Included as part of the PRECAUTIONS section.
Serious Dermatologic Reactions, including Stevens-Johnson
Syndrome And Toxic Epidermal Necrosis
Serious rash requiring hospitalization and
discontinuation of treatment has been reported in association with the use of
NUVIGIL (armodafinil) or modafinil (the racemic mixture of S- and
NUVIGIL 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 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/ Drug Rash with Eosinophilia and Systemic Symptoms
(DRESS) [see Drug Reaction with Eosinophilia and System Symptoms (DRESS)/Multiorgan Hypersensitivity]. 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.
Skin and mouth sores, blistering, and ulceration have
been reported with modafinil and NUVIGIL in the postmarketing setting.
Recurrence of signs and symptoms of serious dermatologic reactions following
rechallenge has been reported in some cases.
Rare cases of serious or life-threatening rash, including
SJS and toxic epidermal necrolysis (TEN), have been reported in adults and
children in worldwide post-marketing experience with modafinil and NUVIGIL.
There are no factors, including duration of therapy, that
are known to predict the risk of occurrence or the severity of rash associated
with modafinil or NUVIGIL. In cases where the time to onset was reported,
serious rash occurred 1 day to 2 months after initiation of treatment, but
isolated cases of serious dermatologic reactions have been reported with
symptoms beginning after prolonged treatment (e.g., 3 months).
Although benign rashes also occur with NUVIGIL, it is not
possible to reliably predict which rashes will prove to be serious.
Accordingly, NUVIGIL should be discontinued at the first sign of rash, skin or
mouth sores, or blistering or ulceration, 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.
Drug Reaction With Eosinophilia And System Symptoms
DRESS, also known as multi-organ hypersensitivity, has
been reported with NUVIGIL. DRESS typically, although not exclusively, presents
with fever, rash, lymphadenopathy, and/or facial swelling, in association with
other organ system involvement, such as hepatitis, nephritis, hematologic
abnormalities, myocarditis, or myositis, sometimes resembling an acute viral
infection. Eosinophilia is often present. This disorder is variable in its
expression, and other organ systems not noted here may be involved. It is
important to note that early manifestations of hypersensitivity (e.g., fever,
lymphadenopathy) may be present even though rash is not evident.
One fatal case of DRESS that occurred in close temporal
association (3 weeks) with the initiation of NUVIGIL treatment has been
reported in the postmarketing setting. In addition, multi-organ
hypersensitivity reactions, including at least one fatality in post-marketing
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.
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.
Angioedema And Anaphylaxis Reactions
Angioedema and hypersensitivity (with rash, dysphagia,
and bronchospasm), were observed with NUVIGIL. 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).
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.
In pre-approval narcolepsy, OSA and SWD controlled trials
of NUVIGIL, 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%). Depression was also a reason for treatment
discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL
0.6% and placebo 0.2%). Cases of suicidal ideation were observed in clinical
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
Psychiatric adverse reactions have been reported in
patients treated with modafinil. Modafinil and NUVIGIL (armodafinil) are very
closely related. Therefore, the incidence and type of psychiatric symptoms
associated with NUVIGIL are expected to be similar to the incidence and type of
these events with modafinil.
Post-marketing adverse reactions associated with the use
of NUVIGIL, some of which have resulted in hospitalization, have included
mania, delusions, hallucinations, suicidal ideation, and aggression. Many, but
not all, patients who developed psychiatric adverse reactions had a prior
psychiatric history. In these cases, reported NUVIGIL total daily doses ranged
from 50 mg to 450 mg, which includes doses below and above the recommended
Effects On Ability To Drive And Use Machinery
Although NUVIGIL has not been shown to produce functional
impairment, any drug affecting the central nervous system (CNS) may alter
judgment, thinking or motor skills. Patients should be cautioned about
operating an automobile or other hazardous machinery until it is reasonably
certain that NUVIGIL therapy will not adversely affect their ability to engage
in such activities.
In clinical studies of modafinil, cardiovascular adverse
reactions, 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. Findings
suggestive 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
findings occurs, consider cardiac evaluation.
Blood pressure monitoring in short term ( ≤ 3 months)
pre-approval controlled trials of OSA, SWD, and narcolepsy showed 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%). There was a small, but consistent, average
increase in pulse rate over placebo in pre-approval controlled trials. This
increase varied from 0.9 to 3.5 BPM. Increased monitoring of heart rate and
blood pressure may be appropriate in patients on NUVIGIL. Caution should be
exercised when prescribing NUVIGIL to patients with known cardiovascular
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Serious Dermatologic Reactions
Advise patients and caregivers about the risk of
potentially fatal serious skin reactions. Educate patients about the signs and
symptoms that may signal a serious skin reaction. Instruct patients to discontinue
NUVIGIL and consult with their healthcare provider immediately if a skin
reaction such as rash, mouth sores, blisters, or peeling skin occurs during
treatment with NUVIGIL [see WARNINGS AND PRECAUTIONS].
Instruct patients that a fever associated with signs of
other organ system involvement (e.g., rash, lymphadenopathy, hepatic
dysfunction) may be drug-related and should be reported to their healthcare
provider immediately [see WARNINGS AND PRECAUTIONS].
Angioedema And Anaphylactic Reactions
Advise patients of life-threatening symptoms suggesting
anaphylaxis or angioedema (such as hives, difficulty in swallowing or
breathing, hoarseness, or swelling of the face, eyes, lips, or tongue) that can
occur with NUVIGIL. Instruct them to discontinue NUVIGIL and immediately report
these symptoms to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Advise patients that treatment with NUVIGIL will not
eliminate their abnormal tendency to fall asleep. Advise patients that they 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. Advise
patients that NUVIGIL is not a replacement for sleep.
Continuing Previously Prescribed Treatments
Inform patients that it may be critical that they
continue to take their previously prescribed treatments (e.g., patients with
OSA receiving CPAP should continue to do so).
Advise patients to stop taking NUVIGIL and contact their
physician right away if they experience, depression, anxiety, or signs of
psychosis or mania.
Advise women that there is a pregnancy exposure registry
that monitors pregnancy outcomes in women exposed to NUVIGIL during pregnancy
[see Use in Specific Populations].
Females Of Reproductive Potential
Caution females regarding the potential increased risk of
pregnancy when using hormonal contraceptives (including depot or implantable
contraceptives) with NUVIGIL and advise females who are using a hormonal method
of contraception to use an additional barrier method or an alternative
non-hormonal method of contraception during treatment with NUVIGIL and for one
month after discontinuation of NUVIGIL.
Advise patients 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.
Advise patients that the use of NUVIGIL in combination
with alcohol has not been studied. Advise patients that it is prudent to avoid
alcohol while taking NUVIGIL.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a mouse carcinogenicity study, armodafinil
(R-modafinil) was administered at oral doses of up to300 mg/kg/day in males and
100 mg/kg/day in females for approximately two years, no tumorigenic effects
In a rat carcinogenicity study modafinil (a mixture of
R-and S-modafinil) was administered at oral doses of up to 60 mg/kg/day for two
years; no tumorigenic effects were observed.
At the highest doses studied in mouse and rat, the plasma
armodafinil exposures (AUC) were less than that in humans at the MRHD of
NUVIGIL (250 mg/day).
Armodafinil was negative in an in vitro bacterial reverse
mutation assay and in an in vitro chromosomal aberration assay in human
Modafinil was negative in a series of in vitro (i.e.,
bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration in human
lymphocytes, cell transformation in BALB/3T3 mouse embryo cells) or in vivo
(mouse bone marrow micronucleus) assays.
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 armodafinil AUC less than that in humans at the MRHD of NUVIGIL.
Use In Specific Populations
There is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to NUVIGIL during pregnancy. Healthcare
providers are encouraged to register pregnant patients, or pregnant women may
enroll themselves in the registry by calling 1-866-404-4106.
Limited available data on armodafinil use in pregnant
women are insufficient to inform a drug associated risk of adverse pregnancy
outcomes. Intrauterine growth restriction and 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, armodafinil shares some pharmacologic properties with this class [see
CLINICAL PHARMACOLOGY]. Some sympathomimetics have been associated with
intrauterine growth restriction and spontaneous abortions.
In animal reproduction studies of armodafinil
(R-modafinil) and modafinil (a mixture of R-and S-modafinil) conducted in
pregnant rats (armodafinil, modafinil) and rabbits (modafinil) during
organogenesis, evidence of developmental toxicity (increased embryofetal and
offspring mortality, decreased fetal growth) was observed at clinically
relevant plasma exposures.
All pregnancies have a background risk of birth defects,
loss, or other adverse outcomes. The estimated background risk of major birth
defects and miscarriage for the indicated populations is unknown. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
Oral administration of armodafinil (60, 200, or 600
mg/kg/day) to pregnant rats throughout organogenesis resulted in decreased
fetal body weight and increased incidences of fetal variations indicative of
growth delay at the highest dose, which was also maternally toxic. The highest
no-effect dose for embryofetal developmental toxicity in rat (200 mg/kg/day)
was associated with a plasma armodafinil exposure (AUC) less than that in
humans at the maximum recommended human dose (MRHD) of NUVIGIL (250 mg/day).
Modafinil (50, 100, or 200 mg/kg/day) administered orally
to pregnant rats throughout organogenesis produced an increase in resorptions
and an increased incidence of fetal variations at the highest dose tested. The
higher no-effect dose for embryofetal developmental toxicity (100 mg/kg/day)
was associated with a plasma armodafinil AUC less than that in humans at the
MRHD of NUVIGIL. However, in a subsequent rat study of up to 480 mg/kg/day of
modafinil, no adverse effects on embryofetal development were observed.
In a study in which modafinil (45, 90, or 180 mg/kg/day)
was orally administered to pregnant rabbits during organogenesis, embryofetal
death was increased at the highest dose. The highest no-effect dose for
developmental toxicity (100 mg/kg/day) was associated with a plasma armodafinil
AUC less than that in humans at the MRHD of NUVIGIL.
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 armodafinil AUC less than that in humans at the MRHD of NUVIGIL. No
effects on postnatal developmental and neurobehavioral parameters were observed
in surviving offspring.
There are no data on the presence of armodafinil or its
metabolites in human milk, the effects on the breastfed infant, or the effect
of this drug on milk production. Modafinil was present in rat milk when animals
were dosed during the lactation period. The developmental and health benefits
of breastfeeding should be considered along with the mother's clinical need for
armodafinil and any potential adverse effects on the breastfed child from
armodafinil or from the underlying maternal condition.
Females And Males Of Reproductive Potential
The effectiveness of hormonal contraceptives may be
reduced when used with NUVIGIL and for one month after discontinuation of
therapy. Advise women who are using a hormonal method of contraception to use
an additional barrier method or an alternative non-hormonal method of
contraception during treatment with NUVIGIL and for one month after
discontinuation of NUVIGIL treatment [see DRUG INTERACTIONS and CLINICAL
Safety and effectiveness in pediatric patients have not
been established. Serious rash has been seen in pediatric patients receiving
modafinil [see WARNINGS AND PRECAUTIONS].
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 and close monitoring in this
population [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
The dosage of NUVIGIL should be reduced in patients with
severe hepatic impairment [see DOSAGE AND ADMINISTRATION and CLINICAL