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| Product NDC Code | 69339-179 | ||||||
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| Drug Name | Armodafinil |
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| Type | Generic | ||||||
| Active Ingredients |
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| Route | ORAL | ||||||
| Dosage Form | TABLET | ||||||
| RxCUI drug identifier | 724859, 724861, 724863, 861960 |
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| Application Number | ANDA202768 | ||||||
| Labeler Name | Natco Pharma USA LLC | ||||||
| Packages |
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Abuse
Information about the types of abuse that can occur with the drug and adverse reactions pertinent to those types of abuse, primarily based on human data. May include descriptions of particularly susceptible patient populations.9.2 Abuse Abuse of armodafinil tablets 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 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).
Controlled substance
Information about the schedule in which the drug is controlled by the Drug Enforcement Administration, if applicable.9.1 Controlled Substance Armodafinil tablets contain armodafinil, a Schedule IV controlled substance.
Dependence
Information about characteristic effects resulting from both psychological and physical dependence that occur with the drug, the quantity of drug over a period of time that may lead to tolerance or dependence, details of adverse effects related to chronic abuse and the effects of abrupt withdrawl, procedures necessary to diagnose the dependent state, and principles of treating the effects of abrupt withdrawal.9.3 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.
Drug abuse and dependence
Information about whether the drug is a controlled substance, the types of abuse that can occur with the drug, and adverse reactions pertinent to those types of abuse.9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Armodafinil tablets contain armodafinil, a Schedule IV controlled substance. 9.2 Abuse Abuse of armodafinil tablets 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 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). 9.3 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 of Armodafinil
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.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.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.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 NATCO PHARMA USA LLC at 1-201-786-6500 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 tablets-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 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 * Adverse reactions that occurred in ≥ 1% of armodafinil tablets-treated patients and greater incidence than that of placebo. 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 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. 6.2 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)
| 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 |
| 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 |
Armodafinil Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.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 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. 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 tablets 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 )
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 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 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. 12.3 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 modafinil (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 modafinil 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) ].
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.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 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
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 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 modafinil (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 modafinil 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) ].
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS 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) ]. Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 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 50,150,200 and 250 mg of armodafinil and the following inactive ingredients: anhydrous lactose, croscarmellose sodium, magnesium stearate, povidone and pregelatinized starch. Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.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 )].
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS 50 mg - Each white to off-white round tablet is debossed with ‘E226’ on one side and plain on the other side. 150 mg - Each white to off-white oval-shaped tablet is debossed with ‘E227’ on one side and plain on the other side. 200 mg: Each white to off-white, rectangular shaped tablets debossed with ‘200’ on one side and ‘N’ on other side. 250 mg - Each white to off-white oval-shaped tablet is debossed with ‘NAT375’ on one side and plain on the other side. Tablets: 50 mg, 150 mg, 200 mg and 250 mg. ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.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.
Spl product data elements
Usually a list of ingredients in a drug product.Armodafinil Armodafinil ARMODAFINIL ARMODAFINIL ANHYDROUS LACTOSE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE POVIDONE STARCH, PREGELATINIZED CORN White to off-white E226 Armodafinil Armodafinil ARMODAFINIL ARMODAFINIL ANHYDROUS LACTOSE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE POVIDONE STARCH, PREGELATINIZED CORN White to off-white E227 Armodafinil Armodafinil ARMODAFINIL ARMODAFINIL ANHYDROUS LACTOSE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE POVIDONE STARCH, PREGELATINIZED CORN White to off-white NAT375 Armodafinil Armodafinil ARMODAFINIL ARMODAFINIL ANHYDROUS LACTOSE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE POVIDONE STARCH, PREGELATINIZED CORN White to off-white NAT375
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 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.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 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.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.Armodafinil Tablets 50mg- Bottle of 30 tablets NDC 69339-177-03 R X Only 30 Tablets Each tablet contains 50 mg armodafinil Dispense in a tight container as defined in the USP. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Store at 20°-25°C (68°-77°F).[See USP Controlled Room Temperature] Usual Dosage: See package insert. bottle-label
Armodafinil Tablets 50mg- Bottle of 1000 tablets NDC 69339-177-10 R X Only 1000 Tablets Each tablet contains 50 mg armodafinil Dispense in a tight container as defined in the USP. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Store at 20°-25°C (68°-77°F).[See USP Controlled Room Temperature] Usual Dosage: See package insert . bottle-label
Armodafinil Tablets 150mg- Bottle of 30 tablets NDC 69339-178-03 R X Only 30 Tablets Each tablet contains 150 mg armodafinil Dispense in a tight container as defined in the USP. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Store at 20°-25°C (68°-77°F).[See USP Controlled Room Temperature] Usual Dosage: See package insert. bottle-label
Armodafinil Tablets 150mg- Bottle of 1000 tablets NDC 69339-178-10 R X Only 1000 Tablets Each tablet contains 150 mg armodafinil Dispense in a tight container as defined in the USP. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Store at 20°-25°C (68°-77°F).[See USP Controlled Room Temperature] Usual Dosage: See package insert. bottle-label
Armodafinil Tablets 200mg- Bottle of 30 tablets NDC 69339-179-03 R X Only 30 Tablets Each tablet contains 200mg armodafinil Dispense in a tight container as defined in the USP. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Store at 20°-25°C (68°-77°F).[See USP Controlled Room Temperature] Usual Dosage: See package insert. bottle-label
Armodafinil Tablets 200mg- Bottle of 1000 tablets NDC 69339-179-10 R X Only 1000 Tablets Each tablet contains 200 mg armodafinil Dispense in a tight container as defined in the USP. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Store at 20°-25°C (68°-77°F).[See USP Controlled Room Temperature] Usual Dosage: See package insert. bottle-label
Armodafinil Tablets 250mg- Bottle of 30 tablets NDC 69339-180-03 R X Only 30 Tablets Each tablet contains 250 mg armodafinil Dispense in a tight container as defined in the USP. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Store at 20°-25°C (68°-77°F).[See USP Controlled Room Temperature] Usual Dosage: See package insert. Bottle-Label
Armodafinil Tablets 250mg-Bottle of 500 tablets NDC 69339-180-05 R X Only 500 Tablets Each tablet contains 250 mg armodafinil Dispense in a tight container as defined in the USP. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Store at 20°-25°C (68°-77°F).[See USP Controlled Room Temperature] Usual Dosage: See package insert. bottle-label
Armodafinil: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Serious Dermatologic Reactions Advise patients and caregivers about the risk of potentially fatal serious skin reactions. Educate patients about the signs and symptoms that may signal a serious skin reaction. Instruct patients to discontinue armodafinil tablets and consult with their healthcare provider immediately if a 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 Hypersensitivity Instruct patients that a 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 Reactions Advise 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 tablets. Instruct them to discontinue armodafinil tablets and immediately report these symptoms to their healthcare provider [see Warnings and Precautions (5.3) ]. Wakefulness Advise patients that treatment with armodafinil tablets 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 tablets has been shown to produce levels of wakefulness that permit such activities. Advise patients that armodafinil tablets are not a replacement for sleep. Continuing Previously Prescribed Treatments Inform 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 Symptoms Advise patients to stop taking armodafinil tablets and contact their physician right away if they experience, depression, anxiety, or signs of psychosis or mania. Pregnancy Advise women that there is a 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 Potential Caution females regarding the potential increased risk of pregnancy when using hormonal contraceptives (including depot or implantable contraceptives) with armodafinil tablets and advise females 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. Concomitant Medication Advise 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 tablets and other drugs. Alcohol Advise patients that the use of armodafinil tablets in combination with alcohol has not been studied. Advise patients that it is prudent to avoid alcohol while taking armodafinil tablets. All the registered trademarks used herein are the property of their respective owners. Manufactured by: NATCO PHARMA LIMITED Kothur - 509 228, India Manufactured for: NATCO Pharma USA LLC, Parsippany, NJ 07054, USA Revised: Dec/2023
Spl medguide
Information about the patient medication guide that accompanies the drug product. Certain drugs must be dispensed with an accompanying medication guide. This field may contain information about when to consult the medication guide and the contents of the medication guide.MEDICATION GUIDE Armodafinil (AR-moe-DAF-i-nil) tablets, for oral use, C-IV What is the most important information I should know about armodafinil tablets? Armodafinil tablet is a federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep armodafinil tablets in a safe place to prevent misuse and abuse. Selling or giving away armodafinil tablets 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 tablets may cause serious side effects including a serious rash or a 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 a hospital and may be life-threatening. Stop taking armodafinil tablets 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 a severe rash with armodafinil tablets, stopping the medicine may not keep the rash from becoming life-threatening or causing you to be permanently disabled or disfigured. Armodafinil tablets are not approved for use in children for any medical condition. It is not known if armodafinil tablets are safe and effective in children under the age of 18. What are armodafinil tablets? Armodafinil tablets are a 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 tablets are used with other medical treatments for this sleep disorder. Armodafinil tablets do 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 tablets will not cure these sleep disorders. Armodafinil tablets may help the sleepiness caused by these conditions, but they may not stop all your sleepiness. Armodafinil tablets do not take the place of getting enough sleep. Follow your doctor’s advice about good sleep habits and using other treatments. Do not take armodafinil tablets: are allergic to any of its ingredients. See the end of this Medication Guide for a complete list of ingredients in armodafinil tablets. have had a rash or allergic reaction to either armodafinil or modafinil. These medicines are very similar. Before you take armodafinil tablets, tell your doctor about all of your medical conditions, including if you: have a history of mental health problems, including psychosis have heart problems or had a heart attack have high blood pressure. Your blood pressure may need to be checked more often while taking armodafinil tablets. have liver or kidney problems have a history of drug or alcohol abuse or addiction are pregnant or planning to become pregnant. It is not known if armodafinil tablets will harm your unborn baby. Pregnancy Registry : There is a registry for women who become pregnant during treatment with armodafinil tablets. The purpose of this registry is to collect information about the safety of armodafinil tablets during pregnancy. Contact the registry as soon as you learn that you are pregnant, or ask your doctor to contact the registry for you. You or your doctor can get information and enroll you in the registry by calling 1-866-404-4106. 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 tablets. Tell your doctor about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Armodafinil tablets and many other medicines can interact with each other, sometimes causing side effects. Armodafinil tablets may affect the way other medicines work, and other medicines may affect how armodafinil tablets work. Your dose of armodafinil tablets 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 tablets. Women who use one of these methods of birth control may have a higher chance for getting pregnant while taking armodafinil tablets, and for 1 month after stopping armodafinil tablets. You should use effective birth control while taking armodafinil tablets and for 1 month after your final dose. Talk to your doctor about birth control choices that are right for you while taking armodafinil tablets. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. Your doctor or pharmacist will tell you if it is safe to take armodafinil tablets and other medicines together. Do not start any new medicines with armodafinil tablets unless your doctor has told you it is okay. How should I take armodafinil tablets? Take armodafinil tablets exactly as prescribed by your doctor. Your doctor will prescribe the dose of armodafinil tablets that is right for you. Do not change your dose of armodafinil tablets without talking to your doctor. Your doctor will tell you the right time of day to take armodafinil tablets. o People with narcolepsy or OSA usually take armodafinil tablets one time each day in the morning. o People with SWD usually take armodafinil tablets about 1 hour before their work shift. Do not change the time of day you take armodafinil tablets unless you have talked to your doctor. If you take armodafinil tablets too close to your bedtime, you may find it harder to go to sleep. You can take armodafinil tablets with or without food. If you take more than your prescribed dose or if you take an overdose of armodafinil tablets, call your doctor or poison control center right away. Symptoms of an overdose of armodafinil tablets may include: Trouble sleeping Confusion Feeling excited Nausea and diarrhea Chest pain Anxiety Restlessness Feeling disoriented Hearing, seeing, feeling, or sensing things that are not really there (hallucinations) A fast or slow heartbeat Increased blood pressure Shortness of breath What should I avoid while taking armodafinil tablets? Do not drive a car or do other dangerous activities until you know how armodafinil tablets affect 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 tablets. What are possible side effects of armodafinil tablets? Armodafinil tablets may cause serious side effects . Stop taking armodafinil tablets 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 I should know about armodafinil tablets?”) mental (psychiatric) symptoms, including: o depression o hearing, seeing, feeling, or sensing things that are not really there (hallucinations) o thoughts of suicide o other mental problems o feeling anxious o an extreme increase in activity and talking (mania) o aggressive behavior symptoms of a heart problem, including chest pain, abnormal heart beats, and trouble breathing. The most common side effects of armodafinil tablets include: headache dizziness nausea 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 I store armodafinil tablets? Store armodafinil tablets at room temperature between 68° to 77° F (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 tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use armodafinil tablets for a condition for which they were not prescribed. Do not give armodafinil tablets to other people, even if they have the same symptoms that you have. It may harm them and it is against the law. You can ask your pharmacist or healthcare provider for information about armodafinil tablets that is written for health professionals. What are the ingredients in armodafinil tablets? Active Ingredient : armodafinil Inactive Ingredients : anhydrous lactose, croscarmellose sodium, magnesium stearate, povidone and pregelatinized starch. All the registered trademarks used herein are the property of their respective owners. Manufactured by: NATCO PHARMA LIMITED Kothur - 509 228, India Manufactured for: NATCO Pharma USA LLC, Parsippany, NJ 07054, USA For more information, call 1-888-483-8279. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: Dec/2023
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 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. 14.2 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 less and the absence of any other clinically significant active medical or psychiatric disorder. The MSLT, an objective polysomnographic assessment of the patient’s ability to fall asleep in an unstimulating environment, measured latency (in minutes) to sleep onset averaged over 4 test sessions at 2-hour intervals. For each test session, the subject was told to lie quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset. 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 CGI-C at the final visit [see Clinical Studies (14.1) for a description of these measures] . Each MWT test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset in this study. Patients treated with armodafinil tablets showed a statistically significantly enhanced ability to remain awake on the MWT at each dose compared to placebo at final visit [ Table 3 ]. A statistically significant greater number of patients treated with armodafinil tablets at each dose showed improvement in overall clinical condition as rated by the CGI-C scale at final visit [ Table 4 ]. The two doses of armodafinil tablets produced statistically significant effects of similar magnitudes on the CGI-C. Although a statistically significant effect on the MWT was observed for each dose, the magnitude of effect was observed to be greater for the higher dose. Nighttime sleep measured with polysomnography was not affected by the use of armodafinil tablets. 14.3 Shift Work Disorder (SWD) The effectiveness of armodafinil tablets in improving wakefulness in patients with excessive sleepiness associated with SWD was demonstrated in a 12-week, multi-center, double-blind, placebo-controlled, parallel-group clinical trial. A total of 254 patients with chronic SWD were randomized to receive armodafinil tablets 150 mg/day or placebo. All patients met the criteria for chronic SWD. The criteria include: 1) either, a) a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms; and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change [jet lag] syndrome). It should be noted that not all patients with a complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWD. In the clinical trial, only patients who were symptomatic for at least 3 months were enrolled. Enrolled patients were also required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score ≤ 6 minutes), and have daytime insomnia documented by a daytime polysomnogram. The primary measures of effectiveness were: 1) sleep latency, as assessed by the Multiple Sleep Latency Test (MSLT) performed during a simulated night shift at the final visit; and 2) the change in the patient’s overall disease status, as measured by the CGI-C at the final visit [see Clinical Studies (14.1) for a description of these measures]. Patients treated with armodafinil tablets showed a statistically significant prolongation in the time to sleep onset compared to placebo-treated patients, as measured by the nighttime MSLT at final visit (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 at final visit ( Table 4 ). Daytime sleep measured with polysomnography was not affected by the use of armodafinil tablets. Table 3: Average Baseline Sleep Latency and Change from Baseline at Final Visit (MWT and MSLT in minutes) Disorder Measure Armodafinil Tablets 150 mg* Armodafinil Tablets 250 mg* Placebo Baseline Change from Baseline Baseline Change from Baseline Baseline Change from Baseline OSA I MWT 21.5 1.7 23.3 2.2 23.2 -1.7 OSA II MWT 23.7 2.3 - - 23.3 -1.3 Narcolepsy MWT 12.1 1.3 9.5 2.6 12.5 -1.9 SWD MSLT 2.3 3.1 - - 2.4 0.4 *Significantly different than placebo for all trials (p<0.05) Table 4: Clinical Global Impression of Change (CGI-C) (Percent of Patients Who Improved at Final Visit) Disorder Armodafinil Tablets 150 mg* Armodafinil Tablets 250 mg* Placebo OSA I 71% 74% 37% OSA II 71% - 53% Narcolepsy 69% 73% 33% SWD 79% - 59% *Significantly different than placebo for all trials (p<0.05).
| OSA I | MWT | 21.5 | 1.7 | 23.3 | 2.2 | 23.2 | -1.7 |
| OSA II | MWT | 23.7 | 2.3 | - | - | 23.3 | -1.3 |
| Narcolepsy | MWT | 12.1 | 1.3 | 9.5 | 2.6 | 12.5 | -1.9 |
| SWD | MSLT | 2.3 | 3.1 | - | - | 2.4 | 0.4 |
| OSA I | 71% | 74% | 37% |
| OSA II | 71% | - | 53% |
| Narcolepsy | 69% | 73% | 33% |
| SWD | 79% | - | 59% |
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 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) ].
Labor and delivery
Information about the drug’s use during labor or delivery, whether or not the use is stated in the indications section of the labeling, including the effect of the drug on the mother and fetus, on the duration of labor or delivery, on the possibility of delivery-related interventions, and the effect of the drug on the later growth, development, and functional maturation of the child.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 armodafinil or from the underlying maternal condition.
Nursing mothers
Information about excretion of the drug in human milk and effects on the nursing infant, including pertinent adverse effects observed in animal offspring.8.3 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 armodafinil tablets of treatment [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 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) ].
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 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 (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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Pregnancy: based on animal data, may cause fetal harm. ( 8.1 ) 8.1 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 (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. 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 armodafinil or from the underlying maternal condition. 8.3 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 armodafinil tablets of treatment [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. 8.4 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) ]. 8.5 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) ]. 8.6 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) ].
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Armodafinil tablets are available as follows: 50 mg: Each white to off-white round tablet is debossed with ‘E226’ on one side and plain on the other side. NDC 69339-177-03 Bottles of 30 NDC 69339-177-10 Bottles of 1000 150 mg: Each white to off-white oval-shaped tablet is debossed with ‘E227’ on one side and plain on the other side. NDC 69339-178-03 Bottles of 30 NDC 69339-178-10 Bottles of 1000 200 mg: Each white to off-white, rectangular shaped tablets debossed with ‘200’ on one side and ‘N’ on other side. NDC 69339-179-03 Bottles of 30 NDC 69339-179-10 Bottles of 1000 250 mg: Each white to off-white oval-shaped tablet is debossed with ‘NAT375’ on one side and plain on the other side. NDC 69339-180-03 Bottles of 30 NDC 69339-180-05 Bottles of 500 16.2 Storage Store at 20º - 25° C (68º - 77º F).
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API