HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`
`
`
`
`
`PROVIGIL safely and effectively. See full prescribing information for
`
`PROVIGIL.
`
`
`PROVIGIL® (modafinil) tablets, for oral use, C-IV
`
`
`
`
`Initial U.S. Approval: 1998
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`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.
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`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)
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Tablets: 100 mg and 200 mg. (3)
`
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`PROVIGIL is contraindicated in patients with known hypersensitivity to
`
`
`
`
`modafinil or armodafinil. (4)
`
`
`-------------------------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)
`
`_______________________________________________________________________________________________________________________________________
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`
`
`
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`
`
`• 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)
`
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`Most common adverse reactions (≥5%): headache, nausea, nervousness,
`
`
`
`
`
`rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. (6.1)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Teva
`
`
`Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or
`
`
`
`
`www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS------------------------------­
`• 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)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide.
`
`
`
`
`
`
`
`
`
`
`Revised: 01/2015
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`
`2
`
`
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`
`
`
`
`2.1 Dosage in Narcolepsy and Obstructive Sleep Apnea (OSA)
`
`
`
`2.2 Dosage in Shift Work Disorder (SWD)
`
`
`
`
`2.3 Dosage Modifications in Patients with Severe Hepatic Impairment
`
`
`
`2.4 Use in Geriatric Patients
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`5.1 Serious Rash, including Stevens-Johnson Syndrome
`
`
`
`5.2 Angioedema and Anaphylaxis Reactions
`
`
`5.3 Multi-organ Hypersensitivity Reactions
`
`
`5.4 Persistent Sleepiness
`
`
`5.5 Psychiatric Symptoms
`
`
`
`
`
`5.6 Effects on Ability to Drive and Use Machinery
`
`
`
`5.7 Cardiovascular Events
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`6
`
`
`7
`
`8
`
`
`
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic Impairment
`
`
`8.7 Renal Impairment
`
`
`DRUG ABUSE AND DEPENDENCE
`9
`
`
`9.1 Controlled Substance
`
`
`9.2 Abuse
`
`
`9.3 Dependence
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Narcolepsy
`
`
`14.2 Obstructive Sleep Apnea (OSA)
`
`
`14.3 Shift Work Disorder (SWD)
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`
`
`
`16.2 Storage
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed.
`
`
`
`
`
`
`Reference ID: 3685660
`
`
`
`
`
`

`

`
`
`INDICATIONS AND USAGE
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`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.
`
`2
`
`
`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)].
`
`
`3
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`
`• 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.
`
`
`
`
`CONTRAINDICATIONS
`
`
`
`4
`
`PROVIGIL is contraindicated in patients with known hypersensitivity to modafinil or armodafinil or its inactive ingredients [see
`
`
`
`
`
`Warnings and Precautions (5.1, 5.2, 5.3)].
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`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
`
`
`
`
`
`Reference ID: 3685660
`
`

`

`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`Reference ID: 3685660
`
`

`

`
`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.
`
`
`
`
`
`Cardiovascular Events
`
`
`
`
`
`ADVERSE REACTIONS
`
`
`5.7
`
`
`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.
`
`
`
`
`
`6
`
`The following serious adverse reactions are described elsewhere in the labeling:
`
`
`• Serious Rash, including Stevens-Johnson Syndrome [see Warnings and Precautions (5.1)]
`
`
`
`• Angioedema and Anaphylaxis Reactions [see Warnings and Precautions (5.2)]
`
`
`
`
`
`• Multi-organ Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
`
`
`
`
`
`• Persistent Sleepiness [see Warnings and Precautions (5.4)]
`
`
`
`
`• Psychiatric Symptoms [see Warnings and Precautions (5.5)]
`
`
`
`
`• Effects on Ability to Drive and Use Machinery [see Warnings and Precautions (5.6)]
`
`
`
`
`
`
`• Cardiovascular Events [see Warnings and Precautions (5.7)]
`
`
`
`
`
`
`
`6.1 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
`
`
`
`
`
` PROVIGIL
`
`
` Placebo
`
`
` (%)
` (%)
`
`
` (n = 934)
` (n = 567)
` 23
`
`
` 34
`
` 11
`
` 3
`
`
` Headache
`
` Nausea
`
`
`
`
`
`
`
`Reference ID: 3685660
`
`
`
`
`
`

`

`
` Placebo
`
` PROVIGIL
`
`
` (%)
` (%)
`
` (n = 567)
`
`
` (n = 934)
` Nervousness
`
` 3
`
` 7
`
` Rhinitis
`
` 6
`
` 7
` Back Pain
`
` 5
`
` 6
`
` Diarrhea
`
` 5
`
` 6
`
` Anxiety
`
` 1
`
` 5
` Dizziness
`
`
` 4
`
` 5
` Dyspepsia
`
`
` 4
`
` 5
`
` Insomnia
`
` 1
`
` 5
`
` Anorexia
`
` 1
`
` 4
`
` Dry Mouth
`
` 2
`
` 4
`
` Pharyngitis
`
` 2
`
` 4
`
` Chest Pain
`
` 1
`
` 3
` Hypertension
`
`
` 1
`
` 3
`
`Abnormal Liver Function
`
` 1
`
` 2
`
` Constipation
`
` 1
`
` 2
`
` Depression
`
` 1
`
` 2
`
` Palpitation
`
` 1
`
` 2
`
` Paresthesia
`
` 0
`
` 2
`
` Somnolence
`
` 1
`
` 2
`
` Tachycardia
`
` 1
`
` 2
` Vasodilatation
`
`
` 0
`
` 2
` Abnormal Vision
`
`
` 0
`
` 1
`
` Agitation
`
` 0
`
` 1
`
` Asthma
`
` 0
`
` 1
`
` Chills
`
` 0
`
` 1
` Confusion
`
`
` 0
`
` 1
` Dyskinesia
`
`
` 0
`
` 1
`
` Edema
`
` 0
`
` 1
`
` Emotional Lability
`
` 0
`
` 1
` Eosinophilia
`
`
` 0
`
` 1
`
` Epistaxis
`
` 0
`
` 1
` Flatulence
`
`
` 0
`
` 1
`
` Hyperkinesia
`
` 0
`
` 1
`
` Hypertonia
`
` 0
`
` 1
` Mouth Ulceration
`
`
` 0
`
` 1
`
` Sweating
`
` 0
`
` 1
` Taste Perversion
`
`
` 0
`
` 1
`
` Thirst
`
` 0
`
` 1
` Tremor
`
` 0
`
` 1
`
`
` 0
`
` 1
` Urine Abnormality
`
` 0
`
` 1
`
` Vertigo
`
` * Adverse Reactions that occurred in > 1% of PROVIGIL-treated patients (either 200, 300, or 400 mg once daily) and greater incidence than placebo
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`Reference ID: 3685660
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`Dose-Dependent Adverse Reactions
`
`
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`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
`
`
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`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%).
`
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`
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`Laboratory Abnormalities
`
`
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`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
`
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`

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` 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.
`
`
`6.2 Postmarketing Experience
`
`
`
`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
`
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`
`
`
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`relationship to drug exposure.
`
`Hematologic: agranulocytosis
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`Psychiatric disorders: psychomotor hyperactivity
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`DRUG INTERACTIONS
`
`
`7
`
`Effects of PROVIGIL on CYP3A4/5 Substrates
`
`
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`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)].
`
`
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`The effectiveness of steroidal contraceptives may be reduced when used with PROVIGIL and for one month after discontinuation of
`
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`therapy. Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g.,
`
`
`
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`ethinyl estradiol) when treated concomitantly with PROVIGIL and for one month after discontinuation of PROVIGIL treatment.
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`Blood levels of cyclosporine may be reduced when used with PROVIGIL. Monitoring of circulating cyclosporine concentrations and
`
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`appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with PROVIGIL.
`
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`
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`Effects of PROVIGIL on CYP2C19 Substrates
`
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`Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be
`
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`
`
`prolonged by PROVIGIL via inhibition of metabolic enzymes, with resultant higher systemic exposure. In individuals deficient in the
`
`
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`
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`CYP2D6 enzyme, the levels of CYP2D6 substrates which have ancillary routes of elimination through CYP2C19, such as tricyclic
`
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`
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`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
`
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`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
`
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`Caution should be used when concomitantly administering MAO inhibitors and PROVIGIL.
`
`
`
`8
`
`
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`8.1 Pregnancy
`
`Pregnancy Category C
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`There are no adequate and well-controlled studies of modafinil in pregnant women. Intrauterine growth restriction and spontaneous
`
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`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
`
`
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`pharmacologic properties with this class. Certain of these drugs have been associated with intrauterine growth restriction and
`
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`spontaneous abortions. Whether the cases reported with modafinil are drug-related is unknown. In studies of modafinil and
`
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`armodafinil conducted in rats (modafinil, armodafinil) and rabbits (modafinil), developmental toxicity was observed at clinically
`
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`relevant plasma exposures. PROVIGIL should be used during pregnancy only if the potential benefit justifies the potential risk to the
`
`fetus.
`
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`USE IN SPECIFIC POPULATIONS
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`Reference ID: 3685660
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` 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
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` highest dose tested. The higher no-effect dose for embryofetal developmental toxicity in rats (100 mg/kg/day) was associated with a
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` plasma modafinil AUC less than that in humans at the recommended human dose (RHD) of PROVIGIL (200 mg/day). However, in a
`
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`subsequent study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed. Oral
`
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`administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in increased incidences
`
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`of fetal visceral and skeletal variations and decreased fetal body weight at the highest dose tested. The highest no-effect dose for
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`
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`embryofetal developmental toxicity in rats (200 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans
`
`
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`at the RHD of PROVIGIL.
`
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`Modafinil administered orally to pregnant rabbits throughout organogenesis at doses of up to 100 mg/kg/day had no effect on
`
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`embryofetal development; however, the doses used were too low to adequately assess the effects of modafinil on embryofetal
`
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`
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`development. In a subsequent developmental toxicity study evaluating doses of 45, 90, and 180 mg/kg/day in pregnant rabbits, the
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`incidences of fetal structural alterations and embryofetal death were increased at the highest dose. The highest no-effect dose for
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`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
`
`
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`of PROVIGIL. No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring.
`
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`Pregnancy Registry
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`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).
`
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`8.3 Nursing Mothers
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`It is not known whether modafinil or its metabolites are excreted in human milk. Because many drugs are excreted in human milk,
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`caution should be exercised when PROVIGIL is administered to a nursing woman.
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`8.4 Pediatric Use
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`Safety and effectiveness in pediatric patients have not been established. PROVIGIL is not approved in this population for any
`
`indication.
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`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)].
`
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`In a controlled 6-week study, 165 pediatric patients (aged 5-17 years) with narcolepsy were treated with modafinil (n=123), or placebo
`
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`(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
`
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`
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`older, treated with modafinil experienced dysmenorrhea compared to 0 of 10 girls who received placebo.
`
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`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
`
`
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`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
`
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`statistically significant differences favoring modafinil over placebo in reducing ADHD symptoms as measured by the ADHD-RS
`
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`(school version), there were 3 cases of serious rash including one case of possible SJS among 933 patients exposed to modafinil in this
`
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`program. Modafinil is not approved for use in treating ADHD.
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`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
`
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`incidence of adverse reactions similar to other age groups. In elderly patients, elimination of modafinil and its metabolites may be
`
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`
`
`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)].
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`Reference ID: 3685660
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`

`

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`DRUG ABUSE AND DEPENDENCE
`
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`8.6 Hepatic Impairment
`
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`In patients with severe hepatic impairment, the dose of PROVIGIL should be reduced to one-half of that recommended for patients
`
`
`with normal hepatic function [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
`
`
`9
`
`
`9.1 Controlled Substance
`
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`PROVIGIL contains modafinil, a Schedule IV controlled substance.
`
`
`9.2 Abuse
`
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`In humans, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of
`
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`
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`other CNS stimulants. In in vitro binding studies, modafinil binds to the dopamine reuptake site and causes an increase in
`
`
`
`extracellular dopamine,