DRUG INTERACTIONS

DRUG INTERACTIONS

Effects of PROVIGIL on CYP3A4/5 Substrates

The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by PROVIGIL via induction of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment of these drugs should be considered when these drugs are used concomitantly with PROVIGIL [see CLINICAL PHARMACOLOGY].

The effectiveness of steroidal contraceptives may be reduced when used with PROVIGIL and for one month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with PROVIGIL and for one month after discontinuation of PROVIGIL treatment.

Blood levels of cyclosporine may be reduced when used with PROVIGIL. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with PROVIGIL.

Effects of PROVIGIL on CYP2C19 Substrates

Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by PROVIGIL via inhibition of metabolic enzymes, with resultant higher systemic exposure. In individuals deficient in the CYP2D6 enzyme, the levels of CYP2D6 substrates which have ancillary routes of elimination through CYP2C19, such as tricyclic antidepressants and selective serotoninreuptake 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].

Warfarin

More frequent monitoring of prothrombin times/INR should be considered whenever PROVIGIL is coadministered with warfarin [see CLINICAL PHARMACOLOGY].

Monoamine Oxidase (MAO) Inhibitors

Caution should be used when concomitantly administering MAO inhibitors and PROVIGIL.

Drug Abuse And Dependence

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 vitro binding 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.

SIDE EFFECTS

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

  • Serious Rash, including Stevens-Johnson Syndrome [see WARNINGS AND PRECAUTIONS]
  • Angioedema and Anaphylaxis Reactions [see WARNINGS AND PRECAUTIONS]
  • Multi-organ Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
  • Persistent Sleepiness [see WARNINGS AND PRECAUTIONS]
  • Psychiatric Symptoms [see WARNINGS AND PRECAUTIONS]
  • Effects on Ability to Drive and Use Machinery [see WARNINGS AND PRECAUTIONS]
  • Cardiovascular Events [see WARNINGS AND PRECAUTIONS]

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.

About PROVIGIL

DESCRIPTION

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:

 

PROVIGIL® (modafinil) Structural Formula Illustration

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.

INDICATIONS

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.

DOSAGE AND ADMINISTRATION

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 and Clinical Studies].

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.

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 and CLINICAL PHARMACOLOGY].

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].

HOW SUPPLIED

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.

Storage And Handling

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. NDC 63459-101-30 – Bottles of 30

200 mg: Each capsule-shaped, white to off white, scored tablet is debossed with “PROVIGIL” on one side and “200 MG” on the other. NDC 63459-201-30 – Bottles of 30

Storage

Store at 20°-25°C (68°-77°F).