Consumer medicine information

Modafinil Mylan

Modafinil

BRAND INFORMATION

Brand name

Modafinil Mylan

Active ingredient

Modafinil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Modafinil Mylan.

What is in this leaflet

This leaflet answers some common questions about MODAFINIL MYLAN. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking MODAFINIL MYLAN against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What MODAFINIL MYLAN is used for

MODAFINIL MYLAN is used to improve wakefulness in people with excessive daytime sleepiness associated with the medical condition known as narcolepsy or with Obstructive Sleep Apnoea/Hypopnoea Syndrome (OSAHS), or shift work sleep disorder (SWSD).

In narcolepsy, there is a sudden and irresistible tendency to fall asleep during normal waking hours. This happens at unpredictable times, even when it is inappropriate or may be unsafe to do so. MODAFINIL MYLAN decreases this unwanted excessive daytime sleepiness.

With OSAHS, daytime sleepiness may occur due to an interrupted night time sleep. MODAFINIL MYLAN only treats the symptom of sleepiness and does not treat the cause of OSAHS. Whilst taking MODAFINIL MYLAN you should continue with treatments intended to help manage your underlying medical condition, such as Continuous Positive Airway Pressure, unless your doctor tells you otherwise.

If you have been diagnosed with moderate to severe chronic Shift Work Sleep Disorder (SWSD) and non-drug therapies have been unsuitable or unsuccessful, MODAFINIL MYLAN may be prescribed to keep you awake during your work shift.

Precisely how MODAFINIL MYLAN works is not known, but it is known that it acts on the central nervous system (the brain). It differs from other stimulant medicines that promote wakefulness. MODAFINIL MYLAN increases wakefulness.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

There is not enough information to recommend the use of this medicine for children under the age of 18 years and patients over 65 years.

This medicine is available only with a doctor's prescription.

Before you take MODAFINIL MYLAN

When you must not take it

Do not take MODAFINIL MYLAN if you have an allergy to:

  • any medicine containing modafinil
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you are pregnant, planning to become pregnant or likely to become pregnant. Modafinil is suspected to cause birth defects if taken during pregnancy You should ensure that you have reliable and effective methods of contraception.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • a history of mental health problems
  • heart problems, including, for example, angina (chest pain), previous heart attack, enlarged heart
  • an abnormal/irregular heart rhythm
  • high blood pressure or your high blood pressure is controlled by medication
  • kidney or liver problems

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Women of childbearing age require a negative pregnancy test the week prior to commencing treatment, as this medicine can harm the foetus.

It is not known whether modafinil passes into breastmilk and may affect your developing baby.

Do not take this medicine if you are under 18 or over 65 years old.

If you have not told your doctor about any of the above, tell them before you start taking MODAFINIL MYLAN.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and MODAFINIL MYLAN may interfere with each other. These include:

  • steroidal hormonal contraceptives, including the contraceptive pill, implants, injectables and hormone releasing intrauterine devices (IUDs)
  • treatment for anxiety or muscle relaxant, such as diazepam (Valium)
  • brain stimulants, such as methylphenidate (Ritalin)
  • medicines to treat depression, including monoamine oxidase inhibitors (MAOIs), such as phenelzine (Nardil) and nialamide (Niamid)
  • medicines to treat epilepsy or fits, such as phenytoin (Dilantin), carbamazepine (Tegretol) and phenobarbitone (phenobarbital)
  • medicines to treat fungal infections, such as ketoconazole and itraconazole
  • medicines to help you sleep (sedatives), such as temazepam and triazolam
  • rifampicin, an antibiotic used to treat tuberculosis
  • ciclosporin, a medicine used to stop organ transplant rejection
  • propranolol, a medicine used to treat high blood pressure, heart problems or migraine
  • warfarin, a medicine used to prevent unwanted blood clotting
  • theophylline, a medicine used to treat asthma and lung problems
  • clomipramine in poor metabolisers (Anafranil)

These medicines may be affected by MODAFINIL MYLAN or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take MODAFINIL MYLAN

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

Each MODAFINIL MYLAN tablet contains 100mg of modafinil.

The usual daily dose of modafinil depends on individual response. For sleepiness associated with narcolepsy or OSAHS, the dose ranges from 200mg to 400mg.

Each day you should take either:

  • two MODAFINIL MYLAN tablets
    or
  • up to four MODAFINIL MYLAN tablets.

For SWSD, a dose of 200 mg is recommended.

Do not exceed the recommended daily dose unless directed to do so by your doctor.

How to take it

Swallow the tablets whole with a little water.

When to take it

For sleepiness associated with narcolepsy or OSAHS, you should take your MODAFINIL MYLAN tablets either:

  • as two separate doses, one in the morning and one at midday,
    or
  • as one dose, in the morning.

For narcolepsy or OSAHS, do not take your MODAFINIL MYLAN tablets later than midday, or you may have trouble sleeping at night.

For SWSD, you should take your MODAFINIL MYLAN tablets as a single dose 1 hour prior to commencing your shift work.

NOTE: Your doctor may start your treatment with less than two tablets a day.

If you need more than two tablets per day, your doctor should increase the dose stepwise, one additional tablet at a time, depending on how you respond to the treatment. The highest dose is four tablets per day.

If you are currently on another treatment for narcolepsy, your doctor will advise you how best to withdraw from that treatment and begin taking MODAFINIL MYLAN. Other stimulants used for narcolepsy may cause a "high" feeling. Be aware therefore that you may feel different as you withdraw from other stimulants.

MODAFINIL MYLAN only treats the symptom of sleepiness. Other treatments intended to help manage your underlying medical condition should still be used regularly, unless your doctor tells you otherwise. You should commence or continue disease-modifying interventions (for example, Continuous Positive Airway Pressure).

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is almost time to take your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much MODAFINIL MYLAN. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking MODAFINIL MYLAN

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking MODAFINIL MYLAN.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, stop taking it and tell your doctor immediately.

Tell your doctor if you believe that MODAFINIL MYLAN is not helping your condition. Your doctor may need to change the dose.

If required, your doctor may monitor your blood pressure and perform an ECG before treatment.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take MODAFINIL MYLAN to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or change the dosage without checking with your doctor.

Things to be careful of

MODAFINIL MYLAN may reduce the effectiveness of steroidal contraceptives. If you are using these forms of contraceptives while taking MODAFINIL MYLAN (and for 2 months after you stop treatment with MODAFINIL MYLAN) you should either use: an alternative birth control method or another effective birth control method together with your current contraceptive.

Be careful driving or operating machinery until you know how MODAFINIL MYLAN affects you. This medicine may cause dizziness in some people.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking MODAFINIL MYLAN.

This medicine helps most people with excessive daytime sleepiness, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • headache
  • nausea
  • diarrhoea
  • constipation
  • dry mouth
  • changes in taste
  • mouth ulcers
  • feeling thirsty
  • poor appetite or weight loss
  • runny nose
  • chills
  • sore throat
  • nose bleed
  • asthma
  • anxious or nervous feeling
  • dizziness
  • back pain
  • stiff neck, muscles
  • muscle spasm, tremor, involuntary movements, muscle weakness or pain
  • confusion or mood changes
  • upset stomach
  • trouble sleeping
  • drowsiness, tiredness or fatigue
  • high or low blood pressure
  • tingling sensation in hands or feet (pins and needles)
  • sweating
  • acne
  • herpes simplex
  • changes in vision, lazy eye, or eye pain
  • blood in the urine, cloudy urine or painful urination

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • mental (psychiatric) symptoms. including depression, anxiety, aggression, agitation, irritability, hallucinations, mania, thoughts of suicide or other mental problems
  • chest pain or abnormal/fast heart beats or palpitations
  • fits or convulsions

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, stop taking the tablets and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • yellowing of the skin or white of the eyes or dark urine
  • fever, skin rash, hives (especially affecting the whole body) and itching
  • sores in your mouth, or your skin blisters and peels
  • sudden wheeziness, difficulty in breathing and swallowing
  • shortness of breath, swelling of the legs
  • cough, swelling of the face, lips, tongue, throat or other parts of the body

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After taking MODAFINIL MYLAN

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store MODAFINIL MYLAN or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

MODAFINIL MYLAN tablets are white, round, biconvex, tablet.

Ingredients

MODAFINIL MYLAN contains 100 mg of modafinil as the active ingredient.

The tablets also contain the following inactive ingredients:

  • lactose monohydrate
  • maize starch
  • croscarmellose sodium
  • povidone
  • magnesium stearate
  • aluminium magnesium silicate
  • purified talc

Each pack contains either 10, 30, 60 or 90 tablets.

Contains sugars (as lactose monohydrate). Contains sulfites.

Sponsor

Southern Cross Pharma Pty Ltd
Suite 5/118 Church Street
Hawthorn VIC 3122

Distributor

MODAFINIL MYLAN is distributed in Australia by:

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

This leaflet was prepared in June 2020.

AUST R 269913

MODAFINIL MYLAN_cmi\0620/06

Published by MIMS August 2020

BRAND INFORMATION

Brand name

Modafinil Mylan

Active ingredient

Modafinil

Schedule

S4

 

1 Name of Medicine

Modafinil.

2 Qualitative and Quantitative Composition

Each Modafinil Mylan tablet contains 100 mg of modafinil.

Excipients with known effect.

Sugars (as lactose monohydrate) and sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Modafinil Mylan is a white, round, biconvex, tablet containing 100 mg of modafinil.

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) (see Section 5.1 Pharmacodynamic Properties, Clinical trials). 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.

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.
Use in pregnancy, and in women who may become pregnant.

4.4 Special Warnings and Precautions for Use

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.
Modafinil is not approved for use in paediatric 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 paediatric 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 paediatric 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 worldwide post-marketing experience (see Section 4.8 Adverse Effects (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. However, isolated cases have been reported after prolonged treatment (e.g. 3 months). Accordingly, 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 drugs that produce this syndrome, the experience with drugs 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 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. Anxiety and nervousness are adverse events that appear to be closely dose related.

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.

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 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 drug 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 foetal harm and is contraindicated in women who are pregnant or may become pregnant (see Section 4.3 Contraindications; Section 4.6 Fertility, Pregnancy and Lactation).
Sexually active women of child-bearing potential should be established on a contraceptive program before taking modafinil. The woman should have a negative pregnancy test in the week prior to commencing treatment with modafinil. The effectiveness of steroidal contraceptives (including the contraceptive pill, implants, injectables and hormone releasing intrauterine devices [IUDs]) may be impaired due to enzyme induction activity of modafinil. Alternative or concomitant methods of contraception are required for patients treated with modafinil, 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, drug 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.

Use in 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 (see Section 4.2 Dose and Method of Administration).

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).

Paediatric use.

Use in children and adolescents (< 18 years of age).

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.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 drug. 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Potential interactions with drugs that inhibit, induce, 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.

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 drugs 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, ciclosporin, 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, ciclosporin 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 (phenobarbitone), 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 drug 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 on 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.
(Category D)
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).
After developmental toxicity was observed in animal studies, the Food and Drug Administration in the United States requested the initiation of the Nuvigil/Provigil Pregnancy Registry to characterise the pregnancy and foetal outcomes associated with Provigil (modafinil) and Nuvigil (armodafinil, the R-enantiomer of modafinil) exposure during pregnancy.
The results of the 2018 annual report of the Nuvigil/Provigil Pregnancy Registry documented cases of spontaneous abortion and of major congenital anomalies, including cardiac congenital anomalies and microcephaly. The frequency of major congenital anomalies (17.3%) and cardiac anomalies (4%) associated with the exposure to modafinil and/or armodafinil was above the frequency observed in the general population (3% and 1%, respectively). Spontaneous abortion and intrauterine growth restriction in association with modafinil have also been observed. There have also been post-marketing reports of congenital malformations and of low foetal growth, as well as cases of babies who failed to thrive (poor physical development).
Therefore, modafinil is contraindicated during pregnancy.
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. Alternative or concomitant methods of contraception are required (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
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 Adverse Effects (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 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.

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 Systemic Symptoms (DRESS), and hyperhidrosis.

Vascular disorders.

Rare: Hypertension.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

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 drugs. Symptoms accompanying modafinil overdose, alone or in combination with other drugs, 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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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-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 parallel-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 (200 mg per day and 400 mg 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 include 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
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 modafinil 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 400 mg 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.
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-10) 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 200 or 300 mg 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-200 mg/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.
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.

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 3.3 mg/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 (< 1 mg/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.

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.
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 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

See Section 5.2 Pharmacokinetic Properties, Metabolism.

Special populations.

Children.

The pharmacokinetics of modafinil have not been studied in children.

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 ≤ 20 mL/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 Mylan tablets contain the excipients lactose monohydrate, maize starch, aluminium magnesium silicate, croscarmellose sodium, povidone, purified talc and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.
This medicinal product does not require any special storage conditions.

6.5 Nature and Contents of Container

It is registered in packs of 10, 30, 60, and 90 tablets supplied in PVC/Al blister strips, each of which contains 10 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Modafinil is a racemic compound and the chemical name is 2-[(diphenylmethyl)sulfinyl] acetamide. The molecular formula is C15H15NO2S and the molecular weight is 273.35.
Modafinil is a white to off-white, crystalline powder that is practically insoluble in water and cyclohexane. It is sparingly to slightly soluble in ethanol and acetone.

Chemical structure.


CAS number.

68693-11-8.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes