MODAFINIL: 3,375 Adverse Event Reports & Safety Profile

Modafinil is a wakefulness-promoting agent for oral administration. Modafinil is a racemic compound. The chemical name for modafinil is 2-[(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: Modafinil, USP is a white to almost white, crystalline powder that is practically insoluble in water and cyclohexane. It is sparingly to slightly soluble in methanol and acetone. Modafinil tablets, USP contain 100 mg or 200 mg of modafinil, USP and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch. Product complies with USP dissolution test 2.

Modafinil

Tablets USP, 100mg and 200mg

INDICATIONS AND USAGE Modafinil is indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift work disorder. In OSA, modafinil is indicated as an adjunct to standard treatment(s) 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 modafinil. If modafinil is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. In all cases, careful attention to the diagnosis and treatment of the underlying sleep disorder(s) is of utmost importance. Prescribers should be aware that some patients may have more than one sleep disorder contributing to their excessive sleepiness. The effectiveness of modafinil in long-term use (greater than 9 weeks in Narcolepsy clinical trials and 12 weeks in OSA and SWD clinical trials) has not been systematically evaluated in placebo-controlled trials. The physician who elects to prescribe modafinil for an extended time in patients with Narcolepsy, OSA, or SWD should periodically reevaluate long-term usefulness for the individual patient.

AND ADMINISTRATION The recommended dosage of modafinil tablets for each indication are as follows:

• Narcolepsy or OSA: 200 mg once a day in the morning. (2.1)
• SWD: 200 mg once a day, taken approximately one hour prior to start of the work shift (2.2)
• Severe Hepatic Impairment: reduce dose to half the recommended dose. (2.3, 12.3)
• Geriatric Patients: consider lower dose. (2.4, 12.3)

2.1 Dosage in Narcolepsy and Obstructive Sleep Apnea (OSA) The recommended dosage of modafinil tablets for patients with narcolepsy or OSA is 200 mg taken orally once a day as a single dose in the morning. Doses up to 400 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that this dose confers additional benefit beyond that of the 200 mg/day dose <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) and Clinical Studies (14.1 , 14.2 )]</span>.

2.2 Dosage in Shift Work Disorder (SWD) The recommended dosage of modafinil tablets for patients with SWD is 200 mg taken orally once a day as a single dose approximately 1 hour prior to the start of their work shift.

2.3 Dosage Modifications in Patients with Severe Hepatic Impairment In patients with severe hepatic impairment, the dosage of modafinil tablets should be reduced to one-half of that recommended for patients with normal hepatic function <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]</span>.

2.4 Use in Geriatric Patients Consideration should be given to the use of lower doses and close monitoring in geriatric patients <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5)]</span> .

2.1 Dosage in Narcolepsy and Obstructive Sleep Apnea (OSA) The recommended dosage of modafinil tablets for patients with narcolepsy or OSA is 200 mg taken orally once a day as a single dose in the morning. Doses up to 400 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that this dose confers additional benefit beyond that of the 200 mg/day dose <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) and Clinical Studies (14.1 , 14.2 )]</span>.

2.2 Dosage in Shift Work Disorder (SWD) The recommended dosage of modafinil tablets for patients with SWD is 200 mg taken orally once a day as a single dose approximately 1 hour prior to the start of their work shift.

2.3 Dosage Modifications in Patients with Severe Hepatic Impairment In patients with severe hepatic impairment, the dosage of modafinil tablets should be reduced to one-half of that recommended for patients with normal hepatic function <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]</span>.

2.4 Use in Geriatric Patients Consideration should be given to the use of lower doses and close monitoring in geriatric patients <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5)]</span> .

Modafinil 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 )] . Modafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil. ( 4 )

ADVERSE REACTIONS Modafinil has been evaluated for safety in over 3500 patients, of whom more than 2000 patients with excessive sleepiness associated with primary disorders of sleep and wakefulness were given at least one dose of modafinil. In clinical trials, modafinil has been found to be generally well tolerated and most adverse experiences were mild to moderate. The most commonly observed adverse events (≥5%) associated with the use of modafinil more frequently than placebo-treated patients in the placebo-controlled clinical studies in primary disorders of sleep and wakefulness were headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. The adverse event profile was similar across these studies. In the placebo-controlled clinical trials, 74 of the 934 patients (8%) who received modafinil discontinued due to an adverse experience compared to 3% of patients that received placebo. The most frequent reasons for discontinuation that occurred at a higher rate for modafinil than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain and nervousness (each <1%). In a Canadian clinical trial, a 35 year old obese narcoleptic male with a prior history of syncopal episodes experienced a 9-second episode of asystole after 27 days of modafinil treatment (300 mg/day in divided doses). Incidence in Controlled Trials The following table (Table 3) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in adult patients treated with modafinil than in placebo-treated patients in the principal, placebo-controlled clinical trials. The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied.

Table

3.

Incidence Of

Treatment-Emergent Adverse Experiences In Parallel-Group, Placebo-Controlled Clinical Trials 1 With Modafinil In Adults With Narcolepsy, OSA, and SWD (200mg, 300mg and 400mg)* Body System Preferred Term Modafinil (n = 934) Placebo (n = 567) Body as a Whole Headache 34% 23% Back Pain 6% 5% Flu Syndrome 4% 3% Chest Pain 3% 1% Chills 1% 0% Neck Rigidity 1% 0% Cardiovascular Hypertension 3% 1% Tachycardia 2% 1% Palpitation 2% 1% Vasodilatation 2% 0% Digestive Nausea 11% 3% Diarrhea 6% 5% Dyspepsia 5% 4% Dry Mouth 4% 2% Anorexia 4% 1% Constipation 2% 1% Abnormal Liver Function 2 2% 1% Flatulence 1% 0% Mouth Ulceration 1% 0% Thirst 1% 0% Hemic/Lymphatic Eosinophilia 1% 0% Metabolic/Nutritional Edema 1% 0% Nervous Nervousness 7% 3% Insomnia 5% 1% Anxiety 5% 1% Dizziness 5% 4% Depression 2% 1% Paresthesia 2% 0% Somnolence 2% 1% Hypertonia 1% 0% Dyskinesia 3 1% 0% Hyperkinesia 1% 0% Agitation 1% 0% Confusion 1% 0% Tremor 1% 0% Emotional Lability 1% 0% Vertigo 1% 0% Respiratory Rhinitis 7% 6% Pharyngitis 4% 2% Lung Disorder 2% 1% Epistaxis 1% 0% Asthma 1% 0% Skin/Appendages Sweating 1% 0% Herpes Simplex 1% 0% Special Senses Amblyopia 1% 0% Abnormal Vision 1% 0% Taste Perversion 1% 0% Eye Pain 1% 0% Urogenital Urine Abnormality 1% 0% Hematuria 1% 0% Pyuria 1% 0% * Six double-blind, placebo-controlled clinical studies in narcolepsy, OSA, and SWD. 1 Events reported by at least 1% of patients treated with modafinil that were more frequent than in the placebo group are included; incidence is rounded to the nearest 1%. The adverse experience terminology is coded using a standard modified COSTART Dictionary. Events for which the modafinil incidence was at least 1%, but equal to or less than placebo are not listed in the table. These events included the following: infection, pain, accidental injury, abdominal pain, hypothermia, allergic reaction, asthenia, fever, viral infection, neck pain, migraine, abnormal electrocardiogram, hypotension, tooth disorder, vomiting, periodontal abscess, increased appetite, ecchymosis, hyperglycemia, peripheral edema, weight loss, weight gain, myalgia, leg cramps, arthritis, cataplexy, thinking abnormality, sleep disorder, increased cough, sinusitis, dyspnea, bronchitis, rash, conjunctivitis, ear pain, dysmenorrhea 4 , urinary tract infection. 2 Elevated liver enzymes. 3 Oro-facial dyskinesias. 4 Incidence adjusted for gender.

Dose

Dependency of Adverse Events In the adult placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of modafinil and placebo, the only adverse events that were clearly dose related were headache and anxiety.

Vital Sign Changes

While there was no consistent change in mean values of heart rate or systolic and diastolic blood pressure, the requirement for antihypertensive medication was slightly greater in patients on modafinil compared to placebo (See PRECAUTIONS ).

Weight Changes

There were no clinically significant differences in body weight change in patients treated with modafinil compared to placebo-treated patients in the placebo-controlled clinical trials.

Laboratory Changes

Clinical chemistry, hematology, and urinalysis parameters were monitored in Phase 1, 2, and 3 studies. In these studies, mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of modafinil, but not placebo. Few subjects, however, had GGT or AP elevations outside of the normal range. Shifts to higher, but not clinically significantly abnormal, GGT and AP values appeared to increase with time in the population treated with modafinil in the Phase 3 clinical trials. No differences were apparent in alanine aminotransferase, aspartate aminotransferase, total protein, albumin, or total bilirubin.

Ecg

Changes No treatment-emergent pattern of ECG abnormalities was found in placebo-controlled clinical trials following administration of modafinil.

Postmarketing Reports

The following adverse reactions have been identified during post-approval use of modafinil. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to modafinil. Hematologic: agranulocytosis

Incidence in Controlled Trials The following table (Table 3) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in adult patients treated with modafinil than in placebo-treated patients in the principal, placebo-controlled clinical trials. The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied.

Table

3.

Incidence Of

Treatment-Emergent Adverse Experiences In Parallel-Group, Placebo-Controlled Clinical Trials 1 With Modafinil In Adults With Narcolepsy, OSA, and SWD (200mg, 300mg and 400mg)* Body System Preferred Term Modafinil (n = 934) Placebo (n = 567) Body as a Whole Headache 34% 23% Back Pain 6% 5% Flu Syndrome 4% 3% Chest Pain 3% 1% Chills 1% 0% Neck Rigidity 1% 0% Cardiovascular Hypertension 3% 1% Tachycardia 2% 1% Palpitation 2% 1% Vasodilatation 2% 0% Digestive Nausea 11% 3% Diarrhea 6% 5% Dyspepsia 5% 4% Dry Mouth 4% 2% Anorexia 4% 1% Constipation 2% 1% Abnormal Liver Function 2 2% 1% Flatulence 1% 0% Mouth Ulceration 1% 0% Thirst 1% 0% Hemic/Lymphatic Eosinophilia 1% 0% Metabolic/Nutritional Edema 1% 0% Nervous Nervousness 7% 3% Insomnia 5% 1% Anxiety 5% 1% Dizziness 5% 4% Depression 2% 1% Paresthesia 2% 0% Somnolence 2% 1% Hypertonia 1% 0% Dyskinesia 3 1% 0% Hyperkinesia 1% 0% Agitation 1% 0% Confusion 1% 0% Tremor 1% 0% Emotional Lability 1% 0% Vertigo 1% 0% Respiratory Rhinitis 7% 6% Pharyngitis 4% 2% Lung Disorder 2% 1% Epistaxis 1% 0% Asthma 1% 0% Skin/Appendages Sweating 1% 0% Herpes Simplex 1% 0% Special Senses Amblyopia 1% 0% Abnormal Vision 1% 0% Taste Perversion 1% 0% Eye Pain 1% 0% Urogenital Urine Abnormality 1% 0% Hematuria 1% 0% Pyuria 1% 0% * Six double-blind, placebo-controlled clinical studies in narcolepsy, OSA, and SWD. 1 Events reported by at least 1% of patients treated with modafinil that were more frequent than in the placebo group are included; incidence is rounded to the nearest 1%. The adverse experience terminology is coded using a standard modified COSTART Dictionary. Events for which the modafinil incidence was at least 1%, but equal to or less than placebo are not listed in the table. These events included the following: infection, pain, accidental injury, abdominal pain, hypothermia, allergic reaction, asthenia, fever, viral infection, neck pain, migraine, abnormal electrocardiogram, hypotension, tooth disorder, vomiting, periodontal abscess, increased appetite, ecchymosis, hyperglycemia, peripheral edema, weight loss, weight gain, myalgia, leg cramps, arthritis, cataplexy, thinking abnormality, sleep disorder, increased cough, sinusitis, dyspnea, bronchitis, rash, conjunctivitis, ear pain, dysmenorrhea 4 , urinary tract infection. 2 Elevated liver enzymes. 3 Oro-facial dyskinesias. 4 Incidence adjusted for gender.

Dose

Dependency of Adverse Events In the adult placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of modafinil and placebo, the only adverse events that were clearly dose related were headache and anxiety.

Vital Sign Changes

While there was no consistent change in mean values of heart rate or systolic and diastolic blood pressure, the requirement for antihypertensive medication was slightly greater in patients on modafinil compared to placebo (See PRECAUTIONS ).

Weight Changes

There were no clinically significant differences in body weight change in patients treated with modafinil compared to placebo-treated patients in the placebo-controlled clinical trials.

Laboratory Changes

Clinical chemistry, hematology, and urinalysis parameters were monitored in Phase 1, 2, and 3 studies. In these studies, mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of modafinil, but not placebo. Few subjects, however, had GGT or AP elevations outside of the normal range. Shifts to higher, but not clinically significantly abnormal, GGT and AP values appeared to increase with time in the population treated with modafinil in the Phase 3 clinical trials. No differences were apparent in alanine aminotransferase, aspartate aminotransferase, total protein, albumin, or total bilirubin.

Ecg

Changes No treatment-emergent pattern of ECG abnormalities was found in placebo-controlled clinical trials following administration of modafinil.

Postmarketing Reports

The following adverse reactions have been identified during post-approval use of modafinil. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to modafinil. Hematologic: agranulocytosis

AND PRECAUTIONS

• Serious Rash, including Stevens - Johnson Syndrome: Discontinue Modafinil tablets at the first sign of rash, unless the rash is clearly not drug-related. (5.1)
• Angioedema and Anaphylaxis Reactions: If suspected, discontinue modafinil tablets. (5.2)
• Multi-organ Hypersensitivity Reactions: If suspected, discontinue modafinil tablets. (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 caution in patients with a history of psychosis, depression, or mania. Consider discontinuing modafinil tablets if psychiatric symptoms develop. (5.5)
• Known Cardiovascular Disease: Consider increased monitoring. (5.7)

5.1 Serious Rash, including Stevens - Johnson Syndrome Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of modafinil. In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age &lt;17 years); these rashes included 1 case of possible Stevens - Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. 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. Modafinil tablets are not approved for use in pediatric patients for any indication <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span>. Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide postmarketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years. There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil tablets. Nearly all cases of serious rash associated with modafinil occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes also occur with modafinil tablets, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, modafinil tablets should be discontinued at the first sign of rash, 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 Angioedema and Anaphylaxis Reactions Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed in patients treated with armodafinil, the R enantiomer of modafinil (which is the racemic mixture). No such cases were observed in modafinil clinical trials. However, angioedema has been reported in postmarketing experience with modafinil. 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).

5.3 Multi-organ Hypersensitivity Reactions 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. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If a multi-organ hypersensitivity reaction is suspected, modafinil tablets 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.

5.4 Persistent Sleepiness Patients with abnormal levels of sleepiness who take modafinil tablets should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking modafinil tablets, 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 Psychiatric adverse reactions have been reported in patients treated with modafinil. In the adult modafinil tablets controlled trials, psychiatric symptoms resulting in treatment discontinuation (at a frequency ≥0.3%) and reported more often in patients treated with modafinil tablets compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (&lt;1%), confusion (&lt;1%), agitation (&lt;1%), and depression (&lt;1%). Postmarketing adverse reactions associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation, and aggression, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil tablets (three times the recommended dose) and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation. Caution should be exercised when modafinil tablets are given to patients with a history of psychosis, depression, or mania. Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in patients treated with modafinil tablets. If psychiatric symptoms develop in association with modafinil tablets administration, consider discontinuing modafinil tablets.

5.6 Effects on Ability to Drive and Use Machinery Although modafinil tablets has not been shown to produce functional impairment, any drug affecting the 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 modafinil tablets therapy will not adversely affect their ability to engage in such activities.

5.7 Cardiovascular Events In modafinil clinical studies, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on ECG occurred in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. In a Canadian clinical trial, a 35 year old obese narcoleptic male with a prior history of syncopal episodes experienced a 9-second episode of asystole after 27 days of modafinil treatment (300 mg/day in divided doses). Modafinil tablets are not recommended 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. Consider increased monitoring in patients with a recent history of myocardial infarction or unstable angina. Blood pressure monitoring in short term (≤3 months) controlled trials showed no clinically significant changes in mean systolic and diastolic blood pressure in patients receiving modafinil tablets as compared to placebo. However, a retrospective analysis of the use of antihypertensive medication in these studies showed that a greater proportion of patients on modafinil tablets required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential use was slightly larger when only studies in OSA were included, with 3.4% of patients on modafinil tablets and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication. Increased monitoring of heart rate and blood pressure may be appropriate in patients on modafinil tablets. Caution should be exercised when prescribing modafinil tablets to patients with known cardiovascular disease.

5.1 Serious Rash, including Stevens - Johnson Syndrome Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of modafinil. In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age &lt;17 years); these rashes included 1 case of possible Stevens - Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. 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. Modafinil tablets are not approved for use in pediatric patients for any indication <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span>. Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide postmarketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years. There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil tablets. Nearly all cases of serious rash associated with modafinil occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes also occur with modafinil tablets, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, modafinil tablets should be discontinued at the first sign of rash, 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 Angioedema and Anaphylaxis Reactions Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed in patients treated with armodafinil, the R enantiomer of modafinil (which is the racemic mixture). No such cases were observed in modafinil clinical trials. However, angioedema has been reported in postmarketing experience with modafinil. 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).

5.3 Multi-organ Hypersensitivity Reactions 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. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If a multi-organ hypersensitivity reaction is suspected, modafinil tablets 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.

5.4 Persistent Sleepiness Patients with abnormal levels of sleepiness who take modafinil tablets should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking modafinil tablets, 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 Psychiatric adverse reactions have been reported in patients treated with modafinil. In the adult modafinil tablets controlled trials, psychiatric symptoms resulting in treatment discontinuation (at a frequency ≥0.3%) and reported more often in patients treated with modafinil tablets compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (&lt;1%), confusion (&lt;1%), agitation (&lt;1%), and depression (&lt;1%). Postmarketing adverse reactions associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation, and aggression, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil tablets (three times the recommended dose) and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation. Caution should be exercised when modafinil tablets are given to patients with a history of psychosis, depression, or mania. Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in patients treated with modafinil tablets. If psychiatric symptoms develop in association with modafinil tablets administration, consider discontinuing modafinil tablets.

5.6 Effects on Ability to Drive and Use Machinery Although modafinil tablets has not been shown to produce functional impairment, any drug affecting the 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 modafinil tablets therapy will not adversely affect their ability to engage in such activities.

5.7 Cardiovascular Events In modafinil clinical studies, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on ECG occurred in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. In a Canadian clinical trial, a 35 year old obese narcoleptic male with a prior history of syncopal episodes experienced a 9-second episode of asystole after 27 days of modafinil treatment (300 mg/day in divided doses). Modafinil tablets are not recommended 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. Consider increased monitoring in patients with a recent history of myocardial infarction or unstable angina. Blood pressure monitoring in short term (≤3 months) controlled trials showed no clinically significant changes in mean systolic and diastolic blood pressure in patients receiving modafinil tablets as compared to placebo. However, a retrospective analysis of the use of antihypertensive medication in these studies showed that a greater proportion of patients on modafinil tablets required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential use was slightly larger when only studies in OSA were included, with 3.4% of patients on modafinil tablets and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication. Increased monitoring of heart rate and blood pressure may be appropriate in patients on modafinil tablets. Caution should be exercised when prescribing modafinil tablets to patients with known cardiovascular disease.

PRECAUTIONS Diagnosis of Sleep Disorders Modafinil should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of either narcolepsy, OSA, and/or SWD has been made in accordance with ICSD or DSM diagnostic criteria (See CLINICAL TRIALS ). Such an evaluation usually consists of a complete history and physical examination, and it may be supplemented with testing in a laboratory setting. Some patients may have more than one sleep disorder contributing to their excessive sleepiness (e.g., OSA and SWD coincident in the same patient).

General

Although modafinil has not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until they are reasonably certain that modafinil therapy will not adversely affect their ability to engage in such activities.

Cpap

Use in Patients with OSA In OSA, modafinil is indicated as an adjunct to standard treatment(s) 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 modafinil. If modafinil is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary.

Cardiovascular System

Modafinil has not been evaluated in patients with a recent history of myocardial infarction or unstable angina, and such patients should be treated with caution. In clinical studies of modafinil, signs and symptoms 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 modafinil 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. Such signs may include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these symptoms occurs, consider cardiac evaluation. Blood pressure monitoring in short-term (<3 months) controlled trials showed no clinically significant changes in mean systolic and diastolic blood pressure in patients receiving modafinil as compared to placebo. However, a retrospective analysis of the use of antihypertensive medication in these studies showed that a greater proportion of patients on modafinil required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential use was slightly larger when only studies in OSA were included, with 3.4% of patients on modafinil and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication. Increased monitoring of blood pressure may be appropriate in patients on modafinil.

Patients Using Steroidal Contraceptives

The effectiveness of steroidal contraceptives may be reduced when used with modafinil tablets and for one month after discontinuation of therapy (See PRECAUTIONS, Drug Interactions ). Alternative or concomitant methods of contraception are recommended for patients treated with modafinil tablets, and for one month after discontinuation of modafinil.

Patients Using Cyclosporine

The blood levels of cyclosporine may be reduced when used with modafinil (See PRECAUTIONS, Drug Interactions ). Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when these drugs are used concomitantly. Patients with Severe Hepatic Impairment In patients with severe hepatic impairment, with or without cirrhosis (See CLINICAL PHARMACOLOGY ), modafinil should be administered at a reduced dose (See DOSAGE AND ADMINISTRATION ). Patients with Severe Renal Impairment There is inadequate information to determine safety and efficacy of dosing in patients with severe renal impairment. (For pharmacokinetics in renal impairment, see CLINICAL PHARMACOLOGY .) Elderly patients In elderly patients, elimination of modafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses in this population. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). Information for Patients Physicians are advised to discuss the following issues with patients for whom they prescribe modafinil. Modafinil is indicated for patients who have abnormal levels of sleepiness. Modafinil has been shown to improve, but not eliminate this abnormal tendency to fall asleep. Therefore, patients 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 modafinil has been shown to produce levels of wakefulness that permit such activities. Patients should be advised that modafinil is not a replacement for sleep. Patients should be informed 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). Patients should be informed of the availability of a Medication Guide, and they should be instructed to read it prior to taking modafinil. The complete text of the Medication Guide is provided at the end of this labeling. Patients should be advised to contact their physician if they experience chest pain, rash, depression, anxiety, or signs of psychosis or mania.

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be cautioned regarding the potential increased risk of pregnancy when using steroidal contraceptives (including depot or implantable contraceptives) with modafinil and for one month after discontinuation of therapy (See Carcinogenesis, Mutagenesis, Impairment of Fertility and Pregnancy ).

Nursing

Patients should be advised to notify their physician if they are breast feeding an infant.

Concomitant Medications

Patients should be advised 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 modafinil and other drugs.

Alcohol

Patients should be advised that the use of modafinil in combination with alcohol has not been studied. Patients should be advised that it is prudent to avoid alcohol while taking modafinil.

Allergic Reactions

Patients should be advised to stop taking modafinil and to notify their physician if they develop a rash, hives, mouth sores, blisters, peeling skin, trouble swallowing or breathing or a related allergic phenomenon.

Drug

Interactions CNS Active Drugs Methylphenidate - In a single-dose study in healthy volunteers, simultaneous administration of modafinil (200 mg) with methylphenidate (40 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of modafinil may be delayed by approximately one hour when coadministered with methylphenidate. In a multiple-dose, steady-state study in healthy volunteers, modafinil was administered once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days. Administration of methylphenidate (20 mg/day) during days 22-28 of modafinil treatment 8 hours after the daily dose of modafinil did not cause any significant alterations in the pharmacokinetics of modafinil. Dextroamphetamine - In a single dose study in healthy volunteers, simultaneous administration of modafinil (200 mg) with dextroamphetamine (10 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of modafinil may be delayed by approximately one hour when coadministered with dextroamphetamine. In a multiple-dose, steady-state study in healthy volunteers, modafinil was administered once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days. Administration of dextroamphetamine (20 mg/day) during days 22-28 of modafinil treatment 7 hours after the daily dose of modafinil did not cause any significant alterations in the pharmacokinetics of modafinil. Clomipramine - The coadministration of a single dose of clomipramine (50 mg) on the first of three days of treatment with modafinil (200 mg/day) in healthy volunteers did not show an effect on the pharmacokinetics of either drug. However, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine has been reported in a patient with narcolepsy during treatment with modafinil. Triazolam – In the drug interaction study between modafinil and ethinyl estradiol (EE 2 ), on the same days as those for the plasma sampling for EE 2 pharmacokinetics, a single dose of triazolam (0.125 mg) was also administered. Mean C max and AUC 0-∞ of triazolam were decreased by 42% and 59%, respectively, and its elimination half-life was decreased by approximately an hour after the modafinil treatment.

Monoamine

Oxidase (MAO) Inhibitors - Interaction studies with monoamine oxidase inhibitors have not been performed. Therefore, caution should be used when concomitantly administering MAO inhibitors and modafinil.

Other Drugs

Warfarin - There were no significant changes in the pharmacokinetic profiles of R- and S- warfarin in healthy subjects given a single dose of racemic warfarin (5 mg) following chronic administration of modafinil (200 mg/day for 7 days followed by 400 mg/day for 27 days) relative to the profiles in subjects given placebo. However, more frequent monitoring of prothrombin times/INR is advisable whenever modafinil is coadministered with warfarin (See CLINICAL PHARMACOLOGY, Pharmacokinetics , Drug-Drug Interactions).

Ethinyl

Estradiol - Administration of modafinil to female volunteers once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days resulted in a mean 11% decrease in C max and 18% decrease in AUC 0-24 of ethinyl estradiol (EE 2 ; 0.035 mg; administered orally with norgestimate). There was no apparent change in the elimination rate of ethinyl estradiol. Cyclosporine - One case of an interaction between modafinil and cyclosporine, a substrate of CYP3A4, has been reported in a 41 year old woman who had undergone an organ transplant. After one month of administration of 200 mg/day of modafinil, cyclosporine blood levels were decreased by 50%. The interaction was postulated to be due to the increased metabolism of cyclosporine, since no other factor expected to affect the disposition of the drug had changed. Dosage adjustment for cyclosporine may be needed.

Potential

Interactions with Drugs That Inhibit, Induce, or are Metabolized by Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes In in vitro studies using primary human hepatocyte cultures, modafinil was shown to slightly induce CYP1A2, CYP2B6 and CYP3A4 in a concentration-dependent manner. Although induction results based on in vitro experiments are not necessarily predictive of response in vivo, caution needs to be exercised when modafinil is coadministered with drugs that depend on these three enzymes for their clearance. Specifically, lower blood levels of such drugs could result (See Other Drugs , Cyclosporine above). The exposure of human hepatocytes to modafinil in vitro produced an apparent concentration-related suppression of expression of CYP2C9 activity suggesting that there is a potential for a metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin and phenytoin). In a subsequent clinical study in healthy volunteers, chronic modafinil treatment did not show a significant effect on the single-dose pharmacokinetics of warfarin when compared to placebo (See Other Drugs , Warfarin above). In vitro studies using human liver microsomes showed that modafinil reversibly inhibited CYP2C19 at pharmacologically relevant concentrations of modafinil. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone. Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with modafinil and may require dosage reduction and monitoring for toxicity. Tricyclic antidepressants - CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) that are primarily metabolized by CYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor metabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. Modafinil may cause elevation of the levels of the tricyclics in this subset of patients. Physicians should be aware that a reduction in the dose of tricyclic agents might be needed in these patients. In addition, due to the partial involvement of CYP3A4 in the metabolic elimination of modafinil, coadministration of potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) could alter the plasma levels of modafinil. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in which modafinil was administered in the diet to mice for 78 weeks and to rats for 104 weeks at doses of 6, 30, and 60 mg/kg/day. The highest dose studied is 1.5 (mouse) or 3 (rat) times greater than the recommended adult human daily dose of modafinil (200 mg) on a mg/m 2 basis. There was no evidence of tumorigenesis associated with modafinil administration in these studies. However, since the mouse study used an inadequate high dose that was not representative of a maximum tolerated dose, a subsequent carcinogenicity study was conducted in the Tg.AC transgenic mouse. Doses evaluated in the Tg.AC assay were 125, 250, and 500 mg/kg/day, administered dermally. There was no evidence of tumorigenicity associated with modafinil administration; however, this dermal model may not adequately assess the carcinogenic potential of an orally administered drug.

Mutagenesis

Modafinil demonstrated no evidence of mutagenic or clastogenic potential in a series of in vitro (i.e., bacterial reverse mutation assay, mouse lymphoma tk assay, chromosomal aberration assay in human lymphocytes, cell transformation assay in BALB/3T3 mouse embryo cells) assays in the absence or presence of metabolic activation, or in vivo (mouse bone marrow micronucleus) assays. Modafinil was also negative in the unscheduled DNA synthesis assay in rat hepatocytes. Impairment of Fertility 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 modafinil exposure (AUC) approximately equal to that in humans at the recommended dose of 200 mg.

Pregnancy Pregnancy

Category C: In studies conducted in rats and rabbits, developmental toxicity was observed at clinically relevant exposures. Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout the period of organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased incidence of visceral and skeletal variations in the offspring at the highest dose. The higher no-effect dose for rat embryofetal developmental toxicity was associated with a plasma modafinil exposure approximately 0.5 times the AUC in humans at the recommended daily dose (RHD) of 200 mg. However, in a subsequent study of up to 480 mg/kg/day (plasma modafinil exposure approximately 2 times the AUC in humans at the RHD) no adverse effects on embryofetal development were observed. Modafinil administered orally to pregnant rabbits throughout the period of organogenesis at doses of 45, 90, and 180 mg/kg/day increased the incidences of fetal structural alterations and embryofetal death at the highest dose. The highest no-effect dose for developmental toxicity was associated with a plasma modafinil AUC approximately equal to the AUC in humans at the RHD. Oral administration of armodafinil (the R-enantiomer of modafinil; 60, 200, or 600 mg/kg/day) to pregnant rats throughout the period of organogenesis resulted in increased incidences of fetal visceral and skeletal variations at the intermediate dose or greater and decreased fetal body weights at the highest dose. The no-effect dose for rat embryofetal developmental toxicity was associated with a plasma armodafinil exposure (AUC) approximately one-tenth times the AUC for armodafinil in humans treated with modafinil at the RHD. 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 (plasma modafinil AUC approximately 0.1 times the AUC in humans at the RHD). No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring. There are no adequate and well-controlled studies in pregnant women. Two cases of intrauterine growth retardation and one case of spontaneous abortion have been reported in association with armodafinil and modafinil. Although the pharmacology of modafinil and armodafinil is not identical to that of the sympathomimetic amines, they do share some pharmacologic properties with this class. Certain of these drugs have been associated with intrauterine growth retardation and spontaneous abortions. Whether the cases reported are drug-related is unknown. Modafinil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy

Registry: A pregnancy registry has been established to collect information on the pregnancy outcomes of women exposed to modafinil. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-866-404-4106 (toll free). Labor and Delivery The effect of modafinil on labor and delivery in humans has not been systematically investigated.

Nursing

Mothers It is not known whether modafinil or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when modafinil tablets are administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients, below age 17, have not been established. Serious skin rashes, including erythema multiforme major (EMM) and Stevens-Johnson Syndrome (SJS) have been associated with modafinil use in pediatric patients (see WARNINGS, Serious Rash, including Stevens-Johnson Syndrome ). In a controlled 6-week study, 165 pediatric patients (aged 5-17 years) with narcolepsy were treated with modafinil (n=123), or placebo (n=42). There were no statistically significant differences favoring modafinil over placebo in prolonging sleep latency as measured by MSLT, or in perceptions of sleepiness as determined by the clinical global impression-clinician scale (CGI-C). In the controlled and open-label clinical studies, treatment emergent adverse events of the psychiatric and nervous system included Tourette’s syndrome, insomnia, hostility, increased cataplexy, increased hypnagogic hallucinations and suicidal ideation. Transient leukopenia, which resolved without medical intervention, was also observed. In the controlled clinical study, 3 of 38 girls, ages 12 or older, treated with modafinil experienced dysmenorrhea compared to 0 of 10 girls who received placebo. There were three 7 to 9 week, double-blind, placebo-controlled, parallel group studies in children and adolescents (aged 6-17 years) with Attention-Deficit Hyperactivity Disorder (ADHD, DSM-IV). Two of the studies were flexible-dose studies (up to 425 mg/day), and the third was a fixed-dose study (340 mg/day for patients <30 kg and 425 mg/day for patients ≥30 kg). Although these studies showed statistically significant differences favoring modafinil over placebo in reducing ADHD symptoms as measured by the ADHD-RS (school version), there were 3 cases of serious rash including one case of possible SJS among 933 patients exposed to modafinil in this program. Modafinil is not approved for use in pediatric patients for any indication, including ADHD (see WARNINGS, Serious Rash, including Stevens-Johnson Syndrome ).

Geriatric Use

Experience in a limited number of patients who were greater than 65 years of age in clinical trials showed an incidence of adverse experiences similar to other age groups. In elderly patients, elimination of modafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses in this population (See CLINICAL PHARMACOLOGY and PRECAUTIONS ).

Diagnosis of Sleep Disorders Modafinil should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of either narcolepsy, OSA, and/or SWD has been made in accordance with ICSD or DSM diagnostic criteria (See CLINICAL TRIALS ). Such an evaluation usually consists of a complete history and physical examination, and it may be supplemented with testing in a laboratory setting. Some patients may have more than one sleep disorder contributing to their excessive sleepiness (e.g., OSA and SWD coincident in the same patient).

Cpap

Use in Patients with OSA In OSA, modafinil is indicated as an adjunct to standard treatment(s) 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 modafinil. If modafinil is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary.

Cardiovascular System

Modafinil has not been evaluated in patients with a recent history of myocardial infarction or unstable angina, and such patients should be treated with caution. In clinical studies of modafinil, signs and symptoms 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 modafinil 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. Such signs may include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these symptoms occurs, consider cardiac evaluation. Blood pressure monitoring in short-term (<3 months) controlled trials showed no clinically significant changes in mean systolic and diastolic blood pressure in patients receiving modafinil as compared to placebo. However, a retrospective analysis of the use of antihypertensive medication in these studies showed that a greater proportion of patients on modafinil required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential use was slightly larger when only studies in OSA were included, with 3.4% of patients on modafinil and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication. Increased monitoring of blood pressure may be appropriate in patients on modafinil.

Patients Using Steroidal Contraceptives

The effectiveness of steroidal contraceptives may be reduced when used with modafinil tablets and for one month after discontinuation of therapy (See PRECAUTIONS, Drug Interactions ). Alternative or concomitant methods of contraception are recommended for patients treated with modafinil tablets, and for one month after discontinuation of modafinil.

Patients Using Cyclosporine

The blood levels of cyclosporine may be reduced when used with modafinil (See PRECAUTIONS, Drug Interactions ). Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when these drugs are used concomitantly.

Patients with Severe Hepatic Impairment In patients with severe hepatic impairment, with or without cirrhosis (See CLINICAL PHARMACOLOGY ), modafinil should be administered at a reduced dose (See DOSAGE AND ADMINISTRATION ).

Patients with Severe Renal Impairment There is inadequate information to determine safety and efficacy of dosing in patients with severe renal impairment. (For pharmacokinetics in renal impairment, see CLINICAL PHARMACOLOGY .)

Elderly patients In elderly patients, elimination of modafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses in this population. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).

Drug

Interactions CNS Active Drugs Methylphenidate - In a single-dose study in healthy volunteers, simultaneous administration of modafinil (200 mg) with methylphenidate (40 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of modafinil may be delayed by approximately one hour when coadministered with methylphenidate. In a multiple-dose, steady-state study in healthy volunteers, modafinil was administered once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days. Administration of methylphenidate (20 mg/day) during days 22-28 of modafinil treatment 8 hours after the daily dose of modafinil did not cause any significant alterations in the pharmacokinetics of modafinil. Dextroamphetamine - In a single dose study in healthy volunteers, simultaneous administration of modafinil (200 mg) with dextroamphetamine (10 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of modafinil may be delayed by approximately one hour when coadministered with dextroamphetamine. In a multiple-dose, steady-state study in healthy volunteers, modafinil was administered once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days. Administration of dextroamphetamine (20 mg/day) during days 22-28 of modafinil treatment 7 hours after the daily dose of modafinil did not cause any significant alterations in the pharmacokinetics of modafinil. Clomipramine - The coadministration of a single dose of clomipramine (50 mg) on the first of three days of treatment with modafinil (200 mg/day) in healthy volunteers did not show an effect on the pharmacokinetics of either drug. However, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine has been reported in a patient with narcolepsy during treatment with modafinil. Triazolam – In the drug interaction study between modafinil and ethinyl estradiol (EE 2 ), on the same days as those for the plasma sampling for EE 2 pharmacokinetics, a single dose of triazolam (0.125 mg) was also administered. Mean C max and AUC 0-∞ of triazolam were decreased by 42% and 59%, respectively, and its elimination half-life was decreased by approximately an hour after the modafinil treatment.

Monoamine

Oxidase (MAO) Inhibitors - Interaction studies with monoamine oxidase inhibitors have not been performed. Therefore, caution should be used when concomitantly administering MAO inhibitors and modafinil.

Other Drugs

Warfarin - There were no significant changes in the pharmacokinetic profiles of R- and S- warfarin in healthy subjects given a single dose of racemic warfarin (5 mg) following chronic administration of modafinil (200 mg/day for 7 days followed by 400 mg/day for 27 days) relative to the profiles in subjects given placebo. However, more frequent monitoring of prothrombin times/INR is advisable whenever modafinil is coadministered with warfarin (See CLINICAL PHARMACOLOGY, Pharmacokinetics , Drug-Drug Interactions).

Ethinyl

Estradiol - Administration of modafinil to female volunteers once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days resulted in a mean 11% decrease in C max and 18% decrease in AUC 0-24 of ethinyl estradiol (EE 2 ; 0.035 mg; administered orally with norgestimate). There was no apparent change in the elimination rate of ethinyl estradiol. Cyclosporine - One case of an interaction between modafinil and cyclosporine, a substrate of CYP3A4, has been reported in a 41 year old woman who had undergone an organ transplant. After one month of administration of 200 mg/day of modafinil, cyclosporine blood levels were decreased by 50%. The interaction was postulated to be due to the increased metabolism of cyclosporine, since no other factor expected to affect the disposition of the drug had changed. Dosage adjustment for cyclosporine may be needed.

Potential

Interactions with Drugs That Inhibit, Induce, or are Metabolized by Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes In in vitro studies using primary human hepatocyte cultures, modafinil was shown to slightly induce CYP1A2, CYP2B6 and CYP3A4 in a concentration-dependent manner. Although induction results based on in vitro experiments are not necessarily predictive of response in vivo, caution needs to be exercised when modafinil is coadministered with drugs that depend on these three enzymes for their clearance. Specifically, lower blood levels of such drugs could result (See Other Drugs , Cyclosporine above). The exposure of human hepatocytes to modafinil in vitro produced an apparent concentration-related suppression of expression of CYP2C9 activity suggesting that there is a potential for a metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin and phenytoin). In a subsequent clinical study in healthy volunteers, chronic modafinil treatment did not show a significant effect on the single-dose pharmacokinetics of warfarin when compared to placebo (See Other Drugs , Warfarin above). In vitro studies using human liver microsomes showed that modafinil reversibly inhibited CYP2C19 at pharmacologically relevant concentrations of modafinil. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone. Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with modafinil and may require dosage reduction and monitoring for toxicity. Tricyclic antidepressants - CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) that are primarily metabolized by CYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor metabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. Modafinil may cause elevation of the levels of the tricyclics in this subset of patients. Physicians should be aware that a reduction in the dose of tricyclic agents might be needed in these patients. In addition, due to the partial involvement of CYP3A4 in the metabolic elimination of modafinil, coadministration of potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) could alter the plasma levels of modafinil.

INTERACTIONS Effects of Modafinil 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 modafinil 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 modafinil [see Clinical Pharmacology (12.3) ] . The effectiveness of steroidal contraceptives may be reduced when used with modafinil 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 modafinil and for one month after discontinuation of modafinil treatment. Blood levels of cyclosporine may be reduced when used with modafinil. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with modafinil. Effects of Modafinil on CYP2C19 Substrates Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by modafinil via inhibition of metabolic enzymes, with resultant higher systemic exposure. In individuals deficient in the CYP2D6 enzyme, the levels of CYP2D6 substrates which have ancillary routes of elimination through CYP2C19, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, may be increased by co-administration of modafinil. Dose adjustments of these drugs and other drugs that are substrates for CYP2C19 may be necessary when used concomitantly with modafinil [see Clinical Pharmacology (12.3) ] .

Warfarin

More frequent monitoring of prothrombin times/INR should be considered whenever modafinil is coadministered with warfarin [see Clinical Pharmacology (12.3) ] .

Monoamine

Oxidase (MAO)

Inhibitors

Caution should be used when concomitantly administering MAO inhibitors and modafinil. To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email [email protected] ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Steroidal contraceptives (e.g., ethinyl estradiol): Use alternative or concomitant methods of contraception while taking modafinil and for one month after discontinuation of modafinil 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)