ADVERSE REACTIONS SECTION.


The following serious adverse reactions are described below and elsewhere in the labeling:Serious Dermatologic Reactions [see WARNINGS AND PRECAUTIONS (5.1)] Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity [see WARNINGS AND PRECAUTIONS (5.2)] Angioedema and Anaphylaxis Reactions [see WARNINGS AND PRECAUTIONS (5.3)] Persistent Sleepiness [see WARNINGS AND PRECAUTIONS (5.4)] Psychiatric Symptoms [see WARNINGS AND PRECAUTIONS (5.5)] Effects on Ability to Drive and Use Machinery [see WARNINGS AND PRECAUTIONS (5.6)] Cardiovascular Events [see WARNINGS AND PRECAUTIONS (5.7)] 6.1 Clinical Trials ExperienceBecause 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.Armodafinil has been evaluated for safety in over 1,100 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy.Most Common Adverse ReactionsIn the placebo-controlled clinical trials, the most common adverse reactions (>= 5%) associated with the use of armodafinil more frequently than in placebo-treated patients were headache, nausea, dizziness, and insomnia. The adverse reaction profile was similar across the studies.Table presents the adverse reactions that occurred at rate of 1% or more and were more frequent in armodafinil-treated patients than in placebo-treated patients in the placebo-controlled clinical trials.Table 1: Adverse Reactions in Pooled Placebo-Controlled Clinical Trials in OSA, Narcolepsy, and SWD with Armodafinil (150 mg and 250 mg) Adverse reactions that occurred in 1% of armodafinil-treated patients and greater incidence than that of placebo.Armodafinil (%) N=645 Placebo (%) N=445 Headache 17 Nausea 3 Dizziness 2 Insomnia 1 Anxiety 1 Diarrhea 2 Dry Mouth 1 Depression 0 Dyspepsia 0 Fatigue 1 Palpitations 1 Rash 0 Upper Abdominal Pain 1 Agitation 0 Anorexia 0 Constipation 0 Contact Dermatitis 0 Decreased Appetite 0 Depressed Mood 0 Disturbance In Attention 0 Dyspnea 0 Hyperhydrosis 0 Increased Gamma-Glutamyltransferase 0 Increased Heart Rate 0 Influenza-Like Illness 0 Loose Stools 0 Migraine 0 Nervousness 0 Pain 0 Paresthesia 0 Polyuria 0 Pyrexia 0 Seasonal Allergy 0 Thirst 0 Tremor 0 Vomiting 0 Dose-Dependent Adverse ReactionsIn the placebo-controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of armodafinil and placebo, the following adverse reactions were dose-related: headache, rash, depression, dry mouth, insomnia, and nausea. See Table for additional information.Table 2: Dose-Dependent Adverse Reactions in Pooled Placebo-Controlled Clinical Trials in OSA, Narcolepsy and SWD Armodafinil 250 mg (%) N=198 Armodafinil 150 mg (%) N=447 Armodafinil Combined (%) N=645 Placebo (%) N=445 Headache 23 14 17 Nausea 6 3 Insomnia 4 1 Dry Mouth 2 <1 Rash 1 <1 Depression 1 <1 Adverse Reactions Resulting in Discontinuation of TreatmentIn placebo-controlled clinical trials, 44 of the 645 patients (7%) who received armodafinil 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 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 armodafinil, 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. single case of mild pancytopenia was observed after 35 days of treatment and resolved with drug discontinuation. 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.6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post approval use of armodafinil. 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.Gastrointestinal DisordersMouth Sores (including mouth blistering and ulceration).

CLINICAL PHARMACOLOGY SECTION.


12.1 Mechanism of ActionThe 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 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 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.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, 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.12.3 PharmacokineticsArmodafinil 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 days of dosing. At steady state, the systemic exposure for armodafinil is 1.8 times the exposure observed after single dose. The concentration-time profiles of the R-enantiomer following administration of single-dose of 50 mg armodafinil or 100 mg PROVIGIL (modafinil, 1:1 mixture of R- and S-enantiomers) are nearly superimposable. However, the Cmax and AUC0-, of armodafinil at steady-state were approximately 37% and 70% higher, respectively, following administration of 200 mg armodafinil 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 hours) as compared to the R-enantiomer.AbsorptionArmodafinil 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 hours in the fasted state. Food effect on the overall bioavailability of armodafinil is considered minimal; however, time to reach peak concentration (tmax) may be delayed by approximately to hours in the fed state. Since the delay in tmax is also associated with elevated plasma concentrations later in time, food can potentially affect the onset and time course of pharmacologic action for armodafinil.DistributionArmodafinil 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 with highly protein-bound drugs is considered to be minimal.EliminationAfter oral administration of armodafinil, armodafinil exhibits an apparent monoexponential decline from the peak plasma concentration. The apparent terminal 1/2 is approximately 15 hours. The oral clearance of armodafinil 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 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. 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 PopulationsAge:In 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 to 45 years of age, N=25). Systemic exposure of armodafinil acid (metabolite) was approximately 61% and 73% greater for Cmax and AUC0-, respectively, compared to young subjects. Systemic exposure of the sulfone metabolite was approximately 20% lower for elderly subjects compared with young subjects. subgroup analysis of elderly subjects demonstrated elderly subjects >=75 and 65 to 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 to 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.SexPopulation pharmacokinetic analysis suggests no gender effect on the pharmacokinetics of armodafinil.EthnicityThe 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 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)].Renal Impairment:In 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 InteractionsIn vitro data demonstrated that armodafinil weakly induces CYP1A2 and possibly CYP3A activities in 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 substrate of P-glycoprotein.Potential Interactions with Drugs That Inhibit, Induce, or Are Metabolized by Cytochrome P450 Isoenzymes and Other Hepatic EnzymesThe existence of multiple pathways for armodafinil metabolism, as well as the fact that non-CYP-related pathway is the most rapid in metabolizing armodafinil, suggest that there is low probability of substantive effects on the overall pharmacokinetic profile of armodafinil 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 InhibitionDrugs Metabolized by CYP3A4/5: In vitro data demonstrated that armodafinil is weak inducer of CYP3A activity in concentration-related manner. 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). 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[see DRUG INTERACTIONS (7)] 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%. No dose adjustment is required. Drugs Metabolized by CYP1A2: In vitro data demonstrated that armodafinil is weak inducer of CYP1A2 in concentration-related manner. However, in clinical study using caffeine as probe substrate, no significant effect on CYP1A2 activity was observed. Drugs Metabolized by CYP2C19: In vitro data demonstrated that armodafinil is reversible inhibitor of CYP2C19 activity. 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 [see DRUG INTERACTIONS (7)] Interactions with CNS Active Drugs: Concomitant administration of armodafinil with quetiapine reduced the systemic exposure of quetiapine. Data specific to armodafinil 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. 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 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 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. 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)].

CONTRAINDICATIONS SECTION.


Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil or its inactive ingredients [see WARNINGS AND PRECAUTIONS (5.1, 5.2, 5.3)].

DESCRIPTION SECTION.


Armodafinil is wakefulness-promoting agent for oral administration. Armodafinil is the R-enantiomer of modafinil which is 1:1 mixture of the R- and S-enantiomers. The chemical name for armodafinil is 2-[(R) (diphenylmethyl)sulfinyl]acetamide. The molecular formula is C15H15NO2S and the molecular weight is 273.35.The chemical structure is:[Image-01]Armodafinil is white to off-white, powder that is slightly soluble in water, sparingly soluble in acetone, and soluble in methanol.Armodafinil tablets contain 50, 150, 200 or 250 mg of armodafinil and the following inactive ingredients: lactose monohydrate, povidone, pregelatinised starch, sodium starch glycolate, sodium stearyl fumarate.

DOSAGE & ADMINISTRATION SECTION.


2.1 Dosage in Obstructive Sleep Apnea (OSA) and NarcolepsyThe recommended dosage of armodafinil tablets for patients with OSA or narcolepsy is 150 mg to 250 mg taken orally once day as single dose in the morning.In patients with OSA, doses up to 250 mg/day, given as single dose, have been well tolerated, but there is no consistent evidence that these doses confer additional benefit beyond that of the 150 mg/day dose [see CLINICAL PHARMACOLOGY (12.3) and CLINICAL STUDIES (14.1, 14.2)].2.2 Dosage in Shift Work Disorder (SWD)The recommended dosage of armodafinil tablets for patients with SWD is 150 mg taken orally once day as single dose approximately hour prior to the start of their work shift.2.3 Dosage Modification in Patients with Severe Hepatic ImpairmentIn patients with severe hepatic impairment, the dosage of armodafinil tablets should be reduced [see USE IN SPECIFIC POPULATIONS (8.6) and CLINICAL PHARMACOLOGY (12.3)].2.4 Use in Geriatric PatientsConsideration should be given to the use of lower doses and close monitoring in geriatric patients [see USE IN SPECIFIC POPULATIONs (8.5)].

DOSAGE FORMS & STRENGTHS SECTION.


50 mg White to off white, round, biconvex tablets debossed with LU on one side X41 on the other side. 150 mg White to off white, oval, biconvex tablets debossed with LU on one side X43 on the other side. 200 mg White to off white, oval, biconvex tablets debossed with LU on one side X44 on the other side. 250 mg White to off white, oval, biconvex tablets debossed with LU on one side X45 on the other side.

DRUG ABUSE AND DEPENDENCE SECTION.


9.1 Controlled SubstanceArmodafinil is Schedule IV controlled substance.9.2 AbuseAbuse of armodafinil has 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 for desired effect. Drug diversion has also been noted. During the postmarketing period, misuse of armodafinil has been observed (e.g., taking armodafinil tablets against physicians advice, and obtaining armodafinil tablets from multiple physicians).Abuse of armodafinil, poses 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 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).9.3 DependencePhysical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of 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 physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at lower dose).Multiple cases of development of tolerance to armodafinil tablets have been reported during the postmarketing period.

DRUG INTERACTIONS SECTION.


Effects of armodafinil on CYP3A4/5 SubstratesThe clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by armodafinil 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 [see CLINICAL PHARMACOLOGY (12.3)].The effectiveness of steroidal contraceptives may be reduced when used with armodafinil 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 and for one month after discontinuation of armodafinil treatment.Blood levels of cyclosporine may be reduced when used with armodafinil. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with armodafinil.Effects of Armodafinil on CYP2C19 SubstratesElimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by armodafinil 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.WarfarinMore frequent monitoring of prothrombin times/INR should be considered whenever armodafinil is coadministered with warfarin [see CLINICAL PHARMACOLOGY (12.3)].Monoamine Oxidase (MAO) InhibitorsCaution should be used when concomitantly administering MAO inhibitors and armodafinil.

HOW SUPPLIED SECTION.


16.1 How SuppliedArmodafinil Tablets are available as follows:50 mg: White to off white, round, biconvex tablets debossed with LU on one side X41 on the other side.- Bottles of 60150 mg: White to off white, oval, biconvex tablets debossed with LU on one side X43 on the other side. Bottles of 60 -Bottles of 500200 mg: White to off white, oval, biconvex tablets debossed with LU on one side X44 on the other side. Bottles of 60- Bottles of 500250 mg: White to off white, oval, biconvex tablets debossed with LU on one side X45 on the other side. Bottles of 60- Bottles of 50016.2 StorageStore at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP ControlledRoom Temperature].

INDICATIONS & USAGE SECTION.


Armodafinil tablets are indicated to improve wakefulness in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD).Limitations of UseIn OSA, armodafinil tablets are indicated to treat excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for patient, maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating armodafinil tablets for excessive sleepiness.

NONCLINICAL TOXICOLOGY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisIn 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 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 (250 mg/day).MutagenesisArmodafinil 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 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 FertilityA 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 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 plasma armodafinil AUC less than that in humans at the MRHD of armodafinil.

OVERDOSAGE SECTION.


Fatal overdoses involving modafinil alone or involving armodafinil or modafinil in combination with other drugs have been reported in the postmarketing setting. Symptoms most often accompanying armodafinil 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 armodafinil overdose. Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


562-30. 150-30.

PATIENT COUNSELING INFORMATION.


Advise the patient to read the FDA-approved patient labeling (Medication Guide).Serious Dermatologic ReactionsAdvise patients and caregivers about the risk of potentially fatal serious skin reactions. Educate patients about the signs and symptoms that may signal serious skin reaction. Instruct patients to discontinue armodafinil tablets and consult with their healthcare provider immediately if skin reaction such as rash, mouth sores, blisters, or peeling skin occurs during treatment with armodafinil tablets [see WARNINGS AND PRECAUTIONS (5.1)].DRESS/Multi-organ HypersensitivityInstruct patients that fever associated with signs of other organ system involvement (e.g., rash, lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately [see WARNINGS AND PRECAUTIONS (5.2)].Angioedema and Anaphylactic ReactionsAdvise patients of life-threatening symptoms suggesting anaphylaxis or angioedema (such as hives, difficulty in swallowing or breathing, hoarseness, or swelling of the face, eyes, lips, or tongue) that can occur with armodafinil tablet. Instruct them to discontinue armodafinil tablet and immediately report these symptoms to their healthcare provider [see WARNINGS AND PRECAUTIONS (5.3)].WakefulnessAdvise patients that treatment with armodafinil tablet will not eliminate their abnormal tendency to fall asleep. Advise patients that they should not alter their previous behavior with regard to potentially dangerous activities (e.g., driving, operating machinery) or other activities requiring appropriate levels of wakefulness, until and unless treatment with armodafinil tablet has been shown to produce levels of wakefulness that permit such activities. Advise patients that armodafinil tablet is not replacement for sleep. Continuing Previously Prescribed TreatmentsInform patients that it may be critical that they continue to take their previously prescribed treatments (e.g., patients with OSA receiving CPAP should continue to do so).Psychiatric SymptomsAdvise patients to stop taking armodafinil tablet and contact their physician right away if they experience, depression, anxiety, or signs of psychosis or mania.PregnancyAdvise women that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to armodafinil tablets during pregnancy [see USE IN SPECIFIC POPULATIONS (8.1)].Females of Reproductive PotentialCaution females regarding the potential increased risk of pregnancy when using hormonal contraceptives (including depot or implantable contraceptives) with armodafinil tablet and advise females who are using hormonal method of contraception to use an additional barrier method or an alternative non-hormonal method of contraception during treatment with armodafinil tablet and for one month after discontinuation of armodafinil tablet.Concomitant MedicationAdvise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, because of the potential for interactions between armodafinil and other drugs.AlcoholAdvise patients that the use of armodafinil tablet in combination with alcohol has not been studied. Advise patients that it is prudent to avoid alcohol while taking armodafinil tablet.Manufactured for:Lupin Pharmaceuticals, Inc.Baltimore, Maryland 21202United States.Manufactured by:Lupin LimitedGoa 403 722INDIA.Revised: May 2017 ID: 251372.

SPL MEDGUIDE SECTION.


MEDICATION GUIDEARMODAFINIL (ar moe daf nil)TABLETS C-IVWhat is the most important information should know about armodafinil tabletsArmodafinil tablet is federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep armodafinil in safe place to prevent misuse and abuse. Selling or giving away armodafinil 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.Armodafinil tablet 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 armodafinil tablet and call your doctor right away or get emergency help if you have any of these symptoms:skin rash, hives, sores in your mouth, or your skin blisters and peels swelling of your face, eyes, lips, tongue, or throat trouble swallowing, breathing or hoarseness 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 armodafinil tablet, stopping the medicine may not keep the rash from becoming life-threatening or causing you to be permanently disabled or disfigured.Armodafinil tablet is not approved for use in children for any medical condition.It is not known if armodafinil tablet is safe and effective in children under the age of 18.What is armodafinil tabletArmodafinil tablet is prescription medicine used to improve wakefulness in adults who are very sleepy due to one of the following diagnosed sleep disorders:narcolepsy obstructive sleep apnea (OSA). Armodafinil tablet is used with other medical treatments for this sleep disorder. Armodafinil tablet does not take the place of using your CPAP machine or other treatments that your doctor has prescribed for this condition. It is important that you continue to use these treatments as prescribed by your doctor. shift work disorder (SWD) Armodafinil tablet will not cure these sleep disorders. Armodafinil tablet may help the sleepiness caused by these conditions, but it may not stop all your sleepiness. Armodafinil tablet does not take the place of getting enough sleep. Follow your doctors advice about good sleep habits and using other treatments.Do not take armodafinil tablet:are allergic to any of its ingredients. See the end of this Medication Guide for complete list of ingredients in armodafinil tablet. have had rash or allergic reaction to either armodafinil or modafinil (PROVIGIL(R)). These medicines are very similar. Before you take armodafinil, tell your doctor about all of your medical conditions, including if you:have history of mental health problems, including psychosis have heart problems or had heart attack have high blood pressure. Your blood pressure may need to be checked more often while taking armodafinil tablet. have liver or kidney problems have history of drug or alcohol abuse or addiction are pregnant or planning to become pregnant. It is not known if armodafinil tablet will harm your unborn baby. are breastfeeding. It is not known if armodafinil passes into your milk. Talk to your doctor about the best way to feed your baby if you take armodafinil tablet. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Armodafinil tablet and many other medicines can interact with each other, sometimes causing side effects. Armodafinil tablet may affect the way other medicines work, and other medicines may affect how armodafinil tablet works. Your dose of armodafinil tablet or certain other medicines may need to be changed.Especially, tell your doctor if you use or take: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 armodafinil tablet. Women who use one of these methods of birth control may have higher chance for getting pregnant while taking armodafinil tablet, and for month after stopping armodafinil tablet. You should use effective birth control while taking armodafinil and for month after your final dose. Talk to your doctor about birth control choices that are right for you while taking armodafinil tablet.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 armodafinil tablet and other medicines together. Do not start any new medicines with armodafinil tablet unless your doctor has told you it is okay.How should take armodafinil tabletTake armodafinil tablet exactly as prescribed by your doctor. Your doctor will prescribe the dose of armodafinil tablet that is right for you. Do not change your dose of armodafinil tablet without talking to your doctor. Your doctor will tell you the right time of day to take armodafinil tablet. People with narcolepsy or OSA usually take armodafinil tablet one time each day in the morning. People with SWD usually take armodafinil tablet about hour before their work shift. Do not change the time of day you take armodafinil tablet unless you have talked to your doctor. If you take armodafinil tablet too close to your bedtime, you may find it harder to go to sleep. You can take armodafinil tablet with or without food. If you take more than your prescribed dose or if you take an overdose of armodafinil tablet, call your doctor or poison control center right away. Symptoms of an overdose of armodafinil tablet may include:Trouble sleeping Restlessness Confusion Feeling disoriented Feeling excited Hearing, seeing, feeling, or sensing things that are not really there (hallucinations) Nausea and diarrhea fast or slow heartbeat Chest pain Increased blood pressure Anxiety Shortness of breath What should avoid while taking armodafinil tabletDo not drive car or do other dangerous activities until you know how armodafinil tablet affects 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. You should avoid drinking alcohol. It is not known how drinking alcohol will affect you when taking armodafinil tablet. What are possible side effects of armodafinil tabletArmodafinil tablet may cause serious side effects. Stop taking armodafinil tablet and call your doctor right away or get emergency help if you get any of the following:a serious rash or serious allergic reaction. (See What is the most important information should know about armodafinil tablet) mental (psychiatric) symptoms, including: depression feeling anxious hearing, seeing, feeling, or sensing things that are not really there (hallucinations) an extreme increase in activity and talking (mania) thoughts of suicide aggressive behavior other mental problems symptoms of heart problem, including chest pain, abnormal heart beats, and trouble breathing.The most common side effects of armodafinil tablets include:headache nausea dizziness trouble sleeping These are not all the possible side effects of armodafinil 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 armodafinil tabletStore armodafinil tablets at room temperature between 68 to 77 (20 to 25 C). Keep armodafinil tablets and all medicines out of the reach of children. General information about the safe and effective use of armodafinil tabletMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use armodafinil tablet for condition for which it was not prescribed. Do not give armodafinil tablet to other people, even if they have the same symptoms that you have. It may harm them and is against the law.You can ask your pharmacist or healthcare provider for information about armodafinil tablet that is written for health professionals. For more information, go to www.lupinpharmaceuticals.com or call 1-800-399-2561What are the ingredients in armodafinil tabletActive ingredient: armodafinilInactive ingredients: lactose monohydrate, povidone, pregelatinised starch, sodium starch glycolate and sodium stearyl fumarateThis Medication Guide has been approved by the U.S. Food and Drug AdministrationPROVIGIL(R) is registered trademark of Cephalon, Inc.Manufactured for:Lupin Pharmaceuticals, Inc.Baltimore, Maryland 21202United StatesManufactured by:Lupin LimitedGoa 403 722INDIA.Revised: May 2017 ID: 251373.

USE IN SPECIFIC POPULATIONS SECTION.


8.1 PregnancyRisk SummaryLimited available data on armodafinil use in pregnant women are insufficient to inform 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 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 to 4% and 15 to 20%, respectively.DataAnimal 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 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 plasma armodafinil AUC less than that in humans at the MRHD of armodafinil tablets. However, in subsequent rat study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed.In 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 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, dose resulting in 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.8.2 LactationRisk SummaryThere 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 mothers clinical need for armodafinil and any potential adverse effects on the breastfed child from armodafinil or from the underlying maternal condition.8.3 Females and Males of Reproductive PotentialThe effectiveness of hormonal contraceptives may be reduced when used with armodafinil and for one month after discontinuation of therapy. Advise women who are using hormonal method of contraception to use an additional barrier method or an alternative non-hormonal method of contraception during treatment with armodafinil and for one month after discontinuation of armodafinil treatment [see DRUG INTERACTIONS (7) and CLINICAL PHARMACOLOGY (12.3)].8.4 Pediatric UseSafety 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)].8.5 Geriatric UseIn elderly patients, elimination of armodafinil 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 ImpairmentThe dosage of armodafinil tablets should be reduced in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION (2.3) and CLINICAL PHARMACOLOGY (12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5.1 Serious Dermatologic Reactions, including Stevens Johnson Syndrome and Toxic Epidermal NecrosisSerious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of armodafinil or modafinil (the racemic mixture of S- and R-enantiomers).Armodafinil has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication.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/Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) [see WARNINGS AND PRECAUTIONS (5.2)]. 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.Skin and mouth sores, blistering, and ulceration have been reported with modafinil and armodafinil in the postmarketing setting. Recurrence of signs and symptoms of serious dermatologic reactions following rechallenge has been reported in some cases.Rare cases of serious or life-threatening rash, including SJS and toxic epidermal necrolysis (TEN), have been reported in adults and children in worldwide post-marketing experience with modafini and armodafinil.There are no factors, including duration of therapy, that are known to predict the risk of occurrence or the severity of rash associated with modafinil or armodafinil. In cases where the time to onset was reported, serious rash occurred day to months after initiation of treatment, but isolated cases of serious dermatologic reactions have been reported with symptoms beginnings after prolonged treatment (e.g., months).Although benign rashes also occur with armodafinil, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, armodafinil should be discontinued at the first sign of rash, skin or mouth sores, or blistering or ulceration, 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 Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan HypersensitivityDRESS, also known as multi-organ hypersensitivity, has been reported with armodafinil. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident.One fatal case of DRESS that occurred in close temporal association (3 weeks) with the initiation of armodafinil treatment has been reported in the postmarketing setting. In addition, multi-organ hypersensitivity reactions, including at least one fatality in post-marketing 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.If multi-organ hypersensitivity reaction is suspected, armodafinil 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.5.3 Angioedema and Anaphylaxis ReactionsAngioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed with armodafinil. 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).5.4 Persistent SleepinessPatients with abnormal levels of sleepiness who take armodafinil should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking armodafinil, 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 SymptomsIn pre-approval narcolepsy, OSA and SWD controlled trials of armodafinil, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on armodafinil compared to placebo (armodafinil 1.2% and placebo 0.3%). Depression was also reason for treatment discontinuation more often in patients on armodafinil compared to placebo (armodafinil 0.6% and placebo 0.2%). Cases of suicidal ideation were observed in clinical trials.Caution should be exercised when armodafinil is given to patients with history of psychosis, depression, or mania. If psychiatric symptoms develop in association with armodafinil administration, consider discontinuing armodafinil.Psychiatric adverse reactions have been reported in patients treated with modafinil. Modafinil and armodafinil are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with armodafinil are expected to be similar to the incidence and type of these events with modafinil.Post-marketing adverse reactions associated with the use of armodafinil, some of which have resulted in hospitalization, have included mania, delusions, hallucinations, suicidal ideation, and aggression. Many, but not all, patients who developed psychiatric adverse reactions had prior psychiatric history. In these cases, reported armodafinil total daily doses ranged from 50 mg to 450 mg, which includes doses below and above the recommended dosages.5.6 Effects on Ability to Drive and Use MachineryAlthough armodafinil has not been shown to produce functional impairment, any drug affecting the central nervous system (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 armodafinil therapy will not adversely affect their ability to engage in such activities.5.7 Cardiovascular EventsIn clinical studies of modafinil, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea and transient ischemic T- wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that armodafinil tablets not be used 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.Blood pressure monitoring in short term (<= months) pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving armodafinil as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also slightly greater proportion of patients on armodafinil requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to 3.5 BPM. Increased monitoring of heart rate and blood pressure may be appropriate in patients on armodafinil. Caution should be exercised when prescribing armodafinil to patients with known cardiovascular disease.