WARNINGS
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.
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 Section). 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).
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. 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. Patients Using Contraceptives
The effectiveness of steroidal contraceptives may be reduced when used with PROVIGIL tablets and for one month after discontinuation of therapy (See Drug Interactions). Alternative or concomitant methods of contraception are recommended for patients treated with PROVIGIL tablets, and for one month after discontinuation of PROVIGIL. Cardiovascular System
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.
Modafinil has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable angina, and such patients should be treated with caution.
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. Central Nervous System
There have been reports of psychotic episodes associated with PROVIGIL use. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of PROVIGIL and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation. Caution should be exercised when PROVIGIL is given to patients with a history of psychosis.
Patients with Severe Renal Impairment
In patients with severe renal impairment (mean creatinine clearance = 16.6 mL/min), a 200 mg single dose of modafinil did not lead to increased exposure to modafinil but resulted in much higher exposure to the inactive metabolite, modafinil acid, than is seen in subjects with normal renal function. There is little information available about the safety of such levels of this metabolite (See CLINICAL PHARMACOLOGY).
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 as the clearance of modafinil was decreased compared to that in normal subjects (See DOSAGE AND ADMINISTRATION).
Elderly Patients
To the extent that elderly patients may have diminished renal and/or hepatic function, dosage reductions should be considered (See 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. 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 Impairment of Fertility and Pregnancy).
Nursing
Patients should be advised to notify their physician if they are breast feeding 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 notify their physician if they develop a rash, hives, 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.
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.
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-(infinity) 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 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 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 represents 1.5 times (mouse) or 3 times (rat) greater than the recommended human daily dose of 200 mg on a mg/m2 basis. There was no evidence of tumorigenesis associated with modafinil administration in these studies, but because the mouse study used an inadequate high dose that was not representative of a maximum tolerated dose, the carcinogenic potential of modafinil has not been fully evaluated. Mutagenesis
There was no evidence of mutagenic or clastogenic potential of modafinil in a series of assays. It was not mutagenic in the in vitro Ames bacterial reverse mutation test, the in vitro mouse lymphoma/TK locus assay in the presence or absence of metabolic activation; and it was not clastogenic in the in vitro human lymphocyte chromosomal aberration assay in the presence or absence of metabolic activation, or in two in vivo mouse bone marrow micronucleus assays. Modafinil did not increase unscheduled DNA synthesis in rat hepatocytes. In a cell transformation assay in BALB/3T3 mouse embryo cells, modafinil did not cause an increase in the frequency of transformed foci in the presence or absence of metabolic activation.
Impairment of Fertility
Oral administration of modafinil to male and female rats had no effects on fertility when administered prior to and throughout mating, and continued in females through day 7 of gestation, at doses up to 480 mg/kg/day (23 times the recommended human dose of 200 mg/day on a mg/m2 basis).
Pregnancy
Pregnancy Category C: Modafinil 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 hydronephrosis and skeletal variations in the offspring at a dose of 200 mg/kg/day (10 times the recommended human dose of 200 mg/day on a mg/m2 basis) but not at 100 mg/kg/day. However, in a subsequent study of up to 480 mg/kg/day (23 times the recommended human dose on a mg/m2 basis), which included maternally toxic doses, no adverse effects on embryofetal development were seen.
Modafinil administered orally to pregnant rabbits throughout the period of organogenesis at doses up to 100 mg/kg/day (10 times the recommended human dose on a mg/m2 basis) had no effects on embryofetal development.
However, in a subsequent study in pregnant rabbits, increased resorptions, and increased alterations in fetuses from a single litter (open eye lids, fused digits, rotated limbs), were observed at 180 mg/kg/day (17 times the recommended human dose on a mg/m2 basis), a dose that was also maternally toxic.
Modafinil administered orally to rats throughout gestation and lactation at doses up to 200 mg/kg/day (5 times the recommended human dose on a mg/m2 basis), had no effects on the postnatal development of the offspring.
There are no adequate and well-controlled studies in pregnant women. 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. Seven normal births occurred in patients who had received modafinil during pregnancy. One patient gave birth 3 weeks earlier than the expected range of delivery dates (estimated using ultrasound) to a healthy male infant. One woman with a history of spontaneous abortions suffered a spontaneous abortion while being treated with modafinil.
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 individuals below 16 years of age have not been established. Leukopenia has been reported in pediatric patients taking PROVIGIL.
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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