Narcolepsy commonly begins in young adulthood, but in many individuals 10 to 15 years may pass between the onset of symptoms and proper diagnosis of the disorder. The most common symptom of narcolepsy is excessive daytime sleepiness (EDS), which is characterized by irresistible sleep attacks that can last from a few seconds to more than an hour. These attacks can take place any time, such as during conversation or while eating or driving, and can occur frequently. As a result, narcolepsy can greatly impair an individual’s ability to perform basic daily activities such as working, studying, and socializing, as well as significantly impacting the quality of life.
Between 60% and 90% of patients with narcolepsy also experience cataplexy, a sudden loss of muscle tone without loss of consciousness. Cataplexy is usually triggered by strong emotions such as laughter, surprise, elation, or anger, and patients who are prone to this problem often try to control these emotions to avoid a cataplectic attack. Other common symptoms of narcolepsy include paralysis upon falling asleep or awakening (sleep paralysis), vivid hallucinations that occur at onset of sleep (hypnagogic hallucinations), and disrupted nighttime sleep.
The treatment of narcolepsy has generally involved naps at various intervals during the day, as well as the use of a central nervous system (CNS) stimulant such as dextroamphetamine or methylphenidate (e.g., Ritalin). Although not a labeled indication, tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) have often been used in the management of the cataplexy component of the disorder.
Provigil is the first agent in 40 years to be approved for the treatment of narcolepsy. It has been described as a wakefulness-promoting agent and is specifically indicated to improve wakefulness in patients with EDS associated with narcolepsy. Provigil is structurally unrelated to previously marketed drugs, and although it shares certain of the pharmacologic properties of the central nervous system stimulants, its action is not associated with generalized stimulation. The precise mechanism(s) by which it acts is not known, but it has been suggested to alter serotonergic mechanisms in a manner that results in decreased gamma-aminobutyric acid (GABA)-mediated neurotransmission.
In the clinical trials, patients treated with Provigil experienced a greater ability to remain awake and a decreased propensity to fall asleep, although it did not affect cataplexy. Data that would permit a direct comparison of Provigil with dextroamphetamine and methylphenidate are very limited. The available information suggests that the new agent is less effective but is better tolerated and has a lower abuse potential. It may be of particular value in patients in whom the previously marketed drugs are not effective and/or poorly tolerated, and the new drug represents an important advance in the management of a condition for which so few therapeutic options are available.
Provigil has also been evaluated in the treatment of other sleep disorders (e.g., sleep apnea), and there have been preliminary studies in military personnel who must remain alert for long periods of time with little or no sleep. However, these are not labeled indications at the present time. There is also the potential for extensive “off-label” use of Provigil by individuals who experience daytime sleepiness for reasons other than narcolepsy (e.g., overwork, stress-related insomnia) and by those whose responsibilities or activities result in prolonged periods of little or no sleep (e.g., truck drivers, physicians, college students).
Because of the potential for Provigil to cause CNS effects, patients should be cautioned about activities such as driving and operating machinery until they are confident that the drug does not adversely affect their ability to engage in such activities. Caution must be exercised when Provigil is used in patients with other neurologic or psychiatric disorders and/or who are also taking other medications that have CNS activity. The consumption of alcoholic beverages is best avoided.
Studies of the abuse potential of Provigil demonstrated psychoactive and euphoric effects and feelings consistent with those of CNS stimulants such as methylphenidate. However, the new drug is considered to have a lesser potential for abuse, and it is classified in Schedule IV of the Controlled Substances Act, whereas methylphenidate and the amphetamines are classified in Schedule II. Patients should be observed for signs of misuse/abuse, especially those with a history of drug or other substance abuse.
Several patients in the clinical studies experienced symptoms such as chest pain, palpitations, dyspnea, and transient electrocardiogram (ECG) changes in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that Provigil not be used in patients with a history of left ventricular hypertrophy or ischemic ECG changes, chest pain, arrhythmia, or other clinically significant manifestations of mitral valve prolapse in association with CNS stimulant use. The new agent has not been evaluated or used to an appreciable extent in patients with a recent history of myocardial infarction or unstable angina, and its use in such patients, as well as those with hypertension, should be more closely monitored.
Provigil undergoes extensive hepatic metabolism through deamidation, oxidation, hydroxylation, and glucuronide conjugation mechanisms. It is an inhibitor of CYP2C19, and the concurrent use of drugs that are primarily metabolized via this pathway (e.g., diazepam [e.g., Valium], phenytoin [e.g., Dilantin], propranolol [e.g., Inderal]) may result in increased concentrations and activity of the latter agents. In addition, in patients who are deficient in the enzyme CYP2D6 (i.e., up to 10% of the Caucasian population), the concentrations of CYP2D6 substrates such as tricyclic antidepressants and SSRIs, which have ancillary routes of elimination through CYP2C19, may be increased by the concurrent use of Provigil and a reduction in dosage may be necessary.
The chronic use of Provigil may cause a modest induction of CYP3A4, thus reducing the concentrations of concurrently administered substrates for that system, such as steroidal contraceptives and cyclosporine (e.g., Neoral). There is an increased possibility of pregnancy in women using steroidal contraceptives (including depot or implantable contraceptives) when Provigil is used concurrently, and even during the month following discontinuation of therapy. Patients should be informed about this potential interaction and advised to use alternative or additional contraceptive measures during and for 1 month after Provigil treatment.
Provigil is metabolized to a certain extent by CYP3A4, and studies suggest that chronic use of the drug causes induction of its own metabolism, resulting in decreased plasma concentrations. It should also be expected that potent inducers of CYP3A4 (e.g., carbamazepine [e.g., Tegretol], phenobarbital, rifampin [e.g., Rifadin]) will reduce its activity and that potent inhibitors of CYP3A4 (e.g., ketoconazole [Nizoral]) will increase its activity.
A suppression of CYP2C9 activity by Provigil has been observed in in vitro studies. Although the clinical importance of this finding is not clear, caution should be exercised when Provigil is used concurrently with medications that are CYP2C9 substrates, such as phenytoin and warfarin (e.g., Coumadin). It is recommended that prothrombin times be monitored more closely in warfarin-treated patients during the first several months of concurrent Provigil therapy and whenever the dosage of Provigil is changed.
Although there have not been studies of the concurrent use of Provigil and a monoamine oxidase inhibitor (e.g., tranylcypromine [Parnate]), concomitant therapy should be closely monitored.
Following oral administration, Provigil is rapidly absorbed and peak plasma concentrations are achieved within 2 to 4 hours. Food may delay absorption but has no effect on overall bioavailability. The drug is primarily eliminated as inactive metabolites via the kidney, and less than 10% of a dose is excreted as the parent compound.
In patients with cirrhosis of the liver, the clearance of Provigil was reported to be decreased by about 60%, and the steady state concentration was doubled, compared with observations in patients with normal hepatic function. The dosage of Provigil should be reduced in patients with severe hepatic impairment, with or without cirrhosis. In one study in patients with severe chronic renal failure, the pharmacokinetics of Provigil were not significantly altered, but the exposure to its inactive metabolite, Provigil acid, was increased ninefold.
The recommended dosage of Provigil is 200 mg a day, administered as a single dose in the morning. A dosage of 400 mg once a day has been well tolerated, but there is no consistent evidence that this dosage provides greater benefits than the 200 mg dosage. In patients with severe hepatic impairment, the recommended dosage is 100 mg once a day. This lower dosage should also be considered for use in elderly patients, in whom the elimination of the drug and its metabolites may be reduced.