4.1. Therapeutic indications

Provigil is indicated in adults for the treatment of excessive sleepiness associated with narcolepsy with or without cataplexy.

Excessive sleepiness is defined as difficulty maintaining wakefulness and an increased likelihood of falling asleep in inappropriate situations.

4.2. Posology and method of administration

Treatment should be initiated by or under the supervision of a physician with appropriate knowledge of indicated disorders (see section 4.1).

A diagnosis of narcolepsy should be made according to the International Classification of Sleep Disorders (ICSD2) guideline.

Patient monitoring and clinical assessment of the need for treatment should be performed on a periodic basis.

Posology

The recommended starting daily dose is 200 mg. The total daily dose may be taken as a single dose in the morning or as two doses, one in the morning and one at noon, according to physician assessment of the patient and the patient's response.

Doses of up to 400 mg in one or two divided doses can be used in patients with insufficient response to the initial 200 mg modafinil dose.

Long-term use

Physicians prescribing modafinil for an extended time should periodically re-evaluate the long-term use for the individual patients as the long-term efficacy of modafinil has not been evaluated (> 9 weeks).

Renal impairment

There is inadequate information to determine safety and efficacy of dosing in patients with renal impairment (see section 5.2).

Hepatic impairment

The dose of modafinil should be reduced by half in patients with severe hepatic impairment (see section 5.2).

Elderly

There are limited data available on the use of modafinil in elderly patients. In view of the potential for lower clearance and increased systemic exposure, it is recommended that patients over 65 years of age commence therapy at 100 mg daily.

Paediatric population

Modafinil should not be used in children aged less than 18 years old because of safety and efficacy concerns (see section 4.4).

Method of administration

For oral use.

Tablets should be swallowed whole.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Uncontrolled moderate to severe hypertension.

Cardiac arrhythmias.

4.4. Special warnings and precautions for use

Diagnosis of sleep disorders

Modafinil should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of narcolepsy, has been made in accordance with ICSD diagnostic criteria. Such an evaluation usually consists, in addition to the patient's history, sleep measurements testing in a laboratory setting and exclusion of other possible causes of the observed hypersomnia.

Serious rash, including Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis and Drug Rash with Eosinophilia and Systemic Symptoms

Serious rash requiring hospitalisation and discontinuation of treatment has been reported with the use of modafinil occurring within 1 to 5 weeks after treatment initiation. Isolated cases have also been reported after prolonged treatment (e.g., 3 months). 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); this includes serious rash. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil. Modafinil should be discontinued at the first sign of rash and not re-started (see section 4.8).

Rare cases of serious or life-threatening rash, including Stevens-Johnson Syndrome (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.

Paediatric population

Because safety and effectiveness in controlled studies in children have not been established and because of the risk of serious cutaneous hypersensitivity and psychiatric adverse reactions, the use of modafinil is not recommended in the paediatric population (below 18 years).

Multi-organ hypersensitivity reaction

Multi-organ hypersensitivity reactions, including at least one fatality in post-marketing experience, have occurred in close temporal association to the initiation of modafinil.

Although there have 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 this disorder 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.

Psychiatric disorders

Patients should be monitored for the development of de novo or exacerbation of pre-existing psychiatric disorders (see below and section 4.8) at every adjustment of dose and then regularly during treatment. If psychiatric symptoms develop in association with modafinil treatment, modafinil should be discontinued and not restarted. 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 (see below).

Anxiety

Modafinil is associated with the onset or worsening of anxiety. Patients with major anxiety should only receive treatment with modafinil in a specialist unit.

Suicide-related behaviour

Suicide-related behaviour (including suicide attempts and suicidal ideation) has been reported in patients treated with modafinil. Patients treated with modafinil should be carefully monitored for the appearance or worsening of suicide-related behaviour. If suicide-related symptoms develop in association with modafinil, treatment should be discontinued.

Psychotic or manic symptoms

Modafinil is associated with the onset or worsening of psychotic symptoms or manic symptoms (including hallucinations, delusions, agitation or mania). Patients treated with modafinil should be carefully monitored for the appearance or worsening of psychotic or manic symptoms. If psychotic or manic symptoms occur, discontinuation of modafinil may be required.

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.

Aggressive or hostile behaviour

The onset or worsening of aggressive or hostile behaviour can be caused by treatment with modafinil. Patients treated with modafinil should be carefully monitored for the appearance or worsening of aggressive or hostile behaviour. If symptoms occur, discontinuation of modafinil may be required.

Cardiovascular risks

An ECG is recommended in all patients before Modafinil treatment is initiated. Patients with abnormal findings should receive further specialist evaluation and treatment before Modafinil treatment is considered.

Blood pressure and heart rate should be regularly monitored in patients receiving modafinil. Modafinil should be discontinued in patients who develop arrhythmia or moderate to severe hypertension and not restarted until the condition has been adequately evaluated and treated.

Modafinil tablets are not recommended in patients with a history of left ventricular hypertrophy or cor pulmonale and in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. This syndrome may present with ischaemic ECG changes, chest pain or arrhythmia.

Insomnia

Because modafinil promotes wakefulness, caution should be paid to signs of insomnia.

Maintenance of sleep hygiene

Patients should be advised that modafinil is not a replacement for sleep and good sleep hygiene should be maintained. Steps to ensure good sleep hygiene may include a review of caffeine intake.

Patients using steroidal contraceptives

Sexually active women of child-bearing potential should be established on a contraceptive programme before taking modafinil. Since the effectiveness of steroidal contraceptives may be reduced when used with modafinil, alternative or concomitant methods of contraception are recommended, and for two months after discontinuation of modafinil (also see section 4.5 with respect to potential interaction with steroidal contraceptives).

Abuse, misuse, diversion

Whilst studies with modafinil have demonstrated a potential for dependence, the possibility of dependence with long-term use cannot be entirely excluded.

Caution should be exercised in administering modafinil to patients with history of alcohol, drug or illicit substance abuse.

Excipients

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Modafinil may increase its own metabolism via induction of CYP3A4/5 activity but the effect is modest and unlikely to have significant clinical consequences.

Anticonvulsants

Co-administration of potent inducers of CYP activity, such as carbamazepine and phenobarbital, could reduce the plasma levels of modafinil. Due to a possible inhibition of CYP2C19 by modafinil and suppression of CYP2C9 the clearance of phenytoin may be decreased when modafinil is administered concomitantly. Patients should be monitored for signs of phenytoin toxicity, and repeated measurements of phenytoin plasma levels may be appropriate upon initiation or discontinuation of treatment with modafinil.

Steroidal contraceptives

The effectiveness of steroidal contraceptives may be impaired due to induction of CYP3A4/5 by modafinil. Alternative or concomitant methods of contraception are recommended for patients treated with modafinil. Adequate contraception will require continuation of these methods for two months after stopping modafinil.

Antidepressants

A number of tricyclic antidepressants and selective serotonin reuptake inhibitors are largely metabolised by CYP2D6. In patients deficient in CYP2D6 (approximately 10 % of a Caucasian population) a normally ancillary metabolic pathway involving CYP2C19 becomes more important. As modafinil may inhibit CYP2C19, lower doses of antidepressants may be required in such patients.

Anticoagulants

Due to possible suppression of CYP2C9 by modafinil the clearance of warfarin may be decreased when modafinil is administered concomitantly. Prothrombin times should be monitored regularly during the first 2 months of modafinil use and after changes in modafinil dosage.

Other medicinal products

Substances that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol and omeprazole may have reduced clearance upon co-administration of modafinil and may thus require dosage reduction. In addition, in vitro induction of CYP1A2, CYP2B6 and CYP3A4/5 activities has been observed in human hepatocytes, which were it to occur in vivo, could decrease the blood levels of drugs metabolised by these enzymes, thereby possibly decreasing their therapeutic effectiveness. Results from clinical interaction studies suggest that the largest effects may be on substrates of CYP3A4/5 that undergo significant presystemic elimination, particularly via CYP3A enzymes in the gastrointestinal tract. Examples include ciclosporin, HIV-protease inhibitors, buspirone, triazolam, midazolam and most of the calcium channel blockers and statins. In a case report, a 50 % reduction in ciclosporin concentration was observed in a patient receiving ciclosporin in whom concurrent treatment with modafinil was initiated.

4.6. Fertility, pregnancy and lactation

Pregnancy

Based on human experience from a pregnancy registry and spontaneous reporting modafinil is suspected to cause congenital malformations when administered during pregnancy.

Studies in animals have shown reproductive toxicity (see section 5.3).

Modafinil should not be used during pregnancy.

Women of childbearing potential have to use effective contraception. As modafinil may reduce the effectiveness of oral contraception alternative additional methods of contraception are required (see section 4.4 and 4.5).

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of modafinil/metabolites in milk (for details see section 5.3).

Modafinil should not be used during breast feeding.

Fertility

No data on fertility are available in humans. At exposures similar to human levels at the recommended human dose, modafinil slightly increased the time to mate in female rats.

4.7. Effects on ability to drive and use machines

Patients with abnormal levels of sleepiness who take modafinil should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking modafinil should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Undesirable effects such as blurred vision or dizziness might also affect ability to drive (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse drug reaction is headache, affecting approximately 21 % of patients. This is usually mild or moderate, dose-dependent and disappears within a few days.

Tabulated list of adverse reactions

The following adverse reactions have been reported in clinical trials and/or post-marketing experience. The frequencies of adverse reactions considered at least possibly related to treatment, in clinical trials involving 1,561 patients taking modafinil were as follows.

System Organ Class

Very common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1000 to <1/100)

Rare

(≥1/10000 to <1/1000)

Frequency not known (cannot be estimated from the available data)

Infections and infestations

Pharyngitis

Sinusitis

Blood and lymphatic system disorders

Eosinophilia

Leucopenia

Immune system disorders

Minor allergic reaction (e.g., hay fever symptoms)

Angioedema

Urticaria (hives)

Hypersensitivity reactions (characterised by features such as fever, rash, lymphadenopathy and evidence of other concurrent organ involvement)

Anaphylaxis

Metabolism and nutrition disorders

Decreased appetite

Hypercholesterolaemia

Hyperglycaemia

Diabetes mellitus

Increased appetite

Psychiatric disorders

Nervousness

Insomnia

Anxiety

Depression

Abnormal thinking

Confusion

Irritability

Sleep disorder

Emotional lability

Decreased libido

Hostility

Depersonalisation

Personality disorder

Abnormal dreams

Agitation

Aggression

Suicidal ideation

Psychomotor hyperactivity

Hallucination

Mania

Psychosis

Delusions

Nervous system disorders

Headache

Dizziness

Somnolence

Paraesthesia

Dyskinesia

Hypertonia

Hyperkinesia

Amnesia

Migraine

Tremor

Vertigo

CNS stimulation

Hypoaesthesia

Incoordination

Movement disorder

Speech disorder

Taste perversion

Eye disorders

Blurred vision

Abnormal vision

Dry eye

Cardiac disorders

Tachycardia

Palpitation

Extrasystoles

Arrhythmia

Bradycardia

Vascular disorders

Vasodilatation

Hypertension

Hypotension

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Increased cough

Asthma

Epistaxis

Rhinitis

Gastrointestinal disorders

Abdominal pain

Nausea

Dry mouth

Diarrhoea

Dyspepsia

Constipation

Flatulence

Reflux

Vomiting

Dysphagia

Glossitis

Mouth ulcers

Skin and subcutaneous tissue disorders

Sweating

Rash

Acne

Pruritus

Serious skin reactions, including erythema multiforme, Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)

Musculoskeletal and connective tissue disorders

Back pain

Neck pain

Myalgia

Myasthenia

Leg cramps

Arthralgia

Twitch

Renal and urinary disorders

Abnormal urine

Urinary frequency

Reproductive system and breast disorders

Menstrual disorder

General disorders and administration site conditions

Asthenia

Chest pain

Peripheral oedema

Thirst

Investigations

Abnormal liver function tests

Dose related increases in alkaline phosphatase and gamma-glutamyl transferase

Abnormal ECG

Weight increase

Weight decrease

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

Death has occurred with modafinil overdose alone or in combination with other drugs. Symptoms most often 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 diarrhoea; and cardiovascular changes such as tachycardia, bradycardia, hypertension and chest pain.

Management

Induced emesis or gastric lavage should be considered. Hospitalisation and surveillance of psychomotor status; cardiovascular monitoring or surveillance until the patient's symptoms have resolved are recommended.