Active ingredients: Modafinil
Provigil 100 mg tablets
Why is Provigil used? What is it for?
The active ingredient contained in the tablets is modafinil.
Modafinil can be taken by adults suffering from narcolepsy to help them stay awake. Narcolepsy is a condition of excessive daytime sleepiness and a tendency to suddenly fall asleep in inappropriate situations (sleep attacks). Modafinil can improve your narcolepsy and decrease the chances of having sleep attacks, but there may also be other ways to improve your condition and your doctor will inform you about them.
Contraindications When Provigil should not be used
Do not take Provigil if you:
- you are allergic (hypersensitive) to modafinil, or to any of the other ingredients of these tablets (see section "What Provigil contains").
- You have an irregular heartbeat.
- You have moderate to severe, uncontrolled high blood pressure (hypertension).
Precautions for use What you need to know before taking Provigil
Take special care with Provigil if you:
- You have heart problems or high blood pressure. Your doctor will need to check you regularly while you are taking Provigil
- You have suffered from depression, low mood, anxiety, psychosis (loss of contact with reality) or mania (hyper arousal or feeling of extreme contentment) or bipolar disorder, because Provigil can make your condition worse.
- You have kidney or liver problems (because you will need to take a lower dose)
- You have had alcohol or drug problems in the past.
Individuals under the age of 18 should not take this medicine.
Other things to ask your doctor or pharmacist:
- Some people have reported having suicidal or aggressive thoughts or behavior while taking this medicine. Tell your doctor immediately if you notice that you are becoming depressed, aggressive or hostile towards other people or if you have thoughts of suicide or other changes in your behavior (see section 4). You may need to consider asking a family member or friend to help you look for signs of depression or other changes in your behavior.
- This medicine has the potential to make you dependent on it after prolonged use. If you need long-term treatment, your doctor will regularly check that modafinil treatment is still the best for you.
Interactions What medications or foods may change the effect of Provigil
Tell your doctor or pharmacist if you are taking, or have recently taken, any other medicines, including those that do not require a prescription. Provigil and certain other medicines can affect each other, and your doctor will need to adjust the doses you are taking. This is especially important if you are taking any of the following medicines together with Provigil:
- Hormonal contraceptives (including the contraceptive pill, implants, intrauterine devices (IUDs) and patches). While taking Provigil, and again for 2 months after stopping treatment, you will need to consider other methods of birth control, as Provigil decreases its effectiveness.
- Omeprazole (for acid reflux, indigestion or ulcers)
- Antiviral medicines to treat HIV infection (protease inhibitors, eg indinavir or ritonavir).
- Ciclosporin (used to prevent organ transplant rejection, or in arthritis or psoriasis).
- Medicines for epilepsy (eg carbamazepine, phenobarbital or phenytoin).
- Medicines for depression (eg amitriptyline, citalopram or fluoxetine) or for anxiety (eg diazepam).
- Medicines to thin the blood (e.g. warfarin). During treatment, your doctor will check how long your blood clots.
- Calcium channel blockers or beta blockers for hypertension or heart problems (eg amlodipine, verapamil or propranolol).
- Statins to lower cholesterol (e.g. atorvastatin or simvastatin).
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are (or think you are) pregnant, planning to become pregnant, or breastfeeding, you should not take Provigil. It is not known whether this medicine will harm the baby.
Ask your doctor which birth control method may work for you while you are taking Provigil (and for another 2 months after stopping it), or if you have any other problems.
Driving and using machines
Provigil can cause blurred vision or dizziness in up to 1 in 10 people being treated. If you suffer from this or find that you feel very drowsy while taking this medicine, you should not drive or operate machinery. Important information about some of the ingredients of Provigil
Provigil contains lactose.
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Dose, Method and Time of Administration How to use Provigil: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The tablets should be swallowed whole with water.
Adults
Usually the dose is 200 mg per day. This can be taken once a day (in the morning) or twice (100 mg in the morning and 100 mg at noon).
In some cases the doctor may decide to increase the daily dosage up to 400 mg.
Elderly patients (over 65 years old)
The usual dose is 100 mg per day. Your doctor may increase this dose (up to a maximum of 400 mg per day), provided you have no liver or kidney problems.
Adults with severe liver and kidney problems
The usual dose is 100 mg per day.
Your doctor will review your treatment regularly to make sure it is right for you.
Overdose What to do if you have taken too much Provigil
If you take more Provigil than you should
If you take too many tablets, you may feel sick, sleepless, disoriented, confused, agitated, anxious or excited. You may also have difficulty falling asleep and have diarrhea, hallucinations (hearing or seeing things that are not real), chest pain, changes in heart rate or increased blood pressure.
Contact the emergency room of the nearest hospital or notify your doctor or pharmacist immediately. Take this leaflet and any remaining tablets with you.
If you forget to take Provigil
If you forget to take your medicine, take your next dose at the usual time, not a double dose to make up for the forgotten one.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist
Side Effects What are the side effects of Provigil
Like all medicines, Provigil can cause side effects, although not everybody gets them.
Stop taking this medicine and tell your doctor immediately if
- You experience sudden difficulty in breathing or wheezing, or if your face, mouth or throat starts to swell.
- You notice a rash or itchiness (especially if it affects the whole body). Severe rashes can cause blistering, skin loss, ulceration of the mouth, eyes, nose, or genitals. You may also have a rise in temperature (fever) and abnormal blood tests.
- She feels some changes in her mental health and well-being. The signs may include:
- mood swings
- abnormal thoughts
- aggression or hostility
- forgetfulness
- confusion
- feeling of extreme happiness
- overexcitation
- hyperactivity
- anxiety or nervousness
- depression, suicidal thoughts or behavior
- agitation or psychosis (a loss of contact with reality may include delusions or hearing or seeing things that are not real), feelings of indifference or lightheadedness, or personality disorder.
Other side effects are the following:
Very common side effects (affecting more than 1 in 10 people):
- Headache
Common side effects (affecting up to 1 in 10 people):
- Dizziness
- Drowsiness, extreme tiredness or difficulty falling asleep (insomnia)
- Perception of one's heartbeat, which may be more frequent than normal.
- Chest pain.
- Hot flashes.
- Dry mouth.
- Loss of appetite, nausea, stomach pains, indigestion, diarrhea or constipation.
- Weakness. Numbness or pins and needles in the hands or feet.
- Blurred vision.
- Abnormal blood test results showing how your liver is working (increase in liver enzymes).
- Irritability.
Uncommon side effects (affecting up to 1 in 100 people):
- Back pain, neck pain, muscle aches, muscle weakness, leg cramps, joint pain, strains or tremors.
- Vertigo (sensation of rotation).
- Difficulty moving muscles smoothly or other movement problems, muscle tension, coordination problems.
- Hay fever symptoms, including itchy / runny nose or watery eyes.
- Increased cough, asthma or shortness of breath.
- Skin rash, acne or itching.
- Sweating.
- Changes in blood pressure (high or low), electrocardiographic abnormalities, and unusually low heart rate.
- Difficulty swallowing, swollen tongue or mouth ulcers.
- Excessive flatulence, reflux (regurgitation of stomach fluid), increased appetite, changes in body weight, thirst or altered taste.
- He retched.
- Migraine (headache).
- Speech problems.
- Diabetes with increased blood sugar.
- High cholesterol.
- Swelling in the hands and feet.
- Disturbed sleep or abnormal dreams.
- Loss of sexual impulses.
- Nosebleeds, sore throats, or inflammation of the nasal passages (sinusitis).
- Abnormal vision or dry eyes.
- Abnormal urine or more frequent urination.
- Abnormal menstrual cycles.
- Abnormal blood test results, showing changes in white blood cells.
- Restlessness with increased body movements.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Side effects can also be reported directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avversei. By reporting side effects you can help provide more information on safety of this medicine.
Expiry and Retention
Keep out of the reach and sight of children.
Do not use this medicine after the expiry date which is stated on the blister and carton after "EXP". The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Provigil contains
The active ingredient is modafinil. Each Provigil 100 mg tablet contains 100 mg of modafinil.
The other ingredients are: lactose monohydrate, pregelatinised starch (maize), microcrystalline cellulose, carmellose sodium, povidone K29 / 32, magnesium stearate as inactive excipients.
What Provigil looks like and contents of the pack
The tablets are in the form of capsules, white to off-white, 13 x 6 mm, with "100" on one side.
Provigil is available in blister packs of 10, 20, 30, 50, 60, 90, 100 or 120 tablets.
Not all pack sizes may be marketed
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
PROVIGIL 100 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 100 mg of modafinil.
Excipients:
Each tablet contains 68 mg of anhydrous lactose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablets.
The tablets are white to off-white, 13 x 6 mm, in the form of capsules with "100" debossed on one side.
04.0 CLINICAL INFORMATION
04.1 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 the difficulty in staying awake and the increased likelihood of falling asleep in inappropriate situations.
04.2 Posology and method of administration
Treatment should be initiated by, or under the supervision of, a physician with adequate knowledge of the indicated disorders (see section 4.1).
A diagnosis of narcolepsy must be made according to the guidelines of the International Classification of Sleep Disorders (ICSD2).
Patient monitoring and clinical assessment of the need for treatment should be performed periodically.
Dosage
The recommended starting daily dose is 200 mg. The total daily dose can be taken at one time in the morning, or divided into two administrations, one in the morning and one at noon, according to the physician's judgment of the patient and his response.
In patients with insufficient response to the initial dose of 200 mg modafinil, up to 400 mg may be given at once or divided into two doses.
Long-term use
Physicians prescribing modafinil for a long period of time should periodically re-evaluate this type of use in individual patients, as the long-term efficacy of modafinil has not been evaluated (> 9 weeks).
Patients with renal insufficiency
There is insufficient information to determine the safety and efficacy of administration in patients with renal insufficiency (see section 5.2).
Patients with hepatic insufficiency
In patients with severe hepatic impairment, the modafinil dose should be reduced by half (see section 5.2).
Senior citizens
There are limited data available on the use of modafinil in elderly patients. In view of the potential for decreased elimination capacity and increased systemic exposure, it is recommended that patients over 65 years of age be initiated with a dose of 100 mg per day. day.
Pediatric population
For reasons of safety and efficacy, modafinil should not be used in individuals below 18 years of age (see section 4.4).
Method of administration
For oral use.The tablets should be swallowed whole.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Uncontrolled moderate to severe hypertension in patients with cardiac arrhythmias.
04.4 Special warnings and appropriate precautions for use
Sleep Disorder Diagnosis
Modafinil should only be used in patients whose excessive sleepiness has been fully evaluated, and in those whose diagnosis of narcolepsy has been made according to ICSD criteria. In addition to collecting the patient's medical history, this evaluation usually consists of measurements of sleep in the laboratory and the exclusion of other possible causes of the observed hypersomnia.
Severe rash, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms
Severe rashes requiring hospitalization and discontinuation of treatment occurred within 1-5 weeks after initiation of modafinil therapy. Isolated cases have also been described after prolonged treatment (e.g. 3 months). In clinical trials of modafinil, the incidence of rash leading to discontinuation was approximately 0.8% (13 of 1,585) in pediatric patients (age Modafinil should be discontinued at the first sign of rash, and administration should not be resumed (see section 4.8.).
Rare cases of severe 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 around the world in adults and children in the post-marketing experience.
Pediatric use
Since the safety and efficacy of modafinil have not been evaluated in controlled studies performed in children, and due to the risk of severe skin hypersensitivity and severe psychiatric adverse reactions, the use of modafinil is not recommended.
Multi-organ hypersensitivity reaction
Multi-organ hypersensitivity reactions, including at least one fatal case in post-marketing experience, occurred in close temporal association with the initiation of modafinil.
Despite the limited number of reports, multi-organ hypersensitivity reactions may require hospitalization or be life-threatening. There are no known risk factors for the occurrence or severity of multi-organ hypersensitivity reactions associated with modafinil. The signs and symptoms of this disorder are varied; however, patients typically, though not exclusively, present with fever and rash associated with other organ and system involvement. Other associated manifestations include myocarditis, hepatitis, liver function test abnormalities, haematological abnormalities (eg, eosinophilia, leukopenia, thrombocytopenia), itching and asthenia.
Since multi-organ hypersensitivity is variable in its expression, symptoms and signs, not reported here, can occur in other organs and systems.
If a multi-organ hypersensitivity reaction is suspected, modafinil should be discontinued.
Psychiatric disorders
Patients should be monitored for development de novo or exacerbation of pre-existing psychiatric disorders (see below, and section 4.8) at each dose adjustment, and then regularly during treatment. If psychiatric symptoms develop in association with modafinil treatment, modafinil should be discontinued and its administration should not be restarted Caution should be exercised in administering modafinil to patients with a history of psychiatric disorders including psychosis, depression, mania, major anxiety, agitation, insomnia, or illicit substance abuse (see below).
Anxiety
Modafinil is associated with the onset of anxiety or its worsening. Patients with increased anxiety should only be treated with modafinil in a specialist ward.
Suicidal behavior
Suicidal behavior (including suicide attempts and suicidal ideation) has been reported in patients treated with modafinil. Modafinil-treated patients should be closely monitored for the onset or worsening of suicidal behavior. If suicidal symptoms occur in association with modafinil therapy, 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 onset or worsening of psychotic or manic symptoms. If such symptoms occur, discontinuation of modafinil may be necessary.
Bipolar Disorders
Care should be taken when using modafinil in patients with concomitant bipolar disorders due to the possible precipitate of a mixed / manic episode in them.
Aggressive or hostile behavior
The appearance or worsening of aggressive or hostile behavior may be due to treatment with modafinil, and should be carefully monitored. If symptoms occur, administration of the medicine may need to be stopped.
Cardiovascular risks
It is recommended that an ECG be performed in all patients prior to initiation of modafinil treatment. In patients with abnormal findings, specialist evaluation and treatment is also required prior to considering modafinil therapy.
In patients treated with modafinil, blood pressure and heart rate should be checked regularly. Modafinil should be discontinued in patients who develop moderate to severe arrhythmia or hypertension, and its administration should not be resumed 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 those with mitral valve prolapse who have previously presented the related syndrome when treated with central nervous system (CNS) stimulants. This syndrome can manifest itself with ischemic changes in the ECG, chest pain or arrhythmia.
Insomnia
Since modafinil promotes alertness, attention should be paid to signs of insomnia.
Maintenance of sleep hygiene
Patients should be advised that modafinil is not a sleep substitute, and that good sleep hygiene must be maintained. Measures to ensure good sleep hygiene may include a review of caffeine intake.
Patients using steroid contraceptives
In sexually active women of childbearing age, a contraceptive program should be started before treatment with modafinil. Since the efficacy of steroid contraceptives may be reduced by the concomitant use of modafinil, alternative or concomitant methods of contraception are recommended, to be followed for up to two months after stopping treatment (regarding potential interaction with steroid contraceptives, see also paragraph 4.5).
Abuse, misuse, deviations
While studies with modafinil have shown addictive potential, with prolonged use this possibility cannot be completely ruled out.
Caution should be exercised when administering modafinil to patients with a history of alcohol, medicinal or illicit substance abuse.
Lactose intolerance
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Modafinil may increase its metabolism by inducing CYP3A4 / 5 activity, but the effect is modest and unlikely to have any significant clinical consequences.
Anticonvulsants: Co-administration of potent inducers of CYP activity, such as carbamazepine and phenobarbital, may decrease plasma levels of modafinil. Due to possible inhibition of CYP2C19 and suppression of CYP2C9 by modafinil, clearance of phenytoin may be reduced when modafinil is concomitantly administered. Patients should be monitored for signs of phenytoin toxicity, and repeated measurements of plasma levels of this anticonvulsant may be appropriate at initiation or discontinuation of modafinil.
Steroid contraceptives: The efficacy of steroid contraceptives may be impaired due to induction of CYP3A4 / 5 by modafinil. In patients treated with modafinil, alternative or concomitant methods of contraception are recommended. For adequate contraception it will be necessary to continue these methods for another two months after the discontinuation of modafinil.
Antidepressants: A number of tricyclic antidepressants and selective serotonin reuptake inhibitors are extensively metabolised by CYP2D6. In patients with deficiency of this isoenzyme (about 10% of the Caucasian population), a normally ancillary metabolic cycle involving CYP2C19 is of greater importance. Since modafinil can inhibit this isoenzyme, lower doses of antidepressants may be needed in these patients.
AnticoagulantsDue to the possible inhibition of CYP2C9 by modafinil, the clearance of warfarin may be decreased when co-administered with modafinil. Prothrombin times should be monitored regularly during the first two months of modafinil use and after any change in drug dosage.
Other Medicines: Medicinal products that are extensively cleared by CYP2C19 metabolism, such as diazepam, propranolol and omeprazole, may exhibit reduced clearance after co-administration with modafinil, and therefore require a reduction in dosage. Furthermore, induction was observed in human hepatocytes in vitro of CYP1A2, CYP2B6 and CYP3A4 / 5 activity, which if in vivo may lower the blood levels of medicinal products metabolised by these isoenzymes, thus potentially decreasing their therapeutic efficacy. The results of clinical interaction studies indicate that the broadest effects may occur on CYP3A4 / 5 substrates which undergo significant presystemic elimination, especially through substrates of the CYP3A isoenzyme in the gastrointestinal tract. Examples include cyclosporine, HIV protease inhibitors, buspirone, triazolam, midazolam, and most calcium channel blockers and statins. In one case report, a 50% reduction in the concentration of ciclosporin was observed in one patient receiving this compound and in whom concomitant treatment with modafinil was initiated.
04.6 Pregnancy and lactation
Pregnancy
There are limited data on the use of modafinil in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3).
The use of modafinil is not recommended during gestation or in women of childbearing potential unless effective contraceptive measures are in place. Since modafinil may reduce the effectiveness of oral contraception, additional alternative contraceptive methods are required (see section 4.5).
Feeding time
In animals, available pharmacodynamic / toxicological data have demonstrated the excretion of modafinil / metabolites in milk (for details, see section 5.3).
Modafinil should not be used while breastfeeding.
Fertility
No fertility data are available
04.7 Effects on ability to drive and use machines
Patients with abnormal sleep levels who take modafinil should be advised that their alertness may not return to normal. Patients with excessive sleepiness, including those taking modafinil, should be reassessed frequently for their degree of sleepiness, and possibly advised to avoid driving vehicles and other potentially dangerous activities. Undesirable effects such as blurred vision or skidding may also affect the ability to drive (see section 4.8).
04.8 Undesirable effects
The following adverse reactions were observed in clinical trials or in post-marketing experience. The frequency of adverse reactions considered possibly related to treatment in clinical trials involving 1561 patients taking modafinil is as follows: very common (≥ 1 / 10), common (≥ 1/100 ma
The most often reported adverse drug effect is headache, affecting approximately 21% of patients. It is usually mild or moderate in severity, is dose dependent, and subsides within a few days.
Infections and infestations
Uncommon: pharyngitis, sinusitis.
Disorders of the blood and lymphatic system
Uncommon: eosinophilia, leukopenia.
Disorders of the immune system
Uncommon: minor allergic reactions (e.g. hay fever symptoms).
not known: angioedema, urticaria. Hypersensitivity reactions (characterized by manifestations such as fever, rash, lymphadenopathy, and signs of simultaneous involvement of other organs), anaphylaxis.
Metabolism and nutrition disorders
Common: decreased appetite.
Uncommon: hypercholesterolaemia, hyperglycemia, diabetes mellitus, increased appetite.
Psychiatric disorders
Common: nervousness, insomnia, anxiety, depression, abnormal thoughts, confusion, irritability.
Uncommon: sleep disturbances, emotional lability, decreased libido, hostility, depersonalization, personality disorders, abnormal dreams, agitation, aggression, suicidal ideation, psychomotor hyperactivity.
Rare: hallucinations, mania, psychosis.
not known: delusions.
Nervous system disorders
Very common: headache.
Common: sense of instability, drowsiness, paraesthesia.
Uncommon: dyskinesia, hypertonia, hyperkinesia, amnesia, migraine, tremor, dizziness, CNS stimulation, hypoesthesia, incoordination, movement disorders, speech disorders, dysgeusia.
Eye disorders
Common: blurred vision.
Uncommon: visual disturbances, dry eyes.
Cardiac pathologies
Common: tachycardia, palpitations.
Uncommon: extrasystoles, arrhythmia, bradycardia.
Vascular pathologies
Common: vasodilation.
Uncommon: hypertension, hypotension.
Respiratory, thoracic and mediastinal disorders
Uncommon: dyspnoea, increased cough, asthma, epistaxis, rhinitis.
Gastrointestinal disorders
Common: abdominal pain, nausea, dry mouth, diarrhea, dyspepsia, constipation.
Uncommon: flatulence, reflux, vomiting, dysphagia, glossitis, oral ulcers.
Skin and subcutaneous system disorders
Uncommon: sweating, rash, acne, itching.
not known: severe 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, involuntary contractions.
Renal and urinary disorders
Uncommon: abnormal urine, pollakiuria.
Diseases of the reproductive system and breast
Uncommon: menstrual disorders.
General disorders and administration site conditions
Common: asthenia, chest pain.
Uncommon: peripheral edema, thirst.
Diagnostic tests
Common: Abnormal liver function tests and dose-related elevations in alkaline phosphatase and gamma-glutamyltransferase have been observed.
Uncommon: ECG abnormal, weight gain, weight loss.
Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Death has occurred in cases of overdose of modafinil alone or in combination with other drugs. Symptoms that most frequently accompany modafinil overdose, taken alone or in combination with other drugs, included: insomnia; CNS symptoms such as restlessness, disorientation, confusion, agitation, anxiety, excitement and hallucinations; digestive disturbances such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension and chest pain.
Treatment
The use of induced vomiting or gastric lavage should be considered. Hospitalization and control of the psychomotor state; Cardiovascular monitoring or careful patient surveillance is recommended until symptoms are resolved.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psychoanaleptics, centrally acting sympathomimetics. ATC code: N06BA07
Modafinil promotes wakefulness in several species, including "man." The exact mechanism (s) by which modafinil promotes wakefulness is not (are) known.
In non-clinical models, modafinil has weak or negligible interactions with receptors involved in the regulation of sleep / wake states (e.g., adenosine, benzodiazepines, dopamine, GABA, histamine, melatonin, noradrenaline, orexin, and serotonin). Furthermore, modafinil does not inhibit the activities of adenyl cyclase, catechol-O-methyltransferase, glutamic acid decarboxylase MAO-A or -B, nitric oxide synthase, phosphodiesterase II-VI, or tyrosine hydroxylase. dopamine, data in vitro And in vivo indicate that it binds to the dopamine transporter and inhibits dopamine reuptake.The wakefulness-promoting effects of modafinil are antagonized by D1 / D2 receptor antagonists, indicating that it has indirect "agonist activity."
Modafinil does not appear to be a direct α1-adrenergic receptor agonist. However, it binds to the noradrenaline transporter preventing its uptake, but these interactions are weaker than those observed with the dopamine transporter. Although modafinil-induced wakefulness may be attenuated by the α1-adrenergic receptor antagonist prazosin, in other test systems (e.g., vas deferens) that respond to α-adrenergic receptor agonists, modafinil is inactive.
In non-clinical models, equal doses of wakefulness-promoting methylphenidate and amphetamine increase neuronal activation throughout the brain, while modafinil, unlike classic psychomotor stimulants, mainly affects brain regions involved in the regulation of awakening, sleep, vigil and vigilance.
In men, modafinil restores and / or improves the levels and duration of wakefulness and daytime alertness in a dose-dependent manner. Modafinil administration results in electrophysiological changes indicative of increased alertness, and improvements in objective measures of the ability to maintain wakefulness. .
The efficacy of modafinil in patients with obstructive sleep apnea (OSA, Obstructive Apnoea Syndrome) who show excessive daytime sleepiness despite treatment with continuous positive airway pressure (CPAP, Continous Positive Airway Pressure) has been studied in randomized, controlled, short-term clinical trials. Although significant improvements in somnolence were observed, the magnitude of modafinil effect and the incidence of responses were low, when assessed by objective measurements, and limited to a small subpopulation of patients treated. known safety profile of the medicine, the risks outweigh the benefit obtained.
Three epidemiological studies, all with long-term observational design in cohorts with incipient disease, were conducted on administrative databases to assess the cardiovascular risk of modafinil. One of the three studies suggested an increased incidence rate of stroke in patients treated with modafinil compared to patients not treated with modafinil but the results of the three studies were not consistent.
05.2 Pharmacokinetic properties
Modafinil is a racemic compound, and the enantiomers have different pharmacokinetics, so in adult humans the R isomer has a triple elimination t½ that of the S isomer.
Linearity / non-linearity
Modafinil pharmacokinetic properties are linear and time independent. Systemic exposure increases in proportion to the dose, in the range of 200 - 600 mg.
Absorption
Modafinil is well absorbed, with maximum plasma concentrations being reached approximately 2 - 4 hours after administration.
Food has no effect on the overall bioavailability of modafinil; however, in the case of ingestion with food, absorption (Tmax) may be delayed by approximately one hour.
Distribution
Modafinil is moderately bound (approximately 60%) to plasma proteins, mainly albumin, indicating a low risk of interaction with highly bound medicinal products.
Biotransformation
Modafinil is metabolised by the liver. The major metabolite (40 - 50% of the dose), modafinil acid, is devoid of pharmacological activity.
Elimination
The excretion of modafinil and its metabolites is primarily renal, with a small proportion being eliminated unchanged (
The elimination half-life of modafinil after multiple doses is approximately 15 hours.
Kidney failure
Severe chronic renal failure (creatinine clearance up to 20 mL / min) does not significantly affect the pharmacokinetics of modafinil administered at the 200 mg dose, but the exposure to modafinil acid increases 9-fold. There is insufficient information to determine the safety and efficacy of administration in patients with renal insufficiency.
Hepatic insufficiency
In cirrhotic patients, the oral clearance of modafinil is reduced by approximately 60%, and the concentration at steady-state doubles, compared to the values in healthy patients. In patients with severe hepatic impairment the modafinil dosage should be halved.
Elderly population
There are limited data available for use in elderly patients. Given the possible reduced elimination capacity and increased systemic exposure, it is advisable to start therapy with 100 mg per day in patients over 65 years of age.
Pediatric population
In patients 6-7 years of age, the estimated half-life is approximately 7 hours and increases with increasing age to values approaching those of adults (approximately 15 hours). This difference in clearance is partially offset by the smaller size and lower weight of younger patients resulting in similar exposure after administration of comparable doses. Compared to adults, children and adolescents have higher concentrations of one of the circulating metabolites, modafinil sulfone.
Furthermore, a time-dependent reduction in systemic exposure was observed after repeated administration of modafinil to children and adolescents, with plateauing at approximately 6 weeks. Once steady-state is reached, the pharmacokinetic properties of modafinil do not appear to change with administration continues for up to approximately 1 year.
05.3 Preclinical safety data
Toxicological studies performed in animals with single and repeated doses did not reveal any particular toxic effects.
Modafinil is not considered to be mutagenic or carcinogenic.
Reproductive toxicity studies performed in rats and rabbits have shown, following clinically relevant exposures, a higher incidence of skeletal modifications (variations in the number of ribs and delayed ossification), embryo-fetal lethality (peri-implant loss and resorption), as well as some increase in stillbirths (in rats only), in the absence of maternal toxicity. There were no demonstrable effects on fertility and no indications of teratogenic potential at systemic exposures equivalent to the maximum recommended human dose.
Reproductive toxicity studies did not reveal any effects on fertility, teratogenic effects, or on the viability, growth or development of the offspring.
Animal exposure to modafinil, based on actual plasma levels in general and reproductive toxicology and carcinogenicity studies, was less than or similar to that expected in humans. This circumstance is the result of metabolic self-induction, as observed in preclinical studies. However, the exposure of animals to modafinil, calculated based on the dose in mg / kg in the general and reproductive toxicity and carcinogenicity studies was greater than that calculated with the same modality expected in man.
In the peri-postnatal study in the rat, the concentration of modafinil in milk was approximately 11.5 times higher than in plasma.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate
Pregelatinised starch (maize)
Microcrystalline cellulose
Carmellose sodium
Povidone K29 / 32
Magnesium stearate
06.2 Incompatibility
Not relevant
06.3 Period of validity
3 years
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Opaque PVC / PVDC / aluminum blister.
Packs of 10,20,30,50,60,90,100 or 120 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Teva Italia S.r.l.
Via Messina, 38
20154 Milan
08.0 MARKETING AUTHORIZATION NUMBER
Provigil 100 mg tablets - pack of 30 tablets - AIC 034369013 / M
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
April 2005
10.0 DATE OF REVISION OF THE TEXT
May 2015
