Provigil

Modafinil comes as a tablet to take by mouth. It is usually taken once a day with or without food. If you are taking modafinil to treat narcolepsy or OSAHS, you will probably take it in the morning. If you are taking modafinil to treat shift work sleep disorder, you will probably take it 1 hour before the beginning of your work shift. Take modafinil at the same time every day. Do not change the time of day that you take modafinil without talking to your doctor. Talk to your doctor if your work shift does not begin at the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take modafinil exactly as directed.

Modafinil may be habit-forming. Do not take a larger dose, take it more often, or take it for a longer period of time than prescribed by your doctor.

Modafinil may decrease your sleepiness, but it will not cure your sleep disorder. Continue to take modafinil even if you feel well-rested. Do not stop taking modafinil without talking to your doctor.

Modafinil should not be used in place of getting enough sleep. Follow your doctor's advice about good sleep habits. Continue to use any breathing devices or other treatments that your doctor has prescribed to treat your condition, especially if you have OSAHS.

Modafinil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• headache
• dizziness
• difficulty falling asleep or staying asleep
• drowsiness
• nausea
• diarrhea
• constipation
• gas
• heartburn
• loss of appetite
• unusual tastes
• dry mouth
• excessive thirst
• nosebleed
• flushing
• sweating
• tight muscles or difficulty moving
• back pain
• confusion
• uncontrollable shaking of a part of your body
• burning, tingling, or numbness of the skin
• difficulty seeing or eye pain

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• rash
• blisters
• peeling skin
• mouth sores
• hives
• itching
• hoarseness
• difficulty breathing or swallowing
• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• chest pain
• fast, pounding, or irregular heartbeat
• frenzied, abnormally excited mood
• hallucinating (seeing things or hearing voices that do not exist)
• anxiety
• depression
• thinking about killing or harming yourself

Modafinil may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include:

• difficulty falling asleep or staying asleep
• agitation
• restlessness
• confusion
• hallucinations (seeing things or hearing voices that do not exist)
• nervousness
• uncontrollable shaking of a part of the body
• fast, slow, or pounding heartbeat
• chest pain
• nausea
• diarrhea

Provigil is a prescription medicine used to improve wakefulness in adults who are very sleepy due to one of the following diagnosed sleep disorders:

• narcolepsy
• obstructive sleep apnea (OSA). Provigil is used with other medical treatments for this sleep disorder.
• shift work disorder (SWD)


This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Provigil may cause serious side effects. Stop taking Provigil and call your doctor right away or get emergency help if you get any of the following:

• a serious rash or serious allergic reaction
• psychiatric (mental) symptoms, including:
  • depression
  • feeling anxious
  • hearing, seeing, feeling, or sensing things that are not really there (hallucinations)
  • an extreme increase in activity and talking (mania)
  • thoughts of suicide aggressive behavior
  • other mental problems
• symptoms of a heart problem, including chest pain, abnormal heart beats, and trouble breathing

Common side effects include:

• back pain
• headache
• nausea
• feeling nervous
• stuffy nose
• diarrhea
• feeling anxious
• dizziness
• upset stomach
• trouble sleeping


Tell your doctor if you get any side effect that bothers you or that does not go away while taking. Some effects of Provigil on the brain are the same as other medicines called “stimulants”. These effects may lead to abuse or dependence on Provigil.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Provigil and many other medicines can interact with each other, sometimes causing side effects. Provigil may affect the way other medicines work, and other medicines may affect how Provigil works. Your dose of Provigil or certain other medicines may need to be changed. Especially, tell your doctor if you use or take a hormonal birth control method such as:

• birth control pills
• shots
• implant
• patches
• vaginal rings
• intrauterine devices (IUDs)

Hormonal birth control methods may not work while you take Provigil. Women who use one of these methods of birth control may have a higher chance for getting pregnant while taking Provigil. This risk lasts for one month after stopping Provigil. Talk to your doctor about birth control choices that are right for you while taking Provigil.

Talk with your doctor about what to do if you miss a dose of modafinil. Avoid taking the medicine if you do not plan to be awake for several hours. Skip the missed dose if it is almost bedtime. Do not take extra medicine to make up the missed dose.

Other drugs may interact with modafinil, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Absorption

Bioavailability

Rapidly absorbed from the GI tract after oral administration, with peak plasma concentrations attained within 2–4 hours.1 b Absolute oral bioavailability not determined due to low aqueous solubility.1 b

Food

Food may delay GI absorption by approximately 1 hour, but does not affect extent of absorption.1

Distribution

Extent

Well distributed into body tissues.1

Not known whether modafinil or its metabolites are distributed into milk.55

Plasma Protein Binding

Approximately 60% (mainly albumin).1

Elimination

Metabolism

Metabolized to inactive metabolites via hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation.1 b

Elimination Route

Excreted in urine (80%) and in feces (1%), mainly as metabolites.1

Half-life

Approximately 10–15 hours after multiple dosing.1 b

Special Populations

In patients with severe hepatic impairment and cirrhosis (Child-Pugh class B, B+, C, or C+), clearance of modafinil is decreased by about 60% and steady-state concentrations are doubled compared with healthy individuals.1

In patients with severe chronic renal impairment (Clcr ≤20 mL/minute), pharmacokinetics of modafinil are not substantially altered, but exposure to modafinil acid (an inactive metabolite) is increased ninefold compared with healthy individuals.1

In geriatric patients, clearance of modafinil and metabolites may be reduced.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.1 34 35

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. If too much is taken, it may become habit-forming.

This medicine comes with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

This medicine does not take the place of getting enough sleep. It should not be used for occasional sleepiness that has not been diagnosed as narcolepsy, sleep apnea, or shift work sleep problems. Ask your doctor for advice about good sleep habits.

If you have sleep apnea and use a continuous positive airway pressure (CPAP) machine at night, continue using this machine with modafinil.

Take this medicine at the same time each day. Do not change the time of day you take modafinil without talking first with your doctor.

You may take this medicine with or without food.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For narcolepsy or obstructive sleep apnea/hypopnea syndrome:
    • Adults and teenagers 17 years of age and older—200 milligrams (mg) once a day, in the morning. Your doctor may increase your dose as needed.
    • Teenagers and children younger than 17 years of age—Use and dose must be determined by your doctor.
  • For shift work sleep disorder:
    • Adults and teenagers 17 years of age and older—200 milligrams (mg) one hour before you begin working.
    • Teenagers and children younger than 17 years of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose of modafinil and you remember it before 12:00 noon the same day, take the missed dose as soon as possible.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

The following serious adverse reactions are described elsewhere in the labeling:

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.

Dose-Dependent Adverse Reactions

In the placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of Provigil and placebo, the following adverse reactions were dose related: headache and anxiety.

Adverse Reactions Resulting in Discontinuation of Treatment

In placebo-controlled clinical trials, 74 of the 934 patients (8%) who received Provigil discontinued due to an adverse reaction compared to 3% of patients that received placebo. The most frequent reasons for discontinuation that occurred at a higher rate for Provigil than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain, and nervousness (each <1%).

Laboratory Abnormalities

Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of Provigil, but not placebo. Few patients, however, had GGT or AP elevations outside of the normal range. Shifts to higher, but not clinically significantly abnormal, GGT and AP values appeared to increase with time in the population treated with Provigil in the placebo-controlled clinical trials. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin.

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 relationship to drug exposure.

Hematologic: agranulocytosis

Psychiatric disorders: psychomotor hyperactivity

Controlled Substance

Provigil contains modafinil, a Schedule IV controlled substance.

Abuse

In humans, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants. In in vitrobinding studies, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. In some studies, modafinil was also partially discriminated as stimulant-like. Physicians should follow patients closely, especially those with a history of drug and/or stimulant (e.g., methylphenidate, amphetamine, or cocaine) abuse. Patients should be observed for signs of misuse or abuse (e.g., incrementation of doses or drug-seeking behavior).

The abuse potential of modafinil (200, 400, and 800 mg) was assessed relative to methylphenidate (45 and 90 mg) in an inpatient study in individuals experienced with drugs of abuse. Results from this clinical study demonstrated that modafinil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate).

Dependence

In one placebo-controlled clinical trial, the effects of modafinil withdrawal were monitored following 9 weeks of modafinil use. There were no reported withdrawal symptoms with modafinil during 14 days of observation, although sleepiness returned in narcoleptic patients.

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 C15H15NO2S 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.

How Supplied

Provigil®(modafinil) tablets are available as follows:

100 mg: Each capsule-shaped, white to off white tablet is debossed with "Provigil"on one side and "100 MG" on the other.

Storage

Store at 20o‑ 25o C (68o‑ 77o F).

Applies to modafinil: oral tablet

Nervous system

Very common (10% or more): Headache (up to 34%)
Common (1% to 10%): Dizziness, paresthesia, somnolence, tremor, taste perversion, vertigo, oro-facial dyskinesia, hyperkinesia, hypertonia
Uncommon (0.1% to 1%): Amnesia, migraine, CNS stimulation, incoordination, movement disorder, speech disorder, hypoesthesia
Very rare (less than 0.01%): Tardive dyskinesia, convulsions
Frequency not reported: Cataplexy[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 11%)
Common (1% to 10%): Diarrhea, dry mouth, dyspepsia, constipation, flatulence, mouth ulceration, abdominal pain
Uncommon (0.1% to 1%): Reflux, vomiting, dysphagia, glossitis
Frequency not reported: Periodontal abscess[Ref]

General

The development of adverse reactions (skin and hypersensitivity, central nervous system [CNS], psychiatric, and cardiovascular) appear to be related to higher doses; cardiovascular and CNS reactions increase significantly after a total daily dose of more than 400 mg.[Ref]

Cardiovascular

Common (1% to 10%): Palpitations, chest pain, hypertension, tachycardia, vasodilation
Uncommon (0.1% to 1%): Extrasystoles, arrhythmia, bradycardia, hypotension, transient ischemic T-wave changes, abnormal ECG
Rare (less than 0.1%): Increased blood pressure
Very rare (less than 0.01%): Ischemic heart disease
Frequency not reported: Asystole[Ref]

Dermatologic

Common (1% to 10%): Sweating, herpes simplex
Uncommon (0.1% to 1%): Rash, acne, pruritus
Rare (less than 0.1%): Eczema
Frequency not reported: Ecchymosis, serious skin reactions (including Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, Drug Rash with Eosinophilia and Systemic Symptoms, erythema multiforme)[Ref]

Genitourinary

Common (1% to 10%): Urine abnormality, hematuria, pyuria
Uncommon (0.1% to 1%): Urinary frequency
Rare (less than 0.1%): Foul urine odor
Frequency not reported: Urinary tract infection[Ref]

Hematologic

Common (1% to 10%): Eosinophilia
Uncommon (0.1% to 1%): Leukopenia
Postmarketing reports: Agranulocytosis[Ref]

Hepatic

Common (1% to 10%): Increased gamma-glutamyltransferase, increased alkaline phosphatase, abnormal liver function, elevated liver enzymes, eosinophilia[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Allergic reaction (e.g., hayfever)
Very rare (less than 0.01%): Multi-organ hypersensitivity reactions, urticaria (hives), angioedema, anaphylaxis[Ref]

Metabolic

Common (1% to 10%): Anorexia, thirst, decreased appetite
Uncommon (0.1% to 1%): Hypercholesterolemia, hyperglycemia, diabetes mellitus, increased appetite, increased weight, decreased weight[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, neck rigidity
Uncommon (0.1% to 1%): Neck pain, myalgia, myasthenia, leg cramps, arthralgia, twitch, arthritis
Rare (less than 0.1%): Muscle weakness[Ref]

Ocular

Common (1% to 10%): Abnormal vision, blurred vision, amblyopia, eye pain
Uncommon (0.1% to 1%): Dry eye
Frequency not reported: Conjunctivitis[Ref]

Other

Common (1% to 10%): Chills, edema, asthenia, flu syndrome, thirst
Uncommon (0.1% to 1%): Peripheral edema, menstrual disorder
Rare (less than 0.1%): Tolerance, aggravated condition, malaise, fatigue
Frequency not reported: Infection, pain, accidental injury, fever, viral infection, tooth disorder, hypothermia, ear pain[Ref]

Psychiatric

Common (1% to 10%): Insomnia, anxiety, depression, agitation, nervousness, confusion, emotional lability, abnormal thinking, irritability
Uncommon (0.1% to 1%): Sleep disorder, decreased libido, hostility, depersonalization, personality disorder, abnormal dreams, aggression, suicidal ideation, psychomotor hyperactivity
Rare (less than 0.1%): Hallucinations, mania, psychosis, delusions, suicide attempt[Ref]

Respiratory

Common (1% to 10%): Rhinitis, pharyngitis, lung disorder, asthma, epistaxis
Uncommon (0.1% to 1%): Sinusitis, dyspnea, increased cough
Frequency not reported: Bronchitis[Ref]

Some side effects of Provigil may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.