Armodafinil

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NUVIGIL (armodafinil) is a wakefulness-promoting agent for oral administration. Armodafinil is the R-enantiomer of modafinil which is a 1:1 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 is a white to off-white, crystalline powder that is slightly soluble in water, sparingly soluble in acetone, and soluble in methanol.

NUVIGIL tablets contain 50, 150, 200 or 250 mg of armodafinil and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch.

Mechanism Of Action

The mechanism(s) through which armodafinil promotes wakefulness is unknown. Armodafinil (R-modafinil) has pharmacological properties similar to those of modafinil (a mixture of R- and S-modafinil), to the extent tested in animal and in vitro studies. The R- and S-enantiomers have similar pharmacological actions in animals.

Armodafinil and modafinil have wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although their pharmacologic profile is not identical to that of the sympathomimetic amines.

Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist, prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to α-adrenergic agonists such as the rat vas deferens preparation.

Armodafinil is an indirect dopamine receptor agonist; both armodafinil and modafinil bind in vitro to the dopamine transporter and inhibit dopamine reuptake. For modafinil, this activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, a dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil.

In addition to its wake-promoting effects and ability to increase locomotor activity in animals, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine; modafinil was also partially discriminated as stimulant-like.

Based on nonclinical studies, two major metabolites, acid and sulfone, of modafinil or armodafinil, do not appear to contribute to the CNS-activating properties of the parent compounds.

Pharmacokinetics

Armodafinil exhibits linear time-independent kinetics following single and multiple oral dose administration. Increase in systemic exposure is proportional over the dose range of 50 to 400 mg. No time-dependent change in kinetics was observed through 12 weeks of dosing. Apparent steady state for armodafinil was reached within 7 days of dosing. At steady state, the systemic exposure for armodafinil is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the R-enantiomer following administration of a single-dose of 50 mg NUVIGIL or 100 mg PROVIGIL (modafinil, a 1:1 mixture of R-and S-enantiomers) are nearly superimposable. However, the Cmax and AUC0-∞, of armodafinil at steady-state were approximately 37% and 70% higher, respectively, following administration of 200 mg NUVIGIL than the corresponding values of modafinil following administration of 200 mg PROVIGIL due to the more rapid clearance of the S-enantiomer (elimination half-life approximately 4 hours) as compared to the R-enantiomer.

NUVIGIL is readily absorbed after oral administration. The absolute oral bioavailability was not determined due to the aqueous insolubility of armodafinil, which precluded intravenous administration. Peak plasma concentrations are attained at approximately 2 hours in the fasted state. Food effect on the overall bioavailability of NUVIGIL is considered minimal; however, time to reach peak concentration (tmax) may be delayed by approximately 2-4 hours in the fed state. Since the delay in tmax is also associated with elevated plasma concentrations later in time, food can potentially affect the onset and time course of pharmacologic action for NUVIGIL.

NUVIGIL has an apparent volume of distribution of approximately 42 L. Data specific to armodafinil protein binding are not available. However, modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of NUVIGIL with highly protein-bound drugs is considered to be minimal.

After oral administration of NUVIGIL, armodafinil exhibits an apparent monoexponential decline from the peak plasma concentration. The apparent terminal t½ is approximately 15 hours. The oral clearance of NUVIGIL is approximately 33 mL/min.

In vitro and in vivo data show that armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the single most prominent metabolic pathway, with sulfone formation by cytochrome P450 (CYP) 3A4/5 being next in importance. The other oxidative products are formed too slowly in vitro to enable identification of the enzyme(s) responsible. Only two metabolites reach appreciable concentrations in plasma (i.e., R-modafinil acid and modafinil sulfone).

Data specific to NUVIGIL disposition are not available. However, modafinil is mainly eliminated via metabolism, predominantly in the liver, with less than 10% of the parent compound excreted in the urine. A total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1.0% in the feces).

Specific Populations

In a clinical study, systemic exposure of armodafinil was approximately 15% higher in elderly subjects ( ≥ 65 years of age, N=24), corresponding to approximately 12% lower oral clearance (CL/F), as compared to young subjects (18-45 years of age, N=25). Systemic exposure of armodafinil acid (metabolite) was approximately 61% and 73% greater for Cmax and AUC0-τ, respectively, compared to young subjects. Systemic exposure of the sulfone metabolite was approximately 20% lower for elderly subjects compared with young subjects. A subgroup analysis of elderly subjects demonstrated elderly subjects ≥ 75 and 65-74 years of age had approximately 21% and 9% lower oral clearance, respectively, compared to young subjects. Systemic exposure was approximately 10% greater in subjects 65-74 years of age (N=17) and 27% greater in subjects ≥ 75 years of age (N=7), respectively, when compared to young subjects. The change is considered not likely to be clinically significant for elderly patients, however, because some elderly patients have greater exposure to armodafinil, consideration should be given to the use of lower doses.

Population pharmacokinetic analysis suggests no gender effect on the pharmacokinetics of armodafinil.

The influence of race/ethnicity on the pharmacokinetics of armodafinil has not been studied.

The pharmacokinetics and metabolism of modafinil were examined in patients with cirrhosis of the liver (6 men and 3 women). Three patients had stage B or B+ cirrhosis and 6 patients had stage C or C+ cirrhosis (per the Child-Pugh score criteria). Clinically 8 of 9 patients were icteric and all had ascites. In these patients, the oral clearance of modafinil was decreased by about 60% and the steady state concentration was doubled compared to normal patients [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

In a single dose 200 mg modafinil study, severe chronic renal failure (creatinine clearance ≤ 20 mL/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to modafinil acid (metabolite) was increased 9-fold.

Drug Interactions

In vitro data demonstrated that armodafinil weakly induces 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.

The existence of multiple pathways for armodafinil metabolism, as well as the fact that a nonCYP-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. However, 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 concentrations of armodafinil.

• Drugs Metabolized by CYP3A4/5
  In vitro data demonstrated that armodafinil is a weak inducer of CYP3A activity in a concentration-related manner. In a clinical study, concomitant administration of NUVIGIL 250 mg resulted in a reduction in systemic exposure to midazolam by 32% after a single oral dose (5 mg) and 17% after a single intravenous dose (2 mg). Therefore, the blood levels and effectiveness of drugs that are substrates for CYP3A enzymes (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be reduced after initiation of concomitant treatment with NUVIGIL [see DRUG INTERACTIONS].
  In a separate clinical study, concomitant administration of NUVIGIL 250 mg with quetiapine (300 mg to 600 mg daily doses) resulted in a reduction in the mean systemic exposure of quetiapine by approximately 29%. No dose adjustment is required.
• Drugs Metabolized by CYP1A2
  In vitro data demonstrated that armodafinil is a weak inducer of CYP1A2 in a concentration-related manner. However, in a clinical study using caffeine as a probe substrate, no significant effect on CYP1A2 activity was observed.
• Drugs Metabolized by CYP2C19
  In vitro data demonstrated that armodafinil is a reversible inhibitor of CYP2C19 activity. In a clinical study, concomitant administration of NUVIGIL 400 mg resulted in a 40% increase in exposure to omeprazole after a single oral dose (40 mg), as a result of moderate inhibition of CYP2C19 activity [see DRUG INTERACTIONS].
• Interactions with CNS Active Drugs
  Concomitant administration of NUVIGIL with quetiapine reduced the systemic exposure of quetiapine.
  Data specific to NUVIGIL drug-drug interaction potential with other CNS active drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to NUVIGIL.
  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 pharmacokinetic 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 NUVIGIL or modafinil drug-drug interaction potential with monoamine oxidase (MAO) inhibitors are not available [see DRUG INTERACTIONS].
• Interaction with P-Glycoprotein
  An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein. The impact of inhibition of P-glycoprotein is not known.
• Interactions with Other Drugs
  Data specific to NUVIGIL 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 NUVIGIL.
  Warfarin: 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, an interaction cannot be ruled out [see DRUG INTERACTIONS].

Clinical Studies

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 clinical studies of outpatients who met the criteria for OSA. The 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 (ESS), 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 3 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 4 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 3). A statistically significant greater number of patients treated with NUVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale (Table 4).

Nighttime sleep measured with polysomnography was not affected by the use of NUVIGIL in either study.

The effectiveness of NUVIGIL in improving wakefulness in patients with excessive sleepiness associated with narcolepsy was established in one 12-week, multi-center, placebo-controlled, parallel-group, double-blind study of outpatients who met the criteria for narcolepsy. A total of 196 patients were randomized to receive NUVIGIL 150 or 250 mg/day, or matching placebo. The 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 CGI-C at the final visit [see Clinical Studies 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 3]. 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 4].

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.

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 criteria for chronic SWD. The 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.

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 CGI-C at the final visit [see Clinical Studies for a 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 3). 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 4).

Daytime sleep measured with polysomnography was not affected by the use of NUVIGIL.

Table 3: Average Baseline Sleep Latency and Change from Baseline at Final Visit (MWT and MSLT in minutes)

Table 4: Clinical Global Impression of Change (CGI-C) (Percent of Patients Who Improved at Final Visit)

NUVIGIL
(nu-vij-el)
(armodafinil) Tablets, for Oral Use

What is the most important information I should know about NUVIGIL?

NUVIGIL is a federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep NUVIGIL in a safe place to prevent misuse and abuse. Selling or giving away NUVIGIL may harm others, and is against the law. Tell your doctor if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.

NUVIGIL may cause serious side effects including a serious rash or a serious allergic reaction that may affect parts of your body such as your liver or blood cells. Any of these may need to be treated in a hospital and may be life-threatening.

Stop taking NUVIGIL and call your doctor right away or get emergency help if you have any of these symptoms:

• skin rash, hives, sores in your mouth, or your skin blisters and peels
• swelling of your face, eyes, lips, tongue, or throat
• trouble swallowing, breathing, or hoarseness
• fever, shortness of breath, swelling of the legs, yellowing of the skin or whites of the eyes, or dark urine.

If you have a severe rash with NUVIGIL, stopping the medicine may not keep the rash from becoming life-threatening or causing you to be permanently disabled or disfigured.

NUVIGIL is not approved for use in children for any medical condition.

It is not known if NUVIGIL is safe and effective in children under the age of 18.

What is NUVIGIL?

NUVIGIL is a prescription medicine used to improve wakefulness in adults who are very sleepy due to one of the following diagnosed sleep disorders:

• narcolepsy
• obstructive sleep apnea (OSA). NUVIGIL is used with other medical treatments for this sleep disorder. NUVIGIL does not take the place of using your CPAP machine or other treatments that your doctor has prescribed for this condition. It is important that you continue to use these treatments as prescribed by your doctor.
• shift work disorder (SWD) NUVIGIL will not cure these sleep disorders.

NUVIGIL may help the sleepiness caused by these conditions, but it may not stop all your sleepiness. NUVIGIL does not take the place of getting enough sleep. Follow your doctor's advice about good sleep habits and using other treatments.

Do not take NUVIGIL:

• are allergic to any of its ingredients. See the end of this Medication Guide for a complete list of ingredients in NUVIGIL.
• have had a rash or allergic reaction to either armodafinil (NUVIGIL) or modafinil (PROVIGIL®). These medicines are very similar.

Before you take NUVIGIL, tell your doctor about all of your medical conditions, including if you:

• have a history of mental health problems, including psychosis
• have heart problems or had a heart attack
• have high blood pressure. Your blood pressure may need to be checked more often while taking NUVIGIL.
• have liver or kidney problems
• have a history of drug or alcohol abuse or addiction
• are pregnant or planning to become pregnant. It is not known if NUVIGIL will harm your unborn baby.
  Pregnancy Registry: There is a registry for women who become pregnant during treatment with NUVIGIL. The purpose of this registry is to collect information about the safety of NUVIGIL during pregnancy. Contact the registry as soon as you learn that you are pregnant, or ask your doctor to contact the registry for you. You or your doctor can get information and enroll you in the registry by calling 1-866-404-4106.
• are breastfeeding. It is not known if NUVIGIL passes into your milk. Talk to your doctor about the best way to feed your baby if you take NUVIGIL.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. NUVIGIL and many other medicines can interact with each other, sometimes causing side effects. NUVIGIL may affect the way other medicines work, and other medicines may affect how NUVIGIL works. Your dose of NUVIGIL or certain other medicines may need to be changed.

Especially, tell your doctor if you use or take:

• a hormonal birth control method, such as birth control pills, shots, implants, patches, vaginal rings, and intrauterine devices (IUDs). Hormonal birth control methods may not work while you take NUVIGIL. Women who use one of these methods of birth control may have a higher chance for getting pregnant while taking NUVIGIL, and for 1 month after stopping NUVIGIL. You should use effective birth control while taking NUVIGIL and for 1 month after your final dose. Talk to your doctor about birth control choices that are right for you while taking NUVIGIL.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. Your doctor or pharmacist will tell you if it is safe to take NUVIGIL and other medicines together. Do not start any new medicines with NUVIGIL unless your doctor has told you it is okay.

How should I take NUVIGIL?

• Take NUVIGIL exactly as prescribed by your doctor. Your doctor will prescribe the dose of NUVIGIL that is right for you. Do not change your dose of NUVIGIL without talking to your doctor.
• Your doctor will tell you the right time of day to take NUVIGIL.
  • People with narcolepsy or OSA usually take NUVIGIL one time each day in the morning.
  • People with SWD usually take NUVIGIL about 1 hour before their work shift.
• Do not change the time of day you take NUVIGIL unless you have talked to your doctor. If you take NUVIGIL too close to your bedtime, you may find it harder to go to sleep.
• You can take NUVIGIL with or without food.
• If you take more than your prescribed dose or if you take an overdose of NUVIGIL, call your doctor or poison control center right away.

Symptoms of an overdose of NUVIGIL may include:

• Trouble sleeping
• Restlessness
• Confusion
• Feeling disoriented
• Feeling excited
• Hearing, seeing, feeling, or sensing things that are not really there (hallucinations)
• Nausea and diarrhea
• A fast or slow heartbeat
• Chest pain
• Increased blood pressure
• Anxiety
• Shortness of breath

What should I avoid while taking NUVIGIL?

• Do not drive a car or do other dangerous activities until you know how NUVIGIL affects you. People with sleep disorders should always be careful about doing things that could be dangerous. Do not change your daily habits until your doctor tells you it is okay.
• You should avoid drinking alcohol. It is not known how drinking alcohol will affect you when taking NUVIGIL.

What are the possible side effects of NUVIGIL?

NUVIGIL may cause serious side effects. Stop taking NUVIGIL and call your doctor right away or get emergency help if you get any of the following:

• a serious rash or serious allergic reaction. (See “What is the most important information I should know about NUVIGIL?”)
• mental (psychiatric) symptoms, including:
  • depression
  • feeling anxious
  • hearing, seeing, feeling, or sensing things that are not really there (hallucinations)
  • an extreme increase in activity and talking (mania)
  • aggressive behavior
  • thoughts of suicide
  • other mental problems
• symptoms of a heart problem, including chest pain, abnormal heart beats, and trouble breathing.

The most common side effects of NUVIGIL include:

• headache
• nausea
• dizziness
• trouble sleeping

These are not all the possible side effects of NUVIGIL.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store NUVIGIL?

• Store NUVIGIL at room temperature between 68° to 77°F (20° to 25°C).
• Keep NUVIGIL and all medicines out of the reach of children.

General information about the safe and effective use of NUVIGIL.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NUVIGIL for a condition for which it was not prescribed. Do not give NUVIGIL to other people, even if they have the same symptoms that you have. It may harm them and is against the law.

You can ask your pharmacist or healthcare provider for information about NUVIGIL that is written for health professionals.

What are the ingredients in NUVIGIL?

Active ingredient: armodafinil

Inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, povidone, and magnesium stearate.

Armodafinil is a prescription medication used to improve wakefulness in adults who are very sleepy due to one of the following diagnosed sleep disorders:

• narcolepsy
• obstructive sleep apnea (OSA). Armodafinil tablets are used with other medical treatments for this sleep disorder. Armodafinil tablets do not take the place of using your CPAP machine or other treatments that your doctor has prescribed for this condition. It is important that you continue to use these treatments as prescribed by your doctor.
• shift work disorder (SWD)

Armodafinil is in a class of medications called wakefulness-promoting agents. It works by changing the amounts of certain natural substances in the area of the brain that controls sleep and wakefulness.

This medication comes in tablet form to take by mouth. It is usually taken once a day and is taken with or without food.

Your doctor will tell you the right time of day to take armodafinil tablets.

• People with narcolepsy or obstructive sleep apnea (OSA) usually take armodafinil tablets one time each day in the morning.
• People with shift work disorder (SWD) usually take armodafinil tablets about 1 hour before their work shift.

Common side effects of armodafinil include headache, nausea, dizziness, and trouble sleeping.

Armodafinil may be found in some form under the following brand names:

• Nuvigil

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of armodafinil, there are no specific foods that you must exclude from your diet when receiving this medication.

If you take too much armodafinil, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Dosage Forms & Strengths

tablet: Schedule IV

• 50mg
• 150mg
• 200mg
• 250mg

Obstructive Sleep Apnea/Hypopnea Syndrome

150-250 mg PO qAM

Narcolepsy

150-250 mg PO qAM

Shift Work Sleep Disorder

150 mg PO qDay 1 hour prior to patient's work shift

Limitation of Use

In obstructive sleep apnea, indicated to treat excessive sleepiness and not as treatment for the underlying obstruction

Dosing Modifications

Hepatic impairment: Reduce dose

Renal impairment: Safety and efficacy not established

Safety and efficacy not established

Consider lower initial dose

Mechanism of Action

Unknown; not sympathomimetic (R-enantiomer of modafinil); may increase dopamine levels in the brain by binding to the dopamine transporter and inhibiting dopamine reuptake

Absorption

Peak plasma time: 2 hr

Distribution

Protein bound: 60%

Vd: 42 L

Metabolism

Hepatic; primarily amide hydrolysis; also sulfone formation by CYP3A4/5

Enzymes induced: CYP1A2, possibly CYP3A4 in a concentration-related manner

Enzymes inhibited: CYP2C19

Pharmacokinetics

Half-life: 15 hr

Excretion: Urine (80%)

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Armodafinil may be habit-forming. Never share armodafinil with another person, especially someone with a history of drug abuse or addiction. Selling or giving away armodafinil is against the law.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Armodafinil is usually taken each morning to prevent daytime sleepiness, or 1 hour before the start of a work shift to treat work-time sleep disorders.

You may take armodafinil with or without food.

Armodafinil is usually given for up to 12 weeks. Follow your doctor's instructions.

If you are taking armodafinil to treat sleepiness caused by obstructive sleep apnea, you may also be treated with a continuous positive airway pressure (CPAP) machine. This machine is an air pump connected to mask that gently blows pressurized air into your nose while you sleep. The pump does not breathe for you, but the gentle force of air helps keep your airway open to prevent obstruction.

Do not stop using your CPAP machine during sleep unless your doctor tells you to. The combination of treatment with CPAP and armodafinil may be necessary to best treat your condition.

Taking this medication does not take the place of getting enough sleep. Talk with your doctor if you continue to have excessive sleepiness even while taking armodafinil. Armodafinil will not cure obstructive sleep apnea or treat its underlying causes. Follow your doctor's instructions about all your other treatments for this disorder.

Store at room temperature away from moisture and heat.

Keep track of the amount of medicine used from each new bottle. Armodafinil is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

Take the missed dose as soon as you remember, but avoid taking the medication if you do not plan to be awake for several hours. If it is close to your normal bedtime hour, you may need to skip the missed dose and wait until the next day to take the medicine again.

Talk with your doctor about what to do if you miss a dose of armodafinil. Do not take extra medicine to make up the missed dose.

Armodafinil may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid other dangerous activity until you know how this medication will affect your level of wakefulness.

Avoid drinking alcohol while taking armodafinil.

Wakefulness-promoting agent; R-enantiomer of racemic modafinil.1 2 3 4 5 6 7 8 10 11 12 13 14 26 34

Administration

Oral Administration

Administer orally once daily.1 Manufacturer makes no specific recommendations regarding administration with regard to meals.1 (See Food under Pharmacokinetics.)

In patients with narcolepsy or OSAHS, usually administer as a single dose in the morning.1 In patients with SWSD, administer dose approximately 1 hour prior to start of work shift.1

Dosage

Adults

150 or 250 mg daily.1

Dosages up to 250 mg daily have been well tolerated, but may not provide additional clinical benefit beyond 150-mg daily dosage.1 2

Long-term efficacy (>12 weeks) not systematically evaluated,1 but use for ≥12 months was associated with sustained improvement in wakefulness in patients with OSAHS in an extension study.24 If clinician elects to prescribe for an extended period, periodically reassess long-term usefulness in the individual patient.1

150 mg or 250 mg daily.1

Long-term efficacy (>12 weeks) not systematically evaluated,1 but use for ≥12 months was associated with sustained improvement in wakefulness in patients with narcolepsy in an extension study.24 If clinician elects to prescribe for an extended period, periodically reassess long-term usefulness in the individual patient.1

150 mg daily.1

Long-term efficacy (>12 weeks) not systematically evaluated,1 but use for ≥12 months was associated with sustained improvement in wakefulness in patients with SWSD in an extension study.24 If clinician elects to prescribe for an extended period, periodically reassess long-term usefulness in the individual patient.1

Special Populations

Hepatic Impairment

Reduce dosage in patients with severe hepatic impairment (with or without cirrhosis).1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Current information inadequate to make specific dosage recommendations in patients with severe renal impairment.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Consider use of lower than usual recommended dosage.1 7 (See Geriatric Use under Cautions.)

Partially metabolized by CYP3A enzymes.1 Slightly induces CYP1A2 and possibly CYP3A, and reversibly inhibits CYP2C19 in vitro.1 7 14 Moderately induces CYP3A4 and moderately inhibits CYP2C19, but does not appear to substantially induce CYP1A2, in vivo.1 7 8 14

Substrate of P-glycoprotein.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent inducers or inhibitors of CYP3A4/5: Potential pharmacokinetic interaction (altered plasma concentrations of armodafinil).1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4/5: Potential pharmacokinetic interaction (decreased plasma concentrations of substrate); dosage adjustment of substrate drug may be necessary.1 7 8 14

Substrates of CYP2C19: Potential pharmacokinetic interaction (increased plasma concentrations of substrate); dosage reduction and monitoring for toxicity of substrate drug may be necessary.1 7 14

Protein-bound Drugs

Potential for interactions with highly protein-bound drugs considered unlikely.1

Specific Drugs

Armodafinil is used to help people who have narcolepsy, obstructive sleep apnea (also called hypopnea syndrome), or shift work sleep disorders to stay awake during the day. armodafinil does not cure these conditions and will only work as long as you continue to take it.

armodafinil is available only with your doctor's prescription.

Dosage in Obstructive Sleep Apnea (OSA) and Narcolepsy

The recommended dosage of Armodafinil tablets for patients with OSA or narcolepsy is 150 mg to 250 mg taken orally once a day 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 these doses confer additional benefit beyond that of the 150 mg/day dose [see Clinical Pharmacology (12.3) and Clinical Studies (14.1, 14.2)].

Dosage in Shift Work Disorder (SWD)

The recommended dosage of Armodafinil tablets for patients with SWD is 150 mg taken orally once a day as a single dose approximately 1 hour prior to the start of their work shift.

Dosage Modification in Patients with Severe Hepatic Impairment

In patients with severe hepatic impairment, the dosage of Armodafinil tablets should be reduced [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Use in Geriatric Patients

Consideration should be given to the use of lower doses and close monitoring in geriatric patients [see Use in Specific Populations (8.5)].

Controlled Substance

Armodafinil tablets contain Armodafinil, a Schedule IV controlled substance.

Abuse

Abuse of Armodafinil tablets have been reported in patients treated with Armodafinil tablets. Patterns of abuse have included euphoric mood and use of increasingly large doses or recurrent use of Armodafinil tablets for a desired effect. Drug diversion has also been noted. During the postmarketing period, misuse of Armodafinil tablets has been observed (e.g., taking Armodafinil tablets against a physician's advice, and obtaining Armodafinil tablets from multiple physicians).

Abuse of Armodafinil, the active ingredient of Armodafinil tablets, poses a risk of overdosage similar to that seen for modafinil, which may lead to tachycardia, insomnia, agitation, dizziness, anxiety, nausea, headache, dystonia, tremor, chest pain, hypertension, seizures, delirium, or hallucinations. Other signs and symptoms of CNS stimulant abuse include tachypnea, sweating, dilated pupils, hyperactivity, restlessness, decreased appetite, loss of coordination, flushed skin, vomiting, and abdominal pain.

In humans, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings, typical of other CNS stimulants. In in vitro binding studies, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. 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 (e.g., methylphenidate, amphetamine, or cocaine) abuse. Patients should be observed for signs of misuse or abuse (e.g., incrementation of doses or drug-seeking behavior).

The abuse potential of modafinil (200, 400, and 800 mg) was assessed relative to methylphenidate (45 and 90 mg) in an inpatient study in individuals experienced with drugs of abuse. Results from this clinical study demonstrated that modafinil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate).

Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Physical dependence can occur in patients treated with Armodafinil tablets. Abrupt cessation or dose reduction following chronic use can result in withdrawal symptoms, including shaking, sweating, chills, nausea, vomiting, confusion, aggression, and atrial fibrillation.

Drug withdrawal convulsions, suicidality, fatigue, insomnia, aches, depression and headache have also been observed during the postmarketing period. Also, abrupt withdrawal has caused deterioration of psychiatric symptoms such as depression.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Multiple cases of development of tolerance to Armodafinil tablets have been reported during the postmarketing period.

NDC 51991-322-90

CIV

Armodafinil Tablets

50 mg

PHARMACIST: Dispense the
accompanying Medication
Guide to each patient.

90 Tablets
Rx Only

Breckenridge
Pharmaceutical, Inc.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Nuvigil: 50 mg, 150 mg, 200 mg, 250 mg

Generic: 50 mg, 150 mg, 200 mg, 250 mg

Refer to adult dosing. Consider lower initial dosage.

There are no dosage adjustments provided in the manufacturer's labeling.

>10%: Central nervous system: Headache (14% to 23%; dose related)

1% to 10%:

Cardiovascular: Palpitations (2%), increased heart rate (1%)

Central nervous system: Insomnia (4% to 6%; dose related), dizziness (5%), anxiety (4%), depression (1% to 3%; dose related), fatigue (2%), agitation (1%), depressed mood (1%), lack of concentration (1%), migraine (1%), nervousness (1%), pain (1%), paresthesia (1%)

Dermatologic: Skin rash (1% to 4%; dose related), contact dermatitis (1%), diaphoresis (1%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (1%), increased thirst (1%)

Gastrointestinal: Nausea (6% to 9%; dose related), xerostomia (2% to 7%; dose related), diarrhea (4%), dyspepsia (2%), upper abdominal pain (2%), anorexia (1%), constipation (1%), decreased appetite (1%), loose stools (1%), vomiting (1%)

Hypersensitivity: Seasonal allergy (1%)

Neuromuscular & skeletal: Tremor (1%)

Renal: Polyuria (1%)

Respiratory: Dyspnea (1%), flu-like symptoms (1%)

Miscellaneous: Fever (1%)

<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, DRESS syndrome, hypersensitivity reaction (including bronchospasm, dysphagia), hypouricemia, increased liver enzymes, increased serum alkaline phosphatase, irritability, multi-organ hypersensitivity, oral mucosa changes (including blistering, sores, ulceration), pancytopenia, skin changes (including blistering, sores, ulceration), Stevens-Johnson syndrome, suicidal ideation, systolic hypertension, toxic epidermal necrolysis

Take the missed dose as soon as you remember, but avoid taking the medication if you do not plan to be awake for several hours. If it is close to your normal bedtime hour, you may need to skip the missed dose and wait until the next day to take the medicine again.

Talk with your doctor about what to do if you miss a dose of armodafinil. Do not take extra medicine to make up the missed dose.

150 to 250 mg orally once a day in the morning

Comments:
-In obstructive sleep apnea (OSA), doses up to 250 mg/day have been well-tolerated but there is no consistent evidence of additional benefit beyond the 150 mg/day dose.
-In OSA, this drug is not a treatment for the underlying obstruction.
-In cases where continuous positive airway pressure (CPAP) is the treatment of choice for excessive sleepiness, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating this drug.

Use: Treatment to improve wakefulness in patients with excessive sleepiness associated with OSA and narcolepsy.

150 to 250 mg orally once a day in the morning

Comments:
-In obstructive sleep apnea (OSA), doses up to 250 mg/day have been well-tolerated but there is no consistent evidence of additional benefit beyond the 150 mg/day dose.
-In OSA, this drug is not a treatment for the underlying obstruction.
-In cases where continuous positive airway pressure (CPAP) is the treatment of choice for excessive sleepiness, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating this drug.

Use: Treatment to improve wakefulness in patients with excessive sleepiness associated with OSA and narcolepsy.