A Review of Modafinil (PROVIGIL) For Narcolepsy

A stimulant widely used to help people to stay awake — which has been shown to be only moderately effective and to cause life-threatening skin reactions — should not be used, except to treat a rare illness, narcolepsy.

The stimulant, modafinil (PROVIGIL), was approved by the Food and Drug Administration (FDA) in 1998 exclusively for the treatment of narcolepsy, a rare sleep disorder characterized by excessive daytime sleepiness. It belongs to the same drug family as amphetamines and methylphenidate (RITALIN).

The drug, also approved in 2004 to treat obstructive sleep apnea/hypopnea syndrome and shift work sleep disorder (see descriptions of these conditions in the box), has been one of the top 200 drugs prescribed in the U.S. for the past four years, with 2.5 million prescriptions filled in 2007.

Part of its boost into the top 200 drugs, given that it was only approved for the relatively rare medical condition of narcolepsy until 2004, can be attributed to the company’s clearly illegal promotion of the drug for a broad array of “problems” involving sleepiness. The illegal promotion, eventually stopped by the FDA in 2002, included recommending the drug for a broad series of unapproved uses including: “When patients complain of fatigue,” “tiredness,” “sleepiness,” “lack of energy,” or “decreased activity.” In addition, the ads claimed that modafinil was superior to other drugs despite the lack of any evidence of this.

The most recent data (2006-2007) from the FDA found that in adults more than 75 percent of the prescriptions were for off-label (unapproved) uses. The most common indication for which the drug was prescribed—even exceeding prescriptions for narcolepsy— was “malaise and fatigue,” one topic of manufacturer Cephalon’s illegal promotion campaign in 2002.

Sleepiness is a legitimate health concern; people who have excess sleepiness are prone to accidents, including falls, and heart problems. However, we urge our readers not to use modafinil unless it has been prescribed to control narcolepsy symptoms.

In 2004 Cephalon attempted to gain approval for the use of modafinil to treat attention deficit hyperactivity disorder (ADHD) but the FDA rejected the request in 2006 because of the concerns about serious skin toxicity in children. Still, almost half of the modafinil prescriptions for children from ages 6 to 17 from March 2004 through March 2007 were for ADHD, according to FDA data. The other half of prescriptions were also off-label because the drug is not approved for any use in children, having also been rejected for use in narcolepsy in children in 2006.

Modafinil belongs to the family of stimulants. It is approved to treat three specific conditions of unusual sleepiness:

• Narcolepsy: A rare neurologic condition of excessive sleepiness marked by a sudden recurrent uncontrollable compulsion to sleep. Narcolepsy is often associated with cataplexy (a sudden loss of muscle tone and paralysis of voluntary muscles associated with experiencing a strong emotion).
• Obstructive sleep apnea/ hypoapnea syndrome: The drug was approved only for use with positive airway pressure treatments, intended to overcome the obstruction, when that alone proves inadequate.
• Shift work sleep disorder: This consists of a constant or recurrent pattern of sleep interruption that results in insomnia or excessive sleepiness. This disorder is common in people who work non-traditional hours, usually between 10:00 p.m. and 6:00 a.m.

Drug has many amphetamine-like adverse effects

Cephalon states that modafinil’s wakefulness-promoting actions are similar to those of amphetamines and methylphenidate not “identical” to these drugs. However, evidence shows modafinil causes a statistically significant increase in hypertension, chest pain, insomnia, anxiety and a decrease in appetite, all of which are found with the amphetamines or amphetamine-like drugs such as methylphenidate.

Drug causes severe skin, psychological reactions

Although the most common side effect of modafinil is a headache, the drug can cause a variety of more serious reactions.

The drug’s maker, Cephalon, sent a warning letter to doctors in September 2007 and the FDA issued a warning in October 2007 concerning cases of life-threatening skin reactions such as Stevens- Johnson Syndrome and toxic epidermal necrolysis (TEN). The company’s warning letter to doctors states that “PROVIGIL can cause life-threatening skin and other serious hypersensitivity reactions… Although benign rashes also occur with modafinil, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, modafinil should ordinarily 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.”

The company admits, “The reporting 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.”

The FDA cites six reported cases of severe skin reactions associated with modafinil, including erythema multiforme (EM; a red, bumpy skin rash), Stevens-Johnson syndrome (a rare, severe form of EM), toxic epidermal necrolysis (the detachment of the top layer of skin from lower layers of skin, leading to severe skin sloughing) and drug rash with eosinophilia and systemic symptoms (DRESS; a severe drug reaction that sometimes involves high fever, rash and swelling of internal organs such as the liver, kidneys, lungs and/or heart). Three of these were in adults but three were in patients under 18. Five of the six cases required hospitalization for management.

Patients experienced rashes on either their arms, hands and legs, or the whole body with some experiencing eruptions in the mouth (lips or tongue), eyes or genitals. In addition, some patients developed skin pigment changes, itchiness, ulcers, burning of the skin, mild skin scaling, sloughing and/or fever.

The letter to doctors also warns about another sometimes lifethreatening allergic reaction known as angioedema (swelling of the skin): “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).”

Both the doctor’s letter and the FDA warning also notify the public about serious drug-associated psychiatric adverse events, including anxiety, mania, hallucinations and suicidal ideation.

Modafinil lowers tolerance to heat and may also increase blood pressure. In addition, modafinil may lower the levels of white blood cells in children.

Drug only moderately effective

The April 26, 2004, Medical Letter, commenting on the 2004 approvals for obstructive sleep apnea/hypopnea syndrome and shift work sleep disorder, stated that “The drug’s benefit appears to be modest … and its long-term safety is unclear.”

For one of the drug’s three approved uses, to treat people on shift work, the key study comparing modafinil to a placebo in such workers found that treated workers still experienced worrisome levels of sleepiness. The study was accompanied by an editorial in the New England Journal of Medicine stating that “workers would still be considered greatly impaired regarding vigilance and wakefulness during the nights they would need to remain awake and alert", and that “the current study does not adequately assess the clinical value of this particular drug in shift-work sleep disorder, nor does it justify writing more prescriptions for modafinil.”

Other concerns

Modafinil reduces the effectiveness of steroid contraceptives. Additional or alternate methods of birth control are advisable while taking modafinil and for one month after stopping modafinil.

Modafinil has caused fetal abnormalities in animals. Studies have not been done in pregnant women. Safety and effectiveness is not established in children under age 16 and the drug has not been studied in people over age 65.

Very tired people who take a stimulant, such as modafinil, may misinterpret the effect as improved cognitive ability. In pilots kept awake for 37 hours, while their performance with modafinil improved overall, it did not return to normal levels, and did not improve all flight maneuvers.

As discussed earlier, modafinil is widely used in conditions for which it is not approved (off-label uses) based on single reports, or small studies of short-duration, some with conflicting findings.

Comparisons have found 600 mg of caffeine to have similar effects to 600 mg of modafinil in people with sleep deprivation. Athletes should be aware that modafinil is listed as a banned drug by the World Anti- Doping Code.

What you can do

The primary treatment for sleepiness is basic: Get more sleep. Exercise also may temporarily improve alertness. Excess sleepiness can be due to other medical conditions, such as anemia, breathing problems, depression, and low blood sugar, or to drugs, such as central nervous system depressants. Modafinil does not cure any cause of excess sleepiness; it simply addresses the symptoms. Before starting use of this or any drug, be sure to examine and rule out all possible causes of the problem that can be controlled without drug therapy.

For obstructive sleep apnea, many people improve sleep with medical devices such as nasal masks for continuous positive airway pressure, or have surgery.