Provigil Drug Information

Dosage in Narcolepsy and Obstructive Sleep Apnea (OSA)

The recommended dosage of PROVIGIL 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 .

Dosage in Shift Work Disorder (SWD)

The recommended dosage of PROVIGIL 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.

Dosage Modifications in Patients with Severe Hepatic Impairment

In patients with severe hepatic impairment, the dosage of PROVIGIL should be reduced to one-half of that recommended for patients with normal hepatic function .

Use in Geriatric Patients Consideration should be given to the use of

lower doses and close monitoring in geriatric patients .

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. PROVIGIL 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 PROVIGIL 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 PROVIGIL-treated patients than in placebo-treated patients in the placebo-controlled clinical trials. Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials Adverse Reactions that occurred in > 1% of PROVIGIL-treated patients (either 200, 300, or 400 mg once daily) and greater incidence than placebo in Narcolepsy, OSA, and SWD PROVIGIL (%) (n = 934) Placebo (%) (n = 567) Headache 34 23 Nausea 11 3 Nervousness 7 3 Rhinitis 7 6 Back Pain 6 5 Diarrhea 6 5 Anxiety 5 1 Dizziness 5 4 Dyspepsia 5 4 Insomnia 5 1 Anorexia 4 1 Dry Mouth 4 2 Pharyngitis 4 2 Chest Pain 3 1 Hypertension 3 1 Abnormal Liver Function 2 1 Constipation 2 1 Depression 2 1 Palpitation 2 1 Paresthesia 2 0 Somnolence 2 1 Tachycardia 2 1 Vasodilatation 2 0 Abnormal Vision 1 0 Agitation 1 0 Asthma 1 0 Chills 1 0 Confusion 1 0 Dyskinesia 1 0 Edema 1 0 Emotional Lability 1 0 Eosinophilia 1 0 Epistaxis 1 0 Flatulence 1 0 Hyperkinesia 1 0 Hypertonia 1 0 Mouth Ulceration 1 0 Sweating 1 0 Taste Perversion 1 0 Thirst 1 0 Tremor 1 0 Urine Abnormality 1 0 Vertigo 1 0 Dose-Dependent Adverse Reactions In the placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of PROVIGIL 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 PROVIGIL 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 PROVIGIL 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 PROVIGIL, 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 with PROVIGIL in the placebo-controlled clinical trials. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of PROVIGIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hematologic: agranulocytosis Psychiatric disorders: psychomotor hyperactivity

Effects of PROVIGIL 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 PROVIGIL 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 PROVIGIL . The effectiveness of steroidal contraceptives may be reduced when used with PROVIGIL 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 PROVIGIL and for one month after discontinuation of PROVIGIL treatment.

Blood levels of cyclosporine may be reduced when used with PROVIGIL. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with PROVIGIL. Effects of PROVIGIL on CYP2C19 Substrates Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by PROVIGIL 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 PROVIGIL. Dose adjustments of these drugs and other drugs that are substrates for CYP2C19 may be necessary when used concomitantly with PROVIGIL . Warfarin More frequent monitoring of prothrombin times/INR should be considered whenever PROVIGIL is coadministered with warfarin . Monoamine Oxidase (MAO) Inhibitors Caution should be used when concomitantly administering MAO inhibitors and PROVIGIL. Steroidal contraceptives (e.g., ethinyl estradiol): Use alternative or concomitant methods of contraception while taking PROVIGIL and for one month after discontinuation of PROVIGIL treatment. Cyclosporine: Blood concentrations of cyclosporine may be reduced.

CYP2C19 substrates, such as omeprazole, phenytoin, and diazepam: Exposure of these medications may be increased.

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. PROVIGIL 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 PROVIGIL (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 PROVIGIL. Modafinil administered orally to pregnant rabbits throughout organogenesis at doses of up to 100 mg/kg/day had no effect on embryofetal development; however, the doses used were too low to adequately assess the effects of modafinil on embryofetal development. In a subsequent developmental toxicity study evaluating doses of 45, 90, and 180 mg/kg/day in pregnant rabbits, the incidences of fetal structural alterations and embryofetal death were increased at the highest dose. The highest no-effect dose for developmental toxicity (100 mg/kg/day) was associated with a plasma modafinil AUC similar to that in humans at the RHD of PROVIGIL. 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, a dose resulting in a plasma modafinil AUC less than that in humans at the RHD of PROVIGIL. No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring.

Pregnancy Registry A pregnancy registry has been established to collect information on the pregnancy outcomes of women exposed to PROVIGIL. 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).

Pediatric Use Safety and effectiveness in pediatric patients have not been established. PROVIGIL is not approved in this population for any indication. Serious skin rashes, including erythema multiforme major (EMM) and Stevens-Johnson Syndrome (SJS) have been associated with modafinil use in pediatric patients . 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 reactions 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). 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 treating ADHD.

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

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 PROVIGIL) 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 PROVIGIL 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 800-1000 mg (50-63 mg/kg) of PROVIGIL. 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 PROVIGIL overdose. Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring.