Nuvigil 150 MG Oral Tablet
Generic Name: ARMODAFINIL
Brand Name: Nuvigil
- Substance Name(s):
- ARMODAFINIL
WARNINGS
Serious Rash, including Stevens-Johnson Syndrome Serious rash requiring hospitalization and discontinuation of treatment has been reported in adults in association with the use of modafinil and armodafinil and in children in association with the use of modafinil.
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 (a racemic mixture of S and R enantiomers), 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 with modafinil.
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, cases of serious rash similar to those observed with modafinil including skin and mouth blistering have been reported in adults in postmarketing experience.
There are no factors that are known to predict the risk of occurrence or the severity of rash associated with armodafinil or modafinil.
Nearly all cases of serious rash associated with these drugs occurred within 1 to 5 weeks after treatment initiation.
However, isolated cases have been reported after prolonged treatment with modafinil (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.
Persistent Sleepiness 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 Symptoms 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.
DRUG INTERACTIONS
Drug-Drug Interactions The existence of multiple pathways for armodafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing armodafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of NUVIGIL due to CYP inhibition by concomitant medications.
In vitro data demonstrated that armodafinil shows a weak inductive response for CYP1A2 and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by armodafinil.
Other CYP activities did not appear to be affected by armodafinil.
An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein.
Chronic administration of NUVIGIL at 250 mg reduced the systemic exposure to midazolam by 32% and 17% after single oral (5 mg) and intravenous (2 mg) doses, respectively, suggesting that administration of NUVIGIL moderately induces CYP3A activity.
Drugs that are substrates for CYP3A4/5, such as cyclosporine, may require dosage adjustment.
(See PRECAUTIONS, Drug Interactions ).
Chronic administration of NUVIGIL at 250 mg did not affect the pharmacokinetics of caffeine (200 mg), a probe substrate for CYP1A2 activity.
Coadministration of a single 400-mg dose of NUVIGIL with omeprazole (40 mg) increased systemic exposure to omeprazole by approximately 40%, indicating that armodafinil moderately inhibits CYP2C19 activity.
Drugs that are substrates for CYP2C19 may require dosage reduction.
(See PRECAUTIONS, Drug Interactions ).
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.
DESCRIPTION
NUVIGIL® (armodafinil) is a wakefulness-promoting agent for oral administration.
Armodafinil is the R-enantiomer of modafinil which is a mixture of the R- and S-enantiomers.
The chemical name for armodafinil is 2-[(R)-(diphenylmethyl)sulfinyl]acetamide.
The molecular formula is C15H15NO2S and the molecular weight is 273.35.
The chemical structure is: Armodafinil exists in multiple crystalline forms.
Form I, which is used in NUVIGIL, is the least soluble form of armodafinil and is a white to off-white, crystalline powder that is very slightly soluble in water, sparingly soluble in acetone and soluble in methanol.
At least 90% of the armodafinil particles used in NUVIGIL have a diameter less than 200 microns.
NUVIGIL tablets contain 50, 150, or 250 mg of armodafinil and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch.
chemical structure
CLINICAL STUDIES
CLINICAL TRIALS The effectiveness of NUVIGIL in improving wakefulness has been established in the following sleep disorders: obstructive sleep apnea (OSA), narcolepsy and shift work disorder (SWD).
For each clinical trial, a p-value of ≤ 0.05 was required for statistical significance.
Obstructive Sleep Apnea Syndrome (OSA) The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness associated with OSA was established in two 12-week, multi-center, placebo-controlled, parallel-group, double-blind studies of outpatients who met the International Classification of Sleep Disorders (ICSD) criteria for OSA (which are also consistent with the American Psychiatric Association DSM-IV criteria).
These criteria include either, 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated features such as loud snoring, morning headaches or dry mouth upon awakening; or 2) excessive sleepiness or insomnia; and polysomnography demonstrating one of the following: more than five obstructive apneas, each greater than 10 seconds in duration, per hour of sleep; and one or more of the following: frequent arousals from sleep associated with the apneas, bradytachycardia, or arterial oxygen desaturation in association with the apneas.
In addition, for entry into these studies, all patients were required to have excessive sleepiness as demonstrated by a score ≥ 10 on the Epworth Sleepiness Scale, despite treatment with continuous positive airway pressure (CPAP).
Evidence that CPAP was effective in reducing episodes of apnea/hypopnea was required along with documentation of CPAP use.
Patients were required to be compliant with CPAP, defined as CPAP use ≥ 4 hours/night on ≥ 70% of nights.
CPAP use continued throughout the study.
In both studies, the primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient’s overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit.
For a successful trial both measures had to show statistically significant improvement.
The MWT measures latency (in minutes) to sleep onset.
An extended MWT was performed with test sessions at 2 hour intervals between 9AM and 7PM.
The primary analysis was the average of the sleep latencies from the first four test sessions (9AM to 3PM).
For each test session, the subject was asked to attempt to remain awake without using extraordinary measures.
Each test session was terminated after 30 minutes if no sleep occurred or immediately after sleep onset.
The CGI-C is a 7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved.
Evaluators were not given any specific guidance about the criteria they were to apply when rating patients.
In the first study, a total of 395 patients with OSA were randomized to receive NUVIGIL 150 mg/day, NUVIGIL 250 mg/day or matching placebo.
Patients treated with NUVIGIL showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT at final visit.
A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale at final visit.
The average sleep latencies (in minutes) in the MWT at baseline for the trials are shown in Table 1 below, along with the average change from baseline on the MWT at final visit.
The percentages of patients who showed any degree of improvement on the CGI-C in the clinical trials are shown in Table 2 below.
The two doses of NUVIGIL produced statistically significant effects of similar magnitudes on the MWT, and also on the CGI-C.
In the second study, 263 patients with OSA were randomized to either NUVIGIL 150 mg/day or placebo.
Patients treated with NUVIGIL showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT [Table 1].
A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale [Table 2].
Nighttime sleep measured with polysomnography was not affected by the use of NUVIGIL in either study.
Narcolepsy The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness (ES) associated with narcolepsy was established in one 12-week, multi-center, placebo-controlled, parallel-group, double-blind study of outpatients who met the ICSD criteria for narcolepsy.
A total of 196 patients were randomized to receive NUVIGIL 150 or 250 mg/day, or matching placebo.
The ICSD criteria for narcolepsy include either 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least three months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy), or 2) a complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes and a Multiple Sleep Latency Test (MSLT) that demonstrates a mean sleep latency of less than 5 minutes and two or more sleep onset REM periods and no medical or mental disorder accounts for the symptoms.
For entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, via MSLT with a sleep latency of 6 minutes or less and the absence of any other clinically significant active medical or psychiatric disorder.
The MSLT, an objective polysomnographic assessment of the patient’s ability to fall asleep in an unstimulating environment, measured latency (in minutes) to sleep onset averaged over 4 test sessions at 2-hour intervals.
For each test session, the subject was told to lie quietly and attempt to sleep.
Each test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset.
The primary measures of effectiveness were: 1) sleep latency as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient’s overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit (See CLINICAL TRIALS, OSA section above for a description of these measures).
Each MWT test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset in this study.
Patients treated with NUVIGIL showed a statistically significantly enhanced ability to remain awake on the MWT at each dose compared to placebo at final visit [Table 1].
A statistically significant greater number of patients treated with NUVIGIL at each dose showed improvement in overall clinical condition as rated by the CGI-C scale at final visit [Table 2].
The two doses of NUVIGIL produced statistically significant effects of similar magnitudes on the CGI-C.
Although a statistically significant effect on the MWT was observed for each dose, the magnitude of effect was observed to be greater for the higher dose.
Nighttime sleep measured with polysomnography was not affected by the use of NUVIGIL.
Shift Work Disorder (SWD) The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness associated with SWD was demonstrated in a 12-week, multi-center, double-blind, placebo-controlled, parallel-group, clinical trial.
A total of 254 patients with chronic SWD were randomized to receive NUVIGIL 150 mg/day or placebo.
All patients met the ICSD criteria for chronic SWD [which are consistent with the American Psychiatric Association DSM-IV criteria for Circadian Rhythm Sleep Disorder: Shift Work Type].
These criteria include 1) either: a) a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms, and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change [jet lag] syndrome).
It should be noted that not all patients with a complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWD.
In the clinical trial, only patients who were symptomatic for at least 3 months were enrolled.
Enrolled patients were also required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score ≤ 6 minutes), and have daytime insomnia documented by a daytime polysomnogram (PSG).
The primary measures of effectiveness were 1) sleep latency, as assessed by the Multiple Sleep Latency Test (MSLT) performed during a simulated night shift at the final visit, and 2) the change in the patient’s overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit.
(See CLINICAL TRIALS , Narcolepsy and OSA sections above for description of these measures).
Patients treated with NUVIGIL showed a statistically significant prolongation in the time to sleep onset compared to placebo-treated patients, as measured by the nighttime MSLT at final visit [Table 1].
A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale at final visit [Table 2].
Daytime sleep measured with polysomnography was not affected by the use of NUVIGIL.
Table 1.
Average Baseline Sleep Latency and Change from Baseline at Final Visit (MWT and MSLT in minutes) Disorder Measure NUVIGIL 150 mg* NUVIGIL 250 mg* Placebo *Significantly different than placebo for all trials (p<0.05) Baseline Change from Baseline Baseline Change from Baseline Baseline Change from Baseline OSA I MWT 21.5 1.7 23.3 2.2 23.2 -1.7 OSA II MWT 23.7 2.3 – – 23.3 -1.3 Narcolepsy MWT 12.1 1.3 9.5 2.6 12.5 -1.9 SWD MSLT 2.3 3.1 – – 2.4 0.4 Table 2.
Clinical Global Impression of Change (CGI-C) (Percent of Patients Who Improved at Final Visit) Disorder NUVIGIL 150 mg* NUVIGIL 250 mg* Placebo *Significantly different than placebo for all trials (p<0.05) OSA I 71% 74% 37% OSA II 71% – 53% Narcolepsy 69% 73% 33% SWD 79% – 59%
HOW SUPPLIED
NUVIGIL® (armodafinil) Tablets [C-IV] 50 mg: Each round, white uncoated tablet is debossed with “C” on one side and “205” on the other.
NDC 63459-205-30 – Bottles of 30 150 mg: Each oval, white uncoated tablet is debossed with “C” on one side and “215” on the other.
NDC 63459-215-30 – Bottles of 30 250 mg: Each oval, white uncoated tablet is debossed with “C” on one side and “225” on the other.
NDC 63459-225-30 – Bottles of 30 Store at 20° – 25° C (68° – 77° F).
Distributed by: Cephalon, Inc.
Frazer, PA 19355 U.S.
Patent Nos.
RE37,516; 7,132,570; 7,297,346 NUVIGIL is a trademark of Cephalon, Inc.
or its affiliates.
© 2007-2010 Cephalon, Inc.
All rights reserved.
October 2010 NUV-006
GERIATRIC USE
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 PRECAUTIONS ).
INDICATIONS AND USAGE
NUVIGIL is indicated to improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea, narcolepsy and shift work disorder.
In OSA, 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.
In all cases, careful attention to the diagnosis and treatment of the underlying sleep disorder(s) is of utmost importance.
Prescribers should be aware that some patients may have more than one sleep disorder contributing to their excessive sleepiness.
The effectiveness of NUVIGIL in long-term use (greater than 12 weeks) has not been systematically evaluated in placebo-controlled trials.
The physician who elects to prescribe NUVIGIL for an extended time in patients should periodically re-evaluate long-term usefulness for the individual patient.
PEDIATRIC USE
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 ).
PREGNANCY
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 NUVIGIL and for one month after discontinuation of therapy (See Carcinogenesis, Mutagenesis, Impairment of Fertility and Pregnancy ).
NUSRING MOTHERS
Nursing Mothers 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.
DOSAGE AND ADMINISTRATION
Obstructive Sleep Apnea (OSA) and Narcolepsy The recommended dose of NUVIGIL for patients with OSA or narcolepsy is 150 mg or 250 mg given as a single dose in the morning.
In patients with OSA, doses up to 250 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that this dose confers additional benefit beyond that of the 150 mg/day dose (See CLINICAL PHARMACOLOGY and CLINICAL TRIALS ).
Shift Work Sleep Disorder (SWD) The recommended dose of NUVIGIL for patients with SWD is 150 mg given daily approximately 1 hour prior to the start of their work shift.
Dosage adjustment should be considered for concomitant medications that are substrates for CYP3A4/5, such as steroidal contraceptives, triazolam, and cyclosporine (See PRECAUTIONS, Drug Interactions ).
Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, and phenytoin may have prolonged elimination upon coadministration with NUVIGIL and may require dosage reduction and monitoring for toxicity (See PRECAUTIONS, Drug Interactions ).
In patients with severe hepatic impairment, NUVIGIL should be administered at a reduced dose (See CLINICAL PHARMACOLOGY and PRECAUTIONS ).
There is inadequate information to determine safety and efficacy of dosing in patients with severe renal impairment (See CLINICAL PHARMACOLOGY 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 in this population (See CLINICAL PHARMACOLOGY and PRECAUTIONS ).