Shire Canada Inc. 2250 Alfred-Nobel Blvd., Suite 500 Saint-Laurent, Quebec H4S 2C9 Date of Preparation: February 26, 1999 Date of Revision: November 14, 2007 * Alertec is a registered trademark of Cephalon, Inc. Control No: 117354
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 11 DRUG INTERACTIONS 16 DOSAGE AND ADMINISTRATION 20 OVERDOSAGE 21 ACTION AND CLINICAL PHARMACOLOGY 21 STORAGE AND STABILITY 22 DOSAGE FORMS, COMPOSITION AND PACKAGING 23
PHARMACEUTICAL INFORMATION 24 CLINICAL TRIALS 24 DETAILED PHARMACOLOGY 29 TOXICOLOGY 31 REFERENCES 34
Alertec(r)
(modafinil)
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablet 100 mg | Lactose For a complete listing see Dosage Forms, Composition and Packaging section. |
Alertec(r)
(modafinil) is indicated for the symptomatic treatment of excessive sleepiness in patients with narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS) and shift work sleep disorder (SWSD).
In OSAHS, Alertec(r) is indicated as an adjunct to successful standard treatment(s) for the underlying obstruction, when excessive sleepiness persists. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient with OSAHS, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating Alertec(r). If Alertec(r) is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary.
Alertec(r)
(modafinil) is indicated for the symptomatic treatment of excessive sleepiness (as confirmed by multiple sleep latency test) in SWSD associated with loss of a normal sleep-wake pattern (as confirmed by polysomnography).
Daytime sleep (as measured by polysomnography) in SWSD is not affected by the use of
Alertec(r). The effect of Alertec(r) on night-shift work performance, sleep deficit in SWSD, or performance following a night-shift have not been adequately evaluated in controlled studies. The effectiveness of modafinil in long-term use (greater than 9 weeks in the narcolepsy clinical trials and 12 weeks in the OSAHS and SWSD clinical trials) has not been systematically evaluated in placebo-controlled trials. The physician who elects to prescribe Alertec(r) for an extended time in patients with narcolepsy, OSAHS or SWSD should periodically reevaluate long-term usefulness for the individual patient. In narcolepsy, Alertec(r) has no significant effect on cataplexy. Alertec(r) should not be used for the treatment of normal fatigue states. The safety and efficacy of Alertec(r) has not been studied in this patient population. See WARNINGS AND PRECAUTIONS. There is no evidence that normal levels of alertness can be heightened by Alertec(r).
Geriatrics:
Dyskinesias have been reported in the elderly with the use of Alertec(r). Elderly patients metabolize Alertec(r) more slowly and have been found to be more sensitive to the effects of Alertec(r); these patients should be started at 100 mg daily. Caution should also be exercised when coadministration of modafinil and clomipramine is deemed necessary. See DRUG INTERACTIONS
Pediatrics ( < 18 years of age):
The number of narcoleptics under the age of 18 included in controlled clinical trials was not adequate to establish the risk/benefit ratio of Alertec(r) in this population. No controlled studies have been conducted in narcoleptics under the age of 13. Alertec(r) is not indicated in children with Attention Deficit Hyperactivity Disorder. 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, Serious Rash, Including Stevens-Johnson Syndrome).
Patients who are hypersensitive to modafinil, armodafinil (the R enantiomer of modafinil; not marketed in Canada) or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING of the product monograph.
Alertec(r) is contraindicated in patients in agitated states and in patients with severe anxiety.
Serious Rash, including Stevens-Johnson Syndrome
Angioedema and Anaphylactoid Reactions
One serious case of angioedema and one case of hypersensitivity (with rash, dysphagia, and bronchospasm), were observed among 1,595 patients treated in clinical trials with armodafinil (not marketed in Canada), the R enantiomer of modafinil (which is the racemic mixture). No such cases were observed in modafinil clinical trials. Angioedema and anaphylactic reaction have 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).
Multi-organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions, including at least one fatality in post-marketing 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 associated with modafinil. 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, Alertec(r) 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.
Persistent Sleepiness
Patients with abnormal levels of sleepiness who take Alertec(r) should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking Alertec(r), should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity.
Psychiatric Symptoms
Psychiatric adverse experiences have been reported in patients treated with Alertec(r). There have been reports of psychotic episodes associated with Alertec(r) use. Postmarketing adverse events associated with the use of modafinil have included mania, delusions, hallucinations, and suicidal ideation, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. In the adult modafinil controlled trials database, psychiatric symptoms resulting in treatment discontinuation (at a frequency >0.3%) and reported more often in patients treated with modafinil compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (<1%), confusion (<1%), agitation (<1%) and depression (<1%). Caution should be exercised when Alertec(r) 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 Alertec(r). If psychiatric symptoms develop in association with Alertec(r)administration, consider discontinuing Alertec(r). In controlled clinical trials of pediatric patients with ADHD, adverse events categorized as signs and symptoms of psychosis or mania and/or suicidal ideation were reported in <1% of patients treated with modafinil and no patients treated with placebo. Aggression and violent behavior were reported in 1% of modafinil-treated patients and no placebo-treated patients in controlled clinical trials of pediatric patients with narcolepsy or OSAHS. There were no reports of psychosis or mania and/or suicidal ideation in clinical trials with this pediatric population.
Normal Fatigue States
Alertec(r) should not be used for the treatment of normal fatigue states. One preliminary study in sleep-deprived subjects, employing a between-subject design (n=42) and a single dose (300mg), suggests that Alertec(r) causes an increased self-estimate of performance which is not commensurate with actual changes in performance (i.e., overconfidence). A subsequent study in sleep-deprived subjects, employing a within-subject design (n=6), using 100 mg administered three times over a period of 24 hours failed to demonstrate an adverse effect on the ability to judge one's own cognitive capabilities.
Occupational Hazards
Because of possible over-stimulation and overconfidence, Alertec(r) may alter the ability of patients to perform hazardous activities. Patients should be cautioned about operating an automobile or other hazardous machinery until they are reasonably certain that Alertec(r) therapy will not adversely affect their ability to engage in such activities.
CPAP Use in Patients with OSAHS
In OSAHS, Alertec(r) is indicated as an adjunct to successful standard treatment(s) 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 Alertec(r). If Alertec(r) is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary.
Cardiovascular
The safety of Alertec(r)has not been established in patients with coronary artery disease, a recent history of myocardial infarction, or unstable angina. Patients with these conditions were not included in the controlled clinical trials. Since transient increases in the blood pressure and heart rate may occur in the immediate period after dosing, the risks of using Alertec(r) in patients with coronary artery disease, a recent history of myocardial infarction, or unstable angina should be carefully weighed against the potential therapeutic benefit. In clinical studies of modafinil, signs and symptoms including chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that Alertec(r) not be used in patients with a history of left ventricular hypertrophy or in patients with ischemic ECG changes, chest pain, arrhythmia, or other clinically significant manifestations of mitral valve prolapse in association with CNS stimulant use. Such signs may include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these symptoms occurs, consider cardiac evaluation. 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 Alertec(r) compared to placebo. However, a retrospective analysis of the use of antihypertensive medication in these studies showed that a greater proportion of patients on Alertec(r) required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential was slightly larger when only studies on OSAHS were included, with 3.4% of patients on Alertec(r) and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication. Increased monitoring of blood pressure may be appropriate in patients on Alertec(r). Cardiovascular adverse reactions increase significantly after single doses of 300 mg and after total daily doses of more than 400 mg.
Use in Combination with Other CNS Stimulants
Caution should be taken when Alertec(r) is used in combination with amphetamines or other similar CNS stimulants, such as methylphenidate. Some CNS stimulants may cause increases in blood pressure and heart rate, and the concomitant use of these drugs may result in additive effects. Clinically important prolongation of the QTc interval may also occur within a few hours after simultaneous administration of modafinil and dextroamphetamine. Alertec and other CNS stimulants should not be taken at the same time. See DRUG INTERACTIONS.
Patients using Steroidal Contraceptives
The effectiveness of steroidal contraceptives may be reduced when used with Alertec(r) and for one month after discontinuation of therapy (See DRUG INTERACTIONS). Alternative or concomitant methods of contraception other than steroidal are recommended for patients treated with Alertec(r), and for one month after discontinuation of Alertec(r).
Patients Using Cyclosporine
The blood levels of cyclosporine may be reduced when used with Alertec(r) (see DRUG INTERACTIONS). Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when these drugs are used concomitantly.
Carcinogenesis and Mutagenesis
Please refer to the TOXICOLOGY section to the animal data.
Dependence/Tolerance
Alertec(r)
is a psychoactive drug. The potential for abuse should be considered when prescribing
Alertec(r). In a study of 24 subjects with polysubstance abuse histories, Alertec(r) doses of 200, 400, and 800 mg showed lower abuse potential relative to methylphenidate, but were discriminated from placebo by subjects and observers. Alertec(r) did not produce a significant amphetamine score on the Addiction Research Center Inventory (ARCI) questionnaire.
Alertec(r) was also clearly distinguishable from amphetamine on this scale in a study of 300 mg in 16 healthy volunteers. Subjective effects of Alertec(r) differed markedly from those induced by 15 mg of d-amphetamine, and to a lesser extent, from those seen with placebo.
Endocrine and Metabolism
Alertec(r)
may cause induction of hepatic microsomal enzymes, especially at doses greater than
400 mg. The metabolism of oral anticoagulants, antidepressant, anticonvulsants, and oral contraceptives may be increased. Patients should be monitored closely for changes in their response to any of these therapies when treatment with Alertec(r) is either initiated or discontinued.
Hepatic/Biliary/Pancreatic
Severe Hepatic Impairment
The elimination half-life of Alertec(r) is doubled in patients with severe hepatic impairment. Doses should be reduced by half.
Liver Function Tests
In Phase 1, 2, and 3 studies, mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of Alertec(r), but not placebo. Few subjects, 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 Alertec(r) in the Phase 3 clinical trials. No differences were apparent in alanine aminotransferase, aspartate aminotransferase, total protein, albumin, or total bilirubin.
Neurologic
Central nervous system adverse reactions increase significantly after single doses of 300 mg and after total daily doses of more than 400 mg.
Renal
Severe Renal Impairment
There is inadequate information to determine the safety and efficacy of dosing in patients with severe renal impairment.
Renal impairment
Compared to healthy individuals, modafinil plasma concentrations were unchanged in patients with chronic renal failure. However, the renal clearance of the inactive metabolite, modafinil acid, was reduced, leading to substantial increases in modafinil acid plasma concentrations. No adverse events were reported in this small number of patients. The clinical significance of increased modafinil acid plasma concentrations is unknown.
Special Populations
Pregnant Women: Embryotoxicity was observed in the absence of maternal toxicity when rats received oral modafinil throughout the period of organogenesis. At a dose 5 times the maximum recommended daily human dose of 400 mg on a mg/m2 basis, there was an increase in resorption, hydronephrosis and skeletal variations. When rabbits received oral modafinil throughout organogenesis at doses up to 5 times the maximum recommended daily human dose of 400 mg on a mg/m2 basis), no embryotoxicity was seen. Animal data show that modafinil is distributed in the placenta and foetus after oral ingestion. One hour after oral dosing of 14C- modafinil the levels of radioactive material in the placenta and the foetus of rats were comparable with the lower levels seen in maternal tissues Alertec(r) is not recommended during pregnancy. Nursing Women: It is not known whether modafinil is excreted in human milk. However, in rats, peak 14C-modafinil concentrations appeared in the milk of lactating animals within one hour and at levels similar to the ones found in plasma. In the absence of human safety data Alertec(r) is therefore not recommended during lactation. Pediatrics (< 18 years of age): The number of narcoleptics under the age of 18 included in controlled clinical trials was not adequate to establish the risk/benefit ratio of Alertec(r) in this population. No controlled studies have been conducted in narcoleptics under the age of 13. Alertec(r) is not indicated in children with Attention Deficit Hyperactivity Disorder. Geriatrics: Dyskinesias have been reported in the elderly with the use of Alertec(r). Elderly patients metabolize Alertec(r) more slowly and have been found to be more sensitive to the effects of Alertec(r); these patients should be started at 100 mg daily. Caution should also be exercised when coadministration of modafinil and clomipramine is deemed necessary. See DRUG INTERACTIONS
Adverse Drug Reaction Overview
The most commonly observed adverse events (>=5%) associated with the use of Alertec(r) and observed more frequently than placebo-treated patients in the placebo-controlled clinical studies in primary disorders of sleep and wakefulness were headache, nausea, rhinitis, nervousness, diarrhea, back pain, anxiety, dizziness, dyspepsia, and insomnia. The adverse event profile was similar across these studies. In the placebo-controlled clinical trials, 74 of the 934 patients (8%) who received Alertec(r) discontinued due to an adverse experience compared to 3% of patients that received placebo. The most frequent reasons for discontinuation that occurred at a higher rate for Alertec(r) than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain and nervousness (each <1%).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The following table presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in patients treated with Alertec(r) than in placebo patients in the principal, placebo-controlled clinical trials.
Table 1 - Incidence Of Treatment-Emergent Adverse Experiences In Parallel-Group, Placebo-Controlled Clinical Trials1 In Narcolepsy and Obstructive Sleep Apnea/Hypopnea Syndrome and Shift Work Sleep Disorder With Alertec(r) (200mg, 300mg and 400mg) *
| Modafinil n = 934 (%) | Placebo n= 567 (%) | |
| Body as Whole | 34% | 23% |
| Headache | ||
| Back Pain | 6% | 5% |
| Flu Syndrome | 4% | 3% |
| Chest Pain | 3% | 1% |
| Chills | 1% | 0% |
| Neck Rigidity | 1% | 0% |
| Cardiovascular | 3% | 1% |
| Hypertension | ||
| Tachycardia | 2% | 1% |
| Palpitation | 2% | 1% |
| Vasodilatation | 2% | 0% |
| Digestive Nausea | 11% | 3% |
| Diarrhea | 6% | 5% |
| Dyspepsia | 5% | 4% |
| Dry Mouth | 4% | 2% |
| Anorexia | 4% | 1% |
| Constipation | 2% | 1% |
| Abnormal Liver Function 2 | 2% | 1% |
| Flatulence | 1% | 0% |
| Mouth Ulceration | 1% | 0% |
| Thirst | 1% | 0% |
| Hemic/Lymphatic Eosiniphilia | 1% | 0% |
| Metabolic/Nutritional Edema | 1% | 0% |
| Nervous | 7% | 3% |
| Nervousness | ||
| Insomnia | 5% | 1% |
| Anxiety | 5% | 1% |
| Dizziness | 5% | 4% |
| Depression | 2% | 1% |
| Paresthesia | 2% | 0% |
| Somnolence | 2% | 1% |
| Hypertonia | 1% | 0% |
| Dyskinesia 3 | 1% | 0% |
| Hyperkinesia | 1% | 0% |
| Agitation | 1% | 0% |
| Confusion | 1% | 0% |
| Tremor | 1% | 0% |
| Emotional Lability | 1% | 0% |
| Vertigo | 1% | 0% |
| Respiratory | 7% | 6% |
| Rhinitis | ||
| Pharyngitis | 4% | 2% |
| Lung Disorder | 2% | 1% |
| Epistaxis | 1% | 0% |
| Asthma | 1% | 0% |
| Skin/ Appendages | 1% | 0% |
| Sweating | ||
| Herpes Simplex | 1% | 0% |
| Special Senses | 1% | 0% |
| Amblyopia | ||
| Abnormal Vision | 1% | 0% |
| Taste Perversion | 1% | 0% |
| Eye Pain | 1% | 0% |
| Urogenital | 1% | 0% |
| Urine Abnormality | ||
| Hematuria | 1% | 0% |
| Pyuria | 1% | 0% |
*
Six double-blind, placebo controlled clinical studies in narcolepsy (200 and 400 mg), OSAHS (200 and 400 mg) and SWSD (200 mg and 300 mg).
Events reported by at least 1% of patients treated with Alertec(r) that were more frequent than in the placebo group are included; incidence is rounded to the nearest 1%. The adverse experience terminology is coded using a standard modified COSTART Dictionary.
Events for which the Alertec(r) incidence was at least 1%, but equal to or less than placebo are not listed in the table. These events included the following: infection, pain, accidental injury, abdominal pain, hypothermia,
allergic reaction, asthenia, fever, viral infection, neck pain, migraine, abnormal electrocardiogram, hypotension,
tooth disorder, vomiting, periodontal abscess, increased appetite, ecchymosis, hyperglycemia, peripheral edema, weight loss, weight gain, myalgia, leg cramps, arthritis, cataplexy, thinking abnormality, sleep disorder, increased cough, sinusitis, dyspnea, bronchitis, rash, conjunctivitis, ear pain, dysmenorrhea4, urinary tract infection.
Elevated liver enzymes.
Oro-facial dyskinesias.
Incidence adjusted for gender.
Less Common Clinical Trial Adverse Drug Reactions (<1%)
In the narcolepsy pivotal clinical trials, adverse events occurring less frequently were:
Nervous system:
CNS stimulation (1.0%), and twitch (0.7%).
Skin and appendages: Special senses: Urogenital system: .
pruritus (1.0%).
conjunctivitis (1.0%).
urinary frequency (0.7%)
Adverse events reported only once in the narcolepsy pivotal clinical trials include:
Body as a whole:
jaw pain (0.3%) and photosensitivity. (0.3%).
Cardiovascular system:
heart arrest (0.3%).
Digestive system:
saliva increase (0.3%).
Hemic and lymphatic system:
leukocytosis (0.3%).
Musculoskeletal system:
myasthenia (0.3%).
Nervous system:
ataxia (0.3%), coordination abnormality (0.3%), dream abnormality (0.3%), libido increase (0.3%), personality disorder (0.3%).
Special senses:
decreased hearing (0.3%), hyperacusis (0.3%).
Urogenital system:
cystitis (0.3%), and impotence (0.3%).
Dose Dependency of Adverse Events
In the placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of Alertec(r) and placebo, the only adverse events that were clearly dose related were headache and anxiety.
Vital Sign Changes
While there was no consistent change in mean values of heart rate or systolic and diastolic blood pressure, the requirement for antihypertensive medication was slightly greater in patients on Alertec(r) compared to placebo.
Weight Changes
There were no clinically significant differences in body weight change in patients treated with
Alertec(r)
compared to placebo-treated patients in the placebo-controlled clinical trials.
Laboratory Changes
Clinical chemistry, hematology, and urinalysis parameters were monitored in Phase 1, 2, and 3 studies. In these studies, mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of Alertec(r), but not placebo. Few subjects, 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 Alertec(r) in the Phase 3 clinical trials. No differences were apparent in alanine aminotransferase, aspartate aminotransferase, total protein, albumin, or total bilirubin.
ECG Changes
No treatment-emergent pattern of ECG abnormalities was found in placebo-controlled clinical trials following administration of Alertec(r). 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). (see WARNINGS AND PRECAUTIONS, Cardiovascular).
Post-Market Adverse Drug Reactions
In addition to the adverse events observed during clinical trials, the following adverse events have been identified during post-approval use of Alertec(r) in clinical practice. Because these adverse effects are reported voluntarily from a population of uncertain size, reliable estimates of their frequency cannot be made. Hematologic: agranulocytosis. The causality of the two cases reported could not be established due to concomitant use of Dyazide(r) (hydrochlorothiazide/triamterene) in the first case and of omeprazole in the second case.
Central nervous system:
symptoms of psychosis, symptoms of mania.
Hypersensitivity:
urticaria (hives), angioedema, anaphylactic reaction
Dermatologic:
rare reports of serious skin reactions [including cases of erythema multiforme, Stevens-Johnson syndrome, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and toxic epidermal necrolysis]
Drug-Drug Interactions
CNS Active Drugs
Methylphenidate
- In a single-dose study in 21 healthy male volunteers, ages 21 - 37, coadministration of modafinil (200mg) with methylphenidate (40 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of modafinil may be delayed by approximately one hour when coadministered with methylphenidate. In a subsequent study, the effects of methylphenidate (20 mg per day) at steady state on the pharmacokinetics of modafinil (400 mg per day) at steady state were examined, with administration of the stimulant 8 hours after the daily dose of modafinil. No effects on the pharmacokinetic parameters of modafinil were observed.
Dextroamphetamine - In a single dose study in healthy volunteers, simultaneous administration of modafinil (200 mg) with dextroamphetamine (10 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of Alertec(r) may be delayed by approximately one hour when coadministered with dextroamphetamine. In a subsequent study, the effects of dextroamphetamine (20 mg per day) at steady state on the pharmacokinetics of modafinil (400 mg per day) at steady state were examined, with administration of the stimulant 7 hours after the daily dose of modafinil. No effects on the pharmacokinetic parameters of modafinil were observed. In the single-dose study, blood pressure and pulse rate were increased at a greater extent after administration of the two drugs combined than after administration of either drug alone. A mean increase in QTc interval of 15 msec, and individual prolonged QTc interval (including one result of clinical importance = 507 ms) were also observed 2 hours after simultaneous administration of the two drugs at their minimum recommended dosage (See WARNINGS AND PRECAUTIONS). The same patient had an prolonged QTc interval of 480 ms when Dexamphetamine was administered alone. Patients who are receiving Alertec(r) with drugs with CNS activity should be monitored closely. See WARNINGS AND PRECAUTIONS
Clomipramine
- In 18 healthy, male volunteers, ages 22-44, the coadministration of a single dose of clomipramine (50 mg) on the first of three days of treatment with modafinil (200 mg/day) did not appear to affect the pharmacokinetics of either drug. However, systolic blood pressure was significantly higher when the two drugs were administered together than following administration of either drug alone [mean increase above baseline 12.4 mmHg (combination) vs
5.7 mmHg (modafinil alone) vs 6.4 mmHg (clomipramine alone)]. Also, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine has been reported in a patient with narcolepsy during treatment with modafinil. The hypertensive effects of coadministration of higher than 50 mg doses of clomipramine and multiple doses of modafinil (200-400 mg daily) is unknown. Therefore, caution should be exercised when coadministration of modafinil and clomipramine is deemed necessary. See WARNINGS AND PRECAUTIONS Triazolam - In a pharmacodynamic study, single doses of modafinil (50, 100 or 200 mg) and triazolam (0.25mg) were given to healthy, male volunteers, ages 19-26. No clinically important alterations in the safety profile of modafinil or triazolam were noted. However, the effects of concomitant adminstration of multiple doses of modafinil (200-400 mg daily) and 0.25 mg triazolam is unknown. In the drug interaction study between Alertec(r) 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. Dosage adjustment for triazolam may be needed.
Monoamine Oxidase (MAO) Inhibitors
- Interaction studies with monoamine oxidase inhibitors have not been performed. Therefore, caution should be used when concomitantly administering MAO inhibitors and modafinil.
Other Drugs
Warfarin - The following changes were observed in the pharmacokinetic profiles of S- warfarin: no changes in mean Cmax, 20% increase in mean AUC for S-warfarin, in 13 healthy subjects given a single dose of racemic warfarin (5 mg) following chronic administration of modafinil (200 mg/day for 7 days followed by 400 mg/day for 27 days) relative to the profiles in 12 subjects given placebo. However, because multiple doses of warfarin in patients were not evaluated, the relevance of these findings in a clinical setting is unknown. For this reason, more frequent evaluations of prothrombin times/INR than the regular monitoring is advisable whenever Alertec(r) is coadministered with warfarin. Oral contraceptives - Administration of modafinil to 16 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 Cmax and 18% decrease in 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. However, higher individual decreases in the AUC0-24 of ethinyl estradiol and increased incidence of metrorrhagia were observed when modafinil and ethinyl estradiol were administered concomitantly. Also, one woman in the study had a decrease of 54% in the AUC0-24 of ethinyl estradiol during concomitant modafinil treatment. She had a negative pregnancy test at study completion, and a positive pregnancy test 25 days after she completed the study. She thereafter was lost to follow-up and further information on her pregnancy is not available. See WARNINGS AND PRECAUTIONS.
Cyclosporine
- One case of an interaction between modafinil and cyclosporine, a substrate of CYP3A4, has been reported in a 41 years 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. Dosage adjustment for cyclosporine may be needed.
Concomitant use of Alertec(r) and other agents that may elevate blood pressure has not been evaluated. Caution should be exercised when prescribing Alertec(r) to patients already taking such agents. Multi-dose treatment (twice daily, one at 8 a.m. and one at noon) with Alertec(r) at 400 mg/day or higher for 7 days was shown to decrease the half-life of antipyrine. This finding suggests that chronic administration of Alertec(r) at 400 mg or higher daily may induce the metabolism of other drugs. The ability of Alertec(r) to induce hepatic cytochrome P-450 (CYP) enzymes was evaluated in vitro using primary human hepatocyte cultures. Alertec(r) produced a slight and variable increase in the activity of a number of cytochrome P-450s. The increases were usually obtained only at higher concentrations (10-4 M and 10-3 M) than the expected concentrations (5 x 10-5 M) at the recommended human dosage. These increases were modest compared to those exerted by the reference inducers (3-methylcholantrene, phenobarbital, rifampicin, and clofibric acid). The results suggest that Alertec(r) should have little effect on drugs metabolized by CYP 1A, 2B, and 2D6, in particular clomipramine. CYP 4A activity was unaffected except at the highest concentration (10 -3 M) with a 2-fold increase. This increase was low when compared to the increase seen with clofibric acid (10-4 M) or the non-specific inducer phenobarbital (3 x 10-3 M). Alertec(r) has a slight induction effect at the concentration of 10-5 M on CYP 3A, a hepatic enzyme associated with the metabolism of oral contraceptives. Chronic administration of modafinil 400 mg per day was found to decrease the systemic exposure to two CYP3A4 substrates, ethinyl estradiol and triazolam, after oral administration suggesting that CYP3A4 had been induced. Caution is therefore recommended with the combination of oral contraceptives and Alertec(r) (See WARNINGS AND PRECAUTIONS). Chronic administration of modafinil can increase the elimination of substrates of CYP3A4. Dosage adjustment should be considered for concomitant medications that are substrates for CYP3A4, such as triazolam and cyclosporine.
In vitro
studies using liver microsomes suggest that formation of the metabolite modafinil sulfone is primarily catalyzed by cytochrome CYP 3A. Potential inhibitors such as itraconazole or ketoconazole may therefore reduce the formation of modafinil sulfone. Because this pathway is of relatively minor importance in humans, such an interaction would not be expected to appreciably alter modafinil elimination.
The exposure of human hepatocytes to modafinil in vitro 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). In a subsequent clinical study in healthy volunteers, chronic modafinil treatment resulted in a 20% increase in mean AUC on the single-dose pharmacokinetics of S-warfarin when compared to placebo. See DRUG INTERACTIONS In vitro studies using human liver microsomes showed that modafinil reversibly inhibited CYP2C19 at pharmacologically relevant concentrations of modafinil. 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. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with Alertec(r) and may require dosage reduction and monitoring for toxicity. In addition, in individuals deficient in the enzyme CYP2D6 (i.e., 7-10% of the Caucasian population; similar or lower in other populations), the levels of CYP2D6 substrates such as tricyclic antidepressants and selective serotonin reuptake inhibitors, which have ancillary routes of elimination through CYP2C19, may be increased by co administration of modafinil. Dose adjustments may be necessary for patients being treated with these and similar medications. It should be noted that evaluation of drug interactions based on in vitro systems may not necessarily reflect those seen in vivo situations. This information should be used as a guide to assess the risks associated with the use of concomitant medications.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
Dosing Considerations
Dosage adjustment should be considered for concomitant medications that are substrates for CYP3A4, such as triazolam and cyclosporine. Drugs that are largely eliminated by CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with Alertec(r) and may require dosage reduction and monitoring for toxicity.
Elderly:
elderly patients should be started at 100 mg daily. See
WARNINGS AND PRECAUTIONS
Severe Hepatic Impairment: in patients with severe hepatic impairment, the dose of Alertec(r) should be reduced to one-half of the usual recommended dose. See WARNINGS AND PRECAUTIONS,
Recommended Dose and Dosage Adjustment
Narcolepsy
The adult daily dosage of Alertec(r) (modafinil) for patients with narcolepsy is between 200 to 400 mg, divided between morning and noon doses. The initial daily dose should be 200 mg in divided doses, increasing in increments of 100 mg as needed and tolerated. The total daily dose can be divided according to the needs and response of the patient. The timing should be aimed to coincide with the periods of greatest excessive daytime sleepiness. The second dose should generally be taken no later than the early afternoon to minimize the risk of insomnia. Although the occasional patient may need and tolerate daily doses of 500 mg, limited data from trials in healthy volunteers suggest that the number and type of side effects increase significantly after single doses of 300 mg and after total daily doses of more than 400 mg, compared to 100 and 200 mg doses b.i.d. Single doses of 300 mg or more, or total daily doses of more than 400 mg are therefore not recommended.
Obstructive Sleep Apnea/Hypopnea Syndrome
In OSAHS, Alertec(r) is indicated as an adjunct to successful standard treatment(s) for the underlying obstruction (see WARNINGS AND PRECAUTIONS). For patients with OSAHS, the adult daily dosage of Alertec(r) is 200 mg taken as a single dose in the morning.
Shift Work Sleep Disorder
For patients with SWSD, the adult daily dosage of Alertec(r) is 200 mg taken approximately 1 hour prior to the start of their work shift.
Missed Dose
If a dose is missed, it can be taken when remembered, unless it is close to the time for the next dose. Taking the medication in the evening or the late afternoon may prevent from falling asleep at usual bedtime, and should, therefore, be avoided.
Symptoms most often accompanying Alertec(r) overdose, alone or in combination with other drugs have included insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, excitation and hallucination; digestive changes such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension, and chest pain.
Mechanism of Action
Modafinil is a central nervous system stimulant. Modafinil increases sub-normal levels of alertness. Its mode of action in man is not completely understood, but in animals it may act through a stimulation or modulation of central a-1 adrenergic receptors. EEG studies in man showed that modafinil increases high frequency a waves and decreases d and th waves, an effect consistent with increased alertness. When taken in the evening, modafinil 200 mg increases sleep latency and decreases total sleep time. Modafinil has weak peripheral sympathomimetic activity: single doses of 200 mg and total daily doses of 400 mg have minimal effect on hemodynamics. Higher doses cause blood pressure and heart rate to increase in a dose-dependent manner.
Pharmacokinetics
Absorption: Alertec(r) is slowly absorbed with an absorption half-life of approximately 1 hour. Peak plasma concentrations (Cmax) of approximately 3.3 mg/L are reached three hours (tmax) after administration of a 200 mg dose. The Cmax is slightly lower and the tmax slightly longer when Alertec(r) is given after a meal but has no effect on overall Alertec(r) bioavailability. Both the area under the plasma concentration curve (AUC), and the peak plasma concentration showed dose- proportionality in the 50 to 400 mg range.
Distribution:
Modafinil has a large volume of distribution (66 L) and is weakly bound (60%) to albumin. Total clearance is approximately 5 L/h.
Metabolism:
Following oral administration of modafinil, less than 10% of the dose is found unchanged in the urine.
Modafinil is principally metabolized by the liver: 40% of a 200 mg oral dose is excreted in the urine as the inactive metabolite, modafinil acid. The other major metabolite (inactive) of modafinil is modafinil sulfone. At doses of 400 mg or higher modafinil may cause enzyme induction: chronic administration of modafinil has been shown to decrease antipyrine half-life in both dogs and man.
Excretion:
Modafinil is eliminated from the plasma with a half-life of 10 hours; this half-life is more than doubled in patients with hepatic insufficiency. In chronic renal failure, modafinil blood levels are similar to the levels in healthy volunteers. In these patients however, the inactive acid metabolite is 2 to 4 times higher.
Special Populations and Conditions
Geriatrics:
Elderly patients metabolize modafinil more slowly: maximal plasma concentrations are double the predicted values (see WARNINGS AND PRECAUTIONS).
Severe Hepatic Impairment: The elimination half-life of Alertec(r) is more than doubled in patients with severe hepatic impairment. Doses should be reduced by half. See WARNINGS AND PRECAUTIONS
Store between 15deg and 30degC
Each white convex tablet of Alertec(r), engraved with "100" on one side, contains modafinil 100 mg. Available in blister strips of 10 tablets, in packages of three strips. Non-Medicinal Ingredients: Lactose, maize starch, magnesium monosilicate, sodium croscarmellose, polyvidone, magnesium stearate, and talc.