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6.18.2017 | Jennifer Bargeman

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

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. Modafinil induces the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as inhibiting CYP2C9 and CYP2C19 in vitro. Urinary excretion of the unchanged drug ranges from 0% to as high as 18.7%, depending on various factors. Half-life is generally in the 10–12 hour range, subject to differences in CYP genotypes, liver function and renal function. 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). 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. C max (peak levels) occurs approximay 2–3 hours after administration. It is metabolized in the liver, and its inactive metabolite is excreted in the urine.

Intravenous LD 50 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). In mice and rats, the median lethal dose (LD 50 ) of modafinil is approximay or slightly greater than 1250 mg/kg. Oral LD 50 values reported for rats range from 1000–3400 mg/kg.

In support of modafinil acting as a dopaminergic agent, its wakefulness-promoting effects are abolished in DAT knockout mice (although it is important to note that DAT knockout mice show D 1 and D 2 receptor and norepinephrine compensatory abnormalities, which might confound this finding), reduced by both D 1 and D 2 receptor antagonists (although conflicting reports exist), and compley blocked by simultaneous inactivation of both D 1 and D 2 receptors. Partial substitution was seen with the DRA dextroamphetamine and the D 2 receptor agonist PNU-91356A, as well as with nicotine (which indirectly elevates dopamine levels through activation of nicotinic acetylcholine receptors ). In any case, there is nonetheless a good deal of evidence to indicate that modafinil is producing at least a portion of its wakefulness-promoting effects by acting as a DRI, or at least via activation of the dopaminergic system. In accordance, modafinil shows full stimulus generalization to other DAT inhibitors including cocaine, methylphenidate, and vanoxerine, and discrimination is blocked by administration of both ecopipam (SCH-39166), a D 1 receptor antagonist, and haloperidol, a D 2 receptor antagonist.

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

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. At least one withdrew its application after early opposition by Cephalon based on the '516 patent. 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. There is some question whether a particle size patent is sufficient protection against the manufacture of generics.

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

Reagent testing can be used to screen for the presence of modafinil in samples.

Modafinil's efficacy in improving vigor and well-being in sleep deprivation subjects is dependent on catechol-O-methyl transferase (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 allele experience very little improvement.

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. Modafinil ( INN, USAN, BAN, JAN ) 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. In most other countries it is a prescription drug but not otherwise legally restricted. In some countries, for example Egypt, it is sold over the counter under the brand name Bravamax. It has also seen widespread off-label use as a purported cognition-enhancing agent.

For instance, modafinil produces wakefulness reportedly without the need for compensatory sleep, and shows a relatively low, if any, potential for abuse. Modafinil has been described as an "atypical" DAT inhibitor, and shows a profile of effects that is very different from those of other dopaminergic stimulants. Aside from modafinil, examples of other atypical DAT inhibitors include vanoxerine and benztropine, which have a relatively low abuse potential similarly to modafinil. These drugs appear to interact molecularly with the DAT in a distinct way relative to "conventional" DAT blockers such as cocaine and methylphenidate.

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. 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 was originally developed in France by neurophysiologist and emeritus experimental medicine professor Michel Jouvet and Lafon Laboratories.

In addition, modafinil fails to reverse reserpine -induced akinesia, whereas dextroamphetamine, a dopamine releasing agent (DRA), is able to do so. Moreover, one of the first published structure-activity relationship studies of modafinil found in 2012 that DAT inhibition did not correlate with wakefulness-promoting effects in animals among modafinil analogues, and a variety of analogues without any significant inhibition of the DAT still produced wakefulness-promoting effects. Furthermore, " neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory", and a study found that modafinil-induced increased locomotor activity in animals was dependent on histamine release and could be abolished by depletion of neuronal histamine, whereas those of methylphenidate were not and could not be. As such, although it is established that modafinil is a clinically significant DRI, its full pharmacology remains unclear and may be more complex than this single property (i.e., may also include DAT-independent actions, such as "activation of the orexin system"). Against the hypothesis that modafinil exerts its effects by acting as a DRI, tyrosine hydroxylase inhibitors (which deplete dopamine) fail to block the effects of modafinil in animals.

Monkeys will self-administer modafinil if they have previously been trained to self-administer cocaine. Although modafinil does not produce reinforcing effects in mice at doses that are equivalent to those used therapeutically in humans, it does do so at higher doses. As such, modafinil is classified by the United States FDA as a schedule IV controlled substance, a category for drugs with valid medical uses and low but significant addiction potential. 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. In accordance, although very rare, case reports of modafinil abuse exist. The addiction and dependence liabilities of modafinil are very low.

Modafinil and/or its major metabolite, modafinil 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. 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. Instrumental techniques involving gas or liquid chromatography are usually employed for these purposes.

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 SJS. In the same alert, the FDA also noted that angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experiences. From the date of initial marketing, December 1998, to January 30, 2007, the US Food and Drug Administration received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS syndrome, involving adult and pediatric patients. The FDA issued a relevant alert. Rare occurrences have been reported of more serious adverse effects, including severe skin rashes and other symptoms that are probably allergy-related.

If not monitored closely, reduced efficacy or withdrawal symptoms can occur. Coadministration with modafinil alongside opioids such as hydrocodone, oxycodone, and fentanyl, as well as various other drugs, may experience a drop in plasma concentrations. The reasoning behind this action is because modafinil is an inducer of the CYP3A4 enzymes.

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

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.

Modafinil has been shown to improve excessive daytime somnolence and fatigue in primary biliary cirrhosis. 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 found to directly inhibit the firing of midbrain dopaminergic neurons in the ventral tegmental area and substantia nigra of rats via activation of D 2 receptors. The ( S )-enantiomer is inactive with respect to the D 2 receptor. The ( R )-(−)- enantiomer of modafinil, known as armodafinil, was also subsequently found to act as a D 2 High receptor partial agonist, with a K i of 16 nM, an intrinsic activity of 48%, and an EC 50 of 120 nM, in rat striatal tissue.

Modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology. In addition to animal research, a human positron emission tomography (PET) imaging study found that 200 mg and 300 mg doses of modafinil resulted in DAT occupancy of 51.4% and 56.9%, respectively, which was described as "close to that of methylphenidate ". In accordance, modafinil increases locomotor activity and extracellular dopamine concentrations in animals in a manner similar to the selective DRI vanoxerine (GBR-12909), and also inhibits methamphetamine -induced dopamine release (a common property of DRIs, since DAT transport facilitates methamphetamine's access to its intracellular targets). Subsequently, it was determined that modafinil binds to the same site on the DAT as cocaine, but in a different manner. The locus of the monoamine action of modafinil was also the target of studies, with effects identified 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. As such, "modafinil is an exceptionally weak, but apparently very selective, inhibitor". Initially, the mechanism of action of modafinil was unknown. Another human PET imaging study similarly found that modafinil occupied the DAT and also determined that it significantly elevated extracellular levels of dopamine in the brain, including in the nucleus accumbens. Research found that modafinil elevates histamine levels in the hypothalamus in animals. Of the sites tested, it was found to significantly affect only the dopamine transporter (DAT), acting as a dopamine reuptake inhibitor (DRI) with an IC 50 value of 4 μM.

Allergy and hypersensitivity are the only contraindications of 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.

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.

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. The Canadian Medical Association Journal also reports that modafinil is used by astronauts on long-term missions aboard the International Space Station.

Patent 4,927,855 was issued to Laboratoire L. After receiving an interim term extension of 1066 days and pediatric exclusivity of six months, it expired on October 22, 2010. U.S. Lafon on May 22, 1990, covering the chemical compound modafinil. With pediatric exclusivity, this patent expired on April 6, 2015. 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.

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.

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 fewer than 10% of participants.

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

Large-scale clinical studies have found no evidence of tolerance with modafinil at therapeutic dosages even with prolonged use (for 40 weeks and as long as three years).

However, modafinil sulfone lacks any wakefulness-promoting effects in animals, indicating that a distinct mechanism may be at play in the anticonvulsant effects of both compounds. Modafinil may possess yet an additional mechanism of action. Both modafinil and its metabolite, modafinil sulfone, possess anticonvulsant properties in animals, and modafinil sulfone is nearly as potent as modafinil in producing this effect.

Modafinil may have an adverse effect on hormonal contraceptives for up to a month after discontinuation.

In 2011, the Indian Air Force announced that modafinil was included in contingency plans. The United Kingdom 's Ministry of Defence commissioned research into modafinil from QinetiQ and spent £300,000 on one investigation. The French government indicated that the Foreign Legion used modafinil during certain covert operations. 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.

However, modafinil sulfone does appear to possess anticonvulsant effects, and this is a property that it shares with modafinil. Both of these metabolites have been described as inactive, and neither appear to contribute to the wakefulness-promoting effects of modafinil. The two major circulating metabolites of modafinil are modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056).

Fatigue levels were self-evaluated on standardized scales. In 2000, Cephalon conducted a study to evaluate modafinil as a potential treatment for MS-related fatigue. Modafinil has also found off-label use with the neurological fatigue reported by some with multiple sclerosis. 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. The higher dose of modafinil was not reported to be significantly more effective. 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.

Although the mechanism of action of modafinil was initially unknown, it now appears that the drug acts as a selective, relatively weak, atypical dopamine reuptake inhibitor. However, it appears that other additional mechanisms may also be at play.

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. RE 37,516 has been declared invalid and unenforceable. Reissue Patent No. section 112. section 102(b); (2) was actually invented by someone else (the French company Laboratoire L. section 103(a); and (4) failed the written description requirement of 35 U.S.C. The patent was also found to be unenforceable due to Cephalon's inequitable conduct during patent prosecution. 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. As of October 31, 2011, U.S.