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. 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. 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. 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.
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. 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. Warfarin–Concomitant administration of
modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of Rand 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: Carcinogenesis: 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.
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.
Mutagenesis: Modafinil demonstrated no evidence of mutagenic or clastogenic potential in a
series of in vitro assays in the absence or presence of metabolic activation, or in vivo 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: Pregnancy Category C: In studies
conducted in rats (armodafinil, modafinil) and rabbits (modafinil), developmental toxicity was
observed at clinically relevant exposures. 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. Whether the cases reported with armodafinil are drug-related is unknown. NUVIGIL
or modafinil should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus. Pregnancy Registry: A pregnancy registry has been established to collect
information on the pregnancy outcomes of women exposed to NUVIGIL. 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). Labor and Delivery: The effect of armodafinil on
labor and delivery in humans has not been systematically investigated. Nursing Mothers: It is
not known whether armodafinil or its metabolites are excreted in human milk. Caution should be
exercised when NUVIGIL tablets are administered to a nursing woman. Pediatric Use: 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). Geriatric Use: 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 PRECAU TIONS).
ADVERSE REACTIONS: Armodafinil has been evaluated for safety in over 1100 patients with
excessive sleepiness associated with primary disorders of sleep and wakefulness. In clinical trials,
NUVIGIL has been found to be generally well tolerated and most adverse experiences were mild to
moderate. In the placebo-controlled clinical studies, the most commonly observed adverse events
(≥5%) associated with the use of NUVIGIL occurring more frequently than in the placebo-treated
patients were headache, nausea, dizziness, and insomnia. The adverse event profile was similar
across the studies. In the placebo-controlled clinical trials, 44 of the 645 patients (7%) who
received NUVIGIL discontinued due to an adverse experience compared to 16 of the 445 (4%) of
patients that received placebo. The most frequent reason for discontinuation was headache (1%).
Incidence in Controlled Trials: The incidence of adverse experiences that occurred at a rate of
≥1% and were more frequent in patients treated with NUVIGIL than in placebo-treated patients
in the principal trials are listed below. Consult full prescribing information on adverse events.
Cardiac Disorders: Palpitations Gastrointestinal Disorders: Nausea, diarrhea, dry mouth,
dyspepsia, abdominal pain upper, constipation, vomiting, loose stools General Disorders and
Administration Site Conditions: Fatigue, thirst, influenza-like illness, pain, pyrexia Immune
System Disorders: Seasonal allergy Investigations: Gamma-glutamyltransferase increased,
heart rate increased Metabolism and Nutrition Disorders: Anorexia, decreased appetite
Nervous System Disorders: Headache, dizziness, disturbance in attention, tremor, migraine,
paresthesia Psychiatric Disorders: Insomnia, anxiety, depression, agitation, nervousness,
depressed mood Renal and Urinary Disorders: Polyuria Respiratory, Thoracic and
Mediastinal Disorders: Dyspnea Skin and Subcutaneous Tissue Disorders: Rash, contact
dermatitis, hyperhydrosis Dose Dependency of Adverse Events: In the placebo-controlled
clinical trials which compared doses of 150 mg/day and 250 mg/day of NUVIGIL and placebo,
the only adverse events that appeared to be dose-related were headache, rash, depression, dry
mouth, insomnia, and nausea. Vital Sign Changes: There were small, but consistent, increases
in average values for mean systolic and diastolic blood pressure in controlled trials. There was
a small, but consistent, average increase in pulse rate over placebo in controlled trials. This
increase varied from 0.9 to 3. 5 BPM. Laboratory Changes: 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 NUVIGIL, but not placebo. Few subjects, however, had GGT or AP elevations
outside of the normal range. No differences were apparent in alanine aminotransferase, aspartate
aminotransferase, total protein, albumin, or total bilirubin, although there were rare cases of
isolated elevations of AST and/or ALT. ECG Changes: No pattern of ECG abnormalities could be
attributed to NUVIGIL administration in placebo-controlled clinical trials.
DRUG ABUSE AND DEPENDENCE: Controlled Substance Class: Armodafinil (NUVIGIL) is
a Schedule IV controlled substance. Abuse Potential and Dependence: Although the abuse
potential of armodafinil has not been specifically studied, its abuse potential is likely to be similar
to that of modafinil (PROVIGIL). In humans, modafinil produces psychoactive and euphoric effects,
alterations in mood, perception, thinking and feelings typical of other CNS stimulants. In some
studies, modafinil was also partially discriminated as stimulant-like. Physicians should follow
patients closely, especially those with a history of drug and/or stimulant abuse, for signs of misuse
OVERDOSAGE: Human Experience: There were no overdoses reported in the NUVIGIL
clinical studies. Symptoms of NUVIGIL overdose are likely to be similar to those of modafinil.
Overdose in modafinil clinical trials included excitation or agitation, insomnia, and slight
or moderate elevations in hemodynamic parameters. From post-marketing experience with
modafinil, there have been no reports of fatal overdoses involving modafinil alone (doses up
to 12 grams). Overdoses involving multiple drugs, including modafinil, have resulted in fatal
outcomes. 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, excitation and hallucination; digestive changes such as nausea and
diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension and chest
pain. Overdose Management: No specific antidote exists for the toxic effects of a NUVIGIL
overdose. Such overdoses should be managed with primarily supportive care, including
cardiovascular monitoring. If there are no contraindications, induced emesis or gastric lavage
should be considered. There are no data to suggest the utility of dialysis or urinary acidification or
alkalinization in enhancing drug elimination. The physician should consider contacting a poison-control center for advice in the treatment of any overdose.
Brief summary of NUVIGIL Prescribing Information NUV-006, revised October, 2010.
Manufactured for: Cephalon, Inc., Frazer, PA 19355
For more information about NUVIGIL, please call Medical Information at 1-800-896-5855 or
visit our Web site at www.NUVIGIL.com.
© 2012 Cephalon, Inc., a wholly-owned subsidiary
of Teva Pharmaceutical Industries Ltd.
All rights reserved. NUV-3267 Apr 2012 Printed in USA.