Armodafinil 50 mg Tablet, 30-count — NDC 72189-464-30 (Billing 72189-0464-30)

5.1Serious Dermatologic Reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrosis Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of armodafinil or modafinil (the racemic mixture of S- and R-enantiomers). Armodafinil has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication. In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction/ Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) [see WARNINGS AND PRECAUTIONS (5.2)].

Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo.

Skin and mouth sores, blistering, and ulceration have been reported with modafinil and armodafinil in the postmarketing setting. Recurrence of signs and symptoms of serious dermatologic reactions following rechallenge has been reported in some cases. Rare cases of serious or life-threatening rash, including SJS and toxic epidermal necrolysis (TEN), have been reported in adults and children in worldwide post-marketing experience with modafinil and armodafinil.

There are no factors, including duration of therapy, that are known to predict the risk of occurrence or the severity of rash associated with modafinil or armodafinil. In cases where the time to onset was reported, serious rash occurred 1 day to 2 months after initiation of treatment, but isolated cases of serious dermatologic reactions have been reported with symptoms beginning after prolonged treatment (e.g., 3 months). Although benign rashes also occur with armodafinil, it is not possible to reliably predict which rashes will prove to be serious.

Accordingly, armodafinil should be discontinued at the first sign of rash, skin or mouth sores, or blistering or ulceration, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.

5.2Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity DRESS, also known as multi-organ hypersensitivity, has been reported with armodafinil. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present.

This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. One fatal case of DRESS that occurred in close temporal association (3 weeks) with the initiation of armodafinil treatment has been reported in the postmarketing setting.

In addition, multi-organ hypersensitivity reactions, including at least one fatality in post-marketing experience, have occurred in close temporal association (median time to detection 13 days; range 4 to 33) to the initiation of modafinil. Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. If a multi-organ hypersensitivity reaction is suspected, armodafinil should be discontinued.

Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be… [Excerpted — this section continues on DailyMed.]

The following serious adverse reactions are described below and elsewhere in the labeling: Serious Dermatologic Reactions [see WARNINGS AND PRECAUTIONS (5.1)] Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity [see WARNINGS AND PRECAUTIONS (5.2)] Angioedema and Anaphylaxis Reactions [see WARNINGS AND PRECAUTIONS (5.3)] Persistent Sleepiness [see WARNINGS AND PRECAUTIONS (5.4)] Psychiatric Symptoms [see WARNINGS AND PRECAUTIONS (5.5)] Effects on Ability to Drive and Use Machinery [see WARNINGS AND PRECAUTIONS (5.6)] Cardiovascular Events [see WARNINGS AND PRECAUTIONS (5.7)]

6.1Clinical 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 has 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 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-treated patients than in placebo-treated patients in the placebo-controlled clinical trials. Table 1: Adverse Reactions in Pooled Placebo-Controlled Clinical Trials* in OSA, Narcolepsy, and SWD with Armodafinil (150 mg and 250 mg) * Adverse reactions that occurred in ≥ 1% of armodafinil-treated patients and greater incidence than that of placebo.

Armodafinil (%) N=645 Placebo (%) N=445 Headache 17 9 Nausea 7 3 Dizziness 5 2 Insomnia 5 1 Anxiety 4 1 Diarrhea 4 2 Dry Mouth 4 1 Depression 2 0 Dyspepsia 2 0 Fatigue 2 1 Palpitations 2 1 Rash 2 0 Upper Abdominal Pain 2 1 Agitation 1 0 Anorexia 1 0 Constipation 1 0 Contact Dermatitis 1 0 Decreased Appetite 1 0 Depressed Mood 1 0 Disturbance In Attention 1 0 Dyspnea 1 0 Hyperhydrosis 1 0 Increased Gamma-Glutamyltransferase 1 0 Increased Heart Rate 1 0 Influenza-Like Illness 1 0 Loose Stools 1 0 Migraine 1 0 Nervousness 1 0 Pain 1 0 Paresthesia 1 0 Polyuria 1 0 Pyrexia 1 0 Seasonal Allergy 1 0 Thirst 1 0 Tremor 1 0 Vomiting 1 0 Dose-Dependent Adverse Reactions In the placebo-controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of armodafinil 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 250 mg (%) N=198 Armodafinil 150 mg (%) N=447 Armodafinil 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 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, 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 mil… [Excerpted — this section continues on DailyMed.]

Effects of Armodafinil 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 via induction of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment of these drugs should be considered when these drugs are used concomitantly with armodafinil [see CLINICAL PHARMACOLOGY (12.3)]. The effectiveness of steroidal contraceptives may be reduced when used with armodafinil and for one month after discontinuation of therapy.

Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with armodafinil and for one month after discontinuation of armodafinil treatment. Blood levels of cyclosporine may be reduced when used with armodafinil. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with armodafinil.

Effects of Armodafinil on CYP2C19 Substrates Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by armodafinil via inhibition of metabolic enzymes, with resultant higher systemic exposure. Dose reduction of these drugs may be required when these drugs are used concomitantly with armodafinil. Warfarin More frequent monitoring of prothrombin times/INR should be considered whenever armodafinil is coadministered with warfarin [see CLINICAL PHARMACOLOGY (12.3)].

Monoamine Oxidase (MAO) Inhibitors Caution should be used when concomitantly administering MAO inhibitors and armodafinil.

9.1Controlled Substance Armodafinil is a Schedule IV controlled substance.

9.2Abuse Abuse of armodafinil has been reported in patients treated with armodafinil. Patterns of abuse have included euphoric mood and use of increasingly large doses or recurrent use of armodafinil for a desired effect. Drug diversion has also been noted.

During the postmarketing period, misuse of armodafinil has been observed (e.g., taking armodafinil against a physician’s advice, and obtaining armodafinil from multiple physicians). Abuse of armodafinil, the active ingredient of armodafinil, 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).

9.3Dependence 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. 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 have been reported during the postmarketing period.