PROVIGIL^® 100 mg tablets

PROVIGIL^®200 mg tablets

Modafinil 100 mg per tablet.

Modafinil 200 mg per tablet.

For excipients, see 6.1.

Tablet

White to off-white, capsule-shaped tablets, debossed with “100” on one side.

White to off-white, scored, capsule-shaped tablets, debossed with “200” on one side.

PROVIGIL is indicated for the symptomatic relief of excessive sleepiness associated with:

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

Diagnosis of SWSD should be made according to the International Classification of Sleep Disorders (ICSD) guideline. The moderate to severe subgroup of patients with SWSD for whom Provigil is indicated is defined by the inclusion criteria in the pivotal clinical trials. See section 5.1 (Pharmacodynamic properties) for further details on these criteria.

For oral use. Tablets should be swallowed whole.

Adults

Narcolepsy and Obstructive Sleep Apnoea / Hypopnoea Syndrome

The recommended daily dose is 200-400 mg, commencing at 200 mg and titrated according to clinical response. PROVIGIL may be taken as two divided doses in the morning and at noon, or as a single dose in the morning, according to physician assessment of the patient and the patient's response.

For patients with OSAHS, PROVIGIL treats the symptom of excessive daytime sleepiness associated with the condition. In addition to this symptomatic treatment, disease-modifying interventions (e.g., Continuous Positive Airway Pressure) should be commenced or continued.

Moderate to Severe Chronic Shift Work Sleep Disorder

The recommended daily dose is 200 mg. PROVIGIL should be taken as a single dose approximately 1 hour prior to the start of the work shift. PROVIGIL should be taken intermittently (i.e. only on the shifts worked).

Elderly

There are limited data available on the use of PROVIGIL in elderly patients. In view of the generally lower hepatic and renal clearance expected in an elderly population, it is recommended that patients over 65 years of age should commence therapy at 100 mg daily. The maximum dose of 400 mg per day should only be used in the absence of renal or hepatic impairment.

Hepatic and renal failure

The dose in patients with severe hepatic or renal failure should be reduced by half (100-200 mg per day).

Children

Because safety and effectiveness in controlled studies in children have not been established the use of PROVIGIL is not recommended in children (see section 4.4).

Additional information for the safe use of this product

Treatment should be initiated by or under the supervision of a physician with appropriate knowledge of relevant sleep disorders.

PROVIGIL treats the symptom of excessive sleepiness associated with the above conditions. Where appropriate, every effort should be made to treat the underlying condition prior to initiating treatment with PROVIGIL.

In patients with excessive sleepiness due to moderate to severe chronic SWSD, appropriate steps to ensure adequate sleep should be taken prior to determining the requirement for PROVIGIL.

PROVIGIL is contraindicated for use during pregnancy and lactation, or in patients with uncontrolled moderate to severe hypertension, or arrhythmia. PROVIGIL is also contraindicated in patients with known hypersensitivity to PROVIGIL or any component of the preparation.

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 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).

Patients with major anxiety should only receive treatment with PROVIGIL in a specialist unit.

Psychiatric adverse experiences, including suicidal ideation, have been reported in patients treated with modafinil. In such circumstances, Modafinil should be discontinued and not re-started. Caution should be exercised in administering modafinil to patients with a history of psychosis, depression or mania, given the possible emergence or exacerbation of psychiatric symptoms (see section 4.8).

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

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

Blood pressure and heart rate should be monitored in hypertensive patients.

It is recommended that PROVIGIL tablets not be used in patients with a history of left ventricular hypertrophy or cor pulmonale. PROVIGIL should not be used 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.

In patients with obstructive sleep apnoea / hypopnoea syndrome, the underlying condition and any associated cardiovascular pathology should be monitored.

Patients should be advised that PROVIGIL 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.

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

PROVIGIL tablets contain lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.

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 PROVIGIL 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 PROVIGIL.

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 PROVIGIL. Adequate contraception will require continuation of these methods for two months after stopping PROVIGIL.

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 PROVIGIL is administered concomitantly. Prothrombin times should be monitored regularly during the first 2 months of PROVIGIL use and after changes in PROVIGIL dosage.

Other drugs: Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol and omeprazole may have reduced clearance upon co-administration of PROVIGIL 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.

There are no adequate data from the use of modafinil in pregnant women.

Modafinil was non-teratogenic in rats and rabbits at doses greater than the maximum clinical dose. However, plasma levels in preclinical studies, due to metabolic auto-induction, were less than or similar to that expected in patients.

Modafinil and its acid and sulphone metabolites pass into milk of lactating rats (see 5.3). It is not known whether modafinil passes into human milk.

Modafinil use during pregnancy and lactation is contraindicated.

There is no information available concerning the effects of PROVIGIL on vehicle driving and/or the ability to use machinery. Undesirable effects such as blurred vision or dizziness might affect ability to drive (see 4.8 Undesirable Effects).

The following undesirable effects have been reported in clinical trials and/or post-marketing experience. The frequency of undesirable effects considered at least possibly related to treatment, in clinical trials involving 1561 patients taking PROVIGIL were as follows: very common1/10, common1/100 to 1/10, uncommon1/1000 to 1/100, unknown (cannot be estimated from available data).

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.

Investigations

Common: abnormal liver function tests, dose related increases in alkaline phosphatase and gamma glutamyl transferase have been observed.

Uncommon: abnormal ECG, weight increase, weight decrease

Cardiac disorders

Common: tachycardia, palpitation

Uncommon: extrasystoles, arrhythmia, bradycardia

Blood and lymphatic system disorders

Uncommon: eosinophilia, leucopenia

Nervous system disorders

Very common: headache

Common: dizziness, somnolence, paraesthesia

Uncommon: dyskinesia, hypertonia, hyperkinesia, amnesia, migraine, tremor, vertigo, CNS stimulation, hypoaesthesia, incoordination, movement disorder, speech disorder, taste perversion

Eye disorders

Common: blurred vision

Uncommon: abnormal vision, dry eye

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea, increased cough, asthma, epistaxis, rhinitis

Gastrointestinal disorders

Common: abdominal pain, nausea, dry mouth, diarrhoea, dyspepsia, constipation

Uncommon: flatulence, reflux, vomiting, dysphagia, glossitis, mouth ulcers

Renal and urinary disorders

Uncommon: abnormal urine, urinary frequency

Skin and subcutaneous tissue disorders

Uncommon: sweating, rash, acne, pruritis

Unknown: 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

Uncommon: back pain, neck pain, myalgia, myasthenia, leg cramps, arthralgia, twitch

Metabolism and nutrition disorders

Common: decreased appetite

Uncommon: hypercholesterolaemia, hyperglycaemia, diabetes mellitus, increased appetite,

Infections and infestations

Uncommon: pharyngitis, sinusitis

Vascular disorders:

Common: vasodilatation

Uncommon: hypertension, hypotension

General disorders and administration site conditions

Common: asthenia, chest pain

Uncommon: peripheral oedema, thirst

Immune system disorders

Uncommon: minor allergic reaction (e.g., hayfever symptoms)

Unknown: Angioedema, urticaria (hives). Hypersensitivity reactions (characterised by features such as fever, rash, lymphadenopathy and evidence of other concurrent organ involvement).

Reproductive system and breast disorders

Uncommon: menstrual disorder

Psychiatric disorders

Common: nervousness, insomnia, anxiety, depression, abnormal thinking, confusion

Uncommon: sleep disorder, emotional lability, decreased libido, hostility, depersonalisation, personality disorder, agitation, abnormal dreams, aggression.

Unknown: psychosis, mania, delusions, hallucinations and suicidal ideation.

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, 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.

Therapeutic class: centrally acting sympathomimetic (ATC Code: N06BA07).

Modafinil promotes wakefulness in a variety of species, including man. The precise mechanism(s) through which modafinil promotes wakefulness is unknown.

In pre-clinical models, modafinil does not appear to be a direct or indirect acting alpha₁-adrenoceptor or dopamine receptor agonist. The wakefulness induced by amfetamine, but not by modafinil, is antagonised by the dopamine receptor antagonist haloperidol. Equal wakefulness-promoting doses of methylphenidate and amfetamine increase neuronal activation throughout the brain, but modafinil selectively and prominently increases neuronal activation in more discrete regions of the brain, especially in the hypothalamus.

In man, modafinil restores and/or improves the level and duration of wakefulness and daytime alertness in a dose-related manner. Administration of modafinil results in electrophysiological changes indicative of increased alertness and improvements in objective measures of ability to sustain wakefulness. Modafinil opposes the impairment of cognitive, psychomotor and neurosensorial performance induced by sleep deprivation. These changes are produced without any adverse changes in behaviour and appetite.

In patients with narcolepsy, morning administration of 400 mg modafinil or administration of 200 mg modafinil in the morning and at noon does not adversely affect nocturnal sleep.

Excessive sleepiness (ES) is defined as difficulty maintaining wakefulness and an increased likelihood of falling asleep in inappropriate situations. ES can be demonstrated by an Epworth Sleepiness Scale score of 11 or more.

Moderate sleepiness describes sleep episodes that are present daily and occur during very mild physical activity requiring, at most, a moderate degree of attention. Onset of sleep may occur for example during concerts, films at the cinema, theatre performances, group meetings and driving. This degree of sleepiness is usually associated with a Multiple Sleep Latency Test (MSLT) mean sleep latency of 5 to 10 minutes. Severe sleepiness describes sleep episodes that are present daily and occur during very mild physical activity requiring mild to moderate attention. Onset of sleep may occur for example during eating, direct personal conversation, driving, walking and physical activities. This degree of sleepiness is usually associated with an MSLT mean sleep latency of less than 5 minutes.

Shift Work Sleep Disorder (SWSD) is recognised as a clinical situation where persistent inability to adjust to changes in work schedules produces transient symptoms of insomnia or excessive sleepiness. All subjects in the pivotal clinical trials for SWSD had a clinical diagnosis made according to ICSD criteria (first edition). Essential criteria include a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase. The symptoms are not accounted for by any other medical or mental disorder and do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness. Polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity).

In the pivotal clinical trials subjects worked at least 5 night shifts per month of which at least 3 were consecutive and complained of excessive sleepiness in relation to these shifts over a period of at least 3 months. The moderate to severe subgroup of patients with SWSD for whom Provigil 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).

Modafinil is a racemic compound, whose enantiomers have different pharmacokinetics. The half-life of l-modafinil is approximately three times that of the d enantiomer, as is the total systemic exposure (AUC) to l-modafinil. Apparent steady state is reached after 2-4 days of dosing.

Absorption

Modafinil is readily absorbed, with peak plasma concentrations occurring at 2-4 hours. Food has no effect on overall modafinil bioavailability but t_max may be delayed by approximately one hour if PROVIGIL is taken with food.

Distribution

Modafinil is well distributed in body tissue with an apparent volume of distribution larger than the volume of total body water. In human plasma, in vitro, modafinil is moderately bound to plasma protein (approximately 60%, mainly to albumin). This degree of protein binding is such that the risk of interaction with strongly bound drugs is unlikely.

Biotransformation

Modafinil is metabolised in the liver to two major metabolites, modafinil acid and modafinil sulphone, by esterase enzymes and CYP3A4/5, respectively. In preclinical models, the metabolites did not appear to contribute to the arousal effects of modafinil. In vitro studies using human hepatocytes have demonstrated that modafinil slightly induces the following in a concentration-dependent manner: CYP1A2, CYP2B6 and CYP3A4. In addition, the activity of CYP2C9 was suppressed in the hepatocytes. In human liver microsomes, modafinil and modafinil sulphone produced partial competitive, reversible inhibition of CYP2C19 at concentrations expected during clinical use (see 4.5).

Elimination

The excretion of modafinil and its metabolites is chiefly renal, with a small proportion being eliminated unchanged (< 10%). The elimination half-life of modafinil after multiple doses is 15 hours and enables a treatment regimen based upon 1 or 2 doses per day.

Linearity/non-linearity

The pharmacokinetics of modafinil are linear and independent of the dose administered in the dose range of 200 to 600 mg once daily. Systemic exposure increases in proportion to doses administered.

Renal failure/hepatic impairment

In severe chronic renal failure the pharmacokinetics of modafinil were unaltered but exposure to modafinil acid was increased 9 fold (see 4.2). There is minimal information available regarding the safety of such levels of this metabolite. In patients with severe hepatic impairment, oral clearance of modafinil was decreased by about 60% and the steady state concentration of modafinil was doubled. The dose of PROVIGIL should be reduced by half in patients with severe hepatic or renal impairment (see 4.2).

Elderly

Elderly patients may have diminished renal and/or hepatic function and dosage reductions should be considered (see 4.2).

Toxicology studies by single and repeated dosing have revealed no particular toxic action in animals.

Reproduction function studies have revealed no effect on fertility, nor any teratogenic effect, nor any effect on viability, growth or development of the offspring.

Modafinil is not considered to be mutagenic or carcinogenic.

Animal exposure to modafinil, based on actual plasma levels in the general toxicology, reproductive and carcinogenicity studies, was less than or similar to that expected in humans. This circumstance is the result of metabolic auto-induction noted in the pre-clinical studies. However, animal exposure on a mg/kg dose basis to modafinil in the general toxicology, reproductive and carcinogenicity studies was greater than the expected exposure, calculated on a similar basis, in humans.

In the rat peri-post-natal study, modafinil concentration in milk was about 11.5 times higher than in plasma.

Lactose monohydrate

Pregelatinised starch

Microcrystalline cellulose

Croscarmellose sodium

Povidone K29/32

Magnesium stearate

Not applicable

Three years.

No special precautions for storage.

Opaque PVC/PVDC/Aluminium blisters containing 10 tablets

Packs containing 30, 60 or 90 tablets.

Not all pack sizes may be marketed.

Not applicable

Cephalon UK Limited

1 Albany Place

Hyde Way

Welwyn Garden City

Hertfordshire

AL7 3BT

United Kingdom

Provigil 100 mg tablets - PL 16260/0001

Provigil 200 mg tablets - PL 16260/0002

PL 16260/0001 - 14 October 1997 / 14 October 2002

PL 16260/0002 – 2 December 2002 / 23 January 2009

29^th May 2009

Provigil and Cephalon are registered trademarks.