Nuvigil (Armodafinil)
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Nuvigil (Armodafinil)

NUVIGIL®
(armodafinil) Tablets

DRUG 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:

NUVIGIL®
  (armodafinil) Structural Formula Illustration

Armodafinil is a white to off-white, crystalline powder that is very slightly soluble in water, sparingly soluble in acetone and soluble in methanol. 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.

What are the possible side effects of armodafinil (Nuvigil)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using armodafinil and call your doctor at once if you have a serious side effect such as:

  • fever, sore throat, headache, and vomiting with a severe blistering, peeling, and red skin rash;
  • the first sign of any type of skin rash, no matter how mild;
  • bruising, severe tingling, numbness, pain, muscle weakness;
  • easy bruising or bleeding;
  • mouth sores, trouble...

Read All Potential Side Effects and See Pictures of Nuvigil »

What are the precautions when taking armodafinil (Nuvigil)?

Before taking armodafinil, tell your doctor or pharmacist if you are allergic to it; or to modafinil; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: certain heart problems (e.g., enlarged heart, mitral valve problem), history of problems (e.g., chest pain, irregular heartbeat) after taking stimulants such as amphetamines.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: high blood pressure, heart problems (e.g., chest pain, heart attack, irregular...

Read All Potential Precautions of Nuvigil »

Last reviewed on RxList: 1/14/2011
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

NUVIGIL (armodafinil) is indicated to improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea, narcolepsy and shift work disorder.

In OSA, NUVIGIL (armodafinil) 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 (armodafinil) . If NUVIGIL (armodafinil) 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 (armodafinil) in long-term use (greater than 12 weeks) has not been systematically evaluated in placebo-controlled trials. The physician who elects to prescribe NUVIGIL (armodafinil) for an extended time in patients should periodically re-evaluate long-term usefulness for the individual patient.

DOSAGE AND ADMINISTRATION

Obstructive Sleep Apnea (OSA) and Narcolepsy

The recommended dose of NUVIGIL (armodafinil) 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 Disorder (SWD)

The recommended dose of NUVIGIL (armodafinil) 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 (armodafinil) and may require dosage reduction and monitoring for toxicity (See PRECAUTIONS: DRUG INTERACTIONS).

In patients with severe hepatic impairment, NUVIGIL (armodafinil) 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).

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 63459-205-60 - Bottles of 60

150 mg: Each oval, white, uncoated tablet is debossed with "C" on one side and "215" on the other.

NDC 63459-215-60 - Bottles of 60

250 mg: Each oval, white, uncoated tablet is debossed with "C" on one side and "225" on the other.

NDC 63459-225-60 - Bottles of 60

Store at 20° - 25° C (68° - 77° F).

Distributed by: Cephalon, Inc, Frazer, PA 19355. Revised: October 2010

Last reviewed on RxList: 1/14/2011
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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 (armodafinil) 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 (armodafinil) 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 (armodafinil) 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 following table (Table 3) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in patients treated with NUVIGIL (armodafinil) than in placebo group patients in the placebo-controlled clinical trials.

The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied.

Table 3. Incidence > 1% (In Percent) Of Treatment-Emergent Adverse Experiences In Parallel-Group, Placebo-Controlled Clinical Trialsa In OSA, Narcolepsy and SWD With NUVIGIL (armodafinil) (150 mg and 250 mg)

System Organ Class MedDRA preferred term NUVIGIL
(Percent, N=645)
Placebo
(Percent, N=445)
Cardiac Disorders
  Palpitations 2 1
Gastrointestinal Disorders
  Nausea 7 3
  Diarrhea 4 2
  Dry Mouth 4 1
  Dyspepsia 2 0
  Abdominal Pain Upper 2 1
  Constipation 1 0
  Vomiting 1 0
  Loose Stools 1 0
General Disorders And Administration Site Conditions
  Fatigue 2 1
  Thirst 1 0
  Influenza-Like Illness 1 0
  Pain 1 0
  Pyrexia 1 0
Immune System Disorders
  Seasonal Allergy 1 0
Investigations
  Gamma-Glutamyltransferase Increased 1 0
  Heart Rate Increased 1 0
Metabolism And Nutrition Disorders
  Anorexia 1 0
  Decreased Appetite 1 0
Nervous System Disorders
  Headache 17 9
  Dizziness 5 2
  Disturbance In Attention 1 0
  Tremor 1 0
  Migraine 1 0
  Paresthesia 1 0
Psychiatric Disorders
  Insomnia 5 1
  Anxiety 4 1
  Depression 2 0
  Agitation 1 0
  Nervousness 1 0
  Depressed Mood 1 0
Renal And Urinary Disorders
  Polyuria 1 0
Respiratory, Thoracic And Mediastinal Disorders
  Dyspnea 1 0
Skin And Subcutaneous Tissue Disorders
  Rash 2 0
  Contact Dermatitis 1 0
  Hyperhydrosis 1 0
a Four double-blind, placebo-controlled clinical studies in SWD, OSA, and narcolepsy; incidence is rounded to the nearest whole percent. Included are only those events for which NUVIGIL incidence is greater than that of placebo.

Dose Dependency of Adverse Events

In the placebo-controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of NUVIGIL (armodafinil) and placebo, the only adverse events that appeared to be dose-related were headache, rash, depression, dry mouth, insomnia, and nausea.

Table 4. Incidence (In Percent) Of Dose-Dependent, Treatment-Emergent Adverse Experiences By Dose and By Treatment In Parallel-Group, Placebo-Controlled Clinical Trialsa In OSA, Narcolepsy and SWD With NUVIGIL (armodafinil) (150 mg and 250 mg)

System Organ Class
MedDRA preferred term
NUVIGIL (armodafinil)
250 mg
(Percent, N=198)
NUVIGIL
150 mg (Percent, N=447)
NUVIGIL Combined (Percent, N=645) Placebo
(Percent, N=445)
Gastrointestinal Disorders
  Nausea 9 6 7 3
  Dry Mouth 7 2 4 < 1
Nervous System Disorders
  Headache 23 14 17 9
Psychiatric Disorders
  Insomnia 6 4 5 1
  Depression 3 1 2 < 1
Skin And Subcutaneous Tissue Disorders
  Rash 4 1 2 < 1
a Four double-blind, placebo-controlled clinical studies in SWD, OSA, and narcolepsy.

Vital Sign Changes

There were small, but consistent, increases in average values for mean systolic and diastolic blood pressure in controlled trials (See PRECAUTIONS). 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 (GOT) and alkaline phosphatase (AP) were found to be higher following administration of NUVIGIL (armodafinil) , 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. A single case of mild pancytopenia was observed after 35-days of treatment and resolved with drug discontinuation. A small mean decrease from baseline in serum uric acid compared to placebo was seen in clinical trials. The clinical significance of this finding is unknown.

ECG Changes

No pattern of ECG abnormalities could be attributed to NUVIGIL (armodafinil) administration in placebo-controlled clinical trials.

Drg Abuse And Dependence

Controlled Substance Class

Armodafinil (NUVIGIL (armodafinil) ) 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 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).

Read the Nuvigil (armodafinil) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Potential Interactions with Drugs That Inhibit, Induce, or Are Metabolized by Cytochrome P450 Isoenzymes and Other Hepatic Enzymes

Due to the partial involvement of CYP3A enzymes in the metabolic elimination of armodafinil, coadministration of potent inducers of CYP3A4/5 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4/5 (e.g., ketoconazole, erythromycin) could alter the plasma levels of armodafinil.

The Potential of NUVIGIL (armodafinil) to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition

Drugs Metabolized by CYP1A2

In vitro data demonstrated that armodafinil shows a weak inductive response for CYP1A2 and possibly CYP3A activities in a concentration related manner and demonstrated that CYP2C19 activity is reversibly inhibited by armodafinil. However, the effect on CYP1A2 activity was not observed clinically in an interaction study performed with caffeine (See Pharmacokinetics, Drug-Drug Interactions).

Drugs Metabolized by CYP3A4/5 (e.g., cyclosporine, ethinyl estradiol, midazolam and triazolam)

Chronic administration ofNUVIGIL (armodafinil) 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 (armodafinil) . A 32% reduction in systemic exposure of oral midazolam was seen upon concomitant administration of armodafinil with midazolam. Dose adjustment may be required (See Pharmacokinetics, Drug-Drug Interactions). Such effects (reduced concentrations) were also seen upon concomitant administration of modafinil with cyclosporine, ethinyl estradiol, and triazolam.

Drugs Metabolized by CYP2C19 (e.g., omeprazole, diazepam, phenytoin, and propranolol)

Administration of NUVIGIL (armodafinil) 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 (armodafinil) . A 40% increase in exposure was seen upon concomitant administration of armodafinil with omeprazole. (See Pharmacokinetics, Drug-Drug Interactions).

Interactions with CNS Active Drugs

Data specific to armodafinil drug-drug interaction potential with CNS active drugs are not available. However, the following available drug-drug interaction information on modafmil should be applicable to armodafinil. (See DESCRIPTION and CLINICAL PHARMACOLOGY).

Concomitant administration of modafinil with methylphenidate, or dextroamphetamine produced no significant alterations on the pharmacokinetic profile of modafinil or either stimulant, even though the absorption of modafinil was delayed for approximately one hour.

Concomitant modafinil or clomipramine did not alter the PK profile of either drug; however, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine was reported in a patient with narcolepsy during treatment with modafinil.

Data specific to armodafinil or modafinil drug-drug interaction potential with Monoamine Oxidase (MAO) inhibitors are not available. Therefore, caution should be used when concomitantly administering MAO inhibitors and NUVIGIL (armodafinil) .

Interactions with Other Drugs

Data specific to armodafinil drug-drug interaction potential for additional other drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to armodafinil.

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, a pharmacodynamic interaction cannot be ruled out. Therefore, more frequent monitoring of prothrombin times/INR should be considered whenever NUVIGIL (armodafinil) is coadministered with warfarin.

Last reviewed on RxList: 1/14/2011
This monograph has been modified to include the generic and brand name in many instances.

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 were 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 (armodafinil) 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 (armodafinil) should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking NUVIGIL (armodafinil) , 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 modafmil. Modafinil and armodafinil (NUVIGIL (armodafinil) ) 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 (armodafinil) database, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on NUVIGIL (armodafinil) compared to placebo (NUVIGIL (armodafinil) 1.2% and placebo 0.3%). In the NUVIGIL (armodafinil) controlled studies, depression was also a reason for treatment discontinuation more often in patients on NUVIGIL (armodafinil) compared to placebo (NUVIGIL (armodafinil) 0.6% and placebo 0.2%). Two cases of suicide ideation were observed in clinical trials. Caution should be exercised when NUVIGIL (armodafinil) is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with NUVIGIL (armodafinil) administration, consider discontinuing NUVIGIL (armodafinil) .

PRECAUTIONS

Diagnosis of Sleep Disorders

NUVIGIL (armodafinil) should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of either narcolepsy, OSA, and/or SWD has been made in accordance with ICSD or DSM diagnostic criteria (See Clinical Trials). Such an evaluation usually consists of a complete history and physical examination, and it may be supplemented with testing in a laboratory setting. Some patients may have more than one sleep disorder contributing to their excessive sleepiness (e.g., OSA and SWD coincident in the same patient).

CPAP Use in Patients with OSA

In OSA, NUVIGIL (armodafinil) 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 (armodafinil) . If NUVIGIL (armodafinil) is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. There was a slight trend for reduced CPAP use over time (mean reduction of 18 minutes for patients treated with NUVIGIL (armodafinil) and a 6 minute reduction for placebo-treated patients from a mean baseline use of 6.9 hours per night) in NUVIGIL (armodafinil) trials.

General

Although NUVIGIL (armodafinil) has not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until they are reasonably certain that NUVIGIL (armodafinil) therapy will not adversely affect their ability to engage in such activities.

Cardiovascular System

NUVIGIL (armodafinil) has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable angina, and such patients should be treated with caution.

In clinical studies of PROVIGIL, signs and symptoms including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that NUVIGIL (armodafinil) tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Signs of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these symptoms occurs, consider cardiac evaluation.

Blood pressure monitoring in short-term ( ≤ 3 months) controlled trials showed only small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL (armodafinil) 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 (armodafinil) requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). Increased monitoring of blood pressure may be appropriate in patients on NUVIGIL (armodafinil) .

Patients Using Steroidal Contraceptives

The effectiveness of steroidal contraceptives may be reduced when used with NUVIGIL (armodafinil) and for one month after discontinuation of therapy (See PRECAUTIONS: DRUG INTERACTIONS). Alternative or concomitant methods of contraception are recommended for patients treated with NUVIGIL (armodafinil) and for one month after discontinuation of NUVIGIL (armodafinil) treatment.

Patients Using Cyclosporine

The blood levels of cyclosporine may be reduced when used with NUVIGIL (See PRECAUTIONS: DRUG INTERACTIONS). Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when these drugs are used concomitantly.

Patients with Severe Hepatic Impairment

In patients with severe hepatic impairment, with or without cirrhosis (See CLINICAL PHARMACOLOGY), NUVIGIL (armodafinil) should be administered at a reduced dose (See DOSAGE AND ADMINISTRATION).

Patients with Severe Renal Impairment

There is inadequate information to determine safety and efficacy of dosing in patients with severe renal impairment. (For pharmacokinetics in renal impairment, see CLINICAL PHARMACOLOGY.)

Elderly Patients

In elderly patients, elimination of armodafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses in this population (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

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 at doses of 6, 30, and 60 mg/kg/day. The highest dose studied represents 1.5 (mouse) or 3 (rat) times greater than the recommended adult human daily dose of modafinil (200 mg) on a mg/m2 basis. There was no evidence of tumorigenesis associated with modafinil administration in these studies. However, since the mouse study used an inadequate high dose that was not representative of a maximum tolerated dose, a subsequent Carcinogenicity study was conducted in the Tg.AC transgenic mouse. Doses evaluated in the Tg.AC assay were 125, 250, and 500 mg/kg/day, administered dermally. There was no evidence of tumorigenicity associated with modafinil administration; however, this dermal model may not adequately assess the carcinogenic potential of an orally administered drug.

Mutagenesis

Armodafinil was evaluated in an in vitro bacterial reverse mutation assay and in an in vitro mammalian chromosomal aberration assay in human lymphocytes. Armodafinil was negative in these assays, both in the absence and presence of metabolic activation. Modafinil demonstrated no evidence of mutagenic or clastogenic potential in a series of in vitro (i.e., bacterial reverse mutation assay, mouse lymphoma tk assay, chromosomal aberration assay in human lymphocytes, cell transformation assay in clasto/3T3 mouse embryo cells) assays in the absence or presence of metabolic activation, or in vivo (mouse bone marrow micronucleus) assays. Modafinil was also negative in the unscheduled DNA synthesis assay in rat hepatocytes.

Impairment of Fertility

A fertility and early embryonic development (to implantation) study was not conducted with armodafinil alone.

Oral administration of modafinil (doses of up to 480 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females through day 7 of gestation produced an increase in the time to mate at the highest dose; no effects were observed on other fertility or reproductive parameters. The no-effect dose of 240 mg/kg/day was associated with a plasma modafinil exposure (AUC) approximately equal to that in humans at the recommended dose of 200 mg.

Pregnancy

Pregnancy Category C.

In studies conducted in rats (armodafinil, modafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant exposures.

Oral administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout the period of organogenesis resulted in increased incidences of fetal visceral and skeletal variations at the intermediate dose or greater and decreased fetal body weights at the highest dose. The no-effect dose for rat embryofetal developmental toxicity was associated with a plasma armodafinil exposure (AUC) approximately 0.03 times the AUC in humans at the maximum recommended daily dose of 250 mg.

Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout the period of organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased incidence of visceral and skeletal variations in the offspring at the highest dose. The higher no-effect dose for rat embryofetal developmental toxicity was associated with a plasma modafinil exposure approximately 0.5 times the AUC in humans at the recommended daily dose (RHD) of 200 mg. However, in a subsequent study of up to 480 mg/kg/day (plasma modafinil exposure approximately 2 times the AUC in humans at the RHD) no adverse effects on embryofetal development were observed.

Modafinil administered orally to pregnant rabbits throughout the period of organogenesis at doses of up to 100 mg/kg/day (plasma modafinil AUC approximately equal to the AUC in humans at the RHD) had no effect on embryofetal development; however, the doses used were too low to adequately assess the effects of modafinil on embryofetal development. In a subsequent developmental toxicity study evaluating doses of 45, 90, and 180 mg/kg/day in pregnant rabbits, the incidences of fetal structural alterations and embryofetal death were increased at the highest dose. The highest no-effect dose for developmental toxicity was associated with a plasma modafinil AUC approximately equal to the AUC in humans at the RHD.

Modafinil administration to rats throughout gestation and lactation at oral doses of up to 200 mg/kg/day resulted in decreased viability in the offspring at doses greater than 20 mg/kg/day (plasma modafinil AUC approximately 0.1 times the AUC in humans at the RHD). No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring.

There are no adequate and well-controlled studies of either armodafinil or modafinil in pregnant women. Two cases of intrauterine growth retardation and one case of spontaneous abortion have been reported in association with armodafinil and modafinil. Although the pharmacology of armodafinil is not identical to that of the sympathomimetic amines, it does share some pharmacologic properties with this class.

Certain of these drugs have been associated with intrauterine growth retardation and spontaneous abortions. Whether the cases reported with armodafinil are drug-related is unknown.

Armodafinil or modafinil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Registry: A pregnancy registry has been established to collect information on the pregnancy outcomes of women exposed to NUVIGIL (armodafinil) . 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. Because many drugs are excreted in human milk, caution should be exercised when NUVIGIL (armodafinil) 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 PRECAUTIONS).

Last reviewed on RxList: 1/14/2011
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Human Experience

There were no overdoses reported in the NUVIGIL (armodafinil) clinical studies. Symptoms of NUVIGIL (armodafinil) 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 (armodafinil) 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.

CONTRAINDICATIONS

NUVIGIL (armodafinil) is contraindicated in patients with known hypersensitivity to modafinil and armodafinil or its inactive ingredients.

Last reviewed on RxList: 1/14/2011
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action and Pharmacology

The precise mechanism(s) through which armodafinil (R-enantiomer) or modafinil (mixture of R- and S-enantiomers) promote wakefulness is unknown. Both armodafinil and modafinil have shown similar pharmacological properties in nonclinical animal and in vitro studies, to the extent tested.

At pharmacologically relevant concentrations, armodafinil does not bind to or inhibit several receptors and enzymes potentially relevant for sleep/wake regulation, including those for serotonin, dopamine, adenosine, galanin, melatonin, melanocortin, orexin-1, orphanin, PACAP or benzodiazepines, or transporters for GABA, serotonin, norepinephrine, and choline or phosphodiesterase VI, COMT, GABA transaminase, and tyrosine hydroxylase. Modafinil does not inhibit the activity of MAO-B or phosphodiesterases II-IV.

Modafinil - induced wakefulness can be attenuated by the αl-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 not a direct- or indirect-acting dopamine receptor agonist. However, in vitro, both armodafinil and modafinil bind 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.

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. 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

The active component of NUVIGIL is armodafinil, which is the longer-lived enantiomer of modafinil. NUVIGIL (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 NUVIGIL (armodafinil) was reached within 7 days of dosing. At steady state, the systemic exposure for NUVIGIL (armodafinil) is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the pure R-enantiomer following administration of 50 mg NUVIGIL (armodafinil) or 100 mg PROVIGIL® (modafinil) are nearly superimposable.

Absorption

NUVIGIL (armodafinil) 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 (armodafinil) 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 levels later in time, food can potentially affect the onset and time course of pharmacologic action for NUVIGIL (armodafinil) .

Distribution

NUVIGIL (armodafinil) 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 (armodafinil) with highly protein-bound drugs is considered to be minimal.

Metabolism

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 (armodafinil) 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).

Elimination

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 (armodafinil) is approximately 33 mL/min.

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 (armodafinil) 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 (armodafinil) 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 (armodafinil) 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 (armodafinil) 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 (armodafinil) 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).

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

Special Populations

Data specific to armodafinil in special populations are not available.

Age Effect: A slight decrease (~20%) in the oral clearance (CL/F) of modafinil was observed in a single dose study at 200 mg in 12 subjects with a mean age of 63 years (range 53 - 72 years), but the change was considered not likely to be clinically significant. In a multiple dose study (300 mg/day) in 12 patients with a mean age of 82 years (range 67 - 87 years), the mean levels of modafinil in plasma were approximately two times those historically obtained in matched younger subjects. Due to potential effects from the multiple concomitant medications with which most of the patients were being treated, the apparent difference in modafinil pharmacokinetics may not be attributable solely to the effects of aging. However, the results suggest that the clearance of modafinil may be reduced in the elderly (See DOSAGE AND ADMINISTRATION).

Race Effect: The influence of race on the pharmacokinetics of modafinil has not been studied.

Renal Impairment: 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 was increased 9-fold (See PRECAUTIONS).

Hepatic Impairment: 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. The dose of NUVIGIL (armodafinil) should be reduced in patients with severe hepatic impairment (See PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Clinical Trials

The effectiveness of NUVIGIL (armodafinil) 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 (OSA)

The effectiveness of NUVIGIL (armodafinil) 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 (armodafinil) 150 mg/day, NUVIGIL (armodafinil) 250 mg/day or matching placebo. Patients treated with NUVIGIL (armodafinil) 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 (armodafinil) 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 (armodafinil) 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 (armodafinil) 150 mg/day or placebo. Patients treated with NUVIGIL (armodafinil) 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 NU VIGIL 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 (armodafinil) in either study.

Narcolepsy

The effectiveness of NUVIGIL (armodafinil) 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 (armodafinil) 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 (armodafinil) 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 (armodafinil) 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 (armodafinil) 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 (armodafinil) .

Shift Work Disorder (SWD)

The effectiveness of NUVIGIL (armodafinil) 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 (armodafinil) 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 (armodafinil) 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 (armodafinil) 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 (armodafinil) .

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
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
* Significantly different than placebo for all trials (p < 0.05)

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
OSA I 71% 74% 37%
OSAII 71% - 53%
Narcolepsy 69% 73% 33%
SWD 79% - 59%
* Significantly different than placebo for all trials (p < 0.05)

Last reviewed on RxList: 1/14/2011
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Physicians are advised to discuss the following issues with patients for whom they prescribe NUVIGIL (armodafinil) .

NUVIGIL (armodafinil) is indicated for patients who have abnormal levels of sleepiness. NUVIGIL (armodafinil) has been shown to improve, but not eliminate, this abnormal tendency to fall asleep. Therefore, patients should not alter their previous behavior with regard to potentially dangerous activities (e.g., driving, operating machinery) or other activities requiring appropriate levels of wakefulness, until and unless treatment with NUVIGIL (armodafinil) has been shown to produce levels of wakefulness that permit such activities. Patients should be advised that NUVIGIL (armodafinil) is not a replacement for sleep.

Patients should be informed that it may be critical that they continue to take their previously prescribed treatments (e.g., patients with OS A receiving CPAP should continue to do so).

Patients should be informed of the availability of a Medication Guide, and they should be instructed to read it prior to taking NUVIGIL (armodafinil) . The complete text of the Medication Guide is provided at the end of this labeling.

Patients should be advised to contact their physician if they experience rash, depression, anxiety, or signs of psychosis or mania.

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 (armodafinil) and for one month after discontinuation of therapy (See Carcinogenesis, Mutagenesis, Impairment of Fertility and Pregnancy).

Nursing

Patients should be advised to notify their physician if they are breastfeeding an infant.

Concomitant Medication

Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, because of the potential for interactions between NUVIGIL (armodafinil) and other drugs.

Alcohol

Patients should be advised that the use of NUVIGIL (armodafinil) in combination with alcohol has not been studied. Patients should be advised that it is prudent to avoid alcohol while taking NUVIGIL (armodafinil) .

Allergic Reactions

Patients should be advised to stop taking NUVIGIL (armodafinil) and to notify their physician if they develop a rash, hives, mouth sores, blisters, peeling skin, trouble swallowing or breathing or a related allergic phenomenon.

Last reviewed on RxList: 1/14/2011
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

Physicians are advised to discuss the following issues with patients for whom they prescribe NUVIGIL (armodafinil) .

NUVIGIL (armodafinil) is indicated for patients who have abnormal levels of sleepiness. NUVIGIL (armodafinil) has been shown to improve, but not eliminate, this abnormal tendency to fall asleep. Therefore, patients should not alter their previous behavior with regard to potentially dangerous activities (e.g., driving, operating machinery) or other activities requiring appropriate levels of wakefulness, until and unless treatment with NUVIGIL (armodafinil) has been shown to produce levels of wakefulness that permit such activities. Patients should be advised that NUVIGIL (armodafinil) is not a replacement for sleep.

Patients should be informed that it may be critical that they continue to take their previously prescribed treatments (e.g., patients with OS A receiving CPAP should continue to do so).

Patients should be informed of the availability of a Medication Guide, and they should be instructed to read it prior to taking NUVIGIL (armodafinil) . The complete text of the Medication Guide is provided at the end of this labeling.

Patients should be advised to contact their physician if they experience rash, depression, anxiety, or signs of psychosis or mania.

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 (armodafinil) and for one month after discontinuation of therapy (See Carcinogenesis, Mutagenesis, Impairment of Fertility and Pregnancy).

Nursing

Patients should be advised to notify their physician if they are breastfeeding an infant.

Concomitant Medication

Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, because of the potential for interactions between NUVIGIL (armodafinil) and other drugs.

Alcohol

Patients should be advised that the use of NUVIGIL (armodafinil) in combination with alcohol has not been studied. Patients should be advised that it is prudent to avoid alcohol while taking NUVIGIL (armodafinil) .

Allergic Reactions

Patients should be advised to stop taking NUVIGIL (armodafinil) and to notify their physician if they develop a rash, hives, mouth sores, blisters, peeling skin, trouble swallowing or breathing or a related allergic phenomenon.

Last reviewed on RxList: 1/14/2011
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Nuvigil Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

ARMODAFINIL - ORAL

(AR-moe-DAF-i-nil)

COMMON BRAND NAME(S): Nuvigil

USES: Armodafinil decreases extreme sleepiness due to narcolepsy and other sleep disorders such as difficult/irregular breathing during sleep (e.g., obstructive sleep apnea/hypopnea syndrome-OSAHS). It is also used to decrease sleepiness due to work schedules that interfere with a normal sleep routine (shift work sleep disorder-SWSD).

It is not known how armodafinil works to increase wakefulness. It is thought to work by affecting certain substances in the brain that control the sleep/wake cycle. Armodafinil does not make up for lack of sleep. It should not be used to treat tiredness or hold off sleep in people who do not have a sleep disorder.

HOW TO USE: Read the Medication Guide provided by your pharmacist before your start using armodafinil and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with or without food, usually once daily in the morning or as directed by your doctor. If you are using armodafinil for shift work sleep disorder, take this medication 1 hour before you start your work shift or as directed by your doctor. If you are using this drug for sleep apnea (OSAHS), also continue your other current treatment (e.g., CPAP machine) unless your doctor tells you to stop.

Dosage is based on your medical condition and response to treatment. Use this medication exactly as prescribed to get the most benefit from it.

Rarely, use of this medication can result in abnormal drug-seeking behavior (addiction). Do not increase your dose, take it more frequently, or use it for a longer time than prescribed. Properly stop this medication when so directed.

Tell your doctor if your condition persists or worsens.

Disclaimer

Nuvigil Consumer (continued)

SIDE EFFECTS: Headache, nausea, dry mouth, anxiety, dizziness, and difficulty sleeping may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these rare but serious side effects occur: easy bleeding/bruising, signs of infection (e.g., fever, persistent sore throat), mental/mood changes (e.g., agitation, confusion, depression, hallucinations, rare thoughts of suicide), unusual tiredness, dark urine, yellowing eyes/skin.

Seek immediate medical attention if any of these rare but very serious side effects occur: severe abdominal pain, chest pain, fast/pounding/irregular heartbeat.

Rarely, this medication may cause a serious (rarely fatal) rash. You may not be able to tell this serious reaction apart from a minor rash. Therefore, stop taking this drug and seek immediate medical attention if you develop any rash.

A very serious allergic reaction to this drug is rare. However, stop taking armodafinil and seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash/hives, skin blisters/peeling, sores in the mouth, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing/swallowing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

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

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Nuvigil (armodafinil) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking armodafinil, tell your doctor or pharmacist if you are allergic to it; or to modafinil; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: certain heart problems (e.g., enlarged heart, mitral valve problem), history of problems (e.g., chest pain, irregular heartbeat) after taking stimulants such as amphetamines.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: high blood pressure, heart problems (e.g., chest pain, heart attack, irregular heartbeat), liver problems, kidney problems, mental/mood disorders (e.g., depression, mania, psychosis), personal or family history of regular use/abuse of drugs/alcohol.

Sleep disorders may decrease your ability to react quickly. Though armodafinil helps keep you awake, you still may not be able to safely perform tasks that require quick reactions (e.g., driving). This drug may also make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages.

Caution is advised when using this drug in children because they may be more sensitive to the effects of the drug, especially serious rashes.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

Disclaimer

Nuvigil Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: alpha blockers (e.g., doxazosin, prazosin), medications for high blood pressure (e.g., beta blockers such as atenolol/metoprolol, clonidine, guanabenz, methyldopa), "blood thinners" (e.g., warfarin), MAO inhibitors (isocarboxazid, linezolid, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine), street drugs (e.g., methamphetamine, MDMA/"ecstasy"), drugs that affect liver enzymes that remove armodafinil from the body (e.g., azole antifungals such as itraconazole/ketoconazole, erythromycin, rifamycins such as rifabutin/rifampin, anti-seizure medications such as carbamazepine/phenobarbital).

Armodafinil can speed up or slow down the removal of other drugs from your body by affecting certain liver enzymes. These affected drugs may include clomipramine, cyclosporine, diazepam, ethinyl estradiol, omeprazole, phenytoin, propranolol, triazolam.

This medication may decrease the effectiveness of hormonal birth control such as pills, patch, or ring. This could cause pregnancy. Discuss with your doctor or pharmacist if you should use additional reliable birth control methods while using this medication and for 1 month after stopping this medication. Also tell your doctor if you have any new spotting or breakthrough bleeding, because these may be signs that your birth control is not working well.

Check the labels on all your medicines (e.g., cough-and-cold products, diet aids) because they may contain ingredients (e.g., pseudoephedrine, ephedra/ma huang) that could increase your heart rate or blood pressure. Ask your pharmacist about using those products safely.

Avoid drinking large amounts of beverages containing caffeine (e.g., coffee, tea, certain soft drinks). Caffeine can increase the side effects of this medication.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose include: fast/irregular heartbeat, restlessness, hallucinations.

NOTES: Do not share this medication with others. It is against the law.

Have your blood pressure checked regularly while taking this medication.

Lifestyle changes (e.g., sleeping in a dark/quiet room, avoiding caffeine close to bedtime) may help improve your sleep if you have shift work sleep disorder. Consult your doctor or pharmacist for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. Do not take missed doses close to bedtime because this drug can interfere with your sleep.

STORAGE: Store at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised October 2011. Copyright(c) 2011 First Databank, Inc.

Nuvigil Patient Information Including Side Effects

Brand Names: Nuvigil

Generic Name: armodafinil (Pronunciation: ar moe DAF i nil)

What is armodafinil (Nuvigil)?

Armodafinil is a medication that promotes wakefulness.

Armodafinil is used to treat excessive sleepiness caused by sleep apnea, narcolepsy, or shift work sleep disorder.

Armodafinil may also be used for purposes not listed in this medication guide.

What are the possible side effects of armodafinil (Nuvigil)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using armodafinil and call your doctor at once if you have a serious side effect such as:

  • fever, sore throat, headache, and vomiting with a severe blistering, peeling, and red skin rash;
  • the first sign of any type of skin rash, no matter how mild;
  • bruising, severe tingling, numbness, pain, muscle weakness;
  • easy bruising or bleeding;
  • mouth sores, trouble swallowing;
  • upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • depression, confusion, hallucinations, aggression, unusual thoughts or behavior;
  • chest pain, uneven heart beats.

Less serious side effects may include:

  • headache, dizziness;
  • feeling nervous or anxious;
  • nausea, diarrhea, upset stomach;
  • trouble sleeping (insomnia); or
  • dry mouth.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Nuvigil (armodafinil) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about armodafinil (Nuvigil)?

You should not use this medication if you are allergic to armodafinil or modafinil (Provigil).

Before using armodafinil, tell your doctor if you have liver or kidney disease, heart disease or high blood pressure, a heart valve disorder, a history of mental illness, a history of drug or alcohol addiction, or if you have recently had a heart attack.

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.

Stop taking armodafinil and call your doctor if you have a skin rash, no matter how mild. A medicine similar to armodafinil has caused severe skin reactions serious enough to require hospitalization. Other signs of a severe reaction include fever, sore throat, headache, and vomiting with a severe blistering, peeling, and red skin rash.

There may be other drugs that can interact with armodafinil. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Side Effects Centers

Nuvigil Patient Information including How Should I Take

What should I discuss with my health care provider before taking armodafinil (Nuvigil)?

You should not use this medication if you are allergic to armodafinil or modafinil (Provigil).

To make sure you can safely take armodafinil, tell your doctor if you have any of these other conditions:

  • cirrhosis or other liver problem;
  • kidney disease;
  • a heart muscle or valve disorder such as mitral valve prolapse;
  • a history of mental illness;
  • a history of drug or alcohol addiction;
  • heart disease or high blood pressure;
  • if you have recently had a heart attack.

Skin rashes serious enough to require hospitalization have occurred in people using a medicine similar to armodafinil. These rashes usually occurred within 1 to 5 weeks after the first dose.

Stop taking armodafinil and call your doctor at the first sign of any skin rash, no matter how minor you think it might be.

FDA pregnancy category C. It is not known whether armodafinil will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Armodafinil can make certain types of birth control less effective for as long as a month after you stop taking armodafinil. Ask your doctor about using a non-hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while taking armodafinil.

It is not known whether armodafinil passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not give armodafinil to anyone younger than 17 years old.

How should I take armodafinil (Nuvigil)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

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

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.

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.

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.

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.

Store at room temperature away from moisture and heat.

Side Effects Centers

Nuvigil Patient Information including If I Miss a Dose

What happens if I miss a dose (Nuvigil)?

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.

What happens if I overdose (Nuvigil)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include confusion, feeling excited or agitated, fast or slow heart rate, and chest pain.

What should I avoid while taking armodafinil (Nuvigil)?

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.

What other drugs will affect armodafinil (Nuvigil)?

Tell your doctor about all other medicines you use, especially:

  • cyclosporine (Neoral, Sandimmune, Gengraf);
  • propranolol (Inderal);
  • omeprazole (Prilosec);
  • St. John's wort;
  • rifabutin (Mycobutin), rifampin (Rifadin, Rifater, Rifamate), or rifapentine (Priftin);
  • an antibiotic such as clarithromycin (Biaxin), dalfopristin/quinupristin (Synercid), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), or telithromycin (Ketek);
  • an antidepressant such as nefazodone or clomipramine (Anafranil);
  • antifungal medication such as clotrimazole (Mycelex Troche), itraconazole (Sporanox), ketoconazole (Nizoral), or voriconazole (Vfend);
  • a barbiturate such as butabarbital (Butisol), secobarbital (Seconal), pentobarbital (Nembutal), or phenobarbital (Solfoton);
  • HIV medication such as efavirenz (Atripla, Sustiva), etravirine (Intelence), nevirapine (Viramune), or ritonavir (Norvir);
  • a sedative such as diazepam (Valium), midazolam (Versed), or triazolam (Halcion); or
  • seizure medication such as carbamazepine (Carbatrol, Tegretol), felbamate (Felbatol), oxcarbazepine (Trileptal), phenytoin (Dilantin), or primidone (Mysoline).

This list is not complete and other drugs may interact with armodafinil. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about armodafinil.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 4.01. Revision date: 6/16/2011.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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Side Effects Centers

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