Pugh score criteria). Clinically 8 of 9 patients were icteric and all had ascites. In these patients, the oral clearance of modafinil was decreased by about 60% and the steady state concentration was doubled compared to normal patients [see Dosage and Administration (2.3) and Use in Specific Populations (8.6) ]. Renal Impairment In a single dose 200 mg modafinil study, severe chronic renal failure (creatinine clearance 20 mL/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to modafinil acid (metabolite) was increased 9-fold. Drug Interactions In vitro data demonstrated that Armodafinil weakly induces CYP1A2 and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by Armodafinil. Other CYP activities did not appear to be affected by Armodafinil. An in vitro study demonstrated that Armodafinil is a substrate of P-glycoprotein. Potential Interactions with Drugs That Inhibit, Induce, or Are Metabolized by Cytochrome P450 Isoenzymes and Other Hepatic Enzymes The existence of multiple pathways for Armodafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing Armodafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of Armodafinil tablets due to CYP inhibition by concomitant medications. However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of Armodafinil, 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 Armodafinil. The Potential of Armodafinil Tablets to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition Drugs Metabolized by CYP3A4/5 In vitro data demonstrated that Armodafinil is a weak inducer of CYP3A activity in a concentration-related manner. In a clinical study, concomitant administration of Armodafinil tablets 250 mg resulted in a reduction in systemic exposure to midazolam by 32% after a single oral dose (5 mg) and 17% after a single intravenous dose (2 mg). 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 Armodafinil tablets [see Drug Interactions (7) ] . In a separate clinical study, concomitant administration of Armodafinil tablets 250 mg with quetiapine (300 mg to 600 mg daily doses) resulted in a reduction in the mean systemic exposure of quetiapine by approximately 29%. No dose adjustment is required. Drugs Metabolized by CYP1A2 In vitro data demonstrated that Armodafinil is a weak inducer of CYP1A2 in a concentration-related manner. However, in a clinical study using caffeine as a probe substrate, no significant effect on CYP1A2 activity was observed. Drugs Metabolized by CYP2C19 In vitro data demonstrated that Armodafinil is a reversible inhibitor of CYP2C19 activity. In a clinical study, concomitant administration of Armodafinil tablets 400 mg resulted in a 40% increase in exposure to omeprazole after a single oral dose (40 mg), as a result of moderate inhibition of CYP2C19 activity [see Drug Interactions (7) ] . Interactions with CNS Active Drugs Concomitant administration of Armodafinil tablets with quetiapine reduced the systemic exposure of quetiapine. Data specific to Armodafinil tablets drug-drug interaction potential with other CNS active drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to Armodafinil tablets. Concomitant administration of modafinil with methylphenidate or dextroamphetamine produced no significant alterations on the pharmacokinetic profile of modafinil or either stimulant, even though the absorption of modafinil was delayed for approximately one hour. Concomitant modafinil or clomipramine did not alter the pharmacokinetic profile of either drug; however, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine was reported in a patient with narcolepsy during treatment with modafinil. Data specific to Armodafinil or modafinil drug-drug interaction potential with monoamine oxidase (MAO) inhibitors are not available [see Drug Interactions (7) ] . Interaction with P-Glycoprotein An in vitro study demonstrated that Armodafinil is a substrate of P-glycoprotein. The impact of inhibition of P-glycoprotein is not known. Interactions with Other Drugs Data specific to Armodafinil drug-drug interaction potential for additional other drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to Armodafinil tablets. Warfarin: Concomitant administration of modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of R- and S-warfarin. However, since only a single dose of warfarin was tested in this study, an interaction cannot be ruled out [see Drug Interactions (7) ] . Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a mouse carcinogenicity study, Armodafinil (R-modafinil) was administered at oral doses of up to 300 mg/kg/day in males and 100 mg/kg/day in females for approximately two years, no tumorigenic effects were observed. In a rat carcinogenicity study modafinil (a mixture of R- and S-modafinil) was administered at oral doses of up to 60 mg/kg/day for two years; no tumorigenic effects were observed. At the highest doses studied in mouse and rat, the plasma Armodafinil exposures (AUC) were less than that in humans at the MRHD of Armodafinil tablets (250 mg/day). Mutagenesis Armodafinil was negative in an in vitro bacterial reverse mutation assay and in an in vitro chromosomal aberration assay in human lymphocytes. Modafinil was negative in a series of in vitro (i.e., bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration in human lymphocytes, cell transformation in BALB/3T3 mouse embryo cells) or in vivo (mouse bone marrow micronucleus) assays. Impairment of Fertility A fertility and early embryonic development (to implantation) study was not conducted with Armodafinil alone. Oral administration of modafinil (doses of up to 480 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females through day 7 of gestation produced an increase in the time to mate at the highest dose; no effects were observed on other fertility or reproductive parameters. The no-effect dose of 240 mg/kg/day was associated with a plasma Armodafinil AUC less than that in humans at the MRHD of Armodafinil tablets. Clinical Studies Obstructive Sleep Apnea (OSA) The effectiveness of Armodafinil tablets in improving wakefulness in patients with excessive sleepiness associated with OSA was established in two 12-week, multi-center, placebo-controlled, parallel-group, double-blind clinical studies of outpatients 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 or 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, or 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 a 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. Patients were required to be compliant with CPAP, defined as CPAP use 4 hours/night on 70% of nights. CPAP use continued throughout the study. 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 patient's overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit. For a successful trial both measures had to show statistically significant improvement. The MWT measures latency (in minutes) to sleep onset. An extended MWT was performed with test sessions at 2 hour intervals between 9AM and 7PM. The primary analysis was the average of the sleep latencies from the first four test sessions (9AM to 3PM). For each test session, the subject was asked to attempt to remain awake without using extraordinary measures. Each test session was terminated after 30 minutes if no sleep occurred or immediately after sleep onset. The CGI-C is a 7-point scale, centered at No Change , and ranging from Very Much Worse to Very Much Improved. Evaluators were not given any specific guidance about the criteria they were to apply when rating patients. In the first study, a total of 395 patients with OSA were randomized to receive Armodafinil tablets 150 mg/day, Armodafinil tablets 250 mg/day or matching placebo. Patients treated with Armodafinil tablets showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT at final visit. A statistically significant greater number of patients treated with Armodafinil tablets showed improvement in overall clinical condition as rated by the CGI-C scale at final visit. The average sleep latencies (in minutes) in the MWT at baseline for the trials are shown in Table 3 below, along with the average change from baseline on the MWT at final visit. The percentages of patients who showed any degree of improvement on the CGI-C in the clinical trials are shown in Table 4 below. The two doses of Armodafinil tablets produced statistically significant effects of similar magnitudes on the MWT, and also on the CGI-C. In the second study, 263 patients with OSA were randomized to either Armodafinil tablets 150 mg/day or placebo. Patients treated with Armodafinil tablets showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT (Table 3). A statistically significant greater number of patients treated with Armodafinil tablets showed improvement in overall clinical condition as rated by the CGI-C scale (Table 4). Nighttime sleep measured with polysomnography was not affected by the use of Armodafinil tablets in either study. Narcolepsy The effectiveness of Armodafinil tablets in improving wakefulness in patients with excessive sleepiness associated with narcolepsy was established in one 12-week, multi-center, placebo-controlled, parallel-group, double-blind study of outpatients who met the criteria for narcolepsy. A total of 196 patients were randomized to receive Armodafinil tablets 150 or 250 mg/day, or matching 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) a 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 and a Multiple Sleep Latency Test (MSLT) that demonstrates a mean sleep latency of less than 5 minutes and two or more sleep onset REM periods and no medical or mental disorder accounts for the symptoms. For entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, via MSLT with a sleep latency of 6 minutes or les charges
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