7 Effects of PROVIGIL on CYP3A4/5 Substrates The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by PROVIGIL 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 PROVIGIL [see Clinical Pharmacology ( 12.3 )] .
The effectiveness of steroidal contraceptives may be reduced when used with PROVIGIL 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 PROVIGIL and for one month after discontinuation of PROVIGIL treatment.
Blood levels of cyclosporine may be reduced when used with PROVIGIL.
Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with PROVIGIL.
Effects of PROVIGIL on CYP2C19 Substrates Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by PROVIGIL via inhibition of metabolic enzymes, with resultant higher systemic exposure.
In individuals deficient in the CYP2D6 enzyme, the levels of CYP2D6 substrates which have ancillary routes of elimination through CYP2C19, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, may be increased by co-administration of PROVIGIL.
Dose adjustments of these drugs and other drugs that are substrates for CYP2C19 may be necessary when used concomitantly with PROVIGIL [see Clinical Pharmacology ( 12.3 )] .
Warfarin More frequent monitoring of prothrombin times/INR should be considered whenever PROVIGIL is coadministered with warfarin [see Clinical Pharmacology ( 12.3 )] .
Monoamine Oxidase (MAO) Inhibitors Caution should be used when concomitantly administering MAO inhibitors and PROVIGIL.
Steroidal contraceptives (e.g., ethinyl estradiol): Use alternative or concomitant methods of contraception while taking PROVIGIL and for one month after discontinuation of PROVIGIL treatment.
( 7 ) Cyclosporine: Blood concentrations of cyclosporine may be reduced.
( 7 ) CYP2C19 substrates, such as omeprazole, phenytoin, and diazepam: Exposure of these medications may be increased.
( 7 )
10 In clinical trials, a total of 151 protocol-specified doses ranging from 1000 to 1600 mg/day (5 to 8 times the recommended daily dose of PROVIGIL) have been administered to 32 subjects, including 13 subjects who received doses of 1000 or 1200 mg/day for 7 to 21 consecutive days.
In addition, several intentional acute overdoses occurred; the two largest being 4500 mg and 4000 mg taken by two subjects participating in foreign depression studies.
None of these study subjects experienced any unexpected or life-threatening effects.
Adverse reactions that were reported at these doses included excitation or agitation, insomnia, and slight or moderate elevations in hemodynamic parameters.
Other observed high-dose effects in clinical studies have included anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, diarrhea, and decreased prothrombin time.
From postmarketing experience, there have been reports of fatal overdoses involving modafinil alone or in combination with other drugs.
Symptoms most often accompanying PROVIGIL overdose, alone or in combination with other drugs have included insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, agitation, anxiety, excitation, and hallucination; digestive changes such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension, and chest pain.
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 three-year-old boy who ingested 800-1000 mg (50-63 mg/kg) of PROVIGIL.
The child remained stable.
The symptoms associated with overdose in children were similar to those observed in adults.
No specific antidote exists for the toxic effects of a PROVIGIL overdose.
Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring.
11 PROVIGIL (modafinil) is a wakefulness‑promoting agent for oral administration.
Modafinil is a racemic compound.
The chemical name for modafinil is 2‑[(diphenylmethyl)sulfinyl]acetamide.
The molecular formula is C 15 H 15 NO 2 S and the molecular weight is 273.35.
The chemical structure is: Modafinil is a white to off-white, crystalline powder that is practically insoluble in water and cyclohexane.
It is sparingly to slightly soluble in methanol and acetone.
PROVIGIL tablets contain 100 mg or 200 mg of modafinil and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch.
14 14.1 Narcolepsy 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.
14.2 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 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 [ see Clinical Studies ( 14.1 ) for a description of these measures].
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.
14.3 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 [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.
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 [ see Clinical Studies ( 14.1 ) for a description of these measures.].
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.
Average Baseline Sleep Latency and Change from Baseline at Final Visit (MWT and MSLT in minutes) Disorder Measure PROVIGIL 200 mg Significantly different than placebo for all trials (p<0.01 for all trials but SWD, which was p<0.05) PROVIGIL 400 mg Placebo Baseline Change from Baseline Baseline Change from Baseline Baseline Change from Baseline Narcolepsy I MWT 5.8 2.3 6.6 2.3 5.8 -0.7 Narcolepsy II MWT 6.1 2.2 5.9 2.0 6.0 -0.7 OSA MWT 13.1 1.6 13.6 1.5 13.8 -1.1 SWD MSLT 2.1 1.7 – – 2.0 0.3 Table 3.
Clinical Global Impression of Change (CGI-C) (Percent of Patients Who Improved at Final Visit) Disorder PROVIGIL 200 mg Significantly different than placebo for all trials (p<0.01) PROVIGIL 400 mg Placebo Narcolepsy I 64% 72% 37% Narcolepsy II 58% 60% 38% OSA 61% 68% 37% SWD 74% —— 36%
16 /STORAGE AND HANDLING Product: 63629-1611
8.5 Geriatric Use In clinical trials, experience in a limited number of modafinil-treated patients who were greater than 65 years of age showed an incidence of adverse reactions similar to other age groups.
In elderly patients, elimination of modafinil and its metabolites may be reduced as a consequence of aging.
Therefore, consideration should be given to the use of lower doses and close monitoring in this population [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )].
DOSAGE FORMS AND STRENGTHS
3 100 mg – capsule-shaped, white to off white, tablet, debossed with “PROVIGIL” on one side and “100 MG” on the other.
200 mg – capsule-shaped, white to off white, scored, tablet, debossed with “PROVIGIL” on one side and “200 MG” on the other.
Tablets: 100 mg and 200 mg.
( 3 )
MECHANISM OF ACTION
12.1 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.
INDICATIONS AND USAGE
1 PROVIGIL is indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea (OSA), or shift work disorder (SWD).
Limitations of Use In OSA, PROVIGIL is indicated to treat excessive sleepiness and not as treatment 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 and during treatment with PROVIGIL for excessive sleepiness.
PROVIGIL is indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea (OSA), or shift work disorder (SWD).
( 1 ) Limitations of Use In OSA, PROVIGIL is indicated to treat excessive sleepiness and not as treatment for the underlying obstruction.
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PROVIGIL is not approved in this population for any indication.
Serious skin rashes, including erythema multiforme major (EMM) and Stevens-Johnson Syndrome (SJS) have been associated with modafinil use in pediatric patients [see Warnings and Precautions ( 5.1 )] .
In a controlled 6-week study, 165 pediatric patients (aged 5-17 years) with narcolepsy were treated with modafinil (n=123), or placebo (n=42).
There were no statistically significant differences favoring modafinil over placebo in prolonging sleep latency as measured by MSLT, or in perceptions of sleepiness as determined by the clinical global impression-clinician scale (CGI-C).
In the controlled and open-label clinical studies, treatment emergent adverse reactions of the psychiatric and nervous system included Tourette’s syndrome, insomnia, hostility, increased cataplexy, increased hypnagogic hallucinations, and suicidal ideation.
Transient leukopenia, which resolved without medical intervention, was also observed.
In the controlled clinical study, 3 of 38 girls, ages 12 or older, treated with modafinil experienced dysmenorrhea compared to 0 of 10 girls who received placebo.
There were three 7 to 9 week, double-blind, placebo-controlled, parallel group studies in children and adolescents (aged 6-17 years) with Attention-Deficit Hyperactivity Disorder (ADHD).
Two of the studies were flexible-dose studies (up to 425 mg/day), and the third was a fixed-dose study (340 mg/day for patients <30 kg and 425 mg/day for patients ≥30 kg).
Although these studies showed statistically significant differences favoring modafinil over placebo in reducing ADHD symptoms as measured by the ADHD-RS (school version), there were 3 cases of serious rash including one case of possible SJS among 933 patients exposed to modafinil in this program.
Modafinil is not approved for use in treating ADHD.
8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of modafinil in pregnant women.
Intrauterine growth restriction and spontaneous abortion have been reported in association with modafinil (a mixture of R- and S-modafinil) and armodafinil (the R-enantiomer of modafinil).
Although the pharmacology of modafinil 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 restriction and spontaneous abortions.
Whether the cases reported with modafinil are drug-related is unknown.
In studies of modafinil and armodafinil conducted in rats (modafinil, armodafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant plasma exposures.
PROVIGIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout 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 tested.
The higher no-effect dose for embryofetal developmental toxicity in rats (100 mg/kg/day) was associated with a plasma modafinil AUC less than that in humans at the recommended human dose (RHD) of PROVIGIL (200 mg/day).
However, in a subsequent study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed.
Oral administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in increased incidences of fetal visceral and skeletal variations and decreased fetal body weight at the highest dose tested.
The highest no-effect dose for embryofetal developmental toxicity in rats (200 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the RHD of PROVIGIL.
Modafinil administered orally to pregnant rabbits throughout organogenesis at doses of up to 100 mg/kg/day 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 (100 mg/kg/day) was associated with a plasma modafinil AUC similar to that in humans at the RHD of PROVIGIL.
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, a dose resulting in a plasma modafinil AUC less than that in humans at the RHD of PROVIGIL.
No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring.
Pregnancy Registry A pregnancy registry has been established to collect information on the pregnancy outcomes of women exposed to PROVIGIL.
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).
8.3 Nursing Mothers It is not known whether modafinil or its metabolites are excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when PROVIGIL is administered to a nursing woman.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Serious Rash, including Stevens-Johnson Syndrome: Discontinue PROVIGIL at the first sign of rash, unless the rash is clearly not drug-related.
( 5.1 ) Angioedema and Anaphylaxis Reactions: If suspected, discontinue PROVIGIL.
( 5.2 ) Multi-organ Hypersensitivity Reactions: If suspected, discontinue PROVIGIL.
( 5.3 ) Persistent Sleepiness: Assess patients frequently for degree of sleepiness and, if appropriate, advise patients to avoid driving or engaging in any other potentially dangerous activity.
( 5.4 ) Psychiatric Symptoms: Use caution in patients with a history of psychosis, depression, or mania.
Consider discontinuing PROVIGIL if psychiatric symptoms develop.
( 5.5 ) Known Cardiovascular Disease: Consider increased monitoring.
( 5.7 ) 5.1 Serious Rash, including Stevens-Johnson Syndrome Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of modafinil.
In clinical trials of modafinil, 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.
PROVIGIL is not approved for use in pediatric patients for any indication [see Use in Specific Populations ( 8.4 )] .
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 postmarketing experience.
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.
There are no factors that are known to predict the risk of occurrence or the severity of rash associated with PROVIGIL.
Nearly all cases of serious rash associated with modafinil occurred within 1 to 5 weeks after treatment initiation.
However, isolated cases have been reported after prolonged treatment (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 PROVIGIL, it is not possible to reliably predict which rashes will prove to be serious.
Accordingly, PROVIGIL should 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.
5.2 Angioedema and Anaphylaxis Reactions Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed in patients treated with armodafinil, the R enantiomer of modafinil (which is the racemic mixture).
No such cases were observed in modafinil clinical trials.
However, angioedema has been reported in postmarketing experience with modafinil.
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).
5.3 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.
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.
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, PROVIGIL 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.
5.4 Persistent Sleepiness Patients with abnormal levels of sleepiness who take PROVIGIL should be advised that their level of wakefulness may not return to normal.
Patients with excessive sleepiness, including those taking PROVIGIL, 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.
5.5 Psychiatric Symptoms Psychiatric adverse reactions have been reported in patients treated with modafinil.
In the adult PROVIGIL controlled trials, psychiatric symptoms resulting in treatment discontinuation (at a frequency ≥0.3%) and reported more often in patients treated with PROVIGIL compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (<1%), confusion (<1%), agitation (<1%), and depression (<1%).
Postmarketing adverse reactions 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 PROVIGIL (three times the recommended dose) and sleep deprivation.
There was no evidence of psychosis 36 hours after drug discontinuation.
Caution should be exercised when PROVIGIL is given to patients with a history of psychosis, depression, or mania.
Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in patients treated with PROVIGIL.
If psychiatric symptoms develop in association with PROVIGIL administration, consider discontinuing PROVIGIL.
5.6 Effects on Ability to Drive and Use Machinery Although PROVIGIL 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 it is reasonably certain that PROVIGIL therapy will not adversely affect their ability to engage in such activities.
5.7 Cardiovascular Events In modafinil clinical studies, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on ECG occurred in three subjects in association with mitral valve prolapse or left ventricular hypertrophy.
In a Canadian clinical trial, a 35 year old obese narcoleptic male with a prior history of syncopal episodes experienced a 9-second episode of asystole after 27 days of modafinil treatment (300 mg/day in divided doses).
PROVIGIL is not recommended 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.
Findings suggestive 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 findings occurs, consider cardiac evaluation.
Consider increased monitoring in patients with a recent history of myocardial infarction or unstable angina.
Blood pressure monitoring in short term (≤ 3 months) controlled trials showed no clinically significant changes in mean systolic and diastolic blood pressure in patients receiving PROVIGIL as compared to placebo.
However, a retrospective analysis of the use of antihypertensive medication in these studies showed that a greater proportion of patients on PROVIGIL required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%).
The differential use was slightly larger when only studies in OSA were included, with 3.4% of patients on PROVIGIL and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication.
Increased monitoring of heart rate and blood pressure may be appropriate in patients on PROVIGIL.
Caution should be exercised when prescribing PROVIGIL to patients with known cardiovascular disease.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Allergic Reactions Advise patients to stop taking PROVIGIL and to notify their physician right away if they develop a rash, hives, mouth sores, blisters, peeling skin, trouble swallowing or breathing, or a related allergic phenomenon.
Driving and Dangerous Activities Advise patients not to 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 PROVIGIL has been shown to produce levels of wakefulness that permit such activities.
Advise patients that PROVIGIL is not a replacement for sleep.
Continuing Previously Prescribed Treatments Inform patients that it may be critical that they continue to take their previously prescribed treatments (e.g., patients with OSA receiving CPAP should continue to do so).
Discontinuing Drug Due to Adverse Reactions Advise patients to stop taking PROVIGIL and contact their physician right away if they experience chest pain, rash, depression, anxiety, or signs of psychosis or mania.
Pregnancy Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy.
Caution patients regarding the potential increased risk of pregnancy when using steroidal contraceptives (including depot or implantable contraceptives) with PROVIGIL and for one month after discontinuation of therapy.
Nursing Advise patients to notify their physician if they are breastfeeding an infant.
Concomitant Medication Advise patients 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 PROVIGIL and other drugs.
Alcohol Advise patients that the use of PROVIGIL in combination with alcohol has not been studied.
Advise patients that it is prudent to avoid alcohol while taking PROVIGIL.
PROV-014 Distributed By: Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454 PROVIGIL is a trademark of Cephalon, Inc., or its affiliates.
©1998 – 2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.
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DOSAGE AND ADMINISTRATION
2 The recommended dosage of PROVIGIL for each indication is as follows: Narcolepsy or OSA: 200 mg once a day in the morning.
( 2.1 ) SWD: 200 mg once a day, taken approximately one hour prior to start of the work shift.
( 2.2 ) Severe Hepatic Impairment: reduce dose to half the recommended dose.
( 2.3 , 12.3 ) Geriatric Patients: consider lower dose.
( 2.4 , 12.3 ) 2.1 Dosage in Narcolepsy and Obstructive Sleep Apnea (OSA) The recommended dosage of PROVIGIL for patients with narcolepsy or OSA is 200 mg taken orally once a day as a single dose in the morning.
Doses up to 400 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 200 mg/day dose [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.1 , 14.2 )] .
2.2 Dosage in Shift Work Disorder (SWD) The recommended dosage of PROVIGIL for patients with SWD is 200 mg taken orally once a day as a single dose approximately 1 hour prior to the start of their work shift .
2.3 Dosage Modifications in Patients with Severe Hepatic Impairment In patients with severe hepatic impairment, the dosage of PROVIGIL should be reduced to one-half of that recommended for patients with normal hepatic function [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] .
2.4 Use in Geriatric Patients Consideration should be given to the use of lower doses and close monitoring in geriatric patients [see Use in Specific Populations ( 8.5 )] .