"The U.S. Food and Drug Administration today approved Hetlioz (tasimelteon), a melatonin receptor agonist, to treat non-24- hour sleep-wake disorder ("non-24") in totally blind individuals. Non-24 is a chronic circadian rhythm (body clock) disorde"...
“The following serious adverse reactions are described below and elsewhere in the labeling:
- Serious Rash, including Stevens-Johnson Syndrome [see WARNINGS AND PRECAUTIONS]
- Angioedema and Anaphylactoid Reactions [see WARNINGS AND PRECAUTIONS]
- Multi-organ Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
- Persistent Sleepiness [see WARNINGS AND PRECAUTIONS]
- Psychiatric Symptoms [see WARNINGS AND PRECAUTIONS]
- Diagnosis of Sleep Disorders [see WARNINGS AND PRECAUTIONS]
- CPAP Use in Patients with OSA [see WARNINGS AND PRECAUTIONS]
- Effects on Ability to Drive and Use Machinery [see WARNINGS AND PRECAUTIONS]
- Cardiovascular System [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
OSA, SWD, and Narcolepsy
NUVIGIL has been evaluated for safety in over 1100 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy.
In the pre-approval controlled clinical trials, the most commonly observed adverse events ( ≥ 5%) associated with the use of NUVIGIL 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 pre-approval controlled clinical trials, 44 of the 645 patients (7%) who received NUVIGIL 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 1) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in patients treated with NUVIGIL than in placebo group patients in the pre-approval 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 1: Incidence 1% or Greater Of Treatment-Emergent
Adverse Experiences In Parallel-Group, Placebo-Controlled Clinical Trials* In
OSA, Narcolepsy and SWD With NUVIGIL (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|
|* 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 pre-approval controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of NUVIGIL and placebo, the only adverse events that appeared to be dose-related were headache, rash, depression, dry mouth, insomnia, and nausea. See Table 2 for additional information.
Table 2: Incidence Of
Dose-Dependent, Treatment-Emergent Adverse Experiences By Dose and By Treatment
In Parallel-Group, Placebo-Controlled Clinical Trials* In OSA, Narcolepsy and
SWD With NUVIGIL (150 mg and 250 mg)
|System Organ Class MedDRA preferred term||NUVIGIL 250 mg
|NUVIGIL 150 mg
|Dry Mouth||7||2||4||< 1|
|Nervous System Disorders|
|Skin And Subcutaneous Tissue Disorders|
|* Four double-blind, placebo-controlled clinical studies in SWD, OSA, and narcolepsy.|
Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of NUVIGIL, but not placebo. Few subjects, however, had GGT or AP elevations outside of the normal range. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), 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.
Vital Sign Changes
Blood pressure monitoring in pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to 3.5 BPM. [see WARNINGS AND PRECAUTIONS]
Read the Nuvigil (armodafinil) Side Effects Center for a complete guide to possible side effects
The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by NUVIGIL via induction of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment of these drugs should be considered when these drugs are used concomitantly with NUVIGIL [see CLINICAL PHARMACOLOGY].
The effectiveness of steroidal contraceptives may be reduced when used with NUVIGIL and for one month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with NUVIGIL and for one month after discontinuation of NUVIGIL treatment.
Blood levels of cyclosporine may be reduced when used with NUVIGIL. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with NUVIGIL.
Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by NUVIGIL via inhibition of metabolic enzymes, with resultant higher systemic exposure. Dose reduction of these drugs may be required when these drugs are used concomitantly with NUVIGIL.
Drug Abuse And Dependence
Armodafinil (NUVIGIL) is a Schedule IV controlled substance.
Although the abuse potential of armodafinil has not been specifically studied, its abuse potential is likely to be similar to that of modafinil. 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 Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 7/30/2013
This monograph has been modified to include the generic and brand name in many instances.
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