Armodafinil

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).

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 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)]

  .
• SWD: 150 mg once a day, taken approximately one hour prior to start of the work shift.
  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.
• Hepatic Impairment: reduced dose in patients with severe hepatic impairment.
  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)].
  ,
  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 or 100 mg modafinil (a 1:1 mixture of R- and S-enantiomers) are nearly superimposable. However, the C_maxand AUC_0-∞, of armodafinil at steady-state were approximately 37% and 70% higher, respectively, following administration of 200 mg armodafinil than the corresponding values of modafinil following administration of 200 mg 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 to 4 hours in the fed state. Since the delay in t_maxis also associated with elevated plasma concentrations later in time, food can potentially affect the onset and time course of pharmacologic action for armodafinil.

  
  
  

  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 with highly protein-bound drugs is considered to be minimal.

  
  
  

  Elimination
  
  

  
  
  After oral administration of armodafinil, armodafinil exhibits an apparent monoexponential decline from the peak plasma concentration. The apparent terminal t_½is approximately 15 hours. The oral clearance of armodafinil is approximately 33 mL/min.

  
  
  

  Metabolism
  
  

  
  
  

  In vitro

  and

  in vivo

  data show that armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the single most prominent metabolic pathway, with sulfone formation by cytochrome P450 (CYP) 3A4/5 being next in importance. The other oxidative products are formed too slowly

  in vitro

  to enable identification of the enzyme(s) responsible. Only two metabolites reach appreciable concentrations in plasma (i.e., R-modafinil acid and modafinil sulfone).

  
  
  

  Excretion

  
  
  
  
  Data specific to armodafinil disposition are not available. However, modafinil is mainly eliminated via metabolism, predominantly in the liver, with less than 10% of the parent compound excreted in the urine. 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 to 45 years of age, N=25). Systemic exposure of armodafinil acid (metabolite) was approximately 61% and 73% greater for C_maxand 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 to 74 years of age had approximately 21% and 9% lower oral clearance, respectively, compared to young subjects. Systemic exposure was approximately 10% greater in subjects 65 to 74 years of age (N=17) and 27% greater in subjects ≥75 years of age (N=7), respectively, when compared to young subjects. The change is considered not likely to be clinically significant for elderly patients, however, because some elderly patients have greater exposure to armodafinil, consideration should be given to the use of lower doses.

  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 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 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 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

  [see Drug Interactions (7)]

  .

  
  
  

  In a separate clinical study, concomitant administration of armodafinil 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 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 with quetiapine reduced the systemic exposure of quetiapine.

  
  
  

  Data specific to armodafinil drug-drug interaction potential with other CNS active drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to armodafinil

  .

  Concomitant administration of modafinil with methylphenidate or dextroamphetamine produced no significant alterations on the pharmacokinetic profile of modafinil or either stimulant, even though the absorption of modafinil was delayed for approximately one hour.

  
  
  

  Concomitant modafinil or clomipramine did not alter the pharmacokinetic profile of either drug; however, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine was reported in 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.

  
  
  

  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)]

  .

  
  
  
• Geriatric Patients: consider lower dose.
  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)].
  ,
  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 or 100 mg modafinil (a 1:1 mixture of R- and S-enantiomers) are nearly superimposable. However, the C_maxand AUC_0-∞, of armodafinil at steady-state were approximately 37% and 70% higher, respectively, following administration of 200 mg armodafinil than the corresponding values of modafinil following administration of 200 mg 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 to 4 hours in the fed state. Since the delay in t_maxis also associated with elevated plasma concentrations later in time, food can potentially affect the onset and time course of pharmacologic action for armodafinil.

  
  
  

  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 with highly protein-bound drugs is considered to be minimal.

  
  
  

  Elimination
  
  

  
  
  After oral administration of armodafinil, armodafinil exhibits an apparent monoexponential decline from the peak plasma concentration. The apparent terminal t_½is approximately 15 hours. The oral clearance of armodafinil is approximately 33 mL/min.

  
  
  

  Metabolism
  
  

  
  
  

  In vitro

  and

  in vivo

  data show that armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the single most prominent metabolic pathway, with sulfone formation by cytochrome P450 (CYP) 3A4/5 being next in importance. The other oxidative products are formed too slowly

  in vitro

  to enable identification of the enzyme(s) responsible. Only two metabolites reach appreciable concentrations in plasma (i.e., R-modafinil acid and modafinil sulfone).

  
  
  

  Excretion

  
  
  
  
  Data specific to armodafinil disposition are not available. However, modafinil is mainly eliminated via metabolism, predominantly in the liver, with less than 10% of the parent compound excreted in the urine. 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 to 45 years of age, N=25). Systemic exposure of armodafinil acid (metabolite) was approximately 61% and 73% greater for C_maxand 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 to 74 years of age had approximately 21% and 9% lower oral clearance, respectively, compared to young subjects. Systemic exposure was approximately 10% greater in subjects 65 to 74 years of age (N=17) and 27% greater in subjects ≥75 years of age (N=7), respectively, when compared to young subjects. The change is considered not likely to be clinically significant for elderly patients, however, because some elderly patients have greater exposure to armodafinil, consideration should be given to the use of lower doses.

  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 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 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 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

  [see Drug Interactions (7)]

  .

  
  
  

  In a separate clinical study, concomitant administration of armodafinil 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 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 with quetiapine reduced the systemic exposure of quetiapine.

  
  
  

  Data specific to armodafinil drug-drug interaction potential with other CNS active drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to armodafinil

  .

  Concomitant administration of modafinil with methylphenidate or dextroamphetamine produced no significant alterations on the pharmacokinetic profile of modafinil or either stimulant, even though the absorption of modafinil was delayed for approximately one hour.

  
  
  

  Concomitant modafinil or clomipramine did not alter the pharmacokinetic profile of either drug; however, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine was reported in 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.

  
  
  

  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,
  50 mg
  are white to off-white, round shaped uncoated tablets debossed with ‘K’ on one side and ‘58’ on the other side.
• Armodafinil Tablets,
  150 mg
  are white to off-white, oval shaped uncoated tablets debossed with ‘K’ on one side and ‘59’ on the other side.
• Armodafinil Tablets, 200 mg
  are white to off-white rounded, rectangular uncoated tablets debossed with ‘10’ on one side and ‘N’ on the other side.
• Armodafinil Tablets,
  250 mg
  are white to off-white, oval shaped uncoated tablets debossed with ‘K’ on one side and ‘60’ on the other side.

Pregnancy: based on animal data, may cause fetal harm.

• Serious Rash, including Stevens-Johnson Syndrome: discontinue armodafinil at the first sign of rash, unless the rash is clearly not drug-related. (
  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 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.
  )
• DRESS/Multi-organ Hypersensitivity Reactions: if suspected, discontinue armodafinil. (
  5.2 Drug 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 a possibility.
  )
• Angioedema and Anaphylaxis Reactions: if suspected, discontinue armodafinil. (
  5.3 Angioedema and Anaphylaxis Reactions

  Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed with armodafinil. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness).
  )
• 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 Persistent Sleepiness

  Patients with abnormal levels of sleepiness who take armodafinil should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking armodafinil, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities.
  )
• Psychiatric Symptoms: use particular caution in treating patients with a history of psychosis, depression, or mania. Consider discontinuing armodafinil if psychiatric symptoms develop. (
  5.5 Psychiatric Symptoms

  In pre-approval narcolepsy, OSA and SWD controlled trials of armodafinil, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on armodafinil compared to placebo (armodafinil 1.2% and placebo 0.3%). Depression was also a reason for treatment discontinuation more often in patients on armodafinil compared to placebo (armodafinil 0.6% and placebo 0.2%). Cases of suicidal ideation were observed in clinical trials.
  
  
  
  Caution should be exercised when armodafinil is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with armodafinil administration, consider discontinuing armodafinil.
  
  
  
  Psychiatric adverse reactions have been reported in patients treated with modafinil. Modafinil and armodafinil are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with armodafinil are expected to be similar to the incidence and type of these events with modafinil.

  
  
  Post-marketing adverse reactions associated with the use of armodafinil, some of which have resulted in hospitalization, have included mania, delusions, hallucinations, suicidal ideation, and aggression. Many, but not all, patients who developed psychiatric adverse reactions had a prior psychiatric history. In these cases, reported armodafinil total daily doses ranged from 50 mg to 450 mg, which includes doses below and above the recommended dosages.
  )
• Known Cardiovascular Disease: consider increased monitoring. (
  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 armodafinil 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 armodafinil 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 armodafinil 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 armodafinil. Caution should be exercised when prescribing armodafinil to patients with known cardiovascular disease.
  )