The
New
Drug
Brief
Modafinil (Modavigil)
CLINICAL USE
• Modafinil is available on authority on the Pharmaceutical Benefits
Scheme (PBS) for narcolepsy but possibly because of its price
($345.71), it is subject to stringent conditions and is only second
choice for narcolepsy after dexamphetamine 1 . Modafinill has
to be prescribed by a sleep specialist or a neurologist after using
a proscribed application form and can only be approved if the
patient has a condition where use of dexamphetamine poses an
unacceptable risk (eg cardiac or psychiatric disorders, or glaucoma)
or where they have developed intolerable adverse effects to
dexamphetamine 1 .
• Modafinil is a wake-promoting agent that is pharmacologically
distinct from CNS stimulants, such as dexamphetamine and
methylphenidate 2. Modafinil is approved for use in the US and
certain European countries for use in patients with excessive
sleepiness associated not only for narcolepsy, but also for patients
with obstructive sleep apnoea or shift work sleep disorder 2 . Oral
Modafinil promotes wakefulness in these patients 2. It has also been
successfully used as effective adjunctive therapy in patients with
residual excessive sleepiness associated with obstructive sleep
apnoea who are already receiving nasal continuous positive airway
pressure (nCPAP) therapy 2. In shift work sleep disorder, the drug
improves night-time wakefulness without disrupting daytime sleep 2 .
MECHANISM OF ACTION
• The exact mechanism of action of Modafinil is not yet clear 3 .
It appears to act selectively in the hypothalamus in neurons that
promote wakefulness 3 .
• Modafinil is both structurally and pharmacologically distinct
from CNS stimulants used in promoting wakefulness(eg dexamphetamine, methylphenidate) and unlike these drugs, does
not promote neuronal activation in other areas of the brain - a
mechanism which appears to give it a more benign adverse effect
profile than the stimulant drugs 3 .
• Modafinil may increase wakefulness by reducing the
neurotransmission of GABA in areas of the brain involved in wakefulness
. (This contrasts with benzodiazepines which may cause sedative
4
effects by enhancing the neurotransmission of GABA in the brain).
• Modafinil may also promote the inhibitory effects of noradrenaline
on neurons that promote sleep although it does not appear that
Modafinil has direct effects on adrenergic receptors 5 .
DOSING INFORMATION
• Cardiac
o Patients with a history of heart attack or angina were
not included in clinical trials so the manufacturers do
not recommend use of modafinil in these patients 6
• Doses of modafinil are 200 to 400mg daily given as
either a once daily dose in the morning or as two divided
doses given on the morning and at noon 6 .
o Cardiovascular events occur more significantly if the
dose exceeds the recommended daily maximum of
400mg daily 6 .
• A maximum dose of 400mg daily is recommended for
patients who do not respond to 200mg daily 6 . Patients
requiring more than 200mg daily should be titrated up to
400mg daily in increments of 100mg 6 .
o No changes in ECG recordings were noted in clinical
trials 9,10,11 .
• Liver failure
o Small but significant increases in blood pressure
and heart rate were recorded in one trial (+5mm
Hg for systolic blood pressure and 0.4mm Hg for
systolic blood pressure) 12 . The rise in systolic blood
pressure was not maintained over a 24 hour period
and returned to normal 13 hours post dose. However,
the small rise in diastolic blood pressure did continue
over the 24 hour period.
o Patients with severe liver failure should have doses of
modafinil reduced by half 6 . In one study, modafinil
maximum blood levels at steady-state were 112%
higher and the half-life was 104% longer in nine
patients with chronic hepatic impairment than in 12
healthy volunteers 7 . This is because modafinil is
primarily metabolised in the liver 6 .
• Kidney failure
o Patients with kidney failure do not appear to affect
the pharmacokinetics of modafinil and doses do
not need to be reduced 6 . However, the inactive
metabolite, modafinil acid, which is excreted renally,
increases nine-fold 6 . It is not clear whether this has
any implications for therapy.
• Dependency
o Preclinical and clinical data suggest a much lower
potential for abuse and addiction than amphetamines
and amphetamine-like products 13 . Modafinil
200-800mg produced no or minimal stimulant-like
subjective effects (e.g. euphoria) in small studies (n
= 6-24) in healthy volunteers and in volunteers with
recent histories of cocaine use 2 . Postmarketing
surveillance data also indicate a low abuse potential
for modafinil 2 .
• Elderly
o The elimination of modafinil and its metabolites may
be reduced in elderly patients. In one study, healthy
elderly males (mean age 63 years) had significantly
higher blood levels than younger healthy males
(mean age 29 years) 8 . Thus doses may need to be
reduced in older patients.
DRUG INTERACTIONS
• Cytochrome P450 enzyme system
o Modafinil is an inhibitor of the cytochrome P450
enzyme system 2C19. Thus, dugs which use this
pathway as a substrate may have their blood levels
increased when given concomitantly with modafinil.
ADVERSE EFFECTS
• Modafinil was generally well tolerated in clinical trials, with
adverse events being described as only mild to moderate
in severity 9,10,11. Averse events are summarised in the
table below. Only headache, nausea and nervousness
were deemed as significantly different to placebo.
Adverse events reported in clinical trials with an incidence of >5% 9,10,11
Trial
Black 9
Pack 10
Kingshott 11
Adverse effect
200mg/d
(n=103)
400mg/d
(n=99)
Placebo
(n=103)
400mg/d
(n=77)
Placebo
(n=80)
400mg/d
(n=31)
Placebo
(n=31)
Headache
Infection
Nausea
Anxiety
Accidental injury
Diarrhoea
Hypertension
Nervousness
Dizziness
Insomnia
Runny nose
Dry mouth
23
19
10
6
8
8
4
6
6
7
6
26
10
10
8
5
5
8
6
5
4
5
13*
28
2*
2
8
8
2
2
3
1
8
23
11*
16
16
6
6
4
1
16
0
12
6
5
8
3
3*
1
3
10
0
*only these adverse events were significantly different to placebo
Drugs which are metabolised by the CYP2C19
enzyme system and which may have their blood
levels increased by the CYP2C19 inhibitor
modafinil and could result in toxic effects
Proton pump inhibitors (lansoprazole,
omeprazole, pantoprazole)
Diazepam (Valium)
Phenytoin (Dilantin)
Amitryptiline (Tryptanol)
Clomipramine (Anafranil)
Citalopram (Cipramil)
Imipramine (Tofranil)
Indomethacin (Indocid)
Moclobemide (Aurorix)
Progesterone
Propranolol (Inderal)
Warfarin
o Modafinil when used chronically is also a modest
inducer of the cytochrome P450 enzyme system
3A4. Thus, dugs which use this pathway as a
substrate may have their blood levels decreased
when given concomitantly with modafinil and
result in a loss of efficacy
Drugs which are metabolised by the CYP3A4
enzyme system and which may have their
blood levels decreased by the CYP3A4 inducer
modafinil and could result in loss of efficacy
Clarithromycin (Klacid)
Erythromycin (Eryc)
Benzodiazepines (alprazolam (Xanax), diazepam
(Valium), midazolam (Hypnovel), triazolam
(Halcion))
Cyclosporine (Neoral)
Calcium channel blockers (amlodipine (Norvasc),
felodipine (Plendil), nifedipine (Adalat),
lercanidipine (Zanidip), verapamil (Isoptin))
Statins (atorvastatin (Lipitor), simvastatin (Lipex))
Oestradiol
Progesterone
Aprepitant (Emend)
Aripiprazole (Abilify)
Codeine
Dexamethasone
Dextromethorphan
Domperidone (Motilium)
Fentanyl (Durogesic)
Haloperidol (Serenace)
Ondansetron (Zofran)
Quetiapine (Seroquel)
Risperidone (Risperdal)
Salmeterol (Seretide)
Sildenafil (Viagra)
Tamoxifen (Nolvadex)
Terfenadine (Telfast)
Zolpidem (Stilnox)
COMPARATIVE DATA
• Vs dexamphetamine
o Unlike dexamphetamine, modafinil at doses of
200mg or 400mg did not have detrimental effects
on nocturnal sleep in either young (mean age 30
years) or older patients (mean age 68 years) using
both subjective and objective measurements 14,15 .
PLACE IN THERAPY
• Modafinil has been shown to be an effective
medication in promoting wakefulness in patients with
narcolepsy and other disorders that are associated with
an increased susceptibility to drowsiness and falling
asleep 2,12. The CNS stimulants dexamphetamine and
methylphenidate are also effective in reducing the
somnolence associated with narcolepsy 2,12
• However, it appears that modafinil has a more
benign adverse effect profile than the CNS stimulants
dexamphetamine and methylphenidate. Although
effective, the use of stimulants are limited by a number
of adverse effects including psychosis, tachycardia,
hypertension, nocturnal sleep disturbances, tolerance
and drug dependence 16 . In contrast, the most
commonly experienced adverse effects associated with
modafini are headache, nausea and dizziness 2,12 .
• Narcolepsy is also associated with cognitive deficits
in attention and memory 12 . Modafinill has been
shown to improve these deficits when administered
to narcolepsy patients 12 .
• Modafinil has been shown to be generally well
tolerated over the longer term in patients with
narcolepsy (mean duration of treatment 22.4 months).
Trial data indicate that overdoses of modafini (up to
4500mg) were not associated with unexpected or
life-threatening events. In addition, no fatal outcomes
associated with overdoses of modafini alone (up
to 12g) have been reported during postmarketing
surveillance, although fatal outcomes have been
associated with overdoses involving multiple drugs
(including modafinil).
CLINICAL TRIALS
• A study of patients with narcolepsy whose sleep
latency (time to fall asleep) was less than 3 mins
(which is indicative of severe disease) used 150mg
(n=63) or 250mg (n=62) of modafinil and placebo
(n=63) 12 . There was improvement in 71% of
patients on modafinil compared with only 33% of
placebo patients. Modafinil was able to sustain
wakefulness throughout the day and improve sleep
latency. Fatigue, memory and attention also improved
in patients taking modafinil in the study.
• One hundred and forty patients (104 male and 36
female) aged 42.26 19.19 (range = 8 to 79.5 years)
with narcolepsy-cataplexy were given modafinil (200
to 400 mg) at the Montpellier sleep disorders centre
from 1984 onwards 17 . The follow-up focused on the
reduction of excessive daytime somnolence (EDS),
side effects and duration of treatment. When modafinil
effect on EDS was evaluated according to a scale
varying from 0 (no effect) to 3 (excellent effect), 64.1%
of the subjects, scored good or excellent.
The mean duration of treatment was 22.05 months
24.9, ranging from 1 to 114 months. Dependency signs
were never observed.
• This study examined the effects of modafinil on the
excessive daytime sleepiness (EDS) of 10 narcoleptic
patients while using a double-blind design and
objective measurements of vigilance 18 . There were
two treatment periods, in which either modafinil
or placebo was used; each lasted four weeks and
was preceded by a 2-week “run-in” period and
separated by a 2-week “wash-out” period. The effects
of treatment on EDS were evaluated by daily home
questionnaires and a psychomotor performance
test, the Four Choice Reaction Time Test (FCRTT).
Modafinil reduced the daily number of sleep attacks
significantly, and markedly improved performances
during the FCRTT.
WEB SITE
• An article on modafinil in the popular and respected
New Scientist is available at:
http://www.newscientist.com/article/
mg18925391.300
cited 30th November, 2006
• A report on clinical trials being conducted in
Australia is available at:
http://ndarc.med.unsw.edu.au/ndarcweb.
nsf/website/Research.current.cp17 cited 30th
November, 2006
• Prescribing information for Modavigil is available at:
http://www.modafinil.com/prescribe/index.html
cited 30th November, 2006
COMPILATION DATE
• 30th November. 2006
REFERENCES
1. Schedule of Pharmaceutical Benefits for approved
pharmacists and medical practitioners. Australian
Government Department of Health and Ageing. 1st
August 2006. Commonwealth of Australia 2006.
available at: www.health.gov.au/pbschedule
2. Keating GM, Raffin MJ. Modafinil: A review of its use
in excessive sleepiness associated with obstructive
sleep apnoea/hypopnoea syndrome and shift work
sleep disorder. CNS Drugs 2005; 19 (9): 785-803
3. Scammell TE, Estabrooke IV, McCarthy MT et al.
Hypothalamic arousal regions are activated during
modafinil-induced wakefulness. J Neurosci 2000; 20
(22): 8620-8.
4. Ferraro L, Tanganelli S, O’Connor WT et al. The
vigilance promoting drug modafinil decreases
GABA release in the medial preoptic area and in the
posterior hypothalamus of the awake rat: possible
involvement of the serotonergic 5-HT3 receptor.
Neurosci Lett 1996; 220: 5-8
5. Gallopin T, Luppi PH, Rambert FA et al. Effect of the
wake- promoting agent modafinil on sleep-promoting
neurons from the ventrolateral preoptic nucleus: an in vitro
pharmacologic study. Sleep 2004 Feb 1; 27 (1): 19-25
6. Modavigil Product Information. CSL Limited.
Parkville, Vic. 21st April, 2005.
7. Moachon G, Matinier D, Lubin S et al.
Pharmacokinetics of multiple doses of modafinil in
hepatic insufficiency. Can J Physiol Pharmacol 1994;
72 Suppl. 1: 303
8. Wong YN, King SP, Simcoe D et al. Open-label,
single-dose pharmacokinetic study of modafinil
tablets: influence of age and gender in normal
subjects. J Clin Pharmacol 1999; 39(3): 281-8
9. Black JE, Hirshkowitz M. Modafinil for treatment of
residual excessive sleepiness in nasal continuous
positive airway pressure-treated obstructive sleep
apnea/hypopnea syndrome. Sleep 2005; 28 (4): 464-71
10.Pack AI, Black JE, Schwartz JR et al. Modafinil as
adjunct therapy for daytime sleepiness in obstructive
sleep apnea. Am J Respir Crit Care Med 2001; 164
(9): 1675-81
11.Kingshott RN, Vennelle M, Coleman EL, et al.
Randomized, double-blind, placebo-controlled
crossover trial of modafinil in the treatment of
residual excessive daytime sleepiness in sleep
apnea/hypopnea syndrome. Am J Respir Crit Care
Med 2001; 163 (4): 918-23
12.Harsh JR, Hayduk R, Rosenberg R et al. The efficacy and
safety of armodafinil as treatment for adults with excessive
sleepiness associated with narcolepsy. Current Medical
Research and Opinion 2006; 22, 4: 761-777.
13.Jasinski DR, Kovacevic-Ristanovic R. Evaluation
of the abuse liability of modafinil and other drugs
for excessive daytime sleepiness associated with
narcolepsy. : Clin Neuropharmacol. 2000 MayJun;23(3):149-56
14.Saletu B, Frey R, Krupka M et al. Differential effects
of a new central adrenergic agonist - modafinil
- and d-amphetamine on sleep and early morning
behaviour in young healthy volunteers. Int J Clin
Pharm Res 1989; 9 (3): 183-95
15.Saletu B, Frey R, Krupka M et al. Differential effects of
the new central adrenergic agonist modafinil and damphetamine on sleep and early morning behaviour in
elderlies. Arzneimittel Forshung 1989; 39: 1268-73
16.Wake up! Treatments for Childhood Narcolepsy Can
Prevent the Development of Serious Social or Academic
Problems. Drug Ther Perspect 17(6):5-8, 2001
17.Besset A, Chetrit M, Carlander B, et al. Use of
modafinil in the treatment of narcolepsy: a longer term
follow-up study. Neurophysiol Clin 1996; 26: 60-6
18. Caldwell JA, Caldwell JL, Smythe NK, Hall KK.
Effects of modafinil on symptomatology of human
narcolepsy. Clin Neuropharmacol 1993;16(1):46-53
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