INTERACTIONS Effects of Armodafinil Tablets on CYP3A4/5 Substrates: The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by armodafinil tablets via induction of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment of these drugs should be considered when these drugs are used concomitantly with armodafinil tablets [see Clinical Pharmacology (12.3) ] . The effectiveness of steroidal contraceptives may be reduced when used with armodafinil tablets and for one month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with armodafinil tablets and for one month after discontinuation of armodafinil tablet treatment. Blood levels of cyclosporine may be reduced when used with armodafinil tablets. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with armodafinil tablets. Effects of Armodafinil Tablets on CYP2C19 Substrates: Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by armodafinil tablets via inhibition of metabolic enzymes, with resultant higher systemic exposure. Dose reduction of these drugs may be required when these drugs are used concomitantly with armodafinil tablets. Warfarin: More frequent monitoring of prothrombin times/INR should be considered whenever armodafinil tablets are coadministered with warfarin [see Clinical Pharmacology (12.3) ] .
Monoamine
Oxidase (MAO) Inhibitors: Caution should be used when concomitantly administering MAO inhibitors and armodafinil tablets.
- Steroidal contraceptives (e.g., ethinyl estradiol): use alternative or concomitant methods of contraception while taking armodafinil tablets and for one month after discontinuation of armodafinil tablet treatment. ( 7 )
- Cyclosporine: blood concentrations of cyclosporine may be reduced. ( 7 )
- CYP2C19 substrates, such as omeprazole, phenytoin, and diazepam: exposure of these medications may be increased. ( 7 )
Drug
Interactions In vitro data demonstrated that armodafinil weakly induces CYP1A2 and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by armodafinil. Other CYP activities did not appear to be affected by armodafinil. An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein.
Potential
Interactions with Drugs That Inhibit, Induce, or Are Metabolized by Cytochrome P450 Isoenzymes and Other Hepatic Enzymes The existence of multiple pathways for armodafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing armodafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of armodafinil tablets due to CYP inhibition by concomitant medications. However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of armodafinil, coadministration of potent inducers of CYP3A4/5 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4/5 (e.g., ketoconazole, erythromycin) could alter the plasma concentrations of armodafinil.
The
Potential of Armodafinil Tablets to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition
- Drugs Metabolized by CYP3A4/5 In vitro data demonstrated that armodafinil is a weak inducer of CYP3A activity in a concentration-related manner. In a clinical study, concomitant administration of armodafinil tablets 250 mg resulted in a reduction in systemic exposure to midazolam by 32% after a single oral dose (5 mg) and 17% after a single intravenous dose (2 mg). Therefore, the blood levels and effectiveness of drugs that are substrates for CYP3A 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 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) ] .
Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil or their inactive ingredients [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil. ( 4 )
AND PRECAUTIONS Serious Rash, including Stevens-Johnson Syndrome: discontinue NUVIGIL at the first sign of rash, unless the rash is clearly not drug-related. ( 5.1 ) DRESS/Multi-organ Hypersensitivity Reactions: if suspected, discontinue NUVIGIL. ( 5.2 ) Angioedema and Anaphylaxis Reactions: if suspected, discontinue NUVIGIL. ( 5.3 )
Persistent
Sleepiness: assess patients frequently for degree of sleepiness and, if appropriate, advise patients to avoid driving or engaging in any other potentially dangerous activity. ( 5.4 )
Psychiatric
Symptoms: use particular caution in treating patients with a history of psychosis, depression, or mania. Consider discontinuing NUVIGIL if psychiatric symptoms develop. ( 5.5 )
Known Cardiovascular
Disease: consider increased monitoring. ( 5.7 )
5.1 Serious 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 NUVIGIL (armodafinil) or modafinil (the racemic mixture of S- and R-enantiomers). NUVIGIL 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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2)]</span> . 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 NUVIGIL 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 postmarketing experience with modafinil and NUVIGIL. 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 NUVIGIL. 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 NUVIGIL, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, NUVIGIL 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.
5.2 Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity DRESS, also known as multi-organ hypersensitivity, has been reported with NUVIGIL. 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 NUVIGIL treatment has been reported in the postmarketing setting. In addition, multi-organ hypersensitivity reactions, including at least one fatality in postmarketing experience, have occurred in close temporal association (median time to detection 13 days; range 4-33) 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, NUVIGIL 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 a possibility.
5.3 Angioedema and Anaphylaxis Reactions Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed with NUVIGIL. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness).
5.4 Persistent Sleepiness Patients with abnormal levels of sleepiness who take NUVIGIL should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking NUVIGIL, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities.
5.5 Psychiatric Symptoms In pre-approval narcolepsy, OSA and SWD controlled trials of NUVIGIL, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 1.2% and placebo 0.3%). Depression was also a reason for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 0.6% and placebo 0.2%). Cases of suicidal ideation were observed in clinical trials. Caution should be exercised when NUVIGIL is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with NUVIGIL administration, consider discontinuing NUVIGIL. Psychiatric adverse reactions have been reported in patients treated with modafinil. Modafinil and NUVIGIL (armodafinil) are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with NUVIGIL are expected to be similar to the incidence and type of these events with modafinil. Postmarketing adverse reactions associated with the use of NUVIGIL, some of which have resulted in hospitalization, have included mania, delusions, hallucinations, suicidal ideation, and aggression. Many, but not all, patients who developed psychiatric adverse reactions had a prior psychiatric history. In these cases, reported NUVIGIL total daily doses ranged from 50 mg to 450 mg, which includes doses below and above the recommended dosages.
5.6 Effects on Ability to Drive and Use Machinery Although NUVIGIL has not been shown to produce functional impairment, any drug affecting the central nervous system (CNS) may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that NUVIGIL therapy will not adversely affect their ability to engage in such activities.
5.7 Cardiovascular Events In clinical studies of modafinil, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that NUVIGIL tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation. Blood pressure monitoring in short term (≤ 3 months) pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to
3.5 BPM. Increased monitoring of heart rate and blood pressure may be appropriate in patients on NUVIGIL. Caution should be exercised when prescribing NUVIGIL to patients with known cardiovascular disease.
5.1 Serious 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 NUVIGIL (armodafinil) or modafinil (the racemic mixture of S- and R-enantiomers). NUVIGIL 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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2)]</span> . 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 NUVIGIL 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 postmarketing experience with modafinil and NUVIGIL. 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 NUVIGIL. 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 NUVIGIL, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, NUVIGIL 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.
5.2 Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity DRESS, also known as multi-organ hypersensitivity, has been reported with NUVIGIL. 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 NUVIGIL treatment has been reported in the postmarketing setting. In addition, multi-organ hypersensitivity reactions, including at least one fatality in postmarketing experience, have occurred in close temporal association (median time to detection 13 days; range 4-33) 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, NUVIGIL 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 a possibility.
5.3 Angioedema and Anaphylaxis Reactions Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed with NUVIGIL. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness).
5.4 Persistent Sleepiness Patients with abnormal levels of sleepiness who take NUVIGIL should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking NUVIGIL, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities.
5.5 Psychiatric Symptoms In pre-approval narcolepsy, OSA and SWD controlled trials of NUVIGIL, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 1.2% and placebo 0.3%). Depression was also a reason for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 0.6% and placebo 0.2%). Cases of suicidal ideation were observed in clinical trials. Caution should be exercised when NUVIGIL is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with NUVIGIL administration, consider discontinuing NUVIGIL. Psychiatric adverse reactions have been reported in patients treated with modafinil. Modafinil and NUVIGIL (armodafinil) are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with NUVIGIL are expected to be similar to the incidence and type of these events with modafinil. Postmarketing adverse reactions associated with the use of NUVIGIL, some of which have resulted in hospitalization, have included mania, delusions, hallucinations, suicidal ideation, and aggression. Many, but not all, patients who developed psychiatric adverse reactions had a prior psychiatric history. In these cases, reported NUVIGIL total daily doses ranged from 50 mg to 450 mg, which includes doses below and above the recommended dosages.
5.6 Effects on Ability to Drive and Use Machinery Although NUVIGIL has not been shown to produce functional impairment, any drug affecting the central nervous system (CNS) may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that NUVIGIL therapy will not adversely affect their ability to engage in such activities.
5.7 Cardiovascular Events In clinical studies of modafinil, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that NUVIGIL tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation. Blood pressure monitoring in short term (≤ 3 months) pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to
3.5 BPM. Increased monitoring of heart rate and blood pressure may be appropriate in patients on NUVIGIL. Caution should be exercised when prescribing NUVIGIL to patients with known cardiovascular disease.