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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
|Abdominal Pain Upper||2||1|
|General Disorders And Administration Site Conditions|
|Immune System Disorders|
|Heart Rate Increased||1||0|
|Metabolism And Nutrition Disorders|
|Nervous System Disorders|
|Disturbance In Attention||1||0|
|Renal And Urinary Disorders|
|Respiratory, Thoracic And Mediastinal Disorders|
|Skin And Subcutaneous Tissue Disorders|
|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)
150 mg (Percent, N=447)
|NUVIGIL Combined (Percent, N=645)|| Placebo
|Dry Mouth||7||2||4||< 1|
|Nervous System Disorders|
|Skin And Subcutaneous Tissue Disorders|
|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.
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.
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 »
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.
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