Modafinil - Modalert Side Effects

Modafinil is a wakefulness-promoting agent (or eugeroic) used for treatment of disorders such as narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea. It has also seen widespread off-label use as a purported cognition-enhancing agent. In English-speaking countries it is sold under the brand names Alertec, Modavigil, and Provigil. In the United States modafinil is classified as a schedule IV controlled substance and restricted in availability and usage, due to concerns about possible addiction potential. In most other countries it is a prescription drug but not otherwise legally restricted.

The mechanism by which modafinil acts on the brain has been difficult to determine. It acts as a blocker of a type of molecule called the dopamine transporter, a mode of action shared with stimulants such as amphetamine and methylphenidate, but its influence is relatively weak and does not easily explain the observed effects of modafinil on wakefulness and cognition.

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Uses

Medical

Modafinil is a wakefulness-promoting agent (or eugeroic) used for treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea.

Because of the risk for development of skin or hypersensitivity reactions and neuropsychiatric disorders, the European Medicines Agency has recommended that new patient prescriptions should only be to treat sleepiness associated with narcolepsy.

Off-label use for fatigue

Modafinil has also found off-label use with the neurological fatigue reported by some with multiple sclerosis. In 2000, Cephalon conducted a study to evaluate modafinil as a potential treatment for MS-related fatigue. A group of 72 people with MS of varying degrees of severity tested two different doses of modafinil and an inactive placebo over nine weeks. Fatigue levels were self-evaluated on standardized scales. Participants taking a lower dose of modafinil reported feeling less fatigued and there was a statistically significant difference in fatigue scores for the lower dose versus the placebo. The higher dose of modafinil was not reported to be significantly more effective.

Modafinil is also used off-label to treat sedation and fatigue in many conditions, including depression, fibromyalgia, chronic fatigue syndrome, myotonic dystrophy, opioid-induced sleepiness, spastic cerebral palsy, and Parkinson's disease. Modafinil has been shown to improve excessive daytime somnolence and fatigue in primary biliary cirrhosis.

Military and astronauts

Militaries of several countries are known to have expressed interest in modafinil as an alternative to amphetamine--the drug traditionally employed in combat situations where troops face sleep deprivation, such as during lengthy missions. The French government indicated that the Foreign Legion used modafinil during certain covert operations. The United Kingdom's Ministry of Defence commissioned research into modafinil from QinetiQ and spent £300,000 on one investigation. In 2011, the Indian Air Force announced that modafinil was included in contingency plans.

In the United States military, modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses. As of November 2012, modafinil is the only drug approved by the Air Force as a "go pill" for fatigue management. The use of dextroamphetamine (a.k.a., Dexedrine) is no longer approved.

The Canadian Medical Association Journal also reports that modafinil is used by astronauts on long-term missions aboard the International Space Station. Modafinil is "available to crew to optimize performance while fatigued" and helps with the disruptions in circadian rhythms and with the reduced quality of sleep astronauts experience.

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Contraindications

There are no specific contraindications to modafinil other than an allergy to the drug, but literature distributed by Cephalon advises that it is important to consult a physician before using it, as problems may arise for people who are sensitive to constituents of the tablets, people with cirrhosis (which may impair the metabolism of the drug), and people with various cardiovascular problems.

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Side effects

Modafinil has been tested in numerous clinical trials, and the overall finding is that the incidence of adverse effects is low. According to documentation distributed by Teva Pharmaceuticals, one-third of participants in clinical trials reported experiencing headaches; 11% reported nausea; other negative side-effects such as nervousness, diarrhea, insomnia, anxiety, dizziness, and gastrointestinal problems were reported by less than 10% or participants.

Rare occurrences have been reported of more serious side effects, including severe skin rashes and other symptoms that are probably allergy-related. From the date of initial marketing, December 1998, to January 30, 2007, the United States FDA received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), SJS, TEN, and DRESS involving adult and pediatric patients. The FDA issued a relevant alert. In the same alert, the FDA also noted that angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experience. In 2007, the FDA ordered Cephalon to modify the Provigil leaflet in bold-face print of several serious and potentially fatal conditions attributed to modafinil use, including toxic epidermal necrolysis (TEN), DRESS syndrome, and Stevens-Johnson syndrome (SJS).

The long term safety and effectiveness of modafinil have not been determined.

Modafinil may have an adverse effect on hormonal contraceptives, lasting for a month after cessation of dosage.

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Overdose

In mice and rats, the median lethal dose (LD₅₀) of modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD₅₀ values reported for rats range from 1000-3400 mg/kg. Intravenous LD₅₀ for dogs is 300 mg/kg. Clinical trials on humans involving taking up to 1200 mg/day for 7-21 days and known incidents of acute one-time overdoses up to 4500 mg did not appear to cause life-threatening effects, although a number of adverse experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, and diarrhea. As of 2004, the FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs, including modafinil).

Addiction and dependence liabilities

The addiction and dependence liabilities of modafinil are very low. It shares biochemical mechanisms with addictive stimulant drugs, and some studies have reported it to have similar mood-elevating properties, although to a lesser degree. Also monkeys will self-administer it if they have previously been trained to self-administer cocaine. These and other observations caused the United States FDA to classify modafinil as a schedule IV controlled substance, a category for drugs with valid medical uses and low but significant addiction potential.

Psychological dependence upon modafinil has only been noted in case reports involving daily overdoses on modafinil for an extended period. Reported withdrawal symptoms include anhedonia, lethargy, anxiety, and insomnia.

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Pharmacology

Pharmacokinetics

Modafinil induces the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as inhibiting CYP2C9 and CYP2C19 in vitro. It may also induce P-glycoprotein (Pgp), which may affect drugs transported by Pgp, such as digoxin. The bioavailability of modafinil is greater than 80% of the administered dose. In vitro measurements indicate that 60% of modafinil is bound to plasma proteins at clinical concentrations of the drug. This percentage actually changes very little when the concentration is varied. C_max (peak levels) occurs approximately 2-3 hours after administration. Food slows absorption, but does not affect the total AUC(AUC - area under the curve - meaning, food may slow absorption, but the total amount of the chemical will be absorbed with or without food). Half-life is generally in the 10-12 hour range, subject to differences in CYP genotypes, liver function and renal function. It is metabolized in the liver, and its inactive metabolite is excreted in the urine. Urinary excretion of the unchanged drug ranges from 0% to as high as 18.7%, depending on various factors.

Modafinil's efficacy in improving vigor and well-being in sleep deprivation subjects is dependent on COMT status. Research suggests that individuals with the Val/Val genotype experience a great improvement in their cognitive function, while those with the Met/Met genotype experience very little improvement.

Pharmacodynamics

Despite extensive research into the interaction of modafinil with numerous neurotransmitter systems, its precise mechanism or mechanisms of action remain unclear. Modafinil elevates hypothalamic histamine levels. Modafinil seems to inhibit the reuptake action of the dopamine transporter, thus leading to an increase in extracellular and thus synaptic concentrations of dopamine.

The locus of the monoamine action of modafinil has also been the target of studies, identifying effects on dopamine in the striatum and, in particular, nucleus accumbens, norepinephrine in the hypothalamus and ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex.

Recently, modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology. Of the sites tested, it was found to significantly act only on the dopamine transporter (DAT), inhibiting the reuptake of dopamine with an IC₅₀ value of 4 ?M. Accordingly, it increases locomotor activity and extracellular dopamine concentrations in a manner similar to the selective dopamine reuptake inhibitor vanoxerine, and also blocks methamphetamine-induced dopamine release. As a result, it appears that modafinil exerts its effects by acting as a weak dopamine reuptake inhibitor, though it cannot be ruled out that other mechanisms may also be at play. On account of its action as a dopamine reuptake inhibitor and lack of abuse potential, modafinil was suggested as a treatment for methamphetamine addiction by the authors of the study.

The (R)-enantiomer of modafinil, known as armodafinil, has also recently been found to act as a D₂ receptor partial agonist, with a K_i of 16 nM, an intrinsic activity of 48%, and an EC₅₀ of 120 nM, in rat striatal tissue. The (S)-enantiomer is inactive with respect to the D₂ receptor (K_i > 10,000).

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Physical and chemical properties

Measurement in body fluids

Modafinil and/or its major metabolite, modafinilic acid, may be quantified in plasma, serum or urine to monitor dosage in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalized patients or to assist in the forensic investigation of a vehicular traffic violation. Instrumental techniques involving gas or liquid chromatography are usually employed for these purposes. As of 2011, it is not specifically tested for by common drug screens (except for anti-doping screens) and is unlikely to cause false positives for other chemically-unrelated drugs such as substituted amphetamines.

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History

Modafinil was originally developed in France by neurophysiologist and emeritus experimental medicine professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide, and has similar activity to the parent drug but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil.

In 1998, modafinil was approved by the U.S. Food and Drug Administration for the treatment of narcolepsy and in 2003 for shift work sleep disorder and obstructive sleep apnea/hypopnea even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil.

It was approved for use in the UK in December 2002. Modafinil is marketed in the US by Cephalon Inc., who originally leased the rights from Lafon, but eventually purchased the company in 2001.

Cephalon began to market the R-enantiomer armodafinil of modafinil in the U.S. in 2007. After protracted patent litigation and negotiations (see below), generic versions of modafinil became available in the U.S. in 2012.

Patent protection and antitrust litigation

U.S. Patent 4,927,855 was issued to Laboratoire L. Lafon on May 22, 1990, covering the chemical compound modafinil. After receiving an interim term extension of 1066 days and pediatric exclusivity of six months, it expired on October 22, 2010. On October 6, 1994, Cephalon filed an additional patent, covering modafinil in the form of particles of defined size. That patent, U.S. Patent 5,618,845 was issued on April 8, 1997, but was reissued in 2002 as RE 37,516, which surrendered the 5618845 patent. With pediatric exclusivity, this patent expired on April 6, 2015.

On December 24, 2002, anticipating the expiration of exclusive marketing rights, generic drug manufacturers Mylan, Teva, Barr, and Ranbaxy applied to the FDA to market a generic form of modafinil. At least one withdrew its application after early opposition by Cephalon based on the '516 patent. There is some question whether a particle size patent is sufficient protection against the manufacture of generics. Pertinent questions include whether modafinil may be modified or manufactured to avoid the granularities specified in the new Cephalon patent, and whether patenting particle size is invalid because particles of appropriate sizes are likely to be obvious to practitioners skilled in the art. However, under United States patent law, a patent is entitled to a legal presumption of validity, meaning that in order to invalidate the patent, much more than "pertinent questions" are required.

As of October 31, 2011, U.S. Reissue Patent No. RE 37,516 has been declared invalid and unenforceable. The District Court for the Eastern District of Pennsylvania ruled that RE 37,516 was invalid because it: (1) was on sale more than one year prior to the date of the application in violation of 35 U.S.C. section 102(b); (2) was actually invented by someone else (the French company Laboratoire L. Lafon); (3) was obvious at the time the invention was made to a person having ordinary skill in the art under 35 U.S.C. section 103(a); and (4) failed the written description requirement of 35 U.S.C. section 112. The patent was also found to be unenforceable due to Cephalon's inequitable conduct during patent prosecution.

Cephalon made an agreement with four major generics manufacturers Teva, Barr Pharmaceuticals, Ranbaxy Laboratories, and Watson Pharmaceuticals between 2005 and 2006 to delay sales of generic modafinil in the US until April 2012 by these companies in exchange for upfront and royalty payments. Litigation arising from these agreements is still pending including an FTC suit filed in April 2008. Apotex received regulatory approval in Canada despite a suit from Cephalon's marketing partner in Canada, Shire Pharmaceuticals. Cephalon has sued Apotex in the US to prevent it from releasing a genericized armodafinil (Nuvigil). Cephalon's 2011 attempt to merge with Teva was approved by the FTC under a number of conditions, including granting generic US rights to another company; ultimately, Par Pharmaceutical acquired the US modafinil rights as well as some others.

In the United Kingdom, Mylan Inc. received regulatory approval to sell generic modafinil produced by Orchid in January 2010; Cephalon sued to prevent sale, but lost the patent trial in November.

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Society and culture

Legal status

Modafinil is currently classified as a Schedule IV controlled substance under United States federal law; it is illegal to import by anyone other than a DEA-registered importer without a prescription. However, one may legally bring modafinil into the United States in person from a foreign country, provided that he or she has a prescription for it, and the drug is properly declared at the border crossing. U.S. residents are limited to 50 dosage units (i.e., pills). Under the US Food and Drug Act, drug companies are not allowed to market their drugs for off-label uses (conditions other than those officially approved by the FDA); Cephalon was reprimanded in 2002 by the FDA because its promotional materials were found to be "false, lacking in fair balance, or otherwise misleading". Cephalon pled guilty to a criminal violation and paid several fines, including $50 million and $425 million fines to the U.S. government in 2008.

The following countries do not classify modafinil as a controlled substance:

• Canada (not listed in the Controlled Drugs and Substances Act, but it is a Schedule F prescription drug, so it is subject to seizure by Canada Border Services Agency)
• Mexico (Not listed as a controlled substance, in the National Health Law)
• United Kingdom (not listed in the Misuse of Drugs Act and is available without legal restrictions by prescription)
• Australia (listed as a Schedule 4 prescription drug)
• In Germany the classification has been changed from controlled substance (BtM) to prescription drug (RP) effective March 1, 2008.
• In India, generic retailing as Modalert is available from Sun Pharmaceuticals; Indian firms are not required to respect patents filed before 1995.

Currently, use of modafinil is controversial in the sporting world, with high-profile cases attracting press coverage since several prominent American athletes have tested positive for the substance (see modafinil as a doping agent). Some athletes who were found to have used modafinil protested that the drug was not on the prohibited list at the time of their offenses. However, the World Anti-Doping Agency (WADA) maintains that it was related to already banned substances. The Agency added modafinil to its list of prohibited substances on August 3, 2004, ten days before the start of the 2004 Summer Olympics.

Brand names

Modafinil is sold under a wide variety of brand names worldwide, including:

• Alertec - Canada, Ecuador
• BravaMax - Egypt, Morocco
• Carim - El Salvador, Guatemala, Honduras, Colombia, Ecuador, Uruguay
• Provake - India (also Modalert, Modapro, Modafil, Modvigil, Modatec)
• Modasomil Austria, Switzerland
• Modvigil - Australia, New Zealand
• Modiodal - Mexico, Philippines, Spain, France, Denmark, Iceland, Greece, Cyprus, Netherlands, Portugal, Sweden, Norway, Turkey, Japan, Iran
• Modiwake - Turkey
• Provigil - Belgium, Ireland, Italy, South Korea, United Kingdom, United States, South Africa, Israel, Finland
• Resotyl - Chile (also Mentix, Alertex, Zalux)
• Stavigile - Brazil
• Vigia - Colombia
• Vigicer - Argentina
• Vigil - Germany

Doping agent

Modafinil has received some publicity in the past when several athletes (such as sprinter Kelli White in 2004, cyclist David Clinger and basketball player Diana Taurasi in 2010) were discovered allegedly using it as a performance-enhancing doping agent. (Taurasi and another player, Monique Coker, tested at the same lab, were later cleared.) It is not clear how widespread this practice is. The BALCO scandal brought to light an as-yet unsubstantiated (but widely published) account of Major League Baseball's all-time leading home-run hitter Barry Bonds' supplemental chemical regimen that included modafinil in addition to anabolic steroids and human growth hormone. Modafinil has been shown to prolong exercise time to exhaustion while performing at 85% of VO_2max and also reduces the perception of effort required to maintain this threshold. Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a prohibited stimulant (see Modafinil Legal Status).

Research

ADHD

Modafinil was shown to be an effective treatment for ADHD with a more favorable overall side effect profile to approved treatments in clinical trials, but those trials also produced non-fatal cases of Stevens-Johnson syndrome rashes. The U.S. Food and Drug Administration approval for attention deficit hyperactivity disorder (ADHD) in children was rejected in 2006 due to concerns about rashes. The label for modafinil says that the drug is not approved for use in children and recommends keeping the drug out of the reach of children.

Depersonalization disorder

Modafinil used alone has been reported to be effective in a subgroup of individuals with depersonalization disorder; the subgroup of people with depersonalization disorder most likely to respond are those who have attentional impairments, under-arousal, and hypersomnia. However, clinical trials have not been conducted. Dr. Evan Torch calls a combination of an SSRI and modafinil "the hidden pearl that can really help depersonalization disorder."

Psychiatric/neurodegenerative disorders

Other potentially effective, but unapproved uses include the treatment of depression, bipolar depression, opiate and cocaine dependence, Parkinson's disease, schizophrenia, and disease-related fatigue, as well as fatigue that is the side effect of another medication.

Modafinil may also be an effective and well-tolerated treatment in patients with seasonal affective disorder.

A randomized double-blind study of modafinil showed that normal healthy volunteers between the ages of 30-44 showed general improvement in alertness as well as mood. In the three-day study, counterbalanced, randomized, crossover, inpatient trial of modafinil 400 mg was administered as well as a placebo to the control group. The conclusion demonstrated that modafinil may have general mood-elevating effects in particular for the adjunctive use in treatment-resistant depression.

Cocaine addiction

Modafinil is under investigation as a possible method to treat cocaine dependence, for several reasons involving biochemical mechanisms of the two drugs, as well as the observation that clinical effects of modafinil are largely opposite to symptoms of cocaine withdrawal.

The pilot 8-week double-blind study of modafinil for cocaine dependence (2004) produced inconclusive results. The number of cocaine-positive urine samples was significantly lower in the modafinil group as compared to the placebo group in the middle of the trial, but by the end of the 8 weeks the difference stopped being significant. Even before the treatment began, the modafinil group had lower cocaine consumption further confounding the results. As compared to placebo, modafinil did not reduce cocaine craving or self-reported cocaine use, and the physicians ratings were only insignificantly better. Dan Umanoff, of the National Association for the Advancement and Advocacy of Addicts, criticized the authors of the study for leaving the negative results out of the discussion part and the abstract of the article.

A later double-blind study of modafinil in people seeking treatment for cocaine dependence found no statistically significant effect on the rate of change in percentage of cocaine non-use days, but noted a significant improvement in some secondary outcomes such as the maximum number of consecutive non-use days for cocaine.

Weight loss

Studies on modafinil (even those on healthy weight individuals) indicate that it has an appetite reducing/weight loss effect. All studies on modafinil in the Medline database that are for one month or longer which report weight changes find that modafinil users experience weight loss compared to placebo. In 2008, one small-scale study on individuals performing simulated shift work quantified the effect as an 18% decrease in total caloric intake on 200 mg/day, and a 38% decrease on 400 mg/day.

However, the prescribing information for Provigil notes that "There were no clinically significant differences in body weight change in patients treated with Provigil compared to placebo-treated patients in the placebo-controlled clinical trials."

In experimental studies, the appetite reducing effect of modafinil appears to be similar to that of substituted amphetamines, but, unlike substituted amphetamines, the dose of modafinil that is effective at decreasing food intake does not significantly increase heart rate. Also, an article published in the Annals of Clinical Psychiatry, presented the case of a 280-pound patient (BMI=35.52) who lost 40 pounds over the course of a year on modafinil (to 30.44 BMI). After three years, his weight stabilized at a 50-pound weight loss (29.59 BMI). The authors conclude that placebo controlled studies should be conducted on using modafinil as a weight loss agent. Conversely, a US patent (#6,455,588) on using modafinil as an appetite stimulating agent has been filed by Cephalon in 2000.

Delayed sleep phase syndrome

It is has been studied as a possible treatment for delayed sleep phase syndrome, which causes excessive daytime somnolence when the natural (delayed) diurnal rhythm is replaced by a socially determined earlier or forward shifted sleep schedule.

Cognitive enhancement

There is disagreement to whether the cognitive effects modafinil showed in healthy non-sleep-deprived people are sufficient to consider it to be a cognitive enhancer. The researchers agree that modafinil improves some aspects of working memory, such as digit span, digit manipulation and pattern recognition memory, but the results related to spatial memory, executive function and attention are equivocal. Some positive effects of modafinil may be limited to "lower-performing" individuals. One study found that modafinil restored normal levels of learning ability in methamphetamine addicts, but had no effect on non-addicts.

Post-chemotherapy cognitive impairment

Modafinil has been used off-label in trials with people with symptoms of post-chemotherapy cognitive impairment, also known as "chemobrain", but in 2011 it was found to be no better than placebo. As of 2011 there was no evidence to support using it to reduce fatigue in palliative care.

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