MODAFINIL

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 is a white to off-white, crystalline powder that is practically insoluble in water and cyclohexane. It is sparingly to slightly soluble in methanol and acetone. Modafinil tablets contain 100 mg or 200 mg of modafinil and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, povidone, and magnesium stearate. chemical structure

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.

The recommended dose of modafinil is 200 mg given once a day. For patients with narcolepsy and OSA, modafinil should be taken as a single dose in the morning. For patients with SWD, modafinil should be taken approximately 1 hour prior to the start of their work shift. 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 dose (See CLINICAL PHARMACOLOGY and CLINICAL TRIALS ). General Considerations Dosage adjustment should be considered for concomitant medications that are substrates for CYP3A4, such as triazolam and cyclosporine (See PRECAUTIONS, Drug Interactions ). 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. In patients with severe hepatic impairment, the dose of modafinil should be reduced to one-half of that recommended for patients with normal hepatic function (See CLINICAL PHARMACOLOGY and PRECAUTIONS ). There is inadequate information to determine safety and efficacy of dosing in patients with severe renal impairment (See CLINICAL PHARMACOLOGY and PRECAUTIONS ). 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 ).

Modafinil is contraindicated in patients with known hypersensitivity to modafinil, armodafinil or its inactive ingredients.

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