Prolert 100 & 200 100 mg or 200 mg Tablets

PROLERT is indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy, as defined by either of the two following DSM IV (Diagnostic and statistical manual of mental disorders) criteria, in the absence of other clinically significant medical or psychotic conditions:

• 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 hallucination, automatic behaviours, disrupted major sleep episodes; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes.

The effectiveness of modafinil as in PROLERT has not been evaluated in placebo-controlled studies of more than 9 weeks.

Posology

Adults

The dose of PROLERT is 200 mg per day, given as a single dose in the morning. Doses of 400 mg per day, given as a single dose, have been well tolerated. There is however no consistent evidence that this dose confers additional benefit beyond that of the 200 mg dose.

Elderly patients (65 years and older)

Elimination of modafinil and its metabolites may be reduced as a consequence of aging. It should therefore be considered to reduce the dose in elderly patients.

Hepatic failure

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

Paediatric population

PROLERT should not be used in children below 16 years of age because of safety and efficacy concerns (see section 4.3).

Method of administration

For oral use. Tablets should be swallowed whole.

• Hypersensitivity to modafinil or to any of the excipients of PROLERT listed in section 6.1.
• Major anxiety (outside specialised units).
• Children and adolescents under the age of 16 years.
• Severe renal impairment.
• Uncontrolled moderate to severe hypertension.
• In patients with cardiac dysrhythmias.

Diagnosis of sleep disorders

PROLERT should be used only in patients who have had a complete evaluation of their excessive sleepiness. 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 SJS (Stevens-Johnson syndrome), TEN (toxic epidermal necrolysis) and DRESS (drug rash with eosinophilia and systemic symptoms)

Serious rash, requiring hospitalisation and discontinuation of treatment has been reported with the use of PROLERT occurring within 1 to 5 weeks after treatment initiation. Cases have also been reported after prolonged treatment (e.g., 3 months).

PROLERT should be discontinued at the first sign of rash and not restarted (see section 4.8). Rare cases of serious or life-threatening rash, including SJS, TEN and DRESS have been reported in worldwide post-marketing experience. Patients should be advised to notify their doctor if they develop a rash, hives, or a related allergic phenomenon.

Paediatric population

Because safety and effectiveness in controlled studies in children (below 16 years) have not been established and because of the risk of serious cutaneous hypersensitivity and psychiatric adverse reactions, the use of PROLERT is not recommended in this population (see section 4.3).

Multi-organ hypersensitivity reaction

Multi-organ hypersensitivity reactions, including fatal reactions, have occurred in close temporal association to the initiation of modafinil (contained in PROLERT). Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalisation 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, PROLERT should be discontinued.

Psychiatric disorders

Patients should be monitored for the development of new, 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 PROLERT treatment, PROLERT should be discontinued and not restarted. Caution should be exercised in giving PROLERT to patients with a history of psychiatric disorders including psychosis, depression, mania, major anxiety, agitation, insomnia or substance abuse (see below).

Anxiety

Modafinil (contained in PROLERT) is associated with the onset or worsening of anxiety. Periodic specialist clinical assessment is necessary. 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 (contained in PROLERT). Patients treated with PROLERT should be carefully monitored for the appearance or worsening of suicide-related behaviour. If suicide-related symptoms develop in association with PROLERT, treatment should be discontinued.

Psychotic or manic symptoms

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

Bipolar disorders

Care should be taken in using PROLERT 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 PROLERT. Patients treated with PROLERT should be carefully monitored for the appearance or worsening of aggressive or hostile behaviour. If symptoms occur, discontinuation of PROLERT may be required.

Cardiovascular risks

An electrocardiogram (ECG) is recommended in all patients before PROLERT treatment is initiated. Patients with abnormal findings should receive further specialist evaluation and treatment before PROLERT treatment is considered. Blood pressure and heart rate should be regularly monitored in patients receiving PROLERT. PROLERT should be discontinued in patients who develop dysrhythmia or moderate to severe hypertension and not restarted until the condition has been adequately evaluated and treated. It is recommended that PROLERT tablets not be used 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 central nervous system (CNS) stimulants. This syndrome may present with ischaemic ECG changes, chest pain or dysrhythmia.

Insomnia

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

Maintenance of sleep hygiene

Patients should be advised that PROLERT 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.

Abuse, misuse, diversion

The potential for dependence with long-term use exists. Caution should be exercised in administering PROLERT to patients with history of alcohol, medicine or illicit substance abuse.

Patients using steroidal contraceptives

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

Patients with severe renal impairment

PROLERT is contraindicated in severe renal impairment (mean creatinine clearance = 16,6 ml/min). See section 4.3. In patients with severe renal impairment, a 200 mg single dose of modafinil as in PROLERT did not lead to increased exposure to modafinil but resulted in much higher exposure to the inactive metabolite, modafinil acid than is seen in subjects with normal renal function. There is little information available about the safety of such levels of this metabolite (see section 5.2).

Patients with severe hepatic impairment

In patients with severe hepatic impairment, with or without cirrhosis (see section 5.1) PROLERT should be administered at a reduced dose as the clearance of modafinil was decreased compared to that in normal persons (see section 4.2).

Elderly patients

To the extent that elderly patients may have diminished renal and/or hepatic function, dosage reductions should be considered (see section 4.2).

Lactose intolerance

PROLERT contains lactose (see section 2). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take PROLERT.

Modafinil (contained in PROLERT) 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 cytochrome P450 enzymes (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 PROLERT 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 PROLERT.

Steroidal contraceptives:

The effectiveness of steroidal contraceptives may be impaired due to induction of CYP3A4/5 by modafinil (contained in PROLERT). Alternative or concomitant methods of contraception are recommended for patients treated with PROLERT, when oral contraceptives are used, a product containing 50 micrograms or more of ethinyl estradiol should be taken. Adequate contraception will require continuation of these methods for two months after stopping PROLERT.

Antidepressants:

A number of tricyclic antidepressants, e.g. clomipramine, desipramine 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 (contained in PROLERT) the clearance of warfarin may be decreased when modafinil is administered concomitantly. Prothrombin times should be monitored regularly during the first 2 months of PROLERT use and after changes in PROLERT dosage.

Other medicines:

Substances that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol and omeprazole may have reduced clearance upon co-administration of PROLERT 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 medicines 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 PROLERT was initiated. Co-administration of potent inducers of CYP3A4 (e.g. 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. As PROLERT causes a modest induction of CYP3A4 the clearance of theophylline, a CYP3A4 substrate, may be increased.

Pregnancy

Studies in animals have shown reproductive toxicity. Safety in pregnancy has not been established. PROLERT should not be used during pregnancy. Patients should be advised to inform their doctor if they become pregnant or intend to become pregnant during therapy. 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). Patients should be cautioned regarding the potential increased risk of pregnancy when using steroidal contraceptives (including depot or implantable contraceptives) with PROLERT and for two months after discontinuation of therapy.

Breastfeeding

Available pharmacodynamic/toxicological data in animals have shown excretion of modafinil/metabolites in milk. Safety during breastfeeding has not been established. PROLERT should not be used during breast feeding.

Fertility

No data on fertility are available in humans.

Patients with abnormal levels of sleepiness who take PROLERT should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking PROLERT 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).

Summary of the safety profile

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

Tabulated summary of adverse reactions

System organ class Adverse reaction

Infections and infestations Less frequent: pharyngitis, sinusitis

Blood and lymphatic system disorders Less frequent: eosinophilia, leukopenia

Immune system disorders Less frequent: minor allergic reaction (e.g., hay fever symptoms) Not known: 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 Frequent: decreased appetite, anorexia Less frequent: hypercholesterolaemia, hyperglycaemia, diabetes mellitus, increased appetite

Psychiatric disorders Frequent: nervousness, insomnia, anxiety, depression, abnormal thinking, confusion, irritability Less frequent: sleep disorder, emotional lability, decreased libido, hostility, depersonalisation, personality disorder, abnormal dreams, agitation, aggression, suicidal ideation, psychomotor hyperactivity, hallucinations, mania, psychosis Not known: delusions

Nervous system disorders Frequent: headache, dizziness, somnolence, paraesthesia, cataplexy, ataxia Less frequent: dyskinesia, hypertonia, hyperkinesia, amnesia, migraine, tremor, vertigo, CNS stimulation, hypoaesthesia, incoordination, movement disorder, speech disorder, taste perversion

Eye disorders Frequent: blurred vision, amblyopia Less frequent: abnormal vision, dry eye

Cardiac disorders Frequent: tachycardia, palpitation Less frequent: extrasystoles, dysrhythmia, bradycardia, abnormal ECG

Vascular disorders Frequent: vasodilatation, syncope Less frequent: hypertension, hypotension

Respiratory, thoracic and mediastinal disorders Frequent: lung disorders Less frequent: dyspnoea, increased cough, asthma, epistaxis, rhinitis

Gastrointestinal disorders Frequent: abdominal pain, nausea, dry mouth, diarrhoea, dyspepsia, constipation, gingivitis Less frequent: flatulence, reflux, vomiting, dysphagia, glossitis, mouth ulcers

Skin and subcutaneous tissue disorders Frequent: herpes simplex, dry skin Less frequent: sweating, rash, acne, pruritus Not known: serious skin reactions, including erythema multiforme, SJS, TEN and DRESS

Musculoskeletal and connective tissue disorders Frequent: joint disorders Less frequent: back pain, neck pain, myalgia, myasthenia, leg cramps, arthralgia, twitch

Renal and urinary disorders Frequent: albuminuria, urinary retention Less frequent: abnormal urine, urinary frequency

Reproductive system and breast disorders Frequent: abnormal ejaculation Less frequent: menstrual disorder

General disorders and administration site conditions Frequent: asthenia, chest pain, chills, rigid neck, fever Less frequent: peripheral oedema, thirst

Investigations Frequent: abnormal liver function tests, dose related increases in alkaline phosphatase and gamma-glutamyl transferase have been observed Less frequent: weight increase, weight decrease Not known: positive test for detection of drug abuse

Drug abuse and dependence

In addition to its wakefulness-promoting effect and increased locomotor activity in animals, in humans, PROLERT produces psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings typical of other CNS stimulants. Modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. Results reported from a clinical study that assessed the abuse potential of modafinil relative to methylphenidate, demonstrated that modafinil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate). Doctors should follow patients closely, especially those with a history of drug and/or stimulant (e.g. methylphenidate, amphetamine, or cocaine) abuse. Patients should be observed for signs of misuse or abuse (e.g. incrementation of doses or drug-seeking behaviour). See section 4.4 u201cAbuse, misuse, diversionu201d.

Symptoms

In overdose, side effects can be precipitated and/or be of increased severity, see section 4.8. Death has occurred with modafinil overdose alone or in combination with other medicines. Symptoms most often accompanying modafinil overdose, alone or in combination with other medicines have included: insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, agitation, anxiety, excitation and hallucination; digestive changes such as nausea and diarrhoea; and cardiovascular changes such as tachycardia, bradycardia, hypertension and chest pain.

Management

Induced emesis should be considered. Hospitalisation and surveillance of psychomotor status, cardiovascular monitoring or surveillance until the patientu2019s symptoms have resolved may be required.