Armodafinil

Warnings and Precautions ( 5.1 , 5.2 , 5.5 ) 02/2017

1 INDICATIONS AND USAGE 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 Use In 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 a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating armodafinil tablets for excessive sleepiness. 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). ( 1 ) Limitations of Use In OSA, armodafinil tablets are indicated to treat excessive sleepiness and not as treatment for the underlying obstruction.

2 DOSAGE AND ADMINISTRATION The recommended dosage of armodafinil tablets for each indication is as follows: • OSA or Narcolepsy: 150 mg to 250 mg once a day in the morning. ( 2.1 ) • SWD: 150 mg once a day, taken approximately one hour prior to start of the work shift. ( 2.2 ) • Hepatic Impairment: reduced dose in patients with severe hepatic impairment. ( 2.3 , 12.3 ) • Geriatric Patients: consider lower dose. ( 2.4 , 12.3 ) 2.1 Dosage in Obstructive Sleep Apnea (OSA) and Narcolepsy The recommended dosage of armodafinil tablets for patients with OSA or narcolepsy is 150 mg to 250 mg taken orally once a day as a single dose in the morning. In patients with OSA, doses up to 250 mg/day, given as a 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 a day as a single dose approximately 1 hour prior to the start of their work shift. 2.3 Dosage Modification in Patients with Severe Hepatic Impairment In 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 Patients Consideration should be given to the use of lower doses and close monitoring in geriatric patients [see Use in Specific Populations (8.5) ] .

2.1 Dosage in Obstructive Sleep Apnea (OSA) and Narcolepsy The recommended dosage of armodafinil tablets for patients with OSA or narcolepsy is 150 mg to 250 mg taken orally once a day as a single dose in the morning. In patients with OSA, doses up to 250 mg/day, given as a 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 a day as a single dose approximately 1 hour prior to the start of their work shift. 2.3 Dosage Modification in Patients with Severe Hepatic Impairment In 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 Patients Consideration should be given to the use of lower doses and close monitoring in geriatric patients [see Use in Specific Populations (8.5)].

50 mg – round, white to off-white tablet with formw on one side and "205" on the other 150 mg – oval, white to off-white tablet with formw on one side and "215" on the other 200 mg – rounded, rectangular, white to off-white tablet with formw on one side and "220" on the other 250 mg – oval, white to off-white tablet with formw on one side and "225" on the other

4 CONTRAINDICATIONS Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil or their inactive ingredients [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil. ( 4 )

6 ADVERSE REACTIONS 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) ] Most common adverse reactions (≥ 5%): headache, nausea, dizziness, and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Armodafinil tablets have been evaluated for safety in over 1,100 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy. Most Common Adverse Reactions In the placebo-controlled clinical trials, the most common adverse reactions (≥ 5%) associated with the use of armodafinil tablets more frequently than in placebo-treated patients were headache, nausea, dizziness, and insomnia. The adverse reaction profile was similar across the studies. Table 1 presents the adverse reactions that occurred at a rate of 1% or more and were more frequent in armodafinil tablet-treated patients than in placebo-treated patients in the placebo-controlled clinical trials. Table 1: Adverse Reactions in Pooled Placebo-Controlled Clinical Trials Adverse reactions that occurred in ≥ 1% of armodafinil tablet-treated patients and greater incidence than that of placebo. in OSA, Narcolepsy, and SWD with Armodafinil Tablets (150 mg and 250 mg) Armodafinil Tablets (%) N = 645 Placebo (%) N = 445 Headache 17 9 Nausea 7 3 Dizziness 5 2 Insomnia 5 1 Anxiety 4 1 Diarrhea 4 2 Dry Mouth 4 1 Depression 2 0 Dyspepsia 2 0 Fatigue 2 1 Palpitations 2 1 Rash 2 0 Upper Abdominal Pain 2 1 Agitation 1 0 Anorexia 1 0 Constipation 1 0 Contact Dermatitis 1 0 Decreased Appetite 1 0 Depressed Mood 1 0 Disturbance In Attention 1 0 Dyspnea 1 0 Hyperhydrosis 1 0 Increased Gamma-Glutamyltransferase 1 0 Increased Heart Rate 1 0 Influenza-Like Illness 1 0 Loose Stools 1 0 Migraine 1 0 Nervousness 1 0 Pain 1 0 Paresthesia 1 0 Polyuria 1 0 Pyrexia 1 0 Seasonal Allergy 1 0 Thirst 1 0 Tremor 1 0 Vomiting 1 0 Dose-Dependent Adverse Reactions In the placebo-controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of armodafinil tablets and placebo, the following adverse reactions were dose-related: headache, rash, depression, dry mouth, insomnia, and nausea. See Table 2 for additional information. Table 2: Dose-Dependent Adverse Reactions in Pooled Placebo-Controlled Clinical Trials in OSA, Narcolepsy and SWD Armodafinil Tablets 250 mg (%) N = 198 Armodafinil Tablets 150 mg (%) N = 447 Armodafinil Tablets Combined (%) N = 645 Placebo (%) N = 445 Headache 23 14 17 9 Nausea 9 6 7 3 Insomnia 6 4 5 1 Dry Mouth 7 2 4 < 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 fo …

7 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 tablet 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. • Steroidal contraceptives (e.g., ethinyl estradiol): use alternative or concomitant methods of contraception while taking armodafinil tablets and for one month after discontinuation of armodafinil tablet treatment. ( 7 ) • Cyclosporine: blood concentrations of cyclosporine may be reduced. ( 7 ) • CYP2C19 substrates, such as omeprazole, phenytoin, and diazepam: exposure of these medications may be increased. ( 7 )

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 enzyme …

8 USE IN SPECIFIC POPULATIONS Pregnancy: based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Pregnancy Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to armodafinil during pregnancy. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-866-404-4106. 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 to 4% and 15 to 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 (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. 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. 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. No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring. 8.2 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 armo …

12.1 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 α 1 -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.

11 DESCRIPTION Armodafinil tablets are 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 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: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch. chemical structure

10 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.

16.1 How Supplied Armodafinil Tablets, 50 mg are white to off-white, round shaped uncoated tablets debossed with ‘K’ on one side and ‘58’ on the other side. Armodafinil Tablets, 150 mg are white to off-white, oval shaped uncoated tablets debossed with ‘K’ on one side and ‘59’ on the other side. Armodafinil Tablets, 200 mg are white to off-white rounded, rectangular uncoated tablets debossed with ‘10’ on one side and ‘N’ on the other side. Armodafinil Tablets, 250 mg are white to off-white, oval shaped uncoated tablets debossed with ‘K’ on one side and ‘60’ on the other side. 16.2 Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

16.1 How Supplied Armodafinil Tablets, 50 mg are white to off-white, round shaped uncoated tablets debossed with ‘K’ on one side and ‘58’ on the other side. Armodafinil Tablets, 150 mg are white to off-white, oval shaped uncoated tablets debossed with ‘K’ on one side and ‘59’ on the other side. Armodafinil Tablets, 200 mg are white to off-white rounded, rectangular uncoated tablets debossed with ‘10’ on one side and ‘N’ on the other side. Armodafinil Tablets, 250 mg are white to off-white, oval shaped uncoated tablets debossed with ‘K’ on one side and ‘60’ on the other side. 16.2 Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

16.1 How Supplied Armodafinil Tablets, 50 mg are white to off-white, round shaped uncoated tablets debossed with ‘K’ on one side and ‘58’ on the other side. Armodafinil Tablets, 150 mg are white to off-white, oval shaped uncoated tablets debossed with ‘K’ on one side and ‘59’ on the other side. Armodafinil Tablets, 200 mg are white to off-white rounded, rectangular uncoated tablets debossed with ‘10’ on one side and ‘N’ on the other side. Armodafinil Tablets, 250 mg are white to off-white, oval shaped uncoated tablets debossed with ‘K’ on one side and ‘60’ on the other side. 16.2 Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].