WARNINGS
Serious Rash, including Stevens-Johnson Syndrome
Serious rash requiring hospitalization and discontinuation of treatment has been reported in adults and children in association with the use of modafinil.
Modafinil is not approved for use in pediatric patients for any indication.
In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. 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. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil.
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 post-marketing 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. 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, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, modafinil should ordinarily 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.
Angioedema and Anaphylactoid Reactions
One serious case of angioedema and one case of hypersensitivity (with rash, dysphagia, and bronchospasm), were observed among 1,595 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).
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 associated with modafinil. 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, PROVIGIL 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.
Persistent Sleepiness
Patients with abnormal levels of sleepiness who take PROVIGIL should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking PROVIGIL, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities.
Psychiatric Symptoms
Psychiatric adverse experiences have been reported in patients treated with modafinil. Postmarketing adverse events 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 and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation.
In the adult modafinil controlled trials database, psychiatric symptoms resulting in treatment discontinuation (at a frequency >0.3%) and reported more often in patients treated with modafinil compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (<1%), confusion (<1%), agitation (<1%), and depression (<1%). Caution should be exercised when PROVIGIL is 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 PROVIGIL. If psychiatric symptoms develop in association with PROVIGIL administration, consider discontinuing PROVIGIL.
PRECAUTIONS
Diagnosis of Sleep Disorders
PROVIGIL should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of either narcolepsy, OSAHS, and/or SWSD 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., OSAHS and SWSD 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 PROVIGIL therapy will not adversely affect their ability to engage in such activities.
CPAP Use in Patients with OSAHS
In OSAHS, PROVIGIL 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 PROVIGIL. If PROVIGIL 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 PROVIGIL, 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 PROVIGIL 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 PROVIGIL 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 PROVIGIL 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 OSAHS were included, with 3.4% of patients on PROVIGIL 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 PROVIGIL.
Patients Using Steroidal Contraceptives
The effectiveness of steroidal contraceptives may be reduced when used with PROVIGIL 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 PROVIGIL tablets, and for one month after discontinuation of PROVIGIL.
Patients Using Cyclosporine
The blood levels of cyclosporine may be reduced when used with PROVIGIL (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), PROVIGIL 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 PROVIGIL.
PROVIGIL is indicated for patients who have abnormal levels of sleepiness. PROVIGIL 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 PROVIGIL has been shown to produce levels of wakefulness that permit such activities. Patients should be advised that PROVIGIL 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 OSAHS receiving CPAP should continue to do so).
Patients should be informed of the availability of a patient information leaflet, and they should be instructed to read the leaflet prior to taking PROVIGIL. See Patient Information at the end of this labeling for the text of the leaflet provided for patients.
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 PROVIGIL 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 breastfeeding an infant.
Concomitant Medication
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 PROVIGIL and other drugs.
Alcohol
Patients should be advised that the use of PROVIGIL in combination with alcohol has not been studied. Patients should be advised that it is prudent to avoid alcohol while taking PROVIGIL.
Allergic Reactions
Patients should be advised to stop taking PROVIGIL 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 PROVIGIL 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 PROVIGIL 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 PROVIGIL and ethinyl estradiol (EE2), on the same days as those for the plasma sampling for EE2 pharmacokinetics, a single dose of triazolam (0.125 mg) was also administered. Mean Cmax and AUC0-∞ 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 PROVIGIL 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 Cmax and 18% decrease in AUC0-24 of ethinyl estradiol (EE2; 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 PROVIGIL 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 PRECAUTIONS, Drug Interactions, Warfarin ).
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 PROVIGIL 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. PROVIGIL 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/m2 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.
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 PROVIGIL tablets are administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients, below age 16, 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.
Geriatric Use
Safety and effectiveness in individuals above 65 years of age have not been established. 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.
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