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Modafinil Fact Pack – Draft 2/28/03
Fact Pack
MODAFINIL
Brand Name: PROVIGIL
Prepared by
Anneke Heitmann
Table of Contents
Summary
1) What is Modafinil ?
Introduction
Chemical Description
Main and Side Effects
2) Clinical Pharmacology (How Does it Work ?)
3) Studies
3.1) Clinical Studies in Patients Groups
Narcolepsy
Sleep Apnea
Parkinson’s Disease
Multiple Sclerosis
Attention Deficit Disorder
Other Clinical Conditions
3.2) Sleep Deprivation and Shiftwork Studies
Studies on Sustained Wakefulness
Shiftwork Studies
4) About Cephalon
General Information
Financial Information
Provigil Market – History and Ongoing Developments
5) Concerns
6) References
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Summary
Modafinil, marketed in the U.S. by Cephalon, Inc. under the brand name Provigil (short
for “promotes vigilance”), is the first drug in a new class of wakefulness-promoting
agents for oral administration, which improve daytime wakefulness, yet preserve the
ability to sleep at night. In Europe, modafinil has been used since at least 1988 to treat
narcolepsy and idiopathic hypersomnolence. Following two large, multicenter trials,
Provigil was approved by the FDA in the U.S. in December 1998 for the treatment of
narcolepsy. The use of the drug is rapidly expanding, with more than 80 percent of the
prescriptions written off-label to treat the fatigue and sleepiness associated with many
other diseases, like multiple sclerosis, sleep apnea, Parkinson’s disease and depression.
Modafinil’s effects are rapid (within 1-2 hours of taking the drug) and long-lasting (i.e.,
up to 15 hours). In controlled clinical trials, modafinil has been found to be generally
well tolerated with a low incidence of adverse events. The most common side effects of
modafinil in clinical trials are headache, nervousness, and nausea. No known risk of
dependence, withdrawal symptoms, or abuse of therapeutic doses exists.
The precise mechanism(s) through which modafinil promotes wakefulness is unknown.
Although modafinil promotes wakefulness, it doesn’t excite the entire nervous system
like other stimulants do. It is not chemically or pharmacologically related to
conventional, wakefulness-promoting stimulants of the central nervous system, such as
amphetamines or methylphenidate. Studies have suggested that modafinil increases
wakefulness by activating alpha-1 noradrenergic transmission or hypothalamic cells that
contain the peptid hypocretin (orexin), that it may work by modulating GABAergic tone,
or that it could involve an amplification of serotonin release mechanisms at the cortical
level. Modafinil seems to have none of the dopaminergic activity associated with
stimulants, but effects on the dopaminergic pathway cannot be exculded.
Clinical studies have demonstrated modafinil’s effectiveness for treating excessive
daytime sleepiness in narcolepsy, sleep apnea, Parkinson’s disease, multiple sclerosis,
and others medical conditions. It has also been shown to be effective for maintaining
alertness and performance in studies on sustained wakefulness and shiftwork. However,
one study indicated that modafinil had a disruptive effect on self-monitoring of
performance, inducing an “overconfidence” effect.
Provigil sales have been climbing steadily and 2002 Provigil sales of $196.3 million
(recommended dose cost about $4.80). Cephalon is seeking to expand the Provigil market
through extended FDA approval of Provigil beyond the treatment of narcolepsy. A
supplemental New Drug Application was filed with the FDA in December 2002 to
include the treatment of excessive sleepiness due to disorders of sleep and wakefulness.
There are several challenges regarding the broad approval of Provigil. In general, experts
are concerned because the long-term effects in healthy people are not sufficiently
investigated. Nor are all the potential interactions with other drugs or effects in special
medical conditions. Sleep experts fear that sleepiness symptoms in sleep disorder patients
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may be treated without evaluating the patient’s specific problem and deciding whether
existing therapies would be more appropriate, or that modafinil treatment may
compromise the patients’ compliance with the primary treatment methods of the actual
causes of a specific medical condition (e.g., using CPAP in sleep apnea patients). One of
the main target populations for expanded Provigil approval would be shiftworkers, as the
sleep and alertness problems resulting from their changing wake-rest patterns could be
diagnosed as Shiftwork Sleep Disorder. However, experts differ as to whether Shiftwork
Sleep Disorder is a real medical condition because it is clearly caused by lifestyle.
Similarly, as with clinical sleep disorders such as apnea, there is the concern that the
wide-spread use of modafinil among shiftworkers may compromise efforts to manage the
root causes of work-related fatigue.
Critics feel that the broader approval of Provigil could lead to its use being extended from
those with sleep disorders to healthy people who are simply sleep-deprived, and that there
would be little to stop the drug from becoming a new lifestyle drug for the 24/7
generation. Sleep is essential. It promotes growth, protects and preserves brain and
immune function, and many important hormones are active during sleep. Sleep
deprivation has been linked to changes in metabolic rate, endocrine functions and activity
of the sympathetic nervous system. Long-term sleep deprivation has been associated with
obesity and a significantly increased risk for heart disease.
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1) What is Modafinil ?
Introduction
Modafinil, marketed in the U.S. by Cephalon, Inc. under the brand name Provigil (short
for “promotes vigilance”), is the first drug in a new class of wakefulness-promoting
agents for oral administration, which improve daytime wakefulness, yet preserve the
ability to sleep at night. This makes modafinil a potentially important tool for treating
excessive diurnal somnolence (EDS) that can accompany sleep disorders such as
narcolepsy, sleep apnea, idiopathic hypersomnolence, and other medical conditions
characterized by poor sleep quality and/or quantity.
In Europe, modafinil has been used since at least 1988 to treat narcolepsy and idiopathic
hypersomnolence. Following two large, multicenter trials (5,6), Provigil was approved by
the FDA in the U.S. in December 1998 for the treatment of narcolepsy, a condition in
which people fall asleep uncontrollably. But the use of the drug is rapidly expanding,
with more than 80 percent of the prescriptions written off-label to treat the fatigue and
sleepiness associated with many other diseases, like multiple sclerosis, sleep apnea,
Parkinson’s disease and depression. In addition to clinical applications, modafinil is
showing signs of becoming a new lifestyle drug for a sleep-deprived 24/7 society.
Chemical Description
The chemical name for modafinil is 2-[(diphenylmethyl)sulfinyl]acetamide. The
molecular formula is C15H15NO2S and the molecular weight is 273.36.
The chemical structure is:
Modafinil is a white to off-white, crystalline powder that is practically insoluble in water
and cyclohexane. It is sparingly to slightly soluble in methanol and acetone. Provigil
tablets contain 100 mg or 200 mg of modafinil and the following inactive ingredients:
lactose, corn starch, magnesium silicate, croscarmellose sodium, povidone, magnesium
stearate, and talc.
Main and Side Effects
Modafinil is a stimulant. It improves alertness and cognitive functions. Modafinil’s
effects are rapid (within 1-2 hours of taking the drug (60)) and long-lasting (i.e., up to 15
hours). It apparently doesn’t interfere with subsequent sleep at therapeutic doses (i.e.,
100-200 mg), even when administered at bedtime (3,16,48). However, some studies
reported insomnia at very high doses (47).
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In controlled clinical trials, modafinil has been found to be generally well tolerated with a
low incidence of adverse events.
Modafinil has several major clinical advantages over other wakefulness-promoting drugs:
- None of the serious adverse CNS effects associated with methylphenidate and
amphetamine (tachycardia, hypertension, dizziness, buzz, jitterness, insomnia, and
psychotic episodes) are seen. The most common side effects of modafinil in clinical
trials are headache (13%), nervousness (8%), and nausea (5%) (34).
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So far, no serious drug interactions are known, and there are no required dietary
restrictions. For example, some studies investigated the potential for a pharmacokinetic
drug-drug interaction between modafinil and other drugs commonly used in narcolepsy
treatment. The administration of low-dose dextroamphetamine (18) and
methylphenidate (RITALIN) (19) does not appear to alter the steady-state
pharmacokinetics of modafinil in healthy volunteers.
- No known risk of dependence, withdrawal symptoms, or abuse of therapeutic doses
exists (23,31,34,46)
- No rebound sleepiness has been observed (30).
Modafinil has a hyperthermic effect (i.e. elevates core body temperature) (28,32) with
temperature increase of 0.15-0.2 degrees. This could have implications on heat tolerance.
However, one study concluded that it is not very clear if the hyperthermic effect with
modafinil may actually result from sleep deprivation alone (27).
Modafinil appears safe, though its long-term effects remain unknown. Such long-term
effects may for example include risks associated with chronic sleep loss if used to
substitute sleep (see Section 5 - Concerns) Also not known are all the potential
interactions with other drugs, or effects in special medical conditions (for example, a case
study reported the exacerbation of schizophrenia while taking modafinil (37).
2) Clinical Pharmacology (How Does it Work ? )
Modafinil taken orally is well absorbed, with peak plasma concentrations occurring
within 2-4 hours of administration (35,68). Apparent steady-state plasma concentrations
of modafinil are attained after 2 to 4 days of treatment (35). The terminal half-life for
elimination from plasma is approximately 10-15 hours (35,68). One study (69) found age
and gender effects on modafinil clearance processes. In this study, the clearance rate of
modafinil in males decreased with age while young females cleared modafinil at a faster
rate than young males.
The precise mechanism(s) through which modafinil promotes wakefulness is unknown.
Although modafinil promotes wakefulness, it doesn’t excite the entire nervous system
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like other stimulants do. It is not chemically or pharmacologically related to
conventional, wakefulness-promoting stimulants of the central nervous system, such as
amphetamines or methylphenidate to which patients are tolerance-prone, and it is listed
as a schedule-IV substance having a relatively low potential for abuse. It is very sitespecific, acting in different brain regions (the hypothalamus and the subcortical areas
involved in the regulation of waking and sleep) than other stimulants (30).
Studies have suggested that modafinil increases wakefulness by activating alpha-1
noradrenergic transmission (11,24,29) or hypothalamic cells that contain the peptid
hypocretin (orexin) (8,44), that it may work by modulating GABAergic tone (12,13,14),
or that it could involve an amplification of serotonin release mechanisms at the cortical
level (57,58). Modafinil seems to have none of the dopaminergic activity associated with
stimulants (30), but effects on the dopaminergic pathway cannot be exculded (67).
3)
Studies
3.1) Clinical Studies in Patients Groups
Narcolepsy
Narcolepsy affects 0.02-0.05% of the U.S. population and 5% of sleep-center patients
(54,62). Narcolepsy is a life-long neurological disorder characterized by excessive
daytime sleepiness, cataplexy, sleep paralysis and hypnagogic halucinations. The cause
of narcolepsy is not fully known. Narcolepsy is a complex disorder, involving genetic,
immune and environmental factors. Patients with narcolepsy have a higher prevalence of
a specific gene type (HLA DQB1*0602 gene) than the general population, however, the
presence of this subtype is not necessary, or specific for the diagnosis of narcolepsy.
Other genetic susceptibility factors may be involved. For example, the functional
polymorphism of the gene for catechol-O-methyltransferase (COMT), which plays a key
modulatory role in the dopaminergic and noradrenergic neurotransmission, is critically
involved in the severity of narcolepsy (and the response to the stimulant modafinil)
(9,56). Some investigators now believe that narcolepsy is caused by an autoimmune
disorder or triggered by an unknown environmental exposure or event. An exciting recent
discovery is hypocretin/orexin (peptide family), which may be the neurotransmitter
primarily implicated as the cause of narcolepsy (30,39). Most narcoleptics seem to have a
dysfunctional hypocretin/orexin system (21,41,51,61).
Excessive daytime sleepiness is the toughest problem for many narcoleptics. Available
treatment of narcolepsy includes stimulants and antidepressants, but recent discovery of
orexin/hypocretin deficiency in narcolepsy opens up new perspectives. Other
pharmacogenetic targets include the orexinergic, noradrenergic and possibly serotonergic
pathways (56). Modafinil, despite its relatively recent development, is now a first-line
treatment in the most recent (2000) update of the American Academy of Sleep
Medicine’s narcolepsy practice parameters (54).
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The efficacy of modafinil has been studied in two large US trials (64,65) which were
placebo-controlled, double-blinded and randomized with parallel groups. A total of 554
patients in 39 sleep centers received either 200 mg or 400 mg of modafinil or placebo for
9 weeks. Modafinil improved wakefulness by 50-70%, as measured by three
standardized, validated sleepiness tests: the Multiple Sleep-Latency Test (MSLT) and the
Maintenance of Wakefulness Test (MWT), which objectively measured the ability to fall
asleep or remain awake, respectively, and the Epworth Sleepiness Scale (ESS), a selfrating measure of sleepiness. A 40-week extension of these two studies assessed the
longterm efficacy of modafinil (34). About half of the subjects with moderate-to-severe
narcolepsy reported near-normal ESS scores after 40 weeks of modafinil therapy. The
most common treatment-related adverse events were headache (13%), nervousness (8%),
and nausea (5%).
A French long-term follow-up study in 104 narcoleptic patients found good or excellent
modafinil effects in 64% of the subjects after a mean treatment duration of 22 months
(range 1-114 months). Dependency signs were never observed (5). Similarly, a Canadian
study found that modafinil continued to be effective and well tolerated after 16 weeks of
treatment (36).
Sleep Apnea
Excessive daytime sleepiness is a standard symptom of sleep-disordered breathing. Nasal
continuous positive airway pressure (CPAP), the treatment of choice for obstructive sleep
apnea, can effectively eliminate excessive daytime sleepiness, along with apnea episodes
and their cardiovascular consequences. In some cases, however, significant excessive
daytime sleepiness remains, for reasons still not understood. Conventional CNS
stimulants are not ideal for treating excessive daytime sleepiness in sleep apnea because
of their interference with sleep and the danger of cardiovascular events in this at-risk
population.
Two recent studies (25,40) have looked at the effectiveness of modafinil in treating
residual excessive daytime sleepiness in sleep apnea. One study (25), using a
randomized, double-blind, placebo controlled crossover design, with 44 CPAP patients
who took 400 mg of modafinil or placebo found significant improvements in alertness
(MWT), but no effects on sleepiness (MSLT) or ESS, and no effects on cognitive
function or quality of life. While these modest results may reflect the small sample size or
the limitations of the measures, the investigators wondered whether the benefits of
modafinil were worth its side effects (reported by 74% of their subjects).
Another study of 157 CPAP patients (40) concluded that modafinil appears to be useful
for compliant CPAP users who display residual excessive daytime sleepiness. The ESS
score returned to normal in more than half of the CPAP patients taking modafinil,
compared to one quarter of those taking placebo.
The two studies also raised concerns: Continued compliance with CPAP should be
monitored as some patients conclude that improved alertness means they are cured of the
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primary disorder, sleep apnea. Also, modafinil should never be prescribed as primary
treatment for sleep apnea, because it has no effect on apnea, oxygen saturation, arousal,
and cardiovascular risks.
Parkinson’s Disease
As in narcolepsy, dopamine imbalance is implicated in Parkinson disease. Thus, several
small group and case studies (17,20,38,43) have begun assessing the effectiveness of
modafinil in improving excessive daytime sleepiness in Parkinson’s disease. Preliminary
results showing diminished sleepiness and no adverse effects on motor activity are
promising.
Multiple Sclerosis
A recent two-center study (44) concluded that modafinil was safe and effective in treating
debilitating fatigue in multiple sclerosis. The 9-week, single-blind, placebo-controlled
study of 72 patients found that 200 mg per day produced significant improvement in selfrated fatigue and ESS scores and no serious adverse events were found. The most
common adverse events were headache, nausea and aesthenia. Another study (70) of 50
patients with multiple sclerosis also found significant improvements in fatigue and
sleepiness at the same daily modafinil dose, however not at the higher test dose of 400
mg. The mechanisms underlying fatigue in multiple sclerosis are not yet fully understood.
Multiple sclerosis shows some similarities with narcolepsy at least in terms of the HLA
association. But there is evidence suggesting additional mechanisms which may be
responsible for the differences in doses required (70).
Attention Deficit Disorder
Modafinil has shown promise in several small, preliminary studies (45,59) of adults and
children 5-15 years old who have attention deficit hyperactivity disorder (ADHS). For
children, modafinil has the important advantage of being a once-daily medication with a
long duration.
A recent study on modafinil’s cognitive enhancing effects in healthy volunteers (63)
indicated that modafinil selectively improved neuropsychological task performance. The
improved performance may be attributable to an enhanced ability to inhibit pre-potent
responses. This effect appears to reduce impulsive responding, suggesting that modafinil
may be of benefit in the treatment of ADHS.
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Other Clinical Conditions
Researchers have been studying modafinil also for other than the above main conditions,
including depression (33), fibromyalgia (50), and spastic cerebral palsy (22).
3.2) Sleep Deprivation and Shiftwork Studies
Studies on Sustained Wakefulness
A small double-blind, placebo-controlled study investigated the effects of profilactic
doses of modafinil for sustaining alertness and performance of six pilots in a helicopter
simulation experiment (7). The pilots were exposed to two 40-hour periods of continuous
wakefulness, and were each given three 200-mg doses of modafinil in one of the two
experiments. Modafinil attenuated sleep deprivation effects on flight performance and
alertness (EEG delta activity and self-reported mood and alertness), particularly between
0330 and 1130 hours, when the combined impact of sleep loss and the circadian trough
was most severe. The most severe side effects were vertigo, nausea and dizziness, which
may have been related to the motion-based testing, “simulator sickness”, and the high
total doses of modafinil.
A French double-blind, placebo controlled study (8 subjects) (4), simulating a long-range
attack mission, found positive effects of modafinil (200 mg) on cognitive performance
during long sleep deprivation periods. The waking and stimulating properties of
modafinil were already demonstrated by the same researchers in an earlier study with 60
hours of sleep deprivation (26). No side effects were reported.
A larger study (41 military subjects) compared the effects of modafinil (300 mg), damphetamine (20 mg) and placebo during 64 hours of sustained mental work (42).
Subjective estimates of mood, fatigue and sleepiness, as well as objective measures of
reaction time, logical reasoning, and short-term memory clearly showed better
performance with both modafinil and amphetamine relative to placebo. According to
subjective reports, modafinil elicited fewer side effects than amphetamine, although more
than the placebo group. The researchers concluded that modafinil appears to be a good
alternative to amphetamine for counteracting the debilitating mood and cognitive effects
of sleep loss during sustained operations.
Sleep data from two recovery nights following the 64-hour period of wakefulness showed
that, in contrary to amphetamine, modafinil did not interfere with sleep efficiency with
sleep patterns close to the placebo group, and decreased the need for a long recovery
sleep usually taken to compensate for lost sleep due to total sleep deprivation (6).
Interestingly, data from the same study on the subjects’ self-monitoring of performance
showed that modafinil had a disruptive effect on self-monitoring, inducing an
“overconfidence” effect (i.e. an overestimation of actual cognitive performance), which
was particularly marked 2-4 hours post-dose (2). Consequently, the researchers
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encouraged more comprehensive understanding of the subjective and performanceenhancing effects before the drug is recommended as a viable fatigue countermeasure.
A very recent placebo-controlled study compared modafinil (200 and 400 mg) versus
caffeine (600 mg) in an extended wakefulness study (54.5 hours) with 50 young adults
(66). Performance and alertness were significantly improved by modafinil relative to
placebo, and effects were comparable to those obtained with caffeine. A slight, nonsignificant trend towards better performance at higher modafinil doses suggested a dosedependent effect. Performance-enhancing effects were especially salient during the
circadian nadir (0600-1000 hours) when the combined effects of sleep loss and the
circadian through were most manifest. Overall, the researchers concluded that modafinil
does not appear to offer advantages over caffeine (which is readily available and less
expensive) for improving performance and alertness during sleep deprivation.
Shiftwork Studies
Shiftworkers often experience sleep and alertness problems due to their changing workrest patterns. The related symptoms can be diagnosed as Shiftwork Sleep Disorder.
According to the International Classification of Sleep Disorders (ICSD), shiftwork sleep
disorder (ICSD 307.45.1) is classified as a circadian rhythm disorder. It consists of
symptoms of insomnia or excessive sleepiness that occur in relation to work scheduled
during habitual hours of sleep. Excessive sleepiness usually occurs during shifts (mainly
nights) and is associated with the propensity to fall asleep and impaired mental ability
because of reduced alertness.
A 12-week, randomized, double-blind, placebo-controlled study included 209 people
with a diagnosis of shiftwork sleep disorder randomized to either 200 mg modafinil or
placebo (10). Participants in the study received modafinil or placebo as a single dose
prior to the start of their night shift. The study showed that modafinil significantly
improved wakefulness compared to placebo, as measured by the Multiple Sleep Latency
Test (MSLT), an objective measure of sleepiness (p<0.01). In addition, the modafinil
group showed significant improvement in their clinical condition as measured by the
Clinical Global Impression of Change (CGI-C) (p<0.0001).
4) About Cephalon
General Information
Founded in 1987, Cephalon, Inc. (West Chester, PA), is an international
biopharmaceutical company dedicated to the discovery, development and marketing of
innovative products to treat sleep and neurological disorders, cancer and pain.
Chairman and CEO of Cephalon is Frank Baldino, Jr., Ph.D. Senior Vice President of
Clinical Research and Regulatory Affairs is Paul Blake, MB, FRCP.
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Cephalon employs 1,200 people in the United States and Europe (400 in Pennsylvania).
Cephalon’s major European offices are located in Guildford, England, and at Laboratoire
L. Lafon in Maisons-Alfort, France.
The company currently markets three major proprietary products in the United States:
Provigil(R) (modafinil) Tablets [C-IV] – a drug for excessive sleepiness,
Gabitril(R) (tiagabine hydrochloride) – an anti-seizure drug, and
Actiq(R) (oral transmucosal fentanyl citrate) [C-II] – a medicine for cancer pain,
and more than 20 products internationally.
Financial Information (Nasdaq: CEPH)
The most recent financial information, the 2002 fourth quarter earnings, was released on
2/19/03. The total reported fourth quarter revenue was $144.3 million with product sales
of $139.0 million. Sales of Provigil, Actiq and Gabitril were $54.8 million, $43.9 million,
and $15.1 million, respectively.
For the entire year 2002, less than four years after the launch of its first product, total
revenue was 506.9 million, with product sales of 465.9 million. Sales of PROVIGIL
(recommended dose cost about $4.80 (30)) were $196.3 million, sales of ACTIQ were
$126.7 million and sales of GABITRIL were $48.8 million. These represent sales
increases over 2001 of 31 percent, 148 percent, and 98 percent, respectively.
Year
Provigil Sales
Total Product Sales
2000
$ 72 million
$ 91.6 million
2001
$ 150 million
$ 226.1 million
2002
$ 196.3 million
2003 (anticipated)
$ 300-315 million
$ 506.9
million
$ 650-660 million
Cephalon’s Provigil Sales and Total Product Sales (2000-2003)
Rising sales of Provigil and Cephalon’s two other main drugs have made Cephalon one
of the fastest growing biotechnology companies and one of the few profitable ones.
Cephalon ranks 12th in the market capitalization value among biotechnology companies
worldwide, according to Ernst & Young (December 2002).
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Cephalon Stock (Past Five Years)
Provigil Market – History and Ongoing Developments
Cephalon licensed Provigil in 1993 from a small French company, LAFON, for $6
million over 6 years, plus royalties. Provigil, Cephalon’s primary product, was approved
by the FDA in December 1998, to treat excessive daytime sleepiness due to narcolepsy.
Narcolepsy is a chronic, lifelong sleep disorder that affects approximately 200,000 people
in the U.S. In February 1999, Cephalon began marketing Provigil in the U.S. with its own
sales force. Worldwide, modafinil is approved in more than 20 countries for the treatment
of excessive daytime sleepiness associated with narcolepsy. In January 2002, Cephalon
acquired Group Lafon for $450 million to gain full control of the drug.
Lafon is responsible for sales of modafinil in France (French trade name: modiodal), and
also sells several other drugs in the French pharmaceutical market. In the U.K., the
company has a marketing agreement with Novartis, whereby Cephalon markets Provigil
and four Novartis drugs (including all versions of Ritalin), with the two concerns sharing
the profits.
In October 2002, marketing approval for modafinil was granted in Australia and New
Zealand (trade name: Modavigil; Cephalon licencee: CSL Limited), and the Republic of
Korea (trade name: Provigil; Cephalon licencee: Choonwae Pharma Corporation) for the
treatment of excessive sleepiness associated with narcolepsy. Launch of the products in
these markets is expected to occur within 6 months.
In December 2002, Cephalon Gained approval in the U.K. for extending modafinil use
(U.K. trade name: Provigil) to treat excessive daytime sleepiness in patients with
obstructive sleep apnea/hypopnea syndrome. At the same time, the higher dose 200-mg
tablet of Provigil was also approved, in addition to the 100-mg dosage currently available
in this territory. The U.K. approval sets the stage for regulatory submissions in other
European countries over the next year.
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Also in December 2002, Cephalon reacquired rights to modafinil in Germany (trade
name: Vigil), Austria and Switzerland (trade name: Modasomil) and certain countries in
Central and Eastern Europe from Merckle GmbH, and in Spain (trade name: Modiodal)
from Cepa Schwarz Pharma.
In the U.S., Cephalon filed a supplemental New Drug Application (sNDA) with the FDA
in an attempt to expand Provigil’s approved use to include the treatment of excessive
sleepiness due to disorders of sleep and wakefulness in adults in December 2002. The
sNDA Drug application is based on positive data from six double-blind, placebocontrolled clinical studies evaluating the safety and effectiveness of Provigil in more than
1,500 patients with excessive sleepiness related to conditions other than narcolepsy,
including obstructive sleep apnea and shiftwork sleep disorder. With The FDA’s targeted
review period for standard sNDAs of 10-12 months, potential approval of the sNDA is
possible by the end of 2003 or early 2004. Experts believe that expanded FDA approval
of Provigil will be necessary to drive total product sales beyond the $ 1 billion mark by
2006 or 2007. Although off-label use of Provigil is significant and continues to grow, a
broader label for the drug would let Cephalon directly market the product in indications
other than narcolepsy in the U.S.
In 2003, the company may begin a Phase III trial of Provigil to treat children with
Attention Deficit Hyperactivity Disorder. The trial would be unrelated to the company’s
recent FDA submission.
According to Cephalon Chairman and CEO, Frank Baldino, Provigil’s market could be as
large as 40 million Americans who battle sleepiness from various disorders: sleep apnea,
night-shift work, and fatigue from depression and other diseases such as multiple
sclerosis. A broader label would allow Cephalon to call on 250,000 general practitioners
across the country. The company currently promotes Provigil to 50,000 sleep specialists,
neurologists and psychiatrists.
Cephalon has heavily marketed Provigil to the extent that the FDA admonished the
company in January 2002 for advertising the drug in journals, on Web sites and via
handouts to doctors as a general remedy for sleepiness and fatigue rather than only for
narcolepsy, and for understating the side effects. Cephalon says it has since changed its
promotional material.
Industry analysts say the only risk to Provigil’s continued growth is lower-cost generic
competition. It was reported in February 2003, that the FDA has accepted an abbreviated
new drug application (ANDA) for a generic form of modafinil, the active ingredient
found in the company's PROVIGIL. Cephalon maintains that, even if an ANDA
application eventually is approved by the FDA, it will be years before a generic
equivalent modafinil product can be sold in the United States. PROVIGIL is protected in
the United States by a patent that does not expire until 2014 and that covers the
pharmaceutical composition of the form of modafinil contained in PROVIGIL.
PROVIGIL also was granted orphan drug exclusivity that prevents the approval of any
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ANDA for a modafinil product prior to June 2006, provided the FDA grants the company
a six-month extension to the December 2005 orphan drug exclusivity upon completion of
a pediatric study.
5) Challenges
This is mainly based on literature and does not represent a complete CTI view. This
chapter will be expanded after internal CTI discussions and meeting with Cephalon.
Ultimately, Cephalon hopes to expand FDA approval so that Provigil can be prescribed to
treat sleepiness that results from any medical condition.
There are several concerns regarding the broad approval of Provigil. In general, experts
are concerned because the long-term effects in healthy people are not sufficiently
investigated. Nor are all the potential interactions with other drugs or effects in special
medical conditions. Sleep experts fear that sleepiness symptoms in sleep disorder patients
may be treated without evaluating the patient’s specific problem and deciding whether
existing therapies would be more appropriate, or that modafinil treatment may
compromise the patients’ compliance with the primary treatment methods of the actual
causes of a specific medical condition. For instance, patients with sleep apnea need to be
treated by traditional methods (e.g., using CPAP while sleeping) to enlarge their airways
and prevent the stopping of breathing and dropping of oxygen levels. Taking modafinil
does not solve this cardiovascular risk.
One of the main target populations for expanded Provigil approval would be shiftworkers
as they could qualify, due to their changing wake-rest patterns, for the medical disease
code – shiftwork sleep disorder. However, experts differ as to whether shiftwork sleep
disorder is a real medical condition because it is clearly caused by lifestyle and is
experienced by the majority of the shiftworker population. In several court cases
(Williams vs. City of Charlotte; Scheffler vs. Dow Jones & Co; Ross vs. Michelin),
shiftwork sleep disorder was not accepted as a reason for disability claims or workers’
compensation claims.
Similarly, as with clinical sleep disorders such as apnea, there is the concern that the
wide-spread use of modafinil among shiftworkers may compromise efforts to manage the
root causes of work-related fatigue (e.g., scheduling practices, on-site napping policies,
lifestyle training). On the other hand, Provigil could help prevent accidents, and make a
big difference to soldiers on sustained operations or emergency rescue workers. It’s an
interesting challenge for society and the FDA. (38)
Critics feel that the broader approval of Provigil could lead to its use being extended from
those with sleep disorders to healthy people who are simply sleep-deprived, and that there
would be little to stop the drug from becoming a new lifestyle drug for the 24/7
generation. It’s happening already as sleep researchers report that patients with
demanding careers and lifestyles are beginning to ask for Provigil to help them stay alert
and burn the midnight oil. Critics of more widespread use of Provigil fear that the drug
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Modafinil Fact Pack – Draft 2/28/03
might give people a false sense that they can cheat on their sleep, while in reality they
may be accumulating a sleep dept that will ultimately harm them.
Sleep is essential. It promotes growth, protects and preserves brain and immune function,
and many important hormones are active during sleep. Sleep deprivation seriously
disrupts immune and hormone systems, at least temporarily. A growing body of research
does indicate that lack of sleep may be even more harmful than previously thought. It
may be contributing to obesity by changing the metabolism of the underslept, and to heart
disease by causing low-grade inflammation. A study on partial sleep deprivation (52),
allowing only 4 hours of sleep per night for one week, found temporary changes in
metabolic rate (glucose, tyrotropin), endocrine functions (cortisol) and activity of the
sympathetic nervous system. The effects were similar to those observed in normal aging,
and therefore the authors concluded that sleep debt may increase the severity of agerelated chronic disorders. The risk of heart disease due to long-term sleep deprivation was
demonstrated in a recent large study on nearly 72,000 nurses (1). Compared to women
who slept eight hours a night, the increase of heart disease risk for those sleeping five or
fewer hours, and those sleeping six hours was 45% and 18%, respectively.
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