Side Effects of Provigil (modafinil)

Provigil (modafinil) is a stimulant used to promote wakefulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea (in addition to treatment of the underlying obstruction), and shift work sleep disorder. 

Like amphetamines, Provigil promotes wakefulness by stimulating the brain. The exact mechanism of action of Provigil is unknown. It may work by increasing the amount of dopamine (a chemical neurotransmitter that nerves use to communicate with each other) in the brain by reducing the reuptake of dopamine into nerves. 

Common side effects of Provigil include

• headache,
• upper respiratory tract infection,
• nausea,
• nervousness,
• anxiety, and
• insomnia.

Serious side effects of Provigil include

• fever,
• easy bruising or bleeding,
• hallucinations,
• depression,
• chest pain,
• fast/pounding/irregular heartbeat, and
• mental/mood changes (such as confusion, depression, hallucinations, rare thoughts of suicide).

Drug interactions of Provigil include cyclosporine, theophylline, and hormonal contraceptives such as progestin-only or estrogen and progesterone containing drugs because Provigil can decrease or increase the activity of enzymes in the liver that metabolize (eliminate) these drugs, which can result in decreased levels of some drugs that reduce their effectiveness, and increased levels of other drugs that lead to their toxicity. 

Drugs that may show increased effects or toxicity if taken with Provigil include

• warfarin,
• diazepam,
• propranolol,
• imipramine,
• desipramine,
• phenytoin, and
• mephenytoin.

Some other drugs that may increase the effectiveness and/or toxicity of Provigil include carbamazepine, phenobarbital, and rifampin. Ketoconazole and itraconazole may reduce the effectiveness of Provigil.

Methylphenidate may delay the action of Provigil. The effect of alcohol on Provigil has not been adequately evaluated. Alcohol probably should be avoided while taking Provigil. 

There are no adequate studies that assess the effects of Provigil in pregnant women. Intrauterine growth retardation and spontaneous abortion have been reported. 

It is unknown if Provigil is excreted in human breast milk. Consult your doctor before breastfeeding. 

The most common side effects of modafinil include:

• headache,
• upper respiratory tract infection,
• nausea,
• nervousness,
• anxiety, and
• insomnia.

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

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

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

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

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.

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

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

Effects of Provigil on CYP2C19 Substrates

Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by Provigil via inhibition of metabolic enzymes, with resultant higher systemic exposure.

In individuals deficient in the CYP2D6 enzyme, the levels of CYP2D6 substrates which have ancillary routes of elimination through CYP2C19, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, may be increased by co-administration of Provigil.

Dose adjustments of these drugs and other drugs that are substrates for CYP2C19 may be necessary when used concomitantly with Provigil.

Warfarin

More frequent monitoring of prothrombin times/INR should be considered whenever Provigil is coadministered with warfarin.

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.