- CLINICAL PHARMACOLOGY
- Mechanism Of Action
- Specific Populations
- Drug Interactions
- Clinical Studies
- Obstructive Sleep Apnea (OSA)
- Shift Work Disorder (SWD)
- SIDE EFFECTS
- CLINICAL PHARMACOLOGY
- Modafinil Side Effects
- In Summary
- For the Consumer
- For Healthcare Professionals
No broad consensus exists on the underlying mechanisms of modafinil pharmacology. Several mechanisms are probably involved.1 The present data raise the possibility that modafinil affects wakefulness by interacting with catecholamine transporters in the brain, in particular dopamine and possibly norepinephrine.1 The finding of dyskinesia in our case may support the role of modafinil in the dopamine metabolism. Furthermore, modafinil has been found to decrease GABA release in the brain, increase glutamate secretion, and activate hypocretin neurons, thus increasing the release of histamine in the brain.1 Modafinil triggers activation of neurons in the hypothalamus-based wakefulness circuits, as opposed to amphetamines, that produce diffuse neuronal activation.1 Therefore, modafinil is considered as a “wakefulness promoting agent” rather than a classic amphetamine-like stimulant. The normal elimination half-life of modafinil in humans is 12 to 15 hours.
The United States Food and Drug Administration (FDA) approved modafinil for the treatment of narcolepsy, obstructive sleep apnea, and shift work sleep disorder. In some countries, it is also approved for idiopathic hypersomnia. Modafinil is also indicated, though not approved, in the treatment of attention deficit hyperactivity disorder (ADHD), depression, cocaine addiction, Parkinson disease, schizophrenia, and disease-related fatigue.2
Reported side effects of modafinil (when prescribed in recommended doses for approved indications) are listed in Table 1. A single case of premature ventricular contractions appeared causally linked to administration of modafinil.3
Reported Side Effects of Modafinil, When Taken in Recommended Doses for Approved Indications, as Compared to Placebo
The side effects that occurred in our patient are noted as well.
Modafinil toxicity levels vary widely among species. In clinical trials on humans,4 taking up to 1200 mg/day for 7 to 21 days or one-time doses up to 4500 mg did not appear to cause life-threatening effects, although a number of adverse experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, and palpitations; cardiovascular changes such as tachycardia, bradycardia, hypertension and chest pain; sleep disturbances; and nausea, and diarrhea. As of 2004, FDA was not aware of any fatal overdoses involving modafinil alone in adults. Overdoses involving multiple drugs including modafinil have resulted in fatal outcomes. Cases of accidental ingestion/overdose have been reported in children as young as 11 months of age. The highest reported accidental ingestion on a mg/kg basis occurred in a 3-year-old boy who ingested 800-1000 mg (50-63 mg/kg) of modafinil. The child remained stable. The symptoms associated with overdose in children are similar to those observed in adults. In a recently reported case series, a retrospective multi-poison center chart review of patients from 11 states in the US was performed; there were 137 patients with single-substance ingestions of modafinil. The most frequently reported clinical effects were tachycardia, insomnia, agitation, dizziness, and anxiety.5
A suicide attempt with modafinil overdose has not been described before. Our patient ingested 5000 milligrams of modafinil at once (102 mg/kg, an ingestion higher than previously reported). The outcome was not fatal. The occurrence of prolonged QTc and dyskinesia may have a causal relationship with ingestion of very high doses of modafinil. The occurrence of dyskinesia is suggestive for the role of modafinil in dopamine metabolism. The prolonged QTc interval may be associated with the sympathetic system, as no changes in the potassium or calcium levels were noted. Further research is required in order to establish more thorough data regarding the adverse effects of very high doses of modafinil.
Modafinil has emerged as the crown prince of smart drugs, that seductive group of pharmaceutical friends that promise enhanced memory, motivation, and an unrelenting ability to focus, all for hours at a time.
In the absence of long-term data, the media, particularly the student media, has tended to be relaxed about potential side-effects. The Oxford Tab, for example, simply shrugs: Who cares?
The novelist MJ Hyland, who suffers from multiple sclerosis, wrote a paean to the drug in the Guardian recently – understandably, for her, any potential side-effects are worth the risk given the benefits she’s experienced.
But should stressed students, tempted by a quick fix, be worried about what modafinil could be doing their brains in the long term?
Professor Barbara Sahakian, at the University of Cambridge, has been researching modafinil as a possible clinical treatment for the cognitive problems of patients with psychosis. She’s fascinated by healthy people taking these drugs and has co-authored a recent book on the subject.
“Some people just want the competitive edge – they want to do better at exams so they can get into a better university or get a better degree. And there’s another group of people who want to function the best they can all the time. But people have also told me that they’ve used these drugs to help them do tasks that they’ve found not very interesting, or things they’ve been putting off.”
How does the drug work? “We believe modafinil is a drug with multiple actions,” Sahakian says. “This is because it acts on several neurotransmitter systems in the brain. I suspect that because it’s got these multiple actions, you’re getting a number of things improving but not all for the same reason.”
Neurotransmitters are the chemicals which transmit signals between cells in the brain and Dr Peter Morgan from Yale University believes that modafinil affects three in particular. “Modafinil definitely affects the dopamine system and dopamine will make you more alert, and also more interested in things,” he says. “It affects norepinephrine which can again make you more alert and better able to focus, and it also affects histamine which can keep you awake.”
But it is modafinil’s boost to the working memory that interests many, in particular students engaged in last-minute cramming. It is believed to enhance the short-term memory by as much as 10%, through its influence on a neurotransmitter called glutamate.
Sahakian sounds urges caution: “A lot of people, especially students, are getting it off the internet so they don’t know what they’re buying – it could be anything. It’s not coming from a reputable source, they don’t know it hasn’t been contaminated, and they don’t know it’s safe for them to take.”
Effects can vary greatly in accordance with the dose taken. One recent study by Dr Nora Volkow and colleagues based on PET scans suggested that doses of 400mg had effects in brain areas known to be involved in substance abuse and dependence.
Sahakian’s research also suggests that prolific use over a prolonged period of time could have a potentially damaging effect on sleep architecture.
“Some professionals tend to use it on specific occasions – when they’re jetlagged or when they’ve had a particularly bad night’s sleep,” she says. “They don’t use it every day and they don’t use it in multiple doses. Whereas, if you talk to students, they’ve often taken a dose and then, when they feel it’s wearing off, they’ve taken another dose.
“And of course that does affect their sleep pattern, because when they should be going to bed, they’ve still got the drug in their system, still exerting its wake-promoting effects. This is of course counter-productive, as we consolidate our memories during sleep.”
I spoke to students who used modafinil during exam periods. They revealed that after several weeks, they had the sensation of permanently being trapped in a twilight zone, neither asleep nor awake.
Morgan researches treatments for cocaine addicts with severe sleep disorders and he has a possible explanation. “If somebody takes modafinil long-term, they may develop some of the same deficits in slow-wave sleep as cocaine users,” he says. “Slow-wave sleep is the deep sleep that we tend to get early in the night. But by taking a stimulant that forces the body to be awake more than it wants to be, you’re disrupting its ability to regulate how much sleep it gets and the kind of sleep it gets, so it never feels properly refreshed.”
He believes that long-term use could damage the memory. “Look at nicotine,” he says. “Nicotine is an amazing cognitive enhancer, purely from a lab perspective! But for people who use nicotine chronically, we know their baseline cognitive function goes down and the nicotine is maybe bringing them back up to normal. So now nicotine is no longer a cognitive enhancer, it’s a cognitive normaliser. Because of the chronic use, the brain has adapted and without it, you’re performing at a lower level. There’s no reason to think that modafinil would be any different.”
But whatever the risks, the likelihood is that the demand for smart drugs will continue to grow. “Psychiatrists at an American Psychiatric Association Meeting in the US approached me to comment that they are frequently put under pressure to give a diagnosis of ADHD to a child even though the psychiatrist feels the symptoms are not sufficiently severe to do so,” Professor Sahakian tells me.
“The psychiatrists believe the parents do this for the cognitive enhancing effects of Ritalin for their child. In my lectures, I try to point out that our brains are still in development up until late adolescence to young adulthood, so if you’re a healthy normal child, what are the effects of manipulating the neurotransmitters while your brain’s still developing?
“We simply don’t know how chronic drug treatment will affect ‘healthy’ brain function in future years.”
Mechanism Of Action
The mechanism(s) through which modafinil promotes wakefulness is unknown. Modafinil has wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although the pharmacologic profile is not identical to that of the sympathomimetic amines.
Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist, prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to α-adrenergic agonists such as the rat vas deferens preparation.
Modafinil is not a direct-or indirect-acting dopamine receptor agonist. However, in vitro, modafinil binds to the dopamine transporter and inhibits dopamine reuptake. This activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, a dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil.
In the cat, equal wakefulness-promoting doses of methylphenidate and amphetamine increased neuronal activation throughout the brain. Modafinil at an equivalent wakefulness-promoting dose selectively and prominently increased neuronal activation in more discrete regions of the brain. The relationship of this finding in cats to the effects of modafinil in humans is unknown.
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.
The optical enantiomers of modafinil have similar pharmacological actions in animals. Two major metabolites of modafinil, modafinil acid and modafinil sulfone, do not appear to contribute to the CNS-activating properties of modafinil.
Modafinil is a 1:1 racemic compound, whose enantiomers have different pharmacokinetics (e.g., the half-life of R-modafinil is approximately three times that of S-modafinil in adult humans). The enantiomers do not interconvert. At steady state, total exposure to R-modafinil is approximately three times that for S-modafinil. The trough concentration (Cmin,ss) of circulating modafinil after once daily dosing consists of 90% of R-modafinil and 10% of S-modafinil. The effective elimination half-life of modafinil after multiple doses is about 15 hours. The enantiomers of modafinil exhibit linear kinetics upon multiple dosing of 200-600 mg/day once daily in healthy volunteers. Apparent steady states of total modafinil and R-modafinil are reached after 2-4 days of dosing.
PROVIGIL is readily absorbed after oral administration, with peak plasma concentrations occurring at 2-4 hours. The bioavailability of PROVIGIL tablets is approximately equal to that of an aqueous suspension. The absolute oral bioavailability was not determined due to the aqueous insolubility ( < 1 mg/mL) of modafinil, which precluded intravenous administration. Food has no effect on overall PROVIGIL bioavailability; however, time to reach peak concentration (tmax) may be delayed by approximately one hour if taken with food.
PROVIGIL has an apparent volume of distribution of approximately 0.9 L/kg. In human plasma, in vitro, modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of PROVIGIL with highly protein-bound drugs is considered to be minimal.
Metabolism and Elimination
The major route of elimination is metabolism (approximately 90%), primarily by the liver, with subsequent renal elimination of the metabolites. Urine alkalinization has no effect on the elimination of modafinil.
Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent compound. In a clinical study using radiolabeled modafinil, 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). The largest fraction of the drug in urine was modafinil acid, but at least six other metabolites were present in lower concentrations. Only two metabolites reach appreciable concentrations in plasma, i.e., modafinil acid and modafinil sulfone. In preclinical models, modafinil acid, modafinil sulfone, 2-acetic acid and 4-hydroxy modafinil, were inactive or did not appear to mediate the arousal effects of modafinil.
In adults, decreases in trough levels of modafinil have sometimes been observed after multiple weeks of dosing, suggesting auto-induction, but the magnitude of the decreases and the inconsistency of their occurrence suggest that their clinical significance is minimal. Significant accumulation of modafinil sulfone has been observed after multiple doses due to its long elimination half-life of 40 hours. Auto-induction of metabolizing enzymes, most importantly cytochrome P-450 CYP3A4, has also been observed in vitro after incubation of primary cultures of human hepatocytes with modafinil and in vivo after extended administration of modafinil at 400 mg/day.
A slight decrease (approximately 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 .
The pharmacokinetics of modafinil are not affected by gender.
The influence of race on the pharmacokinetics of modafinil has not been studied.
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 (an inactive metabolite) was increased 9-fold.
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 .
In vitro data demonstrated that modafinil weakly induces CYP1A2, CYP2B6, and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by modafinil. In vitro data also demonstrated that modafinil produced an apparent concentration-related suppression of expression of CYP2C9 activity. Other CYP activities did not appear to be affected by modafinil.
Potential Interactions with Drugs That Inhibit, Induce, or Are Metabolized by Cytochrome P450 Isoenzymes and Other Hepatic Enzymes
The existence of multiple pathways for modafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing modafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of PROVIGIL due to CYP inhibition by concomitant medications. However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of modafinil, coadministration of potent inducers of CYP3A4/5 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4/5 (e.g., ketoconazole, erythromycin) could alter the plasma concentrations of modafinil.
The Potential of PROVIGIL to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition
- Drugs Metabolized by CYP3A4/5
- In vitro data demonstrated that modafinil is a weak inducer of CYP3A activity in a concentration-related manner. Therefore, the blood levels and effectiveness of drugs that are substrates for CYP3A enzymes (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be reduced after initiation of concomitant treatment with PROVIGIL.
- Ethinyl Estradiol -Administration of modafinil to female volunteers once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days resulted in a mean 11% decrease in mean Cmax and 18% decrease in mean AUC0-24 of ethinyl estradiol (EE2; 0.035 mg; administered orally with norgestimate). There was no apparent change in the elimination rate of ethinyl estradiol.
- Triazolam -In the drug interaction study between PROVIGIL and ethinyl estradiol (EE2), on the same days as those for the plasma sampling for EE2 pharmacokinetics, a single dose of triazolam (0.125 mg) was also administered. Mean Cmax and AUC0-∞ of triazolam were decreased by 42% and 59%, respectively, and its elimination half-life was decreased by approximately an hour after the modafinil treatment.
- Cyclosporine -One case of an interaction between modafinil and cyclosporine, a substrate of CYP3A4, has been reported in a 41 year old woman who had undergone an organ transplant. After one month of administration of 200 mg/day of modafinil, cyclosporine blood levels were decreased by 50%. The interaction was postulated to be due to the increased metabolism of cyclosporine, since no other factor expected to affect the disposition of the drug had changed.
- Midazolam -In a clinical study, concomitant administration of armodafinil 250 mg resulted in a reduction in systemic exposure to midazolam by 32% after a single oral dose (5 mg) and 17% after a single intravenous dose (2 mg).
- Quetiapine -In a separate clinical study, concomitant administration of armodafinil 250 mg with quetiapine (300 mg to 600 mg daily doses) resulted in a reduction in the mean systemic exposure of quetiapine by approximately 29%.
- Drugs Metabolized by CYP1A2
- In vitro data demonstrated that modafinil is a weak inducer of CYP1A2 in a concentration-related manner. However, in a clinical study with armodafinil using caffeine as a probe substrate, no significant effect on CYP1A2 activity was observed.
- Drugs Metabolized by CYP2B6
- In vitro data demonstrated that modafinil is a weak inducer of CYP2B6 activity in a concentration-related manner.
- Drugs Metabolized by CYP2C9
- In vitro data demonstrated that modafinil produced an apparent concentration-related suppression of expression of CYP2C9 activity suggesting that there is a potential for a metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin and phenytoin) .
- Warfarin: Concomitant administration of modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of R-and S-warfarin. However, since only a single dose of warfarin was tested in this study, an interaction cannot be ruled out .
- Drugs Metabolized by CYP2C19
- In vitro data demonstrated that modafinil is a reversible inhibitor of CYP2C19 activity. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone. Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Therefore, exposure to some drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be increased when used concomitantly with PROVIGIL .
- In a clinical study, concomitant administration of armodafinil 400 mg resulted in a 40% increase in exposure to omeprazole after a single oral dose (40 mg), as a result of moderate inhibition of CYP2C19 activity.
- Interactions with CNS Active Drugs
- Concomitant administration of modafinil with methylphenidate or dextroamphetamine produced no significant alterations on the pharmacokinetic profile of modafinil or either stimulant, even though the absorption of modafinil was delayed for approximately one hour.
- Concomitant modafinil or clomipramine did not alter the pharmacokinetic profile of either drug; however, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine was reported in a patient with narcolepsy during treatment with modafinil.
- CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) and selective serotonin reuptake inhibitors that are primarily metabolized by CYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor metabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. PROVIGIL may cause elevation of the levels of the tricyclics in this subset of patients .
- Concomitant administration of armodafinil with quetiapine reduced the systemic exposure of quetiapine.
- Interaction with P-Glycoprotein
- An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein. The impact of inhibition of P-glycoprotein is not known.
The effectiveness of PROVIGIL in improving wakefulness in adult patients with excessive sleepiness associated with narcolepsy was established in two US 9-week, multi-center, placebo-controlled, parallel-group, double-blind studies of outpatients who met the criteria for narcolepsy. A total of 558 patients were randomized to receive PROVIGIL 200 or 400 mg/day, or placebo. The criteria for narcolepsy include either: 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least three months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy); or 2) a complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes. For entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, via a Multiple Sleep Latency Test (MSLT) with two or more sleep onset REM periods 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 15 minutes after sleep onset.
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). For a successful trial, both measures had to show statistically significant improvement.
The MWT measures latency (in minutes) to sleep onset averaged over 4 test sessions at 2 hour intervals following nocturnal polysomnography. For each test session, the subject was asked to attempt to remain awake without using extraordinary measures. Each test session was terminated after 20 minutes if no sleep occurred or 10 minutes 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. Patients were rated by evaluators who had no access to any data about the patients other than a measure of their baseline severity. Evaluators were not given any specific guidance about the criteria they were to apply when rating patients.
Both studies demonstrated improvement in objective and subjective measures of excessive daytime sleepiness for both the 200 mg and 400 mg doses compared to placebo. Patients treated with PROVIGIL showed a statistically significantly enhanced ability to remain awake on the MWT at each dose compared to placebo at final visit (Table 2). A statistically significantly greater number of patients treated with PROVIGIL at each dose showed improvement in overall clinical condition as rated by the CGI-C scale at final visit (Table 3).
Nighttime sleep measured with polysomnography was not affected by the use of PROVIGIL.
Obstructive Sleep Apnea (OSA)
The effectiveness of PROVIGIL in improving wakefulness in patients with excessive sleepiness associated with OSA was established in two multi-center, placebo-controlled clinical studies of patients who met the criteria for OSA. The criteria include either: 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated features such as loud snoring, morning headaches and 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, and arterial oxygen desaturation in association with the apneas. In addition, for entry into these studies, all patients were required to have excessive sleepiness as demonstrated by a score ≥ 10 on the Epworth Sleepiness Scale (ESS), despite treatment with continuous positive airway pressure (CPAP). Evidence that CPAP was effective in reducing episodes of apnea/hypopnea was required along with documentation of CPAP use.
In the first study, a 12-week trial, a total of 327 patients with OSA were randomized to receive PROVIGIL 200 mg/day, PROVIGIL 400 mg/day, or matching placebo. The majority of patients (80%) were fully compliant with CPAP, defined as CPAP use greater than 4 hours/night on > 70% of nights. The remainder were partially CPAP compliant, defined as CPAP use < 4 hours/night on > 30% of nights. CPAP use continued throughout the study. 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 .
Patients treated with PROVIGIL showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT at final visit (Table 2). A statistically significant greater number of patients treated with PROVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale at final visit (Table 3). The 200 mg and 400 mg doses of PROVIGIL produced statistically significant effects of similar magnitude on the MWT, and also on the CGI-C.
In the second study, a 4-week trial, 157 patients with OSA were randomized to receive PROVIGIL 400 mg/day or placebo. Documentation of regular CPAP use (at least 4 hours/night on 70% of nights) was required for all patients. The primary measure of effectiveness was the change from baseline on the ESS at final visit. The baseline ESS scores for the PROVIGIL and placebo groups were 14.2 and 14.4, respectively. At week 4, the ESS was reduced by 4.6 in the PROVIGIL group and by 2.0 in the placebo group, a difference that was statistically significant.
Nighttime sleep measured with polysomnography was not affected by the use of PROVIGIL.
Shift Work Disorder (SWD)
The effectiveness of PROVIGIL in improving wakefulness in patients with excessive sleepiness associated with SWD was demonstrated in a 12-week placebo-controlled clinical trial. A total of 209 patients with chronic SWD were randomized to receive PROVIGIL 200 mg/day or placebo. All patients met the criteria for chronic SWD. The criteria include: 1) either, a) a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms, and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change syndrome).
It should be noted that not all patients with a complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWD. In the clinical trial, only patients who were symptomatic for at least 3 months were enrolled.
Enrolled patients were also required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score < 6 minutes), and have daytime insomnia documented by a daytime polysomnogram.
The primary measures of effectiveness were 1) sleep latency, as assessed by the MSLT performed during a simulated night shift at the final visit and 2) the change in the patient’s overall disease status, as measured by the CGI-C at the final visit .
Patients treated with PROVIGIL 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 2). A statistically significant greater number of patients treated with PROVIGIL showed improvement in overall clinical condition as rated by the CGI-C scale at final visit (Table 3).
Daytime sleep measured with polysomnography was not affected by the use of PROVIGIL.
Table 2: Average Baseline Sleep Latency and Change from Baseline at Final Visit (MWT and MSLT in minutes)
Table 3: Clinical Global Impression of Change (CGI-C) (Percent of Patients Who Improved at Final Visit)
The following serious adverse reactions are described elsewhere in the labeling:
- Serious Rash, including Stevens-Johnson Syndrome
- Angioedema and Anaphylaxis Reactions
- Multi-organ Hypersensitivity Reactions
- Persistent Sleepiness
- Psychiatric Symptoms
- Effects on Ability to Drive and Use Machinery
- Cardiovascular Events
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.
PROVIGIL has been evaluated for safety in over 3,500 patients, of whom more than 2,000 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy.
Most Common Adverse Reactions
In placebo-controlled clinical trials, the most common adverse reactions ( ≥ 5%) associated with the use of PROVIGIL more frequently than placebo-treated patients were headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. The adverse reaction profile was similar across these studies.
Table 1 presents the adverse reactions that occurred at a rate of 1% or more and were more frequent in PROVIGIL-treated patients than in placebo-treated patients in the placebo-controlled clinical trials.
Table 1: Adverse Reactions in Pooled Placebo-Controlled Trials* in Narcolepsy, OSA, and SWD
(n = 934)
(n = 567)
|Abnormal Liver Function||2||1|
|* Adverse Reactions that occurred in ≥ 1% of PROVIGIL-treated patients (either 200, 300, or 400 mg once daily) and greater incidence than placebo|
Dose-Dependent Adverse Reactions
In the placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of PROVIGIL and placebo, the following adverse reactions were dose related: headache and anxiety.
Adverse Reactions Resulting in Discontinuation of Treatment
In placebo-controlled clinical trials, 74 of the 934 patients (8%) who received PROVIGIL discontinued due to an adverse reaction compared to 3% of patients that received placebo. The most frequent reasons for discontinuation that occurred at a higher rate for PROVIGIL than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain, and nervousness (each < 1%).
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 PROVIGIL, but not placebo. Few patients, however, had GGT or AP elevations outside of the normal range. Shifts to higher, but not clinically significantly abnormal, GGT and AP values appeared to increase with time in the population treated with PROVIGIL in the placebo-controlled clinical trials. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin.
The following adverse reactions have been identified during post approval use of PROVIGIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Psychiatric disorders: psychomotor hyperactivity
Read the entire FDA prescribing information for Provigil (Modafinil)
Doctors prescribe modafinil, sold under the brand name Provigil, to improve wakefulness in adults who are experiencing excessive sleepiness as a result of obstructive sleep apnea, shift work sleep disorder, or narcolepsy.
The Food and Drug Administration (FDA) approved modafinil for the treatment of narcolepsy in 1998, and the agency approved its use for shift work sleep disorder and obstructive sleep apnea/hypopnea in 2003.
Researchers are not sure exactly how modafinil promotes wakefulness. One theory is that it may increase dopamine levels in the brain by inhibiting reuptake of dopamine, a neurotransmitter that moderates the way chemical signals move from one nerve cell to another.
Provigil is made by Cephalon, Inc. in two strengths, 100 mg and 200 mg. Various manufacturers, including Mylan Pharmaceuticals, Teva Pharmaceutical Industries, and Par Pharmaceutical Companies make the generic form. (Teva’s version of modafinil is actually brand-name Provigil that has been repackaged and sold as a generic.)
Cephalon Inc., which is now owned by Teva, won a court case that resulted in the dismissal of claims that it conspired with the makers of generics to delay cheaper versions of Provigil.
Modafinil enhances short-term memory allowing users to stay awake for long periods of time. It is sometimes used for performance enhancement by military pilots and soldiers during combat situations, and some now call it a “super drug”. Its off-label uses have contributed to an ongoing debate on how far to push the human body through the use of drugs.
In This Section:
- What Are the Key Things I Need to Know About Modafinil (Provigil)?
- Is There Anything Special I Should Discuss with My Doctor Before Taking Modafinil (Provigil)?
What Are the Key Things I Need to Know About Modafinil (Provigil)?
Modafinil is a federally controlled substance and should be used only as directed. Store it in a safe place to prevent misuse and abuse. It is against the law to sell or give modafinil to another person.
The drug is not approved for use in children for any medical condition, and it’s unknown whether it’s safe or works in children under the age of 17.
For those who have obstructive sleep apnea, modafinil is used in conjunction with other medical treatments. It will not cure this or other sleep disorders, but it can help the sleepiness created by these conditions. It may not stop all your sleepiness, however, and it’s not a substitute for getting proper rest.
Modafinil can lead to serious side effects, including a serious rash or an allergic reaction affecting your liver or blood cells. These side effects may be life threatening and may require hospital treatment. You should stop taking the drug right away and call your doctor if you develop a skin rash, hives, sores in your mouth, blisters, peeling, or yellowing of your skin or eyes, trouble swallowing or breathing, dark urine or fever.
Don’t take modafinil if you are allergic to armodafinil (Nuvigil), lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, povidone and magnesium stearate.
Is There Anything Special I Should Discuss with My Doctor Before Taking Modafinil (Provigil)?
It’s important for people to talk to their doctors about all their health conditions before starting this medication, such as whether they have a history of mental health problems, including psychosis. Make sure your doctor is aware of any heart problems or if you have had a heart attack, have high blood pressure, liver or kidney illness, a history of drug or alcohol abuse or addiction, or if you are pregnant, planning to become pregnant or are breastfeeding. It is unknown whether the drug will pass into breast milk.
Be sure to tell the doctor about any and all medications you are taking, including prescription and non-prescription medicines, vitamins, and herbal supplements. In addition, if you are using hormonal birth control, you could have a higher chance of getting pregnant while on this medication, and one month after stopping it.
For those who do get pregnant while taking the medication, there is a registry available that collects and provides information about the safety of the drug. You can access the information by enrolling in the registry by calling 1-866-404-4106 or logging onto www.PROVIGILpregnancyregistry.com.
Modafinil Side Effects
Medically reviewed by Drugs.com. Last updated on Nov 8, 2018.
- Side Effects
Commonly reported side effects of modafinil include: headache and nausea. Other side effects include: anorexia and xerostomia. See below for a comprehensive list of adverse effects.
For the Consumer
Applies to modafinil: oral tablet
Along with its needed effects, modafinil may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur while taking modafinil:
- Black, tarry stools
- blurred vision or other vision changes
- chest pain
- chills or fever
- clumsiness or unsteadiness
- dizziness or fainting
- increased thirst and urination
- mental depression
- problems with memory
- rapidly changing moods
- shortness of breath
- sore throat
- trembling or shaking
- trouble in urinating
- uncontrolled movements of the face, mouth, or tongue
- unusual bleeding or bruising
- unusual tiredness or weakness
Get emergency help immediately if any of the following symptoms of overdose occur while taking modafinil:
Symptoms of overdose
- Agitation or excitement
- fast or pounding heartbeat
- increased blood pressure
- trouble with sleeping
Some side effects of modafinil may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
- Back pain
- decrease in appetite
- difficulty having a bowel movement
- dryness of the mouth
- dryness of the skin
- feeling of constant movement of self or surroundings
- flushing or redness of the skin
- muscle stiffness
- sores, ulcers, or white spots on the lips or in the mouth
- sour stomach
- stomach discomfort upset or pain
- stuffy or runny nose
- tingling, burning, or prickling sensations in the skin
For Healthcare Professionals
Applies to modafinil: oral tablet
Very common (10% or more): Headache (up to 34%)
Uncommon (0.1% to 1%): Amnesia, migraine, CNS stimulation, incoordination, movement disorder, speech disorder, hypoesthesia
Very rare (less than 0.01%): Tardive dyskinesia, convulsions
Frequency not reported: Cataplexy
Very common (10% or more): Nausea (up to 11%)
Common (1% to 10%): Diarrhea, dry mouth, dyspepsia, constipation, flatulence, mouth ulceration, abdominal pain
Uncommon (0.1% to 1%): Reflux, vomiting, dysphagia, glossitis
Frequency not reported: Periodontal abscess
The development of adverse reactions (skin and hypersensitivity, central nervous system , psychiatric, and cardiovascular) appear to be related to higher doses; cardiovascular and CNS reactions increase significantly after a total daily dose of more than 400 mg.
Common (1% to 10%): Palpitations, chest pain, hypertension, tachycardia, vasodilation
Uncommon (0.1% to 1%): Extrasystoles, arrhythmia, bradycardia, hypotension, transient ischemic T-wave changes, abnormal ECG
Rare (less than 0.1%): Increased blood pressure
Very rare (less than 0.01%): Ischemic heart disease
Frequency not reported: Asystole
Common (1% to 10%): Sweating, herpes simplex
Uncommon (0.1% to 1%): Rash, acne, pruritus
Rare (less than 0.1%): Eczema
Frequency not reported: Ecchymosis, serious skin reactions (including Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, Drug Rash with Eosinophilia and Systemic Symptoms, erythema multiforme)
Common (1% to 10%): Urine abnormality, hematuria, pyuria
Uncommon (0.1% to 1%): Urinary frequency
Rare (less than 0.1%): Foul urine odor
Frequency not reported: Urinary tract infection
Common (1% to 10%): Eosinophilia
Uncommon (0.1% to 1%): Leukopenia
Postmarketing reports: Agranulocytosis
Common (1% to 10%): Increased gamma-glutamyltransferase, increased alkaline phosphatase, abnormal liver function, elevated liver enzymes, eosinophilia
Uncommon (0.1% to 1%): Allergic reaction (e.g., hayfever)
Very rare (less than 0.01%): Multi-organ hypersensitivity reactions, urticaria (hives), angioedema, anaphylaxis
Common (1% to 10%): Anorexia, thirst, decreased appetite
Common (1% to 10%): Back pain, neck rigidity
Uncommon (0.1% to 1%): Neck pain, myalgia, myasthenia, leg cramps, arthralgia, twitch, arthritis
Rare (less than 0.1%): Muscle weakness
Common (1% to 10%): Abnormal vision, blurred vision, amblyopia, eye pain
Uncommon (0.1% to 1%): Dry eye
Frequency not reported: Conjunctivitis
Common (1% to 10%): Chills, edema, asthenia, flu syndrome, thirst
Uncommon (0.1% to 1%): Peripheral edema, menstrual disorder
Rare (less than 0.1%): Tolerance, aggravated condition, malaise, fatigue
Frequency not reported: Infection, pain, accidental injury, fever, viral infection, tooth disorder, hypothermia, ear pain
Uncommon (0.1% to 1%): Sleep disorder, decreased libido, hostility, depersonalization, personality disorder, abnormal dreams, aggression, suicidal ideation, psychomotor hyperactivity
Rare (less than 0.1%): Hallucinations, mania, psychosis, delusions, suicide attempt
Common (1% to 10%): Rhinitis, pharyngitis, lung disorder, asthma, epistaxis
Uncommon (0.1% to 1%): Sinusitis, dyspnea, increased cough
Frequency not reported: Bronchitis
1. “Product Information. Provigil (modafinil).” Cephalon, Inc, West Chester, PA.
Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.
Some side effects may not be reported. You may report them to the FDA.
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Before taking modafinil,
- tell your doctor and pharmacist if you are allergic to modafinil, armodafinil (Nuvigil), or any other medications.
- tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking. Be sure to mention any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin); certain antidepressants such as amitriptyline, amoxapine, clomipramine (Anafranil), desipramine (Norpramin), doxepin (Sinequan), imipramine (Tofranil), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil); certain antifungals such as itraconazole (Sporanox) and ketoconazole (Nizoral); cyclosporine (Neoral, Sandimmune); diazepam (Valium); certain medications for seizures such as carbamazepine (Tegretol), phenobarbital, and phenytoin (Dilantin); monoamine oxidase (MAO) inhibitors, including isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate); propranolol (Inderal); selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft); rifampin (Rifadin, Rimactane); and triazolam (Halcion). Many other medications may also interact with modafinil, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- tell your doctor if you drink or have ever drunk large amounts of alcohol, use or have ever used street drugs, or have overused prescription medications, especially stimulants. Also tell your doctor if you have ever had chest pain, an irregular heartbeat, or other heart problems after taking a stimulant, and if you have or have ever had high blood pressure; a heart attack; chest pain; a mental illness such as depression, mania (frenzied, abnormally excited mood), or psychosis (difficulty thinking clearly, communicating, understanding reality, and behaving appropriately); or heart, liver, or kidney disease.
- you should know that modafinil may decrease the effectiveness of hormonal contraceptives (birth control pills, patches, rings, implants, injections, and intrauterine devices). Use another form of birth control while taking modafinil and for 1 month after you stop taking it. Talk to your doctor about types of birth control that will work for you during and after your treatment with modafinil.
- tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking modafinil, call your doctor.
- if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking modafinil.
- you should know that modafinil may affect your judgment or thinking and may not completely relieve the sleepiness caused by your disorder. Do not drive a car or operate machinery until you know how this medication affects you. If you avoided driving and other dangerous activities because of your sleep disorder, do not start performing these activities again without talking to your doctor even if you feel more alert.
- be aware that you should avoid drinking alcohol while taking modafinil.