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, a racemic mixture of S and R modafinil (the latter is armodafinil).
Armodafinil has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication.
In clinical trials of modafinil (the racemate), 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.
No serious skin rashes have been reported in adult clinical trials (0 per 1,595) of armodafinil. However, because armodafinil is the R isomer of racemic modafinil, a similar risk of serious rash with armodafinil cannot be ruled out.
There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil or armodafinil. 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 armodafinil, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, armodafinil 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. 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. A similar risk of multi-organ hypersensitivity reactions with armodafinil cannot be ruled out.
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, NUVIGIL 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.
Patients with abnormal levels of sleepiness who take NUVIGIL should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking NUVIGIL, 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 adverse experiences have been reported in patients treated with modafinil. Modafinil and armodafinil (NUVIGIL) are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with armodafinil are expected to be similar to the incidence and type of these events 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 controlled trial NUVIGIL database, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 1.2% and placebo 0.3%). In the NUVIGIL controlled studies, depression was also a reason for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 0.6% and placebo 0.2%). Two cases of suicide ideation were observed in clinical trials. Caution should be exercised when NUVIGIL is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with NUVIGIL administration, consider discontinuing NUVIGIL.
Diagnosis of Sleep Disorders
NUVIGIL 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).
CPAP Use in Patients with OSAHS
In OSAHS, NUVIGIL 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 NUVIGIL. If NUVIGIL is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. There was a slight trend for reduced CPAP use over time (mean reduction of 18 minutes for patients treated with NUVIGIL and a 6 minute reduction for placebo-treated patients from a mean baseline use of 6.9 hours per night) in NUVIGIL trials.
Although NUVIGIL 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 NUVIGIL therapy will not adversely affect their ability to engage in such activities.
NUVIGIL 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.
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 NUVIGIL 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. Signs of mitral valve prolapse syndrome 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 only small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). Increased monitoring of blood pressure may be appropriate in patients on NUVIGIL.
Patients Using Steroidal Contraceptives
The effectiveness of steroidal contraceptives may be reduced when used with NUVIGIL and for one month after discontinuation of therapy (See PRECAUTIONS, Drug Interactions). Alternative or concomitant methods of contraception are recommended for patients treated with NUVIGIL and for one month after discontinuation of NUVIGIL treatment.
Patients Using Cyclosporine
The blood levels of cyclosporine may be reduced when used with NUVIGIL (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), NUVIGIL 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).
In elderly patients, elimination of armodafinil 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 NUVIGIL.
NUVIGIL is indicated for patients who have abnormal levels of sleepiness. NUVIGIL 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 NUVIGIL has been shown to produce levels of wakefulness that permit such activities. Patients should be advised that NUVIGIL 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 NUVIGIL. 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 rash, depression, anxiety, or signs of psychosis or mania.
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 NUVIGIL and for one month after discontinuation of therapy (See Carcinogenesis, Mutagenesis, Impairment of Fertility and Pregnancy).
Patients should be advised to notify their physician if they are breastfeeding an infant.
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 NUVIGIL and other drugs.
Patients should be advised that the use of NUVIGIL in combination with alcohol has not been studied. Patients should be advised that it is prudent to avoid alcohol while taking NUVIGIL.
Patients should be advised to stop taking NUVIGIL 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.
Potential Interactions with Drugs That Inhibit, Induce, or Are Metabolized by Cytochrome P450 Isoenzymes and Other Hepatic Enzymes
Due to the partial involvement of CYP3A enzymes in the metabolic elimination of armodafinil, coadministration of potent inducers of CYP3A4/5 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4/5 (e.g., ketoconazole, erythromycin) could alter the plasma levels of armodafinil.
The Potential of NUVIGIL to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition
Drugs Metabolized by CYP1A2
In vitro data demonstrated that armodafinil shows a weak inductive response for CYP1A2 and possibly CYP3A activities in a concentration related manner and demonstrated that CYP2C19 activity is reversibly inhibited by armodafinil. However, the effect on CYP1A2 activity was not observed clinically in an interaction study performed with caffeine (See Pharmacokinetics, Drug-Drug Interactions ).
Drugs Metabolized by CYP3A4/5 (e.g., cyclosporine, ethinyl estradiol, midazolam and triazolam)
Chronic administration of NUVIGIL resulted in moderate induction of CYP3A activity. Hence, the effectiveness of drugs that are substrates for CYP3A enzymes (e.g., cyclosporine, ethinyl estradiol, midazolam and triazolam) may be reduced after initiation of concurrent treatment with NUVIGIL. A 32% reduction in systemic exposure of oral midazolam was seen upon concomitant administration of armodafinil with midazolam. Dose adjustment may be required (See Pharmacokinetics, Drug-Drug Interactions ). Such effects (reduced concentrations) were also seen upon concomitant administration of modafinil with cyclosporine, ethinyl estradiol, and triazolam.
Drugs Metabolized by CYP2C19 (e.g., omeprazole, diazepam, phenytoin, and propranolol)
Administration of NUVIGIL resulted in moderate inhibition of CYP2C19 activity. Hence, dosage reduction may be required for some drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, and propranolol, omeprazole and clomipramine) when used concurrently with NUVIGIL. A 40% increase in exposure was seen upon concomitant administration of armodafinil with omeprazole. (See Pharmacokinetics, Drug-Drug Interactions ).
Interactions with CNS Active Drugs
Data specific to armodafinil drug-drug interaction potential with CNS active drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to armodafinil (See DESCRIPTION and CLINICAL PHARMACOLOGY).
Concomitant administration of modafinil with methylphenidate, or dextroamphetamine produced no significant alterations on the pharmacokinetic profile of modafinil or either stimulant, even though the absorption of modafinil was delayed for approximately one hour.
Concomitant modafinil or clomipramine did not alter the PK profile of either drug; however, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine was reported in a patient with narcolepsy during treatment with modafinil.
Data specific to armodafinil or modafinil drug-drug interaction potential with Monoamine Oxidase (MAO) inhibitors are not available. Therefore, caution should be used when concomitantly administering MAO inhibitors and NUVIGIL.
Interactions with Other Drugs
Data specific to armodafinil drug-drug interaction potential for additional other drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to armodafinil.
Concomitant administration of modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of R- and S-warfarin. However, since only a single dose of warfarin was tested in this study, a pharmacodynamic interaction cannot be ruled out. Therefore, more frequent monitoring of prothrombin times/INR should be considered whenever NUVIGIL is coadministered with warfarin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with armodafinil alone. 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 (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.
Armodafinil was evaluated in an in vitro bacterial reverse mutation assay and in an in vitro mammalian chromosomal aberration assay in human lymphocytes. Armodafinil was negative in these assays, both in the absence and presence of metabolic activation. 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
A fertility and early embryonic development (to implantation) study was not conducted with armodafinil alone.
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 Category C
In studies conducted in rats (armodafinil, modafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant exposures.
Oral administration of armodafinil (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 0.03 times the AUC in humans at the maximum recommended daily dose of 250 mg.
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 up to 100 mg/kg/day (plasma modafinil AUC approximately equal to the AUC in humans at the RHD) 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 was associated with a plasma modafinil AUC approximately equal to the AUC in humans 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 of either armodafinil or modafinil 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 armodafinil 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 retardation and spontaneous abortions. Whether the cases reported with armodafinil are drug-related is unknown.
Armodafinil or modafinil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of armodafinil on labor and delivery in humans has not been systematically investigated.
It is not known whether armodafinil or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NUVIGIL tablets are administered to a nursing woman.
Safety and effectiveness of armodafinil use in individuals below 17 years of age have not been established. Serious rash has been seen in pediatric patients receiving modafinil (See WARNINGS, Serious Rash, including Stevens-Johnson Syndrome).
Safety and effectiveness in individuals above 65 years of age have not been established.