Modafinil

Description

11 DESCRIPTION Modafinil tablets are 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 USP contain 100 mg or 200 mg of modafinil USP and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, mannitol and magnesium stearate. Structure

What Is Modafinil Used For?

1 INDICATIONS AND USAGE Modafinil tablets are indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea (OSA), or shift work disorder (SWD). Limitations of Use In OSA, modafinil tablets are indicated to treat excessive sleepiness and not as treatment 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 and during treatment with modafinil tablets for excessive sleepiness. Modafinil tablets are indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea (OSA), or shift work disorder (SWD). (1) Limitations of Use In OSA, modafinil tablets are indicated to treat excessive sleepiness and not as treatment for the underlying obstruction.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION The recommended dosage of modafinil tablets for each indication is 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 [see Clinical Pharmacology (12.3) and Clinical Studies (14.1, 14.2)] . 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] . 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)] .

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Serious Rash, including Stevens-Johnson Syndrome [see Warnings and Precautions (5.1)] Angioedema and Anaphylaxis Reactions [see Warnings and Precautions (5.2)] Multiorgan Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Persistent Sleepiness [see Warnings and Precautions (5.4)] Psychiatric Symptoms [see Warnings and Precautions (5.5)] Effects on Ability to Drive and Use Machinery [see Warnings and Precautions (5.6)] Cardiovascular Events [see Warnings and Precautions (5.7)] Most common adverse reactions (≥5%): headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Modafinil has been evaluated for safety in over 3,500 patients, of whom more than 2,000 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy. Most Common Adverse Reactions In placebo-controlled clinical trials, the most common adverse reactions (≥ 5%) associated with the use of modafinil more frequently than placebo-treated patients were headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. The adverse reaction profile was similar across these studies. Table 1 presents the adverse reactions that occurred at a rate of 1% or more and were more frequent in modafinil-treated patients than in placebo-treated patients in the placebo-controlled clinical trials. Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials * in Narcolepsy, OSA, and SWD Preferred Term Modafinil (%) (n = 934) Placebo (%) (n = 567) Headache Nausea Nervousness Rhinitis Back Pain Diarrhea Anxiety Dizziness Dyspepsia Insomnia Anorexia Dry Mouth Pharyngitis Chest Pain Hypertension Abnormal Liver Function Constipation Depression Palpitation Paresthesia Somnolence Tachycardia Vasodilatation Abnormal Vision Agitation Asthma Chills Confusion Dyskenesia Edema Emotional Lability Eosinophilia Epistaxis Flatulence Hyperkinesia Hypertonia Mouth Ulceration Sweating Taste Perversion Thirst Tremor Urine Abnormality Vertigo 34 11 7 7 6 6 5 5 5 5 4 4 4 3 3 2 2 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 23 3 3 6 5 5 1 4 4 1 1 2 2 1 1 1 1 1 1 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 * Adverse Reactions that occurred in > 1% of modafinil-treated patients (either 200, 300, or 400 mg once daily) and greater incidence than placebo Dose-Dependent Adverse Reactions In the placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of modafinil and placebo, the following adverse reactions were dose related: headache and anxiety. Adverse Reactions Resulting in Discontinuation of Treatment In placebo-controlled clinical trials, 74 of the 934 patients (8%) who received modafinil discontinued due to an adverse reaction 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%). Laboratory Abnormalities Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of modafinil, but not placebo. Few patients, 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...

Drug Interactions

7 DRUG 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 coadministration 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. · 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)

Contraindications

4 CONTRAINDICATIONS 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)

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of modafinil in pregnant women. Intrauterine growth restriction and spontaneous abortion have been reported in association with modafinil (a mixture of R-and S-modafinil) and armodafinil (the R-enantiomer of modafinil). Although the pharmacology of modafinil is not identical to that of the sympathomimetic amines, it does share some pharmacologic properties with this class. Certain of these drugs have been associated with intrauterine growth restriction and spontaneous abortions. Whether the cases reported with modafinil are drug-related is unknown. In studies of modafinil and armodafinil conducted in rats (modafinil, armodafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant plasma exposures. Modafinil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout 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 tested. The higher no-effect dose for embryofetal developmental toxicity in rats (100 mg/kg/day) was associated with a plasma modafinil AUC less than that in humans at the recommended human dose (RHD) of modafinil (200 mg/day). However, in a subsequent study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed. Oral administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in increased incidences of fetal visceral and skeletal variations and decreased fetal body weight at the highest dose tested. The highest no-effect dose for embryofetal developmental toxicity in rats (200 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the RHD of modafinil....

8.3 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 is administered to a nursing woman.

Overdosage

10 OVERDOSAGE In clinical trials, a total of 151 protocol-specified doses ranging from 1000 to 1600 mg/day (5 to 8 times the recommended daily dose of modafinil) have been administered to 32 subjects, including 13 subjects who received doses of 1000 or 1200 mg/day for 7 to 21 consecutive days. In addition, several intentional acute overdoses occurred; the two largest being 4500 mg and 4000 mg taken by two subjects participating in foreign depression studies. None of these study subjects experienced any unexpected or life-threatening effects. Adverse reactions that were reported at these doses included excitation or agitation, insomnia, and slight or moderate elevations in hemodynamic parameters. Other observed high-dose effects in clinical studies have included anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, diarrhea, and decreased prothrombin time. From postmarketing experience, there have been reports of fatal overdoses involving modafinil alone or in combination with other drugs. Symptoms most often accompanying modafinil overdose, alone or in combination with other drugs have included insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, agitation, anxiety, excitation, and hallucination; digestive changes such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension, and chest pain. Cases of accidental ingestion/overdose have been reported in children as young as 11 months of age. The highest reported accidental ingestion on a mg/kg basis occurred in a three-year-old boy who ingested 800 to 1000 mg (50 to 63 mg/kg) of modafinil. The child remained stable. The symptoms associated with overdose in children were similar to those observed in adults. No specific antidote exists for the toxic effects of a modafinil overdose. Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Modafinil Tablets USP 100 mg: White to off-white color, round shape, biconvex, uncoated tablets with ‘L233’ debossed on one side and plain on other side. NDC 46708-385-30 bottle of 30 tablets NDC 46708-385-60 bottle of 60 tablets NDC 46708-385-90 bottle of 90 tablets NDC 46708-385-91 bottle of 1000 tablets NDC 46708-385-10 100 (10 x 10) unit dose blisters tablets 200 mg: White to off-white color, round shape, biconvex, uncoated tablets with ‘L234’ debossed on one side and breakline on other side. NDC 46708-386-30 bottle of 30 tablets NDC 46708-386-60 bottle of 60 tablets NDC 46708-386-90 bottle of 90 tablets NDC 46708-386-91 bottle of 1000 tablets NDC 46708-386-10 100 (10 x 10) unit dose blisters tablets 16.2 Storage Store at 20°-25°C (68°-77°F). [See USP Controlled Room Temperature]