NEW ZEALAND DATA SHEET

1 PRODUCT NAME
Modafinil 100 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100 mg of modafinil.
Excipients with known effect: Lactose
For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM
Tablet

A white to off white capsule shape tablet embossed with ‘100’.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Modafinil is indicated:
• to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy;
• to treat excessive sleepiness associated with moderate to severe chronic shift work sleep disorder
where nonpharmacological interventions are unsuccessful or inappropriate;
• as an adjunct to continuous positive airways pressure (CPAP) in obstructive sleep
apnoea/hypopnoea syndrome in order to improve wakefulness.

4.2 Dose and method of administration

Modafinil should be used only in patients who have had a complete evaluation of their excessive
sleepiness, and in whom a diagnosis of either narcolepsy, OSAHS, and/or SWSD has been made in
accordance with ICSD or DSM diagnostic criteria. Such an evaluation usually consists of a complete
history and physical examination, and testing in a laboratory setting. Some patients may have more
than one sleep disorder contributing to their excessive sleepiness (e.g., OSAHS and SWSD coincident
in the same patient).
Treatment with modafinil should be initiated and supervised by physicians with appropriate
experience in the treatment of sleep disorders who have access to sleep laboratory diagnostic
facilities.
Narcolepsy
The dose of modafinil is 200 to 400 mg/day, given as a single dose in the morning, or as two divided
doses, in the morning and at noon. Tablets should be swallowed whole.
Doses of 400 mg/day have been well tolerated, but there is no statistically significant evidence that
this dose confers additional benefit beyond that of the 200 mg dose.
For patients who require more than 200 mg/day, the dose should be increased, to a maximum of 400
mg/day, in increments of 100 mg as needed and tolerated.

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Obstructive Sleep Apnoea/Hypopnoea Syndrome
In OSAHS, modafinil is indicated as an adjunct to continuous positive airway pressure (CPAP). A
maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating
modafinil. If modafinil is used adjunctively with CPAP, the encouragement of and periodic assessment
of CPAP compliance is necessary.
The dose of modafinil is 200 to 400 mg/day, given as a single dose in the morning, or as two divided
doses, in the morning and at noon. Tablets should be swallowed whole.
Doses of 400 mg/day have been well tolerated, but there is no statistically significant evidence that
this dose confers additional benefit beyond that of the 200 mg dose.
For patients who require more than 200 mg/day, the dose should be increased, to a maximum of 400
mg/day, in increments of 100 mg as needed and tolerated.
Moderate to Severe Chronic Shift Work Sleep Disorder
The recommended daily dose is 200 mg. modafinil should be taken as a single dose approximately 1
hour prior to the start of the work shift. Tablets should be swallowed whole.
Dosing in Special Populations
In patients with severe hepatic impairment, the dose of modafinil should be reduced to one-half of
that recommended for patients with normal hepatic function (see section 4.4 “Special warnings and
precautions for use”).
There is inadequate information to determine safety and efficacy of modafinil dosing in patients with
severe renal impairment (see section 4.4 “Special warnings and precautions for use”).
In elderly patients, elimination of modafinil and its metabolites may be reduced as a consequence of
aging. Therefore, consideration should be given to the use of lower doses in this population (see
section 4.4 “Special warnings and precautions for use”).

4.3 Contraindications
• Hypersensitivity to modafinil or any other component of the product.
• Patients who are pregnant or may become pregnant.

4.4 Special warnings and precautions for use

General
Although modafinil has not been shown to produce functional impairment, any drug affecting the CNS
may alter judgment, thinking or motor skills. Patients with major anxiety should only receive
treatment with modafinil in a specialist unit.
If a hypersensitivity reaction is suspected, modafinil treatment should be discontinued.
In patients with obstructive sleep apnoea/hypopnoea syndrome, the underlying condition and any
associated cardiovascular pathology should be monitored.
Patients should be advised that modafinil is not a replacement for sleep and good sleep hygiene should
be maintained.
Serious Skin Rash, including Stevens-Johnson Syndrome
Serious rash requiring hospitalization and discontinuation of treatment has been reported in adults
and children in association with the use of modafinil.

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Modafinil is not approved for use in pediatric patients for any indication.
In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8%
(13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-
Johnson Syndrome (SJS) and 1 case of apparent multiorgan hypersensitivity reaction. Several of the
cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median
time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380
pediatric patients who received placebo. No serious skin rashes have been reported in adult clinical
trials (0 per 4,264) of modafinil.
Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN) and Drug
Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in
world-wide post-marketing experience (see section 4.8 Undesirable effects “Post Marketing
Experience”). The reporting rate of TEN and SJS associated with modafinil use which is generally
accepted to be an underestimate due to underreporting, exceeds the background incidence rate.
Estimates of the background incidence rate for these serious skin reactions in the general population
range between 1 to 2 cases per million-person years.
While little is known about factors that can predict the risk of occurrence or the severity of rash
associated with modafinil, the risk may increase with higher doses. Nearly all cases of serious rash
associated with modafinil occurred within 1 to 5 weeks after treatment initiation. Isolated cases have
been reported after prolonged treatment (e.g. 3 months). Duration of therapy cannot be relied upon
as a means to predict the potential risk heralded by the first appearance of a rash.
Although benign rashes also occur with modafinil, it is not possible to reliably predict which rashes
will prove to be serious. Accordingly, modafinil should ordinarily be discontinued at the first sign of
rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash
from becoming life-threatening or permanently disabling or disfiguring.
Multi-organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have occurred in close temporal association to the initiation of
modafinil. Although there have only been a limited number of reports, multi-organ hypersensitivity
reactions may result in hospitalization or be life-threatening. There are no factors that are known to
predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions associated with
modafinil. Signs and symptoms of these reactions were diverse; however, patients typically, although
not exclusively, presented with fever and rash associated with other organ system involvement. Other
associated manifestations included myocarditis, hepatitis, liver function test abnormalities,
haematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and
asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system
symptoms and signs, not noted here, may occur.
If a multi-organ hypersensitivity reaction is suspected, modafinil should be discontinued and not
restarted. Although there are no case reports to indicate cross-sensitivity with other medicines that
produce this syndrome, the experience with medicines associated with multi-organ hypersensitivity
would indicate this to be a possibility
Psychiatric Symptoms and Disorders
Psychiatric adverse experiences have been reported in patients treated with modafinil in clinical trials
and from post-marketing experience. Patients should be monitored for the development of de novo
psychiatric disorders or exacerbation of pre-existing psychiatric disorders at every adjustment of dose
and regularly during treatment. If psychiatric symptoms develop in association with modafinil

Page 3 of 19
treatment, discontinuation of modafinil may be required. Caution should be exercised in giving
modafinil to patients with a history of psychiatric disorders including psychosis, depression, mania,
major anxiety, agitation, insomnia or substance abuse.
Aggressive or hostile behaviour
The onset or worsening of aggressive or hostile behaviour has been reported in patients treated with
modafinil. Patients treated with modafinil should be carefully monitored for the appearance or
worsening of aggressive or hostile behaviour. If symptoms occur, modafinil should be discontinued.
Suicidal ideation and suicide-related behaviour
Suicidal ideation and suicide-related behaviour (including suicide attempts) have been reported in
patients treated with modafinil. Patients treated with modafinil should be carefully monitored for the
appearance or worsening of suicidal thinking and/or suicide-related behaviour. If suicide-related
symptoms develop in association with modafinil, treatment should be discontinued.
Psychotic or manic symptoms
The onset or worsening of psychotic symptoms or manic symptoms (including hallucinations,
delusions, agitation or mania) has been reported in patients treated with modafinil. Patients treated
with modafinil should be carefully monitored for the appearance or worsening of psychotic or manic
symptoms. If psychotic or manic symptoms occur, modafinil should be discontinued.
Bipolar disorders
Care should be taken in using modafinil in patients with co-morbid bipolar disorder because of concern
for possible precipitation of a mixed/manic episode in such patients.
Depression
The onset of depression or the aggravation of underlying depressive disorder has been reported in
patients treated with modafinil. Patients treated with modafinil should be carefully monitored for the
appearance of or worsening of depression.
Anxiety
The onset or worsening of anxiety has been reported in patients treated with modafinil. Anxiety and
nervousness are adverse events that appear to be closely dose related.
Cardiovascular System
In hypertensive patients, blood pressure should be adequately controlled before initiating treatment
with modafinil and monitored regularly during treatment. Blood pressure, heart rate and general
cardiovascular status should be monitored in all patients during treatment with modafinil.
In clinical studies of modafinil, signs and symptoms including chest pain, palpitations, dyspnoea and
transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral
valve prolapse or left ventricular hypertrophy. It is recommended that modafinil not be used in
patients with a history of left ventricular hypertrophy or ischaemic ECG changes, chest pain,
arrhythmia or other clinically significant manifestations of mitral valve prolapse in association with
CNS stimulant use.
The safety of modafinil has not been established in patients with coronary artery disease, a recent
history of myocardial infarction or unstable angina. Patients with these conditions were not included
in the controlled clinical trials. Post marketing adverse events of ischaemic heart disease have been
reported in patients with and without a history of cardiovascular disease while being treated with

Page 4 of 19
modafinil. The risks of using modafinil in patients with coronary artery disease, a recent history of
myocardial infarction or unstable angina should be carefully weighed against the potential therapeutic
benefit. It is recommended that such patients receive further specialist evaluation before modafinil
treatment is considered.
Postmarketing adverse events of cardiac arrhythmia, such as atrial fibrillation and premature
ventricular contractions, have been reported in patients treated with modafinil. In some of these cases
there was a close temporal association to the use of modafinil, a resolution of the arrhythmia upon
medicine discontinuation and, in a few cases, a recurrence of arrhythmia after modafinil rechallenge.
It is recommended that patients have an ECG before modafinil is initiated. Patients with abnormal
findings should receive further specialist evaluation before modafinil treatment is considered.
Dose Dependency and adverse effects
The development of skin and hypersensitivity reactions, central nervous system, psychiatric and
cardiovascular system adverse reactions appear to be related to higher doses of modafinil.
Cardiovascular and central nervous system adverse reactions increase significantly after a total daily
dose of more than 400 mg. Always start at the lowest recommended dose (see section 4.2 “Dose and
method of administration”).
Patients (Women) Using Contraception
Based on post-marketing reports, modafinil may cause fetal harm and is contraindicated in women
who are pregnant or may become pregnant (see Section 4.3 CONTRAINDICATIONS and Section 4.6
FERTILITY, PREGNANCY AND LACTATION). Females of reproductive potential should have a negative
pregnancy test within a week prior to starting treatment with modafinil.
Sexually active women of child-bearing potential should be established on a contraceptive program
before taking MODAVIGIL®. The effectiveness of steroidal contraceptives (including the
contraceptive pill, implants, injectables and hormone releasing intrauterine devices [IUDs]) may be
reduced when used with MODAVIGIL® and after discontinuation of MODAVIGIL® therapy due to the
enzyme induction activity of MODAVIGIL®. Alternative or concomitant methods of contraception are
recommended for patients treated with MODAVIGIL®, and for two months after discontinuation of
treatment (see Section 4.5 “INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF
INTERACTIONS).
Abuse and Dependence Potential
In addition to its wakefulness-promoting effect and increased locomotor activity in animals, in
humans, modafinil may produce psychoactive and euphoric effects, alterations in mood, perception,
thinking and feelings. In in vitro binding studies, modafinil binds with low affinity to the dopamine
reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release.
Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-
administer cocaine. In some studies, modafinil was also partially discriminated as stimulant-like.
Caution should be exercised in administering modafinil to patients with history of alcohol, medicine
or illicit substance abuse. Patients with such history should be monitored for signs of misuse or abuse
(e.g. increasing the recommended dosage).
Withdrawal:
In one US Phase 3 clinical trial of nine weeks of modafinil use, the effects of modafinil cessation were
monitored for 14 days. No specific symptoms of withdrawal were observed during the 14 days;
however, sleepiness returned in patients with narcolepsy.

Page 5 of 19
Use in hepatic impairment
Hepatic Impairment: The dose of modafinil should be reduced by half in patients with severe hepatic
impairment (see Section 4.2 “DOSE AND METHOD OF ADMINISTRATION”).
Use in renal impairment
In a single-dose 200 mg modafinil study, severe chronic renal failure (creatinine clearance ≤ 20
mL/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to modafinil
acid (an inactive metabolite) was increased 9-fold (Section 4.2 “DOSE AND METHOD OF
ADMINISTRATION”).
Paediatric use
The efficacy and safety of modafinil in this age group has not been established. modafinil is not
approved for use in paediatric patients for any indication. The use of modafinil in this age group is not
recommended. Neuropsychiatric and serious skin reactions have been reported in children and
adolescents treated with modafinil.
Use in the Elderly:
There are no satisfactory data on the safety and efficacy of modafinil in patients ≥ 65 years of age. The
clearance of modafinil may be reduced in the elderly (see section 4.2 “Dose and method of
administration”).
Effects on laboratory tests
No data available.

4.5 Interaction with other medicines and other forms of interaction

CNS Active Drugs
Methylphenidate – The absorption of modafinil may be delayed by approximately one hour when co-
administered with methylphenidate.
Clomipramine – The coadministration of a single dose of clomipramine (50 mg) on the first three days
of treatment with modafinil (200 mg/day) in healthy volunteers did not show an effect on the
pharmacokinetics of either medicine. However, one incident of increased levels of clomipramine and
its active metabolite desmethylclomipramine has been reported in a CYP2D6 poor metabolizer with
narcolepsy during treatment with modafinil. (See below “Potential Interactions with Drugs That Inhibit
or are Metabolised by Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes”).
Triazolam – In healthy, female volunteers, who were receiving long-term treatment with ethinyl
estradiol, the co-administration of two single doses of 0.125 mg of triazolam (one administered before
and the other at the end of treatment) with modafinil (200 mg for seven days, followed by 400 mg for
21 days) indicated that, for triazolam, the Cmax and AUC0-∞ were reduced by 59% and 42%
respectively, and the elimination rate was increased by approximately 50%. Therefore, dosage
adjustment of triazolam may be necessary when co-administered with modafinil.
Monoamine Oxidase (MAO) Inhibitors – Interaction studies with monoamine oxidase inhibitors have
not been performed. Therefore, caution should be used when concomitantly administering MAO
inhibitors and modafinil.

Page 6 of 19
Potential Interactions with Drugs That Inhibit, Induce, or are Metabolised by Cytochrome P-450
Isoenzymes and Other Hepatic Enzymes
Diazepam, Phenytoin, Propranolol, Tricyclic Antidepressants, Selective Serotonin Reuptake Inhibitors
– Because modafinil is a reversible inhibitor of the drug-metabolising enzyme CYP2C19, co-
administration of modafinil with medicines such as diazepam, phenytoin, and propranolol, which are
largely eliminated via that pathway, may increase the circulating levels of those compounds. In
addition, in individuals deficient in the enzyme CYP2D6, the levels of CYP2D6 substrates such as
tricyclic antidepressants and selective serotonin reuptake inhibitors, which have ancillary routes of
elimination through CYP2C19, may be increased by co-administration of modafinil. Dose adjustments
may be necessary for patients being treated with these and similar medications.
Steroidal Contraceptives, Cyclosporin, Theophylline – Chronic administration of modafinil also causes
modest induction of the metabolising enzyme CYP3A4, thus reducing the levels of co-administered
substrates for that enzyme system, such as steroidal contraceptives, cyclosporin and to a lesser
degree, theophylline. Dose adjustments may be necessary for patients being treated with these and
similar medications.
Inducers or Inhibitors of CYP3A4 – Co-administration of potent inducers of CYP3A4 (e.g.,
carbamazepine, phenobarbital, rifampicin) or inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole)
could alter the levels of modafinil due to the partial involvement of that enzyme in the metabolic
elimination of the compound (see section 4.4 Special warnings and precautions for use: “Patients
(Women) Using Contraception”).
Warfarin, Phenytoin – The exposure of human hepatocytes to modafinil in vitro produced an apparent
concentration-related suppression of expression of CYP2C9 activity. The clinical relevance of this
finding is unclear, since no other indication of CYP2C9 suppression has been observed. However,
monitoring of prothrombin times is suggested as a precaution for the first several months of co-
administration of modafinil and warfarin, a CYP2C9 substrate, and thereafter whenever modafinil
dosing is changed. In addition, patients receiving modafinil and phenytoin, a CYP2C9 substrate,
concomitantly should be monitored for signs of phenytoin toxicity.
It should be noted that evaluation of medicine interactions based on in vitro systems might not
necessarily reflect those seen in vivo situations. This information should be used as a guide to assess
the risks associated with the use of concomitant medications.

4.6 Fertility, pregnancy and lactation

Effects of Fertility
No effects on fertility were observed in male or female rats treated with modafinil prior and
throughout mating and gestation at oral doses up to 100 mg/kg/day (the highest dose investigated
would have achieved systemic exposure levels less than human exposure at the maximum
recommended dose). However, sufficiently high enough doses or large enough sample sizes to
adequately assess effects on fertility were not used in the study.
Studies in animals have shown reproductive toxicity.

Use in Pregnancy - Pregnancy Category D

Modafinil is suspected to cause congenital malformations when administered during pregnancy. There
are no adequate and well-controlled trials with modafinil in pregnant women. Based on interim data
from a pregnancy registry and spontaneous reporting; the rate of major congenital malformations is
approximately 17.3% compared to 3% in the general population. There have also been reports of

Page 7 of 19
spontaneous abortion and intrauterine growth restriction in association with modafinil. modafinil
should therefore not be used during pregnancy (see Section 4.3 CONTRAINDICATIONS and Section 4.4
SPECIAL WARNINGS AND PRECAUTIONS FOR USE).
Patients should be cautioned regarding the potential increased risk of pregnancy when using steroidal
contraceptives (including the contraceptive pill, implants, injectables and hormone releasing
intrauterine devices [IUDs]) with modafinil and for two months after discontinuation of therapy (see
Section 4.5 “INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS”).
Animal studies to assess the effects of modafinil on reproduction and the developing foetus were not
conducted at adequately high doses or according to guidelines which would have been able to provide
a comprehensive evaluation of the potential of modafinil to adversely affect fertility, or cause
embryolethality or teratogenicity.
Embryotoxicity, in the absence of maternal toxicity, was observed in rats receiving oral modafinil
throughout the period of organogenesis. At a dose of 200 mg/kg/day (less than human exposure at
the maximum recommended daily clinical dose of 400 mg), there was an increase in resorption,
hydronephrosis and skeletal variations. The no effect dose for these effects was 100 mg/kg/day.
Embryotoxicity was not observed in rabbits receiving oral modafinil throughout organogenesis at
doses up to 100 mg/kg/day (0.6 times the human exposure at the maximum recommended daily dose
of 400 mg, based on AUC). However, neither of these studies used optimal doses for the evaluation of
embryotoxicity. Although a threshold dose for embryotoxicity has been identified, the full spectrum
of potential toxic effects on the foetus has not been characterised. Modafinil was embryotoxic in rats
dosed during late gestation and lactation, or prior to and throughout mating and gestation, at oral
doses ≥ 50 mg/kg/day; the no effect dose was 20 mg/kg/day (less than human exposure at the
maximum recommended clinical daily dose of 400 mg).
Use in Lactation
No developmental toxicity was noted postnatally in the offspring of rats given oral modafinil up to 100
mg/kg/day during late gestation and throughout lactation. The highest dose studied in these studies
would have achieved systemic exposure levels less than human exposure at the maximum
recommended dose.
Modafinil and/or its metabolites have been found in the milk of lactating rats. It is not known whether
modafinil or its metabolites are excreted in human milk. Therefore, breastfeeding is not
recommended during administration of modafinil.

4.7 Effects on ability to drive and use machines

Patients should be cautioned about operating an automobile or other hazardous machinery until they
are reasonably certain that modafinil therapy will not adversely affect their ability to engage in such
activities.

4.8 Undesirable effects

Modafinil has been evaluated for safety in over 3500 patients, of whom more than 2000 patients with
excessive sleepiness associated with primary disorders of sleep and wakefulness were given at least
one dose of modafinil. In clinical trials, modafinil has been found to be generally well tolerated and
most adverse experiences were mild to moderate.
The most commonly observed adverse events (≥5%) associated with the use of modafinil more
frequently than placebo-treated patients in the placebo-controlled clinical studies in primary disorders

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of sleep and wakefulness were headache, nausea, nervousness, rhinitis, diarrhoea, back pain, anxiety,
insomnia, dizziness, and dyspepsia. The adverse event profile was similar across these studies.
In the placebo-controlled clinical trials, 74 of the 934 patients (8%) who received modafinil
discontinued due to an adverse experience compared to 3% of patients that received placebo. The
most frequent reasons for discontinuation that occurred at a higher rate for modafinil than placebo
patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain and nervousness (each
<1%). In a Canadian clinical trial, a 35 year old obese narcoleptic male with a prior history of syncopal
episodes experienced a 9-second episode of asystole after 27 days of modafinil treatment (300
mg/day in divided doses).
Incidence in Controlled Trials
The following table (Table 1) presents the adverse experiences that occurred at a rate of 1% or more
and were more frequent in patients treated with modafinil than in placebo patients in the principal,
placebo-controlled clinical trials.
The prescriber should be aware that the figures provided below cannot be used to predict the
frequency of adverse experiences in the course of usual medical practice, where patient
characteristics and other factors may differ from those occurring during clinical studies. Similarly, the
cited frequencies cannot be directly compared with figures obtained from other clinical investigations
involving different treatments, uses, or investigators. Review of these frequencies, however, provides
prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the
incidence of adverse events in the population studied.
Table 1: Incidence of Treatment-Emergent Adverse Experiences in Parallel-Group, Placebo-
Controlled Clinical Trials1 in Narcolepsy, OSAHS, and SWSD with modafinil (200mg. 300mg. 400mg).
Body System Preferred Term Modafinil Placebo
(n=934, %) n=567, %
Body as a whole Headache 34 23
Back pain 6 5
Flu syndrome 4 3
Chest pain 3 1
Chills 1 0
Neck rigidity 1 0
Cardiovascular system Hypertension 3 1
Tachycardia 2 1
Palpitation 2 1
Vasodilatation 2 0
Digestive system Nausea 11 3
Diarrhoea 6 5
Dyspepsia 5 4
Dry mouth 4 2
Anorexia 4 1
Constipation 2 1
Abnormal liver function2 2 1
Flatulence 1 0
Mouth ulceration 1 0
Thirst 1 0
Haemic/Lymphatic Eosinophilia 1 0
system
Metabolic/Nutritional Oedema 1 0

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 Nervous Nervousness 7 3
Insomnia 5 1
Anxiety 5 1
Dizziness 5 4
Depression 2 1
Paraesthesia 2 0
Somnolence 2 1
Hypertonia 1 0
Dyskinesia3 1 0
Hyperkinesia 1 0
Agitation 1 0
Confusion 1 0
Tremor 1 0
Emotional lability 1 0
Vertigo 1 0
Respiratory Rhinitis 7 6
Pharyngitis 4 2
Lung disorder 2 1
Epistaxis 1 0
Asthma 1 0
Skin/Appendages Sweating 1 0
Herpes simplex 1 0
Special Senses Amblyopia 1 0
Abnormal vision 1 0
Taste perversion 1 0
Eye pain 1 0
Urogenital Urine abnormality 1 0
Haematuria 1 0
Pyuria 1 0
*Six double-blind, placebo controlled clinical studies in narcolepsy, OSAHS and SWSD
1. Events reported by at least 1% of patients treated with modafinil that were more frequent than
in the placebo group are included; incidence is rounded to the nearest 1%. The adverse experience
terminology is coded using a standard modified COSTART Dictionary.
Events for which the modafinil incidence was at least 1%, but equal to or less than placebo are not
listed in the table. These events included the following: infection, pain, accidental injury,
abdominal pain, hypothermia, allergic reaction, asthenia, fever, viral infection, neck pain,
migraine, abnormal electrocardiogram, hypotension, tooth disorder, vomiting, periodontal
abscess, increased appetite, ecchymosis, hyperglycaemia, peripheral oedema, weight loss, weight
gain, myalgia, leg cramps, arthritis, cataplexy, thinking abnormally, sleep disorder, increased
cough, sinusitis, dyspepsia, bronchitis, rash, conjunctivitis, ear pain, dysmenorrhoea4, urinary tract
infection
2. Elevated liver enzymes
3. Oro-facial dyskinesias
4. Incidence adjusted for gender

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Post Marketing Experience
Post Marketing Experience for modafinil, principally from spontaneous reporting based on reporting
rates and not incidence rates, has documented the following adverse events:
Common 1/100 to <1/10
Uncommon 1/1,000 to <1/100
Rare 1/10,000 to <1/1,000
Very rare <1/10,000

Cardiac disorders
Rare Palpitations
Very rare Ischaemic heart disease, cardiac arrhythmias

Gastrointestinal disorders
Rare Dry mouth, nausea, diarrhoea, vomiting, abdominal pain

General disorders
Rare Tolerance, chest pain, lack of efficacy, condition aggravated, malaise, fatigue
Very rare Oedema

Immune system disorders

Very rare Multi-organ system hypersensitivity reactions, urticaria (hives), angioedema,
anaphylaxis

Investigations
Rare Increased hepatic enzymes, increased gamma-GT, weight increase, weight decrease,
blood pressure increased
Very Rare Abnormal ECG

Musculoskeletal and connective tissue disorders

Rare Muscle weakness

Nervous system disorders

Uncommon Headache
Rare Dizziness, tremor, paraesthesia, dyskinesia
Very rare Dyskinesias, including reports of tardive dyskinesia; convulsions

Psychiatric disorders
Rare Nervousness, agitation, irritability, psychomotor hyperactivity, depression, anxiety,
confusion, insomnia, suicide attempt, aggravated depression, psychosis, mania,
delusions, hallucinations, suicidal ideation, thinking abnormal and aggression

Renal and urinary disorders

Rare Foul urine odour

Skin and subcutaneous tissue disorders

Rare Rash, acne, eczema, pruritus
Very rare Serious or life threatening rash, including erythema multiforme, Stevens Johnson
Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia
and System Symptoms (DRESS), and hyperhidrosis

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Vascular disorders
Rare Hypertension

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows
continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked
to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/

4.9 Overdose
Symptoms
A small number of individuals have each taken modafinil at doses of 1000 mg/day (2.5 times the
maximum recommended daily dose of 400 mg) or more. The adverse experiences observed were
limited, expected and non-life threatening, and the patients recovered fully by the following day. The
adverse experiences included excitation or agitation, insomnia and slight or moderate elevations in
haemodynamic parameters. No specific organ toxicities were observed. Other observed high dose
effects in clinical studies have included anxiety, irritability, aggressiveness, confusion, nervousness,
tremor, palpitations, sleep disturbances, nausea, diarrhoea and decreased prothrombin time.
Death has occurred with modafinil overdose alone or in combination with other medicines.
Symptoms accompanying modafinil overdose, alone or in combination with other medicines, have
included: insomnia; central nervous system symptoms such as restlessness, disorientation, confusion,
agitation, anxiety, excitation and hallucination; digestive changes such as nausea and diarrhea; and
cardiovascular changes such as tachycardia, bradycardia, hypertension and chest pain.
Management
Management of overdosage is primarily symptomatic, as no specific antidote to the toxic effects of
modafinil overdose has been identified. Overdoses should be managed empirically, with supportive
care, including cardiovascular monitoring. As for any overdose, the physician should consider
contacting a Poison-control centre regarding treatment.

For advice on the management of overdose please contact the National Poisons Centre on 0800
POISON (0800 764766).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Psychoanaleptics, centrally acting sympathomimetics
ATC code: N06BA07
The precise mechanism(s) through which modafinil promotes wakefulness is unknown. Modafinil has
wake-promoting actions but a pharmacological profile that is distinct from sympathomimetic amines,
which increase wakefulness by other mechanisms.
Modafinil does not bind to most of the potentially relevant receptors for sleep/wake regulation,
including those for noradrenaline, serotonin, dopamine, GABA, adenosine, histamine-3 and
benzodiazepines. Modafinil is not a direct- or indirect-acting dopamine receptor agonist and is inactive
in several in vivo preclinical models capable of detecting enhanced dopaminergic activity. In vitro,
modafinil binds to the dopamine reuptake site with low affinity and causes an increase in extracellular
dopamine, but no increase in dopamine release. Modafinil does not appear to be a direct or indirect
α1-adrenergic agonist. Although modafinil-induced wakefulness can be attenuated by the α1-

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adrenergic receptor antagonist prazosin, modafinil has no activity in assay systems known to be
responsive to the α-adrenergic agonists.
In rats, the wakefulness induced by amphetamine, but not modafinil, was antagonised by the
dopamine receptor antagonist haloperidol. In cats, modafinil evoked neuronal activation in brain
regions different from methylphenidate and amphetamine. Modafinil served as a positive reinforcer
for cocaine in monkeys and was partially discriminated as stimulant-like in rats (see section 4.4 Special
warnings and precautions for use: “Abuse and Dependence Potential”).
The optical enantiomers of modafinil have similar pharmacological actions in mice, but have not been
studied individually in humans. The two major metabolites of modafinil, modafinil acid and modafinil
sulfone, showed little CNS-activating activity in animal studies.
Modafinil in humans restores and/or improves the level of wakefulness. Changes are found in
electrophysiological parameters reflecting alertness (ratio of power of alpha rhythm to power of theta
rhythm), starting from a dose of 100 mg in the morning. An increase is seen in latency periods in the
multiple sleep latency test, starting from 200 mg in the morning. Modafinil opposes the impairment
of cognitive (in particular, memory), psychomotor and neurosensory performance induced by sleep
deprivation. This activity is observed in the absence of any modifications of appetite or behaviour.
Morning administration of 200 mg does not appear to affect nocturnal sleep. Administration of 100
mg morning and noon may prolong the subjective time taken to fall asleep. Evening administration
may disturb sleep. This pharmacodynamic activity does not appear to affect the autonomic nervous
system.

CLINICAL TRIALS
Studies reported here were multicenter, randomized, double-blind, placebo-controlled parellel-group
clinical trials. The efficacy criteria reported for the trials included:
• Maintenance of Wakefulness Test (MWT), which quantitatively measures the patient’s ability to
resist sleep and maintain wakefulness. The patients were asked to attempt to remain awake
without using extraordinary measures. The test was terminated after 20 minutes if no sleep
occurred or 10 minutes after sleep onset.
• Clinical Global Impression of Change (CGI-C), which is a 7-point scale ranging from “Very Much
Worse” to “Very Much Improved” from baseline; it was assessed by an independent clinician who
had no access to any data about the patients other than a measure of their baseline severity.
• Epworth Sleepiness Scale (ESS), which is a recall-based questionnaire devised to provide a
measurement of the subject’s general level of day-to-day sleepiness, or preferably, sleep
propensity.
Narcolepsy:
The effectiveness of modafinil in reducing the excessive sleepiness (ES) associated with narcolepsy
was established in two US 9-week, multicentre, placebo-controlled, two-dose (200mg per day and
400mg per day) parallel-group, double-blind studies of outpatients who met the ICD-9 and American
Sleep Disorders Association criteria for narcolepsy (which are also consistent with the American
Psychiatric Association DSM-IV criteria). These criteria included either:
• Recurrent daytime naps or lapses into sleep that occur almost daily for at least three months,
plus sudden bilateral loss of postural muscle tone in association with intense emotion
(cataplexy), or

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• A complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep
paralysis, hypnagogic hallucinations, automatic behaviours, disrupted major sleep episode; and
polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid
eye movement (REM) sleep latency less than 20 minutes.
In addition, for entry into these studies, all patients were required to have objectively documented
excessive daytime sleepiness, a Multiple Sleep Latency Test with two or more sleep onset REM
periods, and the absence of any clinically significant active medical or psychiatric disorder.
In both studies, the primary measures of effectiveness were:
1. sleep latency, as assessed by the MWT, and
2. the change in the patient’s overall disease status, as measured by the CGI-C.
For a successful trial, both measures had to show significant improvement.
Patients in both modafinil treatment groups were able to stay awake longer than those receiving
placebo and were rated by an independent clinician as having a significant improvement in illness. A
statistically significantly enhanced ability to remain awake was shown on the MWT and the CGI-C scale
(see Tables 2 and 3).
Obstructive Sleep Apnoea/Hypopnoea Syndrome (OSAHS):
The results from two major phase 3 clinical trials of modafinil in patients with OSAHS are presented in
Tables 2 and 3. The effectiveness of MODAVIGIL® in reducing the excessive sleepiness associated with
OSAHS was established in two clinical trials. In both studies, patients were enrolled who met the
International Classification of Sleep Disorders (ICSD) criteria for OSAHS (which are also consistent with
the American Psychiatric Association DSM-IV criteria). These criteria include either, 1) excessive
sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated
features such as loud snoring, morning headaches and dry mouth upon awakening; or 2) excessive
sleepiness or insomnia and polysomnography demonstrating one of the following: more than five
obstructive apnoeas, each greater than 10 seconds in duration, per hour of sleep and one or more of
the following: frequent arousals from sleep associated with the apnoeas, bradytachycardia, and
arterial oxygen desaturation in association with the apnoeas. In addition, for entry into these studies,
all patients were required to have excessive sleepiness as demonstrated by a score ≥10 on the Epworth
Sleepiness Scale, despite treatment with continuous positive airway pressure (CPAP). Evidence that
CPAP was effective in reducing episodes of apnoea/hypopnea was required along with documentation
of CPAP use.
Study 303 (n = 327) assessed the efficacy and safety of two doses of modafinil (200 mg and 400 mg
per day) in the treatment of excessive sleepiness in patients with established OSAHS, despite partial
or satisfactory use of continuous positive airway pressure (CPAP) therapy. The primary efficacy
variables for study 303 were MWT and CGI-C. Study 402 (n = 157) provides supportive data for
modafinil 400mg per day in the treatment of excessive sleepiness in patients with established OSAHS,
despite the use of effective CPAP therapy. The primary efficacy variable for study 402 was ESS.
Clinically significant improvements were reported for each parameter and for both doses of modafinil
compared to placebo in Study 303 out to 12 weeks’ double-blind treatment, and Study 402 out to 4
weeks’ double-blind treatment (see Tables 2 and 3).
In a 12 month open-label extension period for Study 303 in which patients titrated their daily dose of
modafinil according to clinical response, ESS scores remained consistently improved compared to
baseline values in both those previously on modafinil and those previously on placebo.

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For OSAHS, modafinil has been shown to produce clinically meaningful reductions in excessive
sleepiness and its adverse effects on quality of life, in both the short and long term.
Shift Work Sleep Disorder (SWSD):
Two clinical trials conducted in patients with shift work sleep disorder provide information on the
efficacy of modafinil in this indication. The moderate to severe subgroup of patients with SWSD for
whom modafinil is indicated is defined by the inclusion criteria in the pivotal clinical trials. These
criteria included a CGI-S (Clinical Global Impression of Severity) rating of at least “moderately ill”
(relating to ES on shift nights) at baseline, a mean sleep latency of no more than 6 minutes on the
Multiple Sleep Latency Test (MSLT) and no more than 87.5% sleep efficiency (time sleeping/time in
bed).
All patients met the International Classification of Sleep Disorders (ICSD) criteria for chronic SWSD
(which are consistent with the American Psychiatric Association DSM-IV criteria for Circadian Rhythm
Sleep Disorder: Shift Work Type).
Patients were enrolled if they worked at least 5 night shifts per month (of which at least 3 nights were
consecutive) and planned to maintain this schedule for the duration of the double-blind portion of the
study. Each night shift was no longer than 12 hours in duration and included at least 6 hours between
the hours of 2200 and 0800. Patients with any other disorder that might account for their excessive
sleepiness were excluded.
Placebo or modafinil was taken 30 to 60 minutes before each night shift. Having worked three
consecutive night shifts, patients were admitted to the sleep centre for a fourth, simulated night shift
(= a study visit), during which the various efficacy parameters were assessed.
Study 305 (n = 209) evaluated the efficacy and safety of 12 weeks’ therapy with modafinil at a dose of
200 mg as treatment for adults with excessive sleepiness associated with chronic shift work sleep
disorder. The primary efficacy variables were MSL-MSLT and CGI-C. Statistically significant
improvements were seen for patients in the modafinil group when compared to patients in the
placebo group for both of the primary endpoint measures (see Tables 2 and 4).
Study 306 (n = 278) evaluated the safety and impact on Quality of Life of 12 weeks of modafinil therapy
at dosages of 200mg or 300mg once daily as treatment for adults with excessive sleepiness associated
with shift work sleep disorder. The potential impact of modafinil treatment on quality-of-life was
assessed by measuring the mean changes from baseline to week 12 using the following measures:
• Functional Outcomes of Sleep Questionnaire (FOSQ)
• 36-Item Short Form Health Survey (SF-36)
In Study 306, modafinil treatment appeared to have a clinically meaningful effect on patient quality
of life as assessed by the FOSQ. For the patients in the modafinil 300 mg/day group, improvement
from baseline to week 12 was statistically significant for the total score (p = 0.0126), and for the
individual scores for vigilance (p = 0.0123), activity level (p = 0.0055) and general productivity (p =
0.0041) when compared with placebo. Although not statistically significant, the p-values for the
change from baseline for the modafinil-200mg/day treatment group showed a trend toward
significance.
Improvement was observed in the mental component score of SF-36 at all time points for patients in
the modafinil-treated groups compared with the placebo-treated group. Statistical significance was
observed at endpoint with the modafinil 300 mg/day group for the mental component summary (p =
0.0113), vitality (p < 0.0001) and role emotion (p = 0.0444) when compared with placebo.

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In a 12-month open label extension period for Study 306, improvements in FOSQ total score and in
the SF-36 mental composite score at endpoint were of the same magnitude as those seen in the
double-blind period, and were considered clinically meaningful.
In SWSD, modafinil has been shown to produce clinically meaningful reductions in excessive sleepiness
and had positive impact on quality of life, in both the short and long term.
Table 2. Summary of the pivotal US clinical studies of modafinil as measured by defined CGI-C
responder rates

Table 3: Summary of clinical trial data in patients with narcolepsy or OSAHS following treatment
with modafinil

Data in changes from baseline to endpoint for modafinil vs placebo, unless otherwise stated
a Positive value = modafinil better than placebo, negative value = modafinil worse than placebo
b Difference in absolute value over placebo at endpoint

Table 4: SWSD study 305 sleep latency (mins) from MSLT at endpoint

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5.2 Pharmacokinetic properties
Modafinil is a racemic compound, whose enantiomers have different pharmacokinetics (e.g. the half-
life of the l-isomer is approximately three times that of the d-isomer in humans). The enantiomers do
not interconvert. At steady state, total exposure to the l-isomer is approximately three times that of
the d-isomer. The trough concentration (Cminss) of circulating modafinil after once daily dosing consists
of 90% of the l-isomer and 10% of the d-isomer.
Absorption
Modafinil is slowly absorbed with an absorption half-life of approximately 1 hour. Peak plasma
concentrations (Cmax) of approximately 3.3mg/L are reached 3 hours (tmax) after administration of a
200 mg dose. Both the area under the plasma concentration curve (AUC), and the peak plasma
concentration show dose-proportionality in the 50 to 400 mg range. The absolute oral bioavailability
could not be determined due to the aqueous insolubility (< 1mg/mL) of modafinil, which precluded
intravenous administration. Food has no effect on the overall bioavailability of modafinil, however, its
absorption (tmax) may be delayed by approximately one hour if taken with food.
Distribution
Modafinil is well distributed in body tissue with an apparent volume of distribution (~0.9 L/kg) larger
than the volume of total body water (0.6 L/kg). Modafinil is weakly bound to plasma proteins (62%),
mainly to albumin. At serum concentrations obtained at steady state after doses of 200 mg/day,
modafinil exhibits no displacement of protein binding of warfarin, diazepam, or propranolol.
Metabolism
Metabolism occurs through hydrolytic deamination, S-oxidation, aromatic ring hydroxylation, and
glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent compound.
In a clinical study using radiolabelled modafinil, a total of 81% of the administered radioactivity was
recovered in 11 days post-dose, predominantly in the urine (80% vs. 1% in the faeces).
The chief metabolite (40-50% of the dose) is acid modafinil, which has no pharmacological activity.
The excretion of modafinil and its metabolites is chiefly renal, with a small proportion being eliminated
unchanged (< 10%).
Only two metabolites reach appreciable concentrations in plasma, i.e., acid modafinil and modafinil
sulfone. In preclinical models, modafinil acid, modafinil sulfone, 2-[(diphenylmethyl)sulfonyl]acetic
acid and 4-hydroxy modafinil, were inactive or did not appear to mediate the arousal effects of
modafinil.
In humans, modafinil shows a possible induction effect on its own metabolism after chronic
administration of doses ≥ 400 mg/day. In vitro studies with human hepatocytes and liver microsomes
have shown induction of metabolising enzymes CYP3A4 and CYP1A1/2, and inhibition of CYP2C19 (see
section 4.5 Interaction with other medicines and other forms of interaction).
Excretion
The major route of elimination (~90%) is metabolism, primarily by the liver, with subsequent renal
elimination of the metabolites. The elimination half-life of modafinil after multiple doses is about 10-
12 hours. Urine alkalinisation has no effect on the elimination of modafinil.
Special Populations
Children: The pharmacokinetics of modafinil have not been studied in children.

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Age effect: A slight decrease (~20%) in the oral clearance of modafinil was observed in subjects with a
mean age of 63 years (range: 53 to 73 years). The clearance of modafinil may be reduced in the elderly.
Gender Effect: The pharmacokinetics of modafinil are not affected by gender.
Race effect: The influence of race on the pharmacokinetics of modafinil has not been studied.
Renal impairment: The pharmacokinetics of modafinil were not significantly influenced in patients
with severe chronic renal failure (creatinine clearance ≤ 20mL/min), but the exposure to modafinil
acid (an inactive metabolite) was increased 9-fold.
Hepatic impairment: The oral clearance of modafinil was decreased by about 60% and the steady state
concentration was doubled in patients with severe chronic hepatic impairment.

5.3 Preclinical safety data

Genotoxicity
There was no consistent evidence for genotoxic activity of modafinil in in vitro assays of gene mutation
(reverse mutation in S. typhimurium and E. coli, forward mutation in Chinese hamster V79 fibroblasts)
or in the chromosomal damage assay (human lymphocytes in vitro, Chinese hamster bone marrow
cells in vivo, mouse micronucleus assay). Modafinil did not increase unscheduled DNA synthesis in rat
hepatocytes. In a cell transformation assay in BALB/3T3 mouse embryo cells, modafinil did not cause
an increase in the frequency of transformed foci in the presence or absence of metabolic activation.
Carcinogenicity
Carcinogenicity studies were conducted in which modafinil was administered in the diet to mice for
78 weeks and to rats for 104 weeks at doses up to 60 mg/kg/day. The highest dose studied in these
studies would have achieved systemic exposure levels less than human exposure at the maximum
recommended dose. There was no evidence of tumourigenesis associated with modafinil
administration in these studies; however, the carcinogenic potential of modafinil has not been fully
evaluated.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Modafinil tablets contain the following excipients:

Lactose monohydrate
Crospovidone
Povidone K30
Lactose Anhydrous
Talc
Silica, Colloidal Anhydrous
Sodium Stearyl fumarate.

6.2 Incompatibilities
Not applicable.

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6.3 Shelf life

24 months

6.4 Special precautions for storage

Store below 25 °C

6.5 Nature and contents of container

Blister packs of 30 tablets (3 blisters strips containing 10 tablets).

6.6 Special precautions for disposal and other handling

Any unused medicine or waste material should be disposed of in accordance with local
requirements.

7 MEDICINE SCHEDULE
Prescription Medicine

8 SPONSOR

Max Health Ltd

PO Box 44452
Pt Chevalier, Auckland 1246
Telephone: (09) 815 2664.

9 DATE OF FIRST APPROVAL

10 October 2019

10 DATE OF REVISION OF THE TEXT

21 July 2022

SUMMARY TABLE OF CHANGES

Section Changed Summary of new information

4.2 Amended wording for OSAHS
4.3 Amended pregnancy indication
4.4 Inclusion of additional information concerning the nature and magnitude
of the risk of using modafinil during pregnancy
4.6 Inclusion of additional information concerning the nature and magnitude
of the risk ,of using modafinil during pregnancy
8 Sponsor details update

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