Modafinil

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Modafinil
Systematic (IUPAC) name
(±)-2-(benzhydrylsulfinyl)acetamide
Clinical data
Trade names Provigil
AHFS/Drugs.com monograph
MedlinePlus a602016
Pregnancy cat. B3 (AU) C (US)
Legal status Prescription Only (S4) (AU) ℞-only (CA) POM (UK) Schedule IV (US)
Routes Oral
Pharmacokinetic data
Bioavailability Not determined due to the aqueous insolubility
Protein binding 60%
Metabolism Hepatic, including CYP3A4 and other pathways
Half-life 12–15 hours
Excretion Urine (as metabolites)
Identifiers
CAS number 68693-11-8 YesY
ATC code N06BA07
PubChem CID 4236
DrugBank DB00745
ChemSpider 4088 YesY
UNII R3UK8X3U3D YesY
KEGG D01832 YesY
ChEMBL CHEMBL1373 YesY
Chemical data
Formula C15H15NO2S 
Mol. mass 273.35 g/mol
 YesY (what is this?)  (verify)

Modafinil is an analeptic drug. It is approved by the United States' Food and Drug Administration (FDA) for the treatment of narcolepsy, shift work sleep disorder[1][2] and excessive daytime sleepiness associated with obstructive sleep apnea.[3]

Contents

[edit] Pharmacology

Despite extensive research into the interaction of modafinil with a large number of neurotransmitter systems, a precise mechanism or set of mechanisms of action remains unclear.[4][5] It seems that modafinil, like other stimulants, increases the release of monoamines – specifically, the catecholamines norepinephrine and dopamine – from synaptic terminals. However, modafinil also elevates hypothalamic histamine levels,[6] leading some researchers to consider modafinil a "wakefulness promoting agent" rather than a classic amphetamine-like stimulant.[7] Evidence in this direction includes the effects of the co-administration of a dopamine antagonist, which is known to decrease the stimulant effect of amphetamine, but does not entirely negate the wakefulness-promoting actions of modafinil.

The locus of the monoamine action of modafinil has also been the target of studies, identifying effects on dopamine in the striatum and nucleus accumbens,[8][9] noradrenaline in the hypothalamus and ventrolateral preoptic nucleus,[10][11] and serotonin in the amygdala and frontal cortex.[12]

A considered mechanism of action involves brain peptides called orexins, also known as hypocretins. Orexin neurons are found in the hypothalamus but project to many different parts of the brain, including several areas that regulate wakefulness. Activation of these neurons increases dopamine and norepinephrine in these areas, and excites histaminergic tuberomammillary neurons increasinghistamine levels there. It has been shown in rats that modafinil increases histamine release in the brain, and this may be a possible mechanism of action in humans.[13] There are two receptors for hypocretins, namely hcrt1 and hcrt2. Animal studies have shown that animals with defective orexin systems show signs and symptoms similar to narcolepsy for which Modafinil is FDA approved. Modafinil seems to activate these orexin neurons in animal models, which would be expected to promote wakefulness.[14][15] However, a study of genetically modified dogs lacking orexin receptors showed that modafinil still promoted wakefulness in these animals, suggesting that orexin activation is not required for the effects of modafinil.[citation needed] Additionally, a study looking at orexin-knockout mice, found that not only modafinil promoted wakefulness in these mice but did so even more effectively than in the wild-type mice.[16]

Modafinil's substantial, but incomplete, independence from both monoaminergic systems and those of the orexin peptides has proven baffling with respect to the better understood mechanisms of stimulants such as cocaine. Alternative mechanisms of action that have been proposed include the activation of glutamatergic circuits while inhibiting GABAergic neurotransmission.[17][18] Enhanced electrotonic coupling by enhancing the effectiveness of direct gap junctions between neurons has also been suggested by several studies. Most neurons are separated by synapses, and communication between cells is accomplished via release and diffusion of neurotransmitters. However, some neurons are directly connected to one another via gap junctions, and it is proposed that modafinil influences the effectiveness of these connections. Urbano et al. determined that modafinil increased activity via this mechanism in the thalamocortical loop, which is critical in organizing sensory input and modulating global brain activity.[19] Administration of the gap junction blocker mefloquine abolished this effect, providing good evidence that this result was a consequence of improved electrical coupling. Further research by the same group also noted the capacity of the calmodulin kinase II (CaMKII) inhibitor, KN-93, to abolish modafinil's enhancement of electrotonic coupling. They came to the conclusion that modafinil's effect is mediated, at least in part, by a CaMKII-dependent exocytosis of gap junctions between GABAergicinterneurons and possibly even glutamatergic pyramidal cells. Additionally, Garcia-Rill et al. discovered that modafinil has pro electrotonic effects on specific populations of neurons in two sites in the reticular activating system. These sites, the subcoeruleus nucleus and thepedunculopontine nucleus, are thought to enhance arousal via cholinergic inputs to thethalamus.[20]

Looking more closely at electrotonic coupling, gap junctions permit the diffusion of current across linked cells and result in higher resistance to action potential induction since excitatory post-synaptic potentials must to diffuse across a greater membrane area. This means, however, that when action potentials do arise in coupled cell populations, the entire populations tend to fire in a synchronized manner.[21] Thus enhanced electrotonic coupling results in lower tonic activity of the coupled cells while increasing rhythmicity. Agreeing with data implicating catecholaminergic mechanisms, modafinil increases phasic activity in the locus coeruleus (the source for CNS norepinephrine) while reducing tonic activity with respect to interconnections with the prefrontal cortex.[22] This implies an increased signal-to-noise ratio in the circuits connecting the two regions. Greater neuronal coupling theoretically could enhance gamma band rhythmicity, a potential explanation for modafinil'snootropic effects.[23] Modafinil's beneficial effects on working memory and motor networks are suggestive of heightened gamma band activity.[23]

Direct links between electrotonic coupling and wakefulness were provided by Beck et al. who showed that administration of modafinil enhanced arousal-specific P13 evoked potentials in a gap-junction dependent manner.[24] Tying into inconclusive effects on monoamine systems, enhanced electrotonic coupling is thought to reduce activity in localized populations of GABAergic neurons whose normal function is to reduce neurotransmitter release in other cells.[21] For example, dopamine release in the nucleus accumbens has been demonstrated to be the result of decreased GABAergic tone.[25] Thus, while modafinil's unique stimulant profile features interactions with monoamine systems, these may very well be downstream events secondary to effects on specific, electrotonically-coupled populations of GABAergic interneurons. It is likely that modafinil's exact pharmacology will feature the interaction of direct effects on electrotonic coupling and various receptor-mediated events.

Recently, modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology.[26] Of the sites tested, it was found to significantly act only on the dopamine transporter (DAT), inhibiting the reuptake of dopamine with anIC50 value of 4 μM.[26] Accordingly, it produceslocomotor activity and extracellular dopamine concentrations in a manner similar to theselective dopamine reuptake inhibitor (DRI) vanoxerine, and also blocksmethamphetamine-induced dopamine release.[26] As a result, it appears that modafinil exerts its effects by acting as a weak DRI, though it cannot be ruled out that other mechanisms may also be at play.[26] On account of its action as a DRI and lack of abuse potential, modafinil was suggested as a treatment for methamphetamine addictionby the authors of the study.[26]

The (R)-enantiomer of modafinil has also recently been found to act as a D2receptor partial agonist, with a Ki of 16 nM, an intrinsic activity of 48%, and an EC50 of 120 nM, in rat striatal tissue.[27] The (S)-enantiomer is inactive (Ki > 10,000).[27]

[edit] Pharmacokinetics

Modafinil induces the cytochrome P450 enzymes CYP1A2, CYP2B6 andCYP3A4, as well as inhibiting CYP2C9 and CYP2C19 in vitro. It may also induceP-glycoprotein, which may affect drugs transported by Pgp, such as digoxin. Thebioavailability 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.[28] Cmax occurs approximately 2–3 hours after administration. Food slows absorption, but does not affect the total AUC. 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.[28]

[edit] Detection 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.[29][30] As of 2011, it is not specifically tested for by common drug screens (with the exception of anti-doping screens) and is unlikely to cause false positives for other chemically-unrelated drugs such as amphetamines.[31]

[edit] History

Modafinil was originally developed in France by neurophysiologist and emeritusexperimental medicine professor Michel Jouvet and Lafon Laboratories.[32] Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil. Adrafinil was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil and has similar activity 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. It was approved for use in the UK in December 2002. Modafinil is marketed in the US by Cephalon Inc., who leased the rights from Lafon. Cephalon eventually purchased Lafon in 2001.

[edit] Indications and off-label uses

[edit] Approved uses

In the United States, modafinil is approved by the U.S. Food and Drug Administration only for the treatment of narcolepsy, shift work sleep disorder, and as an adjunct treatment for obstructive sleep apnea/hypopnea.[33] In some countries, it is also approved for idiopathic hypersomnia (all forms of excessive daytime sleepiness where causes can't be established). The usual prescribed dosage for these disorders is 200 mg once a day (less commonly, 100 to 400 mg/day in one or two doses).

For conditions other than shift work sleep disorder, modafinil is normally taken in one dose in the morning or in two doses in the morning and at midday. It is generally not recommended to take modafinil after noon: modafinil is a relatively long-acting drug with a half-life of 15 hours, and taking it during the later part of the day carries a risk of sleep disturbances.[34][unreliable medical source?]

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.[35] Because any serious side effects will usually appear within the first twelve weeks, the guidance does not require patients already receiving treatment to stop taking the drug.[36]

[edit] ADHD

Modafinil was shown to be an effective treatment for attention deficit hyperactivity disorder(ADHD);[37] however, in 2006, it was found by the FDA to be unfit for use by children for that purpose. It was rejected primarily due to two cases of serious skin rash, suspected to have beenErythema multiforme or Stevens–Johnson syndrome, among 933 subjects receiving the drug.[38][39][40][41] Cephalon's own label for Provigil now discourages its use by children for any purpose.[37]


[edit] Mood disorders

Other potentially effective, but unapproved uses include the treatment of depression,[42] bipolar depression,[43][44] opiate[45] and cocaine dependence,[46] Parkinson's disease,[47] schizophrenia,[48] and disease-related fatigue,[49][50] as well as fatigue that is the side effect of another medication.[51] }

Modafinil may be also an effective and well-tolerated treatment in patients with seasonal affective disorder.[52]

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.[53]

[edit] Depersonalization disorder

Modafinil used alone has been reported to be effective in a subgroup of individuals with depersonalisation disorder; the subgroup of people with depersonalisation disorder most likely to respond are those who have attentional impairments, under-arousal and hypersomnia. However, clinical trials have not been conducted.[54] Dr. Evan Torch calls a combination of an SSRI and Modafinil "the hidden pearl that can really help depersonalization disorder".[55]

[edit] 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.[56][57][58] 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.[56][57][58][59] Some of the positive effects of modafinil may be limited to "lower-performing"[59] individuals or to individuals with lower IQ.[60] One study found that modafinil restored normal levels of learning ability in methamphetamine addicts, but had no effect on non-addicts.[61]

There is evidence of neuroprotective effects in rats.[62]

[edit] Fatigue

Modafinil is also used off-label to treat sedation and fatigue in many conditions, including depression,[63][64] fibromyalgia,chronic fatigue syndrome, myotonic dystrophy,[65] opioid-induced sleepiness,[66] spastic cerebral palsy,[67] andParkinson's disease.[68] Modafinil has been shown to improve excessive daytime somnolence and fatigue in primary biliary cirrhosis.[53] It 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.[69][70]

It has been known to help jet-lag[71] and increase subjective mood and friendliness among shift workers.[72] It has also been prescribed by some doctors for delayed sleep phase syndrome .

[edit] 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.[73] 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.[74][75]

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.[76]


[edit] 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".[77] A University of Rochester study of 68 subjects had significant results. "We knew from previous studies that modafinil does alleviate problems with memory and attention, and were hoping it would do the same for breast-cancer patients experiencing chemo-brain, which it did," related the study's lead author Sadhna Kohli, Ph.D, a research assistant professor at the University of Rochester's James P. Wilmot Cancer Center.[78]

[edit] Weight loss

Studies on modafinil (even those on healthy weight individuals) indicate that it has an appetite reducing/weight loss effect.[72][79][80][81][82] 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.[83] In 2008, one small-scale study on individuals performing simulated shift work quantified the effect as a 18% decrease in total caloric intake on 200 mg/day, and a 38% decrease on 400 mg/day.[84]

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." [85]

In experimental studies, the appetite reducing effect of modafinil appears to be similar to that of amphetamines, but, unlike 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.[79] Conversely, a US patent (#6,455,588) on using modafinil as an appetite stimulating agent has been filed by Cephalon in 2000.


[edit] Doping agent

Modafinil has received some publicity in the past when several athletes (such as sprinter Kelli White in 2004, cyclist David Clinger [86] and basketball player Diana Taurasi[87] 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.[88]) 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.[89] Modafinil has been shown to prolong exercise time to exhaustion while performing at 85% of VO2max and also reduces the perception of effort required to maintain this threshold.[90] Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a prohibited stimulant (see Modafinil Legal Status).


In the 1980s, modafinil was used by some French students.[91] Recently modafinil has become popular in performance-enhancing use by university students in the United Kingdom. Some students obtain the drug through illicit means (diversion of prescribed medication), whilst others obtain it through online pharmacies.[92]


[edit] Military and law enforcement

Militaries of several countries are known to have expressed interest in Modafinil as an alternative toamphetamines—the drug traditionally employed in combat situations where troops face sleep deprivation, such as during lengthy missions. The French government indicated that theForeign Legion used modafinil during certain covert operations. The United Kingdom's Ministry of Defence commissioned research into Modafinil[93] from QinetiQ and spent £300,000 on one investigation.[94] In 2011, the Indian Air Force announced that modafinil was included in contingency plans.[95] The Indian Armed Forces Medical Services is researching its use.

In the United States military, Modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses.[96] One study of helicopter pilots suggested that 600 mg of modafinil given in three doses can be used to keep pilots alert and maintain their accuracy at pre-deprivation levels for 40 hours without sleep.[97] However, significant levels of nausea and vertigo were observed. Another study of fighter pilots showed that modafinil given in three divided 100 mg doses sustained the flight control accuracy of sleep-deprived F-117pilots to within about 27 percent of baseline levels for 37 hours, without any considerable side effects.[98] In an 88-hour sleep loss study of simulated military grounds operations, 400 mg/day doses were mildly helpful at maintaining alertness and performance of subjects compared to placebo, but the researchers concluded that this dose was not high enough to compensate for most of the effects of complete sleep loss.[99] In law enforcement, tactical paramedics in Maryland (US) may administer 200 mg of modafinil once daily in order to "enhance alertness / concentration" and "facilitate functioning with limited rest periods."[100]


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.[101]

[edit] Contraindications and warnings

Literature distributed by maker Cephalon advises that it is important to consult with your physician before using Modafinil, particularly for those with:

  • Hypersensitivity to the drug or other constituents of the tablets (such as lactose or lactose monohydrate), or
  • Previous cardiovascular problems, particularly while using other stimulants, or
  • Cirrhosis, or should not be taken with alcohol, a recent study conducted showed slight euphoria, increased blood pressure, heart rate and some subjects also presented with mild to moderate effects mimicking amphetamines.
  • Cardiac conditions, particularly:
  • Modafinil can make certain types of birth control pills less effective, which could result in an unplanned pregnancy.

Modafinil in combination with Yohimbine causes a dangerous increase in heart rate and blood pressure.[102]

[edit] Side effects

Common side effects[103] of modafinil include:

  • Back pain
  • Headache
  • Nausea
  • Feeling nervous
  • Stuffy nose
  • Diarrhea
  • Feeling anxious
  • Dizziness
  • Upset stomach
  • Trouble sleeping

Serious side effects include:

  • Serious rash
  • Serious allergic reaction involving the liver or blood cells
  • Hives
  • Mouth sores
  • Blistering or peeling skin
  • Swelling of the face, eyes, lips, tongue, legs, or throat
  • Trouble swallowing or breathing
  • Fever
  • Shortness of breath
  • Yellowing of the skin or whites of the eyes
  • Dark urine

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 TEN, DRESS syndrome, and Stevens-Johnson Syndrome (SJS).

The long term safety and effectiveness of modafinil has not been determined.[104]

Modafinil may have an adverse effect on hormonal contraceptives, lasting for a month after cessation of dosage.[105]

[edit] Toxicity

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 mg/kg to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. Clinical trials on humans involving taking up to 1200 mg/day for 7 to 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.[106] As of 2004, FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs, including modafinil).[106] Consequently, oral LD50 of modafinil in humans is not known exactly. However, it appears to be higher than oral LD50 of caffeine. Bastuji and Jouvet (1988) describe a suicide attempt using 4500 mg of modafinil; the patient survived with no long-term effects but temporary nervousness, nausea, and insomnia.[107] A similar incident involving a suicide attempt by a 15 year old female using 5000 mg of the drug (102 mg/kg) was observed in 2008 in Israel; the patient experienced severe headache, nausea, abdominal pain, dyskinesia, insomnia, and mild tachycardia, but no cardiovascular distress or abnormalities in liver and kidney function, and recovered in a few days without any apparent long-term effects.[108]


Modafinil may induce severe dermatologic reactions requiring hospitalization. From the date of initial marketing, December 1998, to January 30, 2007, FDA received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (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.[109]


[edit] Addictive potential

A National Institute on Alcohol Abuse and Alcoholism (NIAAA) study highlighted "the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations" due to the drug's effect on dopamine in the brain's reward center.[110] However, the synergistic actions of modafinil on both catecholaminergic andhistaminergic pathways lower abuse potential as compared to traditional stimulant drugs while maintaining the effectiveness of the drug as a wakefulness promoting agent. Studies have suggested that modafinil "has limited potential for large-scale abuse"[111] and "does not possess an addictive potential in naive individuals."[112]


[edit] 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 was due to expire on April 6, 2015.[113][114]

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.[115] At least one withdrew its application after early opposition by Cephalon based on the '516 patent. There is some question as to 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.[116] 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.[117] The patent was also found to be unenforceable due to Cephalon's inequitable conduct during patent prosecution.[117]

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.[118] Litigation arising from these agreements is still pending including an FTC suit filed in April 2008.[119] Apotex received regulatory approval in Canada despite a suit from Cephalon's marketing partner in Canada, Shire Pharmaceuticals.[120][121] Cephalon has sued Apotex in the US to prevent it from releasing a genericized Nuvigil.[122] 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;[123] ultimately, Par Pharmaceutical acquired the US modafinil rights as well as some others.[124]

In England, 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.[125]

[edit] 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.[126] 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).[127] Note that Adrafinil, a drug that is closely related to Modafinil, is currently not classified as a controlled substance and therefore is not as severely regulated. 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);[128] Cephalon was reprimanded in 2002 by the FDA because its promotional materials were found to be "false, lacking in fair balance, or otherwise misleading".[129] 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.[130][131]

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

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.

[edit] Availability

Modafinil is sold under a wide variety of brand names world wide.

  • Alertec - Canada, Ecuador
  • Carim - Colombia, Ecuador, Honduras, Uruguay
  • Modalert - India (also Provake, Modapro, Modafil)
  • Modasomil Áustria, Switzerland
  • Modavigil - Australia, New Zealand
  • Modiodal - France, Denmark, Greece, Mexico, Netherlands, Portugal, Sweden, Turkey, Japan
  • Provigil - Belgium, Ireland, Italy, South Korea, United Kingdom, United States
  • Resotyl - Chile (also Mentix, Alertex, Zalux)
  • Stavigile - Brazil
  • Vigia - Colombia
  • Vigil - Germany

[edit] See also

Portal icon Pharmacy and Pharmacology portal

[edit] References

  1. ^ Erman MK, Rosenberg R, For The U S Modafinil Shift Work Sleep Disorder Study Group. "Modafinil for excessive sleepiness associated with chronic shift work sleep disorder: effects on patient functioning and health-related quality of life." Primary Care Companion to the Journal of Clinical Psychiatry 2007;9(3):188-94. Full Text
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