Tegretol - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Carbamazepine

TEGRETOL 200 mg tablets
TEGRETOL 400 mg tablets
TEGRETOL 200 mg modified release tablets
TEGRETOL 400 mg modified release tablets
TEGRETOL Children 20 mg / ml Syrup

Tegretol package inserts are available for pack sizes:
  • TEGRETOL 200 mg tablets, TEGRETOL 400 mg tablets, TEGRETOL 200 mg modified-release tablets, TEGRETOL 400 mg modified-release tablets, TEGRETOL Children 20 mg / ml Syrup
  • TEGRETOL 100 mg chewable tablets

Why is Tegretol used? What is it for?

Pharmacotherapeutic group

Antiepileptic. Antineuralgic of the trigeminal. Antimanic.

Therapeutic indications

Modified Release Tablets / Tablets

Epilepsies (psychomotor or temporal, generalized tonic-clonic seizures, mixed forms, focal seizures).

Essential neuralgia of the trigeminal.

Mania.

Syrup

Convulsive states of childhood.

Epilepsies with the same characteristics of Tegretol tablets (psychomotor or temporal, generalized tonic-clonic seizures, mixed forms, focal seizures).

Tegretol can be used both in mono and in polytherapy. Normally Tegretol does not act on petit mal (absences) and myoclonic attacks (see section "Special warnings").

Contraindications When Tegretol should not be used

  • Hypersensitivity to the active substance, to drugs with a similar structure (e.g. tricyclic antidepressants), or to any of the excipients.
  • Patients with atrioventricular block.
  • Patients with a history of bone marrow depression.
  • Patients with a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegated porphyria, tarda porphyria).
  • The concomitant administration of monoamine oxidase inhibitors (MAOIs) and Tegretol is contraindicated (see section "Interactions").
  • Generally contraindicated in pregnancy and during lactation.

Precautions for use What you need to know before taking Tegretol

Therapy must be conducted under medical supervision.

In patients with a history of liver, heart or kidney damage, haematological side effects to other drugs or to previous carbamazepine therapy courses, Tegretol should only be prescribed after the benefit-risk balance has been assessed and under close monitoring.

Hematological effects

Cases of aplastic anemia and agranulocytosis associated with the use of Tegretol have been reported; however, given the very low incidence of these conditions, it is difficult to calculate the significant risk associated with the use of Tegretol.

A temporary or persistent decrease in the number of platelets and white blood cells may occur during treatment with Tegretol; in most cases, however, these effects are temporary and are not signs of the onset of aplastic anemia or agranulocytosis. However, a complete blood test (including platelets and, if possible, reticulocytes and serum iron) is recommended before treatment and periodically during treatment.

If significantly low white blood cells or platelets are observed during treatment, the patient's blood parameters should be closely monitored. Tegretol should be discontinued if any symptoms of bone marrow depression appear.

Patients should be informed of early symptoms of toxicity and potential haematological problems, as well as liver or dermatological reactions. If symptoms such as fever, sore throat, rash, mouth ulcers, capillary fragility, petechiae or purple haemorrhages appear, the patient should immediately report this to his / her doctor.

Serious dermatological reactions

Serious skin side effects may rarely occur during treatment with Tegretol. In some populations (for example in the population of Chinese, Thai, Japanese, Caucasian origin, in some indigenous American populations, in Hispanic populations, in South India or of Arab descent) this risk can be predicted through a blood test. of belonging to one of the aforementioned ethnic origins, consult your doctor before taking the drug.

Life-threatening skin rashes (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported with the use of Tegretol: these initially appear as round red spots or circular patches that often accompany blisters in the midsection of the trunk. to notice include ulcers in the mouth, throat, nose, genitals and conjunctivitis (red and swollen eyes).

These life-threatening rashes are often accompanied by flu-like symptoms. The rash may progress to the development of widespread blistering or peeling of the skin. The highest risk of severe skin reactions occurs in the first months of treatment.

If you have developed Stevens-Johnson syndrome or toxic epidermal necrolysis with the use of Tegretol, Tegretol should no longer be used. If you develop a rash or these skin symptoms, stop taking Tegretol, consult a doctor urgently. doctor and inform him that you are taking this drug. Abrupt discontinuation of Tegretol treatment may trigger seizures (see "Dose Reduction and Treatment Discontinuation"). Patients experiencing serious dermatological reactions may require hospitalization as these conditions may pose a threat to the life and can be fatal.

Other dermatological reactions

Mild skin reactions may also occur (eg isolated episodes of macular or maculopapular exanthematous reactions), which are generally transient and not dangerous; these usually disappear within a few days or weeks, either by continuing treatment or by reducing the doses. However, as it may be difficult to distinguish the first signs of more serious skin reactions from those of mild and transient reactions, patients should be closely monitored during therapy, with immediate discontinuation of therapy if, during administration of the medicinal product, there is worsening of symptoms observed.

Hypersensitivity

Tegretol may trigger hypersensitivity reactions, including drug-induced rash with eosinophilia and systemic symptoms (DRESS), a delayed multi-organ hypersensitivity reaction, which can occur in different combinations, such as fever, rash, vasculitis, lymphadenopathy, pseudo- lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests and evanescent bile duct syndrome (destruction and disappearance of intrahepatic bile ducts). Other organs may also be affected, such as lungs, kidneys, pancreas, myocardium, colon (see section "Undesirable effects").

Patients who have experienced episodes of hypersensitivity reactions to carbamazepine should be advised that hypersensitivity reactions to oxcarbazepine (Tolep) may occur in approximately 25-30% of these cases.

Cross-hypersensitivity can also occur between carbamazepine and phenytoin. In general, if signs and symptoms of hypersensitivity reactions occur, Tegretol therapy should be discontinued immediately.

Seizures

Tegretol should be used with caution in patients with mixed seizures, which include typical or atypical absences. In these cases, Tegretol can exacerbate the attacks. If attacks worsen, Tegretol therapy should be discontinued.

Liver function

Especially in patients with liver disorders and the elderly, liver function checks should be performed at the beginning and during treatment. The administration of Tegretol should be discontinued immediately in case of worsening of hepatic dysfunction or active liver disease.

Renal function

It is recommended that a complete analysis of urine and blood urea nitrogen be performed periodically.

Hyponatremia

Hyponatremia is known to occur with carbamazepine. In patients with pre-existing renal conditions associated with low sodium levels or in patients treated concomitantly with drugs that lower sodium levels (e.g. diuretics, drugs associated with abnormal ADH secretion), serum sodium levels should be measured before initiate carbamazepine therapy. Serum sodium levels should therefore be measured after approximately two weeks and at monthly intervals thereafter during the first three months of therapy, or as needed clinically. These risk factors can mainly affect elderly patients. If hyponatremia is observed, reducing the fluid intake may represent an "important countermeasure, where clinically indicated.

Hypothyroidism

Carbamazepine can reduce serum concentrations of thyroid hormones by enzyme induction. It is suggested to monitor thyroid function; in patients with hypothyroidism, dose adjustments of thyroid replacement therapy may be necessary.

Anticholinergic effects

Tegretol showed weak anticholinergic activity; therefore, patients with elevated ocular pressure and urinary retention should be closely monitored during therapy (see section "Undesirable effects").

Psychiatric Effects

We must not forget the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation.

Suicidal ideation and behavior

A small number of patients being treated with antiepileptic drugs such as Tegretol have developed thoughts of self-harm or suicide. Anytime such thoughts arise, contact your doctor immediately.

Endocrinological effects

Blood loss has been reported in women taking oral contraceptives concomitantly with Tegretol; the safety of oral contraceptives may be compromised by the use of Tegretol. Therefore, women of childbearing age receiving Tegretol are advised to use alternative methods of contraception. The enzymatic induction determined by Tegretol can in fact cancel the therapeutic effect of drugs containing estrogen and / or progesterone.

Monitoring of plasma levels

Although the correlation between carbamazepine dose, plasma levels and clinical efficacy-tolerability is rather weak, the control of plasma levels can be useful in the following conditions: significant increase in the frequency of attacks (verification of compliance), in pregnancy, in the treatment of children and adolescents, in cases of suspected abnormal absorption, in cases of suspected toxicity when multiple drugs are being administered (see section "Interactions").

Hypericum perforatum preparations should not be taken concomitantly with carbamazepine containing medicines, due to the risk of decreased plasma levels and decreased therapeutic efficacy of carbamazepine (see section "Interactions").

Reduction of doses and effects upon discontinuation of treatment

Abrupt discontinuation of Tegretol treatment can trigger epileptic fits: carbamazepine therapy should therefore be gradually discontinued over at least 6 months. If treatment with Tegretol is to be abruptly stopped in an epileptic patient, a switch to a new antiepileptic preparation should be made using adequate drug coverage.

Interactions Which drugs or foods can modify the effect of Tegretol

Tell your doctor or pharmacist if you have recently taken any medicines, even those without a prescription.

Interactions that determine a contraindication to use

The use of Tegretol is contraindicated in combination with monoamine oxidase inhibitors (MAOIs). Before using Tegretol the administration of MAOIs should be interrupted for at least 2 weeks or longer if the clinical condition permits (see section "Contraindications" ).

Drugs that can raise carbamazepine plasma levels

Since increased carbamazepine plasma levels can cause side effects (e.g. dizziness, somnolence, ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and / or the plasma levels monitored when the following drugs are administered concomitantly.

Analgesics, anti-inflammatories: dextropropoxyphene, ibuprofen.

Androgens: donazole.

Antibiotics: macrolide antibiotics (e.g. erythromycin, troleandomycin, iosamycin, clarithromycin, ciprofloxacin).

Antidepressants: probably desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine.

Antiepileptics: stiripentol, vigabatrin Antifungals: azoles (e.g. itraconazole, ketoconazole, fluconazole), voriconazole.

Antihistamines: loratidine, terfenadine.

Antipsychotics: olanzapine.

Antituberculosis: isoniazid.

Antivirals: HIV protease inhibitors (eg ritonavir).

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular drugs: verapamil, diltiazem.

Gastrointestinal drugs: probably cimetidine, omeprazole.

Muscle relaxants: oxybutynin, dantrolene.

Inhibitors of platelet aggregation: ticlopidine.

Other interactions: grapefruit juice, nicotinamide (in adults only in high doses).

Drugs that may raise plasma levels of the carbamazepine-10,11-epoxide metabolite

Since elevated plasma levels of carbamazepine-10,11-epoxide may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and / or plasma levels monitored when Tegretol is administered concomitantly. with the substances listed below:

Loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.

Drugs that can reduce carbamazepine plasma levels

The dosage of Tegretol may need to be adjusted when the drugs described below are administered concurrently.

Antiepileptics: felbamate, mesuximide, oxcarbazepine, phenobarbital, fensuximide, phenytoin and fosphenytoin, primidone and, although the data are partially contradictory, also clonazepam.

Antineoplastics: cisplatin, doxorubicin.

Antituberculosis: rifampicin.

Bronchodilators or anti-asthmatics: theophylline, aminophylline.

Dermatological drugs: isotretinoin.

Other interactions: Carbamazepine serum levels may be reduced by concomitant administration of Hypericum perforatum preparations. This is due to the induction of the enzymes responsible for drug metabolism by preparations based on Hypericum perforatum which, therefore, should not be administered concomitantly with carbamazepine. The induction effect may persist for at least 2 weeks after discontinuation. treatment with Hypericum perforatum products. If a patient is taking Hypericum perforatum products at the same time, carbamazepine blood levels should be monitored and therapy with Hypericum perforatum products discontinued. Carbamazepine blood levels may be discontinued. increase with stopping Hypericum perforatum. The dosage of carbamazepine may need to be adjusted.

Effect of Tegretol on plasma levels of concomitant drugs

Carbamazepine can cause a decrease in the plasma levels of certain drugs, and can also lead to a decrease or even cancellation of their activity. The dosage of the following drugs may need to be adjusted according to specific clinical needs:

Analgesics, anti-inflammatories: buprenorphine, methadone, paracetamol (long-term administration of carbamazepine and paracetamol (acetaminophen) may be associated with hepatotoxicity), phenazone (antipyrine), tramadol.

Antibiotics: doxycycline.

Anticoagulants: oral anticoagulants (warfarin, phenprocoumon, dicumarol and acenocoumarol).

Antidepressants: bupropion, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (eg imipramine, amitriptyline, nortriptyline, clomipramine).

Antiemetics: aprepitant.

Antiepileptics: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. Carbamazepine has rarely raised the plasma levels of mephenytoin.

Antifungals: itraconazole, voriconazole.

Pesticides: praziquantel, albendazole.

Antineoplastics: imatinib, cyclophosphamide, lapatinib, temsirolimus.

Antipsychotics: clozapine, haloperidol and bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone.

Antivirals: HIV protease inhibitors (eg indinavir, ritonavir, saquinavir).

Anxiolytics: alprazolam, midazolam.

Bronchodilators or antiasthmatics: theophylline.

Contraceptives: hormonal contraceptives (the use of alternative methods is recommended).

Cardiovascular drugs: calcium channel blockers (dihydropyridine derivatives) eg. felodipine, digoxin, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.

Corticosteroids: corticosteroids (e.g. prednisolone, dexamethasone).

Drugs used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.

Thyroid preparations: levothyroxine.

Other drug interactions: products containing estrogen and / or progesterone.

Concurrent treatments to be carefully evaluated

Concomitant administration of carbamazepine and levetiracetam increases the toxicity induced by carbamazepine.

Concomitant administration of carbamazepine and isoniazid increases the hepatotoxicity induced by isoniazid.

The administration of carbamazepine and lithium or metoclopramide, or carbamazepine and neuroleptics (haloperidol, thioridazine) can cause an increase in neurological side effects (with the second combination, even in the presence of therapeutic plasma levels).

Concomitant administration of Tegretol with some diuretics (hydrochlorothiazide, furosemide) may lead to a decrease in sodium in the blood with possible onset of side effects. Carbamazepine may antagonize the effect of some non-depolarising muscle relaxants (eg pancuronium); their dosage should be increased and patients closely monitored to prevent resolution of neuromuscular block from happening too quickly.

Carbamazepine, like other psychoactive drugs, can reduce alcohol tolerability; it is therefore advisable for the patient to refrain from alcohol consumption.

Interference with serological tests

Carbamazepine can give false positives on HPLC analysis for perphenazine concentrations due to interference with the latter.

Carbamazepine and the metabolite 10,11, epoxide can give false positives with the immunological method based on polarized fluorescence measurements regarding the concentrations of tricyclic antidepressants.

Warnings It is important to know that:

Fertility, pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine.

Pregnancy

Patients who may become pregnant or are of childbearing age should be given specialist advice.

The need for antiepileptic treatment should be re-evaluated when the patient plans to become pregnant.

The risk of congenital defects is increased by a factor of 2 to 3 times in the offspring of mothers treated with an antiepileptic, the most frequently reported being cleft lip, cardiovascular malformations, neural tube defects, hypospadias.

Polytherapy with antiepileptic drugs may be associated with a higher risk of congenital malformations than monotherapy. The risk of malformations following exposure to carbamazepine administered in polypharmacy may vary depending on the antiepileptic drugs used and may be greater in the case of polytherapies that include valproate. Therefore it is important that monotherapy is practiced whenever possible.

It is recommended that the lowest effective dose be administered and plasma levels monitored. There is evidence to suggest that the risk of malformations with carbamazepine may be dose-dependent, i.e. at doses below 400 mg / day the frequency of malformations was less than with higher doses of carbamazepine.

Abrupt discontinuation of antiepileptic therapy should not be practiced due to the danger of a resumption of seizures which could have serious consequences for both mother and baby

Monitoring and prevention

Additional folic acid treatment is recommended before and during pregnancy.

Newborn

Vitamin K1 is recommended for both the mother during the last weeks of pregnancy and the neonate.Some episodes of seizures and / or respiratory depression have occurred in neonates whose mothers were treated with Tegretol and concomitantly with other anticonvulsant drugs ; in some cases, vomiting, diarrhea and / or decreased food intake in the newborn have also been reported. These reactions could signal a neonatal withdrawal syndrome.

Women of childbearing age and contraceptive measures

The use of Tegretol may cancel the therapeutic effect of oral contraceptives containing estrogen and / or progesterone. Patients of childbearing potential should be advised to use alternative methods of contraception during therapy with Tegretol.

Feeding time

Carbamazepine passes into breast milk. In the event that the doctor is in favor and the baby is strictly controlled, the patient can also breastfeed the baby. However, if any side effects occur (eg allergic skin reactions) or if the baby sleeps more than usual, stop breastfeeding and contact the doctor. There have been some reports of colostatic hepatitis in newborns exposed to carbamazepine in the prenatal period. or while breastfeeding. Infants of carbamazepine-treated and breast-fed mothers should be carefully monitored for the occurrence of hepatobiliary adverse events.

Fertility

Very rare cases of impaired male fertility and / or abnormalities in spermatogenesis have been reported.

Effects on ability to drive or use machines

Patients' ability to react may be impaired by underlying disease (seizures) and adverse reactions including somnolence, dizziness, ataxia, diplopia, accommodation disturbances and blurred vision reported with Tegretol especially at the start of treatment or when adjusting the doses. It is therefore necessary to be very careful when driving motor vehicles, using machines or in activities that require particular attention.

Important information about some of the ingredients:

TEGRETOL Children 20 mg / ml Syrup contains sorbitol. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

TEGRETOL Children 20 mg / ml Syrup contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. They can cause allergic reactions (even delayed).

TEGRETOL 200 mg modified-release tablets contain hydrogenated polyhydric castor oil. It can cause stomach upset and diarrhea.

TEGRETOL 400 mg modified-release tablets contain hydrogenated polyhydric castor oil. It can cause stomach upset and diarrhea.

Dosage and method of use How to use Tegretol: Dosage

Tegretol is a drug that must be taken regularly and exactly at the dosage prescribed by the doctor. This allows you to get the best results and reduce the risk of unwanted effects. It is recommended not to exceed the doses and frequency of administration recommended by the doctor.

The tablets and the syrup (the bottle must be shaken before use) can be taken before, during or after meals; the tablets must be taken with a little liquid.

Modified-release tablets (either whole or broken in half) should be swallowed, without chewing, with some liquid. Secretol, with the exception of the first day of treatment, should always be given in several daily doses, usually 2 or 3 times a day.

Due to drug interactions and the different pharmacokinetics of antiepileptic drugs, the dosage of Tegretol should be carefully established in elderly patients.

Epilepsy

Where possible Tegretol should be given as monotherapy and the dosage should be individually adjusted. It is recommended that therapy be instituted with a progressive posology.

Determination of plasma concentrations can help to find the optimal posology particularly in combination treatment.

Adults: Treatment of epilepsy generally begins with 100-200 mg once or twice a day. The dosage is then gradually increased up to 800-1200 mg per day (some patients require dosages of 1600 or even 2000 mg per day) , divided into 2 or 3 administrations.

Children: A starting dose of 20-60 mg / day, increased by 20-60 mg every 2 days, is recommended in children up to 4 years of age. For children over 4 years of age, therapy can be started with 100 mg / day and increased by 100 mg weekly.

The recommended daily maintenance dose in children for the treatment of epilepsy (= 10-20 mg / kg body weight, daily in divided doses) is:

less than 1 year 100-200 mg / day (= 5-10 ml = 1-2 scoops of syrup)

from 1 to 5 years 200-400 mg / day (= 10-20 ml = 2 x 1-2 scoops of syrup)

from 6 to 10 years 400-600 mg / day (= 20-30 ml = 2 x 2-3 scoops of syrup)

11 to 15 years 600-1000 mg / day (= 30-50 ml = 3 x 2-3 scoops of syrup)

over 15 years: 800-1200 mg / day (the same dose as indicated in adults).

From 200 mg per day it is recommended to divide the dose during the day into 2-3 administrations.

The maximum recommended maintenance dose in children is:

up to 6 years: 35 mg / kg / day

from 6 to 15 years: 1000 mg / day

over 15 years: 1200 mg / day.

Tegretol tablets, modified release tablets and chewable tablets are not recommended in very young children (less than 5 years of age)

Trigeminal neuralgia

The starting dose of 200-400 mg per day is slowly increased until pain subsides (usually at a dose of 200 mg 3-4 times a day); then the dose is gradually reduced until the minimum effective maintenance dose is reached. The maximum recommended dose is 1200 mg / day.

Once the pain subsides, attempts should be made to gradually discontinue therapy until a new attack occurs.

A lower starting dose, 100 mg twice a day, is recommended in the elderly and in particularly sensitive patients.

Mania

The dosage varies from 400 mg to 1600 mg per day; the usual dosage is 400-600 mg per day divided into 2-3 doses.

In the treatment of elderly patients, the posology must be carefully established by the doctor who will have to evaluate a possible reduction of the dosages indicated above.

The dose prescribed by your doctor may differ from what is stated in this leaflet. In this case it is recommended to follow the doctor's instructions.

Special populations

Renal / hepatic impairment No data on the pharmacokinetics of carbamazepine are available in patients with renal or hepatic insufficiency.

Overdose What to do if you have taken too much Tegretol

If symptoms of the respiratory system (e.g. difficulty breathing), cardiovascular system (e.g. rapid and irregular heartbeat), central nervous system (loss of consciousness), gastrointestinal system (e.g. nausea or vomiting) occur the musculoskeletal system (e.g. rhabdomyolysis), the dose you are taking may be too high. Do not take any other doses of the drug and contact your doctor immediately.In case of accidental ingestion / intake of an excessive dose of Tegretol, notify your doctor immediately or go to the nearest hospital.

If you have any questions about the use of Tegretol, ask your doctor or pharmacist.

Side Effects What are the side effects of Tegretol

Like all medicines, Tegretol can cause side effects, although not everybody gets them.

Particularly at the beginning of treatment with Tegretol, or if the starting dose is too high or in elderly patients, some adverse reactions may occur very frequently or frequently, for example in the CNS (dizziness, headache, ataxia, somnolence, fatigue, diplopia ), gastrointestinal tract (nausea, vomiting) and allergic skin reactions.

Dose-related adverse reactions usually disappear within a few days, either spontaneously or after temporary dose reduction.

CNS adverse reactions may be the expression of overdose or significant fluctuations in plasma levels. In these cases it is suggested to check the plasma levels.

Adverse reactions are listed below by type and frequency. Within each frequency class, adverse reactions are listed in order of decreasing severity.

Disorders of the blood and lymphatic system

Very common: leukopenia.

Common: thrombocytopenia, eosinophilia.

Rare: leukocytosis, lymphadenopathy.

Very rare: Agranulocytosis, aplastic anemia, pancytopenia, pure red cell aplasia, anemia, anemiamegaloblastic, reticulocytosis, haemolytic anemia.

Disorders of the immune system

Rare: Multiple organ delayed hypersensitivity response with disorders, which can manifest in different combinations, such as fever, rash, vasculitis, lymphadenopathy, pseudo-lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function and evanescent bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts). Other organs may also be affected, such as lungs, kidneys, pancreas, myocardium, colon.

Very rare: anaphylactic reactions, angioedema, hypogammaglobulinemia.

Endocrine pathologies

Common: edema, water retention, weight gain, hyponatremia and reduction in blood osmolarity due to an "action similar to" ADH, which can in rare cases lead to water intoxication accompanied by vomiting, lethargy, headache, confusion, neurological disorders.

Very rare: galactorrhea, gynaecomastia.

Metabolism and nutrition disorders

Rare: folic acid deficiency, decreased appetite.

Very rare: acute porphyria (acute intermittent porphyria and variegated porphyria), non-acute porphyria (tarda porphyria).

Psychiatric disorders

Rare: hallucinations (visual or auditory), depression, aggression, agitation, restlessness, confusion.

Very rare: activation of psychosis.

Nervous system disorders

Very common: ataxia, dizziness, somnolence.

Common: diplopia, headache.

Uncommon: involuntary abnormal movements (e.g. tremor, asterypsis, dystonia, tics), nystagmus.

Rare: dyskinesia, ocular motility disorders, speech disorders (dysarthria, indistinct speech), choreoathetosis, peripheral neuropathies, paraesthesia, paresis.

Very rare: neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

Eye disorders

Common: accommodation disturbances (eg blurred vision).

Very rare: lens opacity, conjunctivitis.

Ear and labyrinth disorders

Very rare: hearing disorders (eg tinnitus, hyperacusis, hypoacusis, altered perception of tone).

Cardiac pathologies

Rare: cardiac conduction disturbances.

Very rare: arrhythmia, atrioventricular block with syncope, bradycardia, congestive heart failure, aggravation of coronary artery disease.

Vascular pathologies

Rare: hypertension or hypotension.

Very rare: circulatory collapse, embolism (eg pulmonary embolism), thrombophlebitis [312].

Respiratory, thoracic and mediastinal disorders

Very rare: pulmonary hypersensitivity characterized for example by fever, dyspnoea, pneumonia.

Gastrointestinal disorders

Very common: vomiting, nausea.

Common: dry mouth.

Uncommon: diarrhea, constipation.

Rare: abdominal pain.

Very rare: pancreatitis, glossitis, stomatitis.

Hepatobiliary disorders

Rare: cholestatic, parenchymal (hepatocellular) or mixed liver disease, evanescent bile duct syndrome, jaundice.

Very rare: hepatic failure, granulomatous hepatitis.

Skin and subcutaneous tissue disorders

Very common: urticaria which can be severe, allergic dermatitis.

Uncommon: exfoliative dermatitis.

Rare: systemic lupus erythematosus, pruritus.

Very rare: life-threatening skin rashes (Steven-Johnson syndrome (*), toxic epidermal necrolysis) (see "Precautions for use"), photosensitivity reactions, erythema multiforme, erythema nodosum, skin pigmentation change, purpura, acne , hyperhidrosis, alopecia, hirsutism.

Musculoskeletal and connective tissue disorders

Rare: muscle weakness.

Very rare: bone metabolism disorders (decrease in plasma calcium concentrations and blood 25-hydroxy-cholecalciferol concentrations) leading to osteomalacia / osteoporosis, arthralgia, myalgia, muscle spasms.

Renal and urinary disorders

Very rare: tubulointerstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria, increased blood urea / azotaemia), urinary retention, pollakiuria.

Diseases of the reproductive system and breast

Very rare: sexual dysfunction / erectile dysfunction, abnormalities in spermatogenesis (with decreased sperm count and / or motility).

General disorders and administration site conditions

Very common: fatigue

Diagnostic tests

Very common: gamma-GT elevation (due to induction of liver enzymes), usually not clinically relevant.

Common: increased blood concentrations of alkaline phosphatase.

Uncommon: elevation of transaminases.

Very rare: increased intraocular pressure, increased blood levels of cholesterol, high density lipoprotein, and triglycerides. Alteration of functional parameters of the thyroid: decrease in L-Thyroxine (free thyroxine, thyroxine, triiodothyroxine) and increase in blood concentrations of thyroid stimulating hormone, usually without clinical manifestations, increase in blood levels of prolactin

(*) In some Asian countries the frequency is "rare". See also "Precautions for use".

Additional adverse reactions resulting from spontaneous reporting (frequency not known)

The following adverse reactions derive from post-marketing experience with Tegretol and refer to spontaneous reports and cases described in the literature. As these reactions arise spontaneously from a population of uncertain size, it is not possible to estimate with certainty the frequency which is therefore indicated. as “not known.” Within each class, adverse reactions are listed in order of decreasing severity.

Infections and infestations

Reactivation of Human Herpesvirus Infections 6.

Disorders of the blood and lymphatic system

Medullary depression.

Nervous system disorders

Sedation, memory disturbances.

Gastrointestinal disorders

Colitis.

Disorders of the immune system

Drug-induced rash with eosinophilia and systemic symptoms (DRESS).

Skin and subcutaneous tissue disorders

Acute generalized exanthematous pustulosis (AGEP), lichenoid keratosis, onychomadesis.

Musculoskeletal and connective tissue disorders

Fractures.

Diagnostic tests

Decrease in bone density.

Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

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. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Expiry date: see the expiry date shown on the package.The expiry date refers to the product in intact packaging, correctly stored. Warning: do not use the medicine after the expiry date shown on the package.

Syrup: protect from heat and light.

200 and 400 mg tablets: protect from moisture.

Modified-release tablets of 200 and 400 mg: protect from moisture. Store at a temperature not exceeding 25 ° C.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

Keep this medicine out of the sight and reach of children.

Composition and pharmaceutical form

Composition

TEGRETOL 200 mg tablets

One tablet contains: active ingredient: carbamazepine 200 mg.

Excipients: microcrystalline cellulose; carmellose sodium; anhydrous colloidal silica; magnesium stearate.

TEGRETOL 400 mg tablets

One tablet contains: active ingredient: carbamazepine 400 mg.

Excipients: microcrystalline cellulose; carmellose sodium; anhydrous colloidal silica; magnesium stearate.

TEGRETOL 200 mg modified release tablets

One tablet contains: active ingredient: carbamazepine 200 mg.

Excipients: anhydrous colloidal silica; aqueous dispersion of ethyl cellulose; microcrystalline cellulose; polyacrylate dispersion 30%; magnesium stearate; croscarmellose sodium; talc; hypromellose; hydrogenated polyhydric castor oil; red iron oxide; yellow iron oxide; titanium dioxide.

TEGRETOL 400 mg modified release tablets

One tablet contains: active ingredient: carbamazepine 400 mg.

Excipients: anhydrous colloidal silica; aqueous dispersion of ethyl cellulose; microcrystalline cellulose; polyacrylate dispersion 30%; magnesium stearate; croscarmellose sodium; talc; hypromellose; hydrogenated polyhydric castor oil; red iron oxide; yellow iron oxide; titanium dioxide.

TEGRETOL Children 20 mg / ml Syrup

100 ml of syrup contain: active ingredient: carbamazepine 2 g.

Excipients: polyethylene glycol stearate; microcrystalline cellulose / carmellose sodium; 70% sorbitol (not crystallizable); methyl parahydroxybenzoate; propyl parahydroxybenzoate; sodium saccharin; hydroxyethylcellulose; sorbic acid; propylene glycol; caramel flavor; purified water.

Pharmaceutical form and content

Tablets.

Modified-release tablets.

Syrup.

Tegretol 200 mg tablets

Box of 50 tablets

Tegretol 400 mg tablets

Box of 30 tablets

Tegretol 200 mg modified release tablets

Box of 30 modified-release tablets

Tegretol 400 mg modified release tablets

Box of 30 modified-release tablets

Tegretol Children 20 mg / ml Syrup

250 ml bottle

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.

More information on Tegretol can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

TEGRETOL

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

TEGRETOL 200 mg tablets

One tablet contains:

active ingredient: carbamazepine 200 mg.

TEGRETOL 400 mg tablets

One tablet contains:

active ingredient: carbamazepine 400 mg.

TEGRETOL 200 mg modified release tablets

One modified-release film-coated tablet contains:

active ingredient: carbamazepine 200 mg.

excipients with known effects: hydrogenated polyhydric castor oil

TEGRETOL 400 mg modified release tablets

One modified-release film-coated tablet contains:

active ingredient: carbamazepine 400 mg.

excipients with known effects: hydrogenated polyhydric castor oil

TEGRETOL Children 20 mg / ml Syrup

100 ml of syrup contain:

active ingredient: carbamazepine 2 g.

excipients with known effects: sorbitol, methyl parahydroxybenzoate, propyl parahydroxybenzoate.

TEGRETOL 100 mg chewable tablets

One chewable tablet contains:

active ingredient: carbamazepine 100 mg.

excipients with known effects: sucrose.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablets.

Modified-release tablets.

Chewable tablets.

Syrup.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Tablets / Modified Release Tablets / Chewable Tablets

Epilepsies (psychomotor or temporal, generalized tonic-clonic seizures, mixed forms, focal seizures).

Essential neuralgia of the trigeminal.

Mania.

Syrup

Convulsive states of childhood.

Epilepsies with the same characteristics of Tegretol tablets (psychomotor or temporal, generalized tonic-clonic seizures, mixed forms, focal seizures).

Tegretol can be used both in mono and in polytherapy.

Normally Tegretol does not act on petit mal (absences) and myoclonic attacks (see section 4.4).

04.2 Posology and method of administration

The tablets and the syrup (the bottle must be shaken before use) can be taken before, during or after meals; the tablets must be taken with a little liquid and any residual chewable tablets must be eliminated with a some liquid.

Modified-release tablets (either whole or broken in half) should be swallowed, without chewing, with some liquid. The syrup and chewable tablets are particularly suitable for those patients who have difficulty swallowing tablets or who require a careful adjustment of the dosage.

Due to the slow and modified release of carbamazepine, the modified release tablets are formulated to be taken twice daily.

Since the same dose of Tegretol syrup produces higher plasma peaks than a tablet, it is recommended to start with low doses and increase them slowly to avoid the onset of side effects.

In case it is necessary to switch from a therapy with tablets to one with syrup it is recommended to administer the same number of mg per day, but with more close doses (for example three times a day for the syrup instead of twice a day). day for tablets).

If you want to switch from normal to modified release tablets, clinical experience shows that the dosage of the modified release form may need to be increased.

Due to the drug interactions and the different pharmacokinetics of antiepileptic drugs, the dosage of Tegretol must be identified with care in elderly patients.

Epilepsy

Where possible Tegretol should be given as monotherapy.

Treatment should be started with low daily doses, which should be slowly increased until optimal effect is achieved. After good seizure control is achieved, the dosage can be very gradually decreased to the lowest effective level.

The carbamazepine dose should be adjusted to the needs of the individual patient to achieve adequate seizure control. Determining plasma concentrations can help find the optimal posology.In the treatment of epilepsy the carbamazepine dose generally requires total plasma concentrations of approximately 4-12 μg / mL (17-50 μmol / liter) to be achieved (see section 4.4).

When Tegretol is added to a pre-existing antiepileptic therapy, it should be done gradually, maintaining the initial therapy and adjusting the dosage, if necessary, of the other antiepileptics (see section 4.5).

Adults

Initial dose 100-200 mg 1-2 times a day, then slowly increase until the optimal dose is reached, which is generally around 400 mg 2-3 times a day. In some patients the required dosage may be 1600 or even 2000 mg per day.

Children

In children up to 4 years, an initial dose of 20-60 mg / day is recommended, increased by 20-60 mg every 2 days. For children over 4 years of age, therapy can be started with 100 mg / day and increased by 100 mg weekly.

The recommended daily maintenance dose in children for the treatment of epilepsy (= 10-20 mg / kg body weight, daily in divided doses) is:

less than 1 year: 100-200 mg / day (= 5-10 ml = 1-2 scoops of syrup)

from 1 to 5 years: 200-400 mg / day (= 10-20 ml = 2 x 1-2 scoops of syrup)

from 6 to 10 years: 400-600 mg / day (= 20-30 ml = 2 x 2-3 scoops of syrup)

11 to 15 years: 600-1000 mg / day (= 30-50 ml = 3 x 2-3 scoops of syrup)

over 15 years: 800-1200 mg / day (the same dose as indicated in adults).

From 200 mg per day it is recommended to divide the dose during the day into 2-3 administrations.

The maximum recommended maintenance dose in children is:

up to 6 years: 35 mg / kg / day

from 6 to 15 years: 1000 mg / day

over 15 years: 1200 mg / day.

Tegretol tablets, modified release tablets and chewable tablets are not recommended in very young children (less than 5 years of age)

Trigeminal neuralgia

The initial dose of 200-400 mg per day is slowly increased until the painful symptoms disappear (usually 200 mg 3 or 4 times a day); then the dose is gradually reduced until the minimum effective maintenance dose is reached. The maximum recommended dose is 1200 mg / day. Once the pain subsides, attempts should be made to gradually discontinue therapy until a new attack occurs.

In elderly people and particularly sensitive patients, start with 100 mg twice a day.

Mania

The dosage varies from 400 mg to 1600 mg per day; generally 400-600 mg per day are given divided into 2-3 doses.

In the treatment of elderly patients, the posology must be carefully established by the doctor who will have to evaluate a possible reduction of the dosages indicated above.

Before deciding to initiate treatment, patients of Chinese origin of Han ethnicity or of Thai descent should, whenever possible, be screened for HLA-B * 1502 as this type of allele is strongly predictive of the risk of severe syndrome. of Stevens-Johnson (SJS) associated with carbamazepine (see information on genetic testing and skin reactions in section 4.4).

Special populations

Impaired renal / hepatic function

There are no data on the pharmacokinetics of carbamazepine in patients with renal or hepatic impairment.

04.3 Contraindications

• Hypersensitivity to the active substance, drugs with a similar structure (eg tricyclic antidepressants) or to any of the excipients listed in section 6.1.

• Patients with atrioventricular block.

• Patients with a history of bone marrow depression.

• Patients with a history of hepatic porphyrias (eg acute intermittent porphyria, variegated porphyria, porphyria cutanea tarda).

• The concomitant administration of inhibitors is contraindicated

monoamine oxidase (MAOI) and Tegretol (see section 4.5).

• Generally contraindicated during pregnancy and breastfeeding.

04.4 Special warnings and appropriate precautions for use

Therapy must be conducted under medical supervision.

In patients with a history of liver, heart or kidney damage, haematological side effects to other drugs or to previous carbamazepine therapy courses, Tegretol should only be prescribed after the benefit-risk balance has been assessed and under close monitoring.

Hematological effects

Cases of aplastic anemia and agranulocytosis associated with the use of Tegretol have been reported; however, given the very low incidence of these conditions, it is difficult to calculate the significant risk associated with the use of Tegretol. An overall risk in the untreated population of approximately 4.7 people per million annually for agranulocytosis and 2 people per million annually for aplastic anemia was estimated.

A temporary or persistent decrease in the number of platelets and white blood cells may occur during treatment with Tegretol; in most cases, however, these effects are temporary and are not signs of the onset of aplastic anemia or agranulocytosis. However, a complete blood test (including platelets and, if possible, reticulocytes and serum iron) is recommended before treatment and periodically during treatment.

If significantly low white blood cells or platelets are observed during treatment, the patient's blood parameters should be closely monitored. Tegretol should be discontinued if any symptoms of bone marrow depression appear.

Patients should be informed of early symptoms of toxicity and potential haematological problems, as well as liver or dermatological reactions. If symptoms such as fever, sore throat, rash, mouth ulcers, capillary fragility, petechiae or purple haemorrhages appear, the patient should immediately report this to his / her doctor.

Dermatological reactions

Serious and sometimes fatal skin reactions including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment with carbamazepine. The occurrence of these reactions is estimated to be 1 to 6 in every 10,000 new patients in countries with a predominantly Caucasian population, but the risk in some Asian countries is estimated to be approximately 10 times higher.

Patients should be informed of the signs and symptoms and monitored

carefully for skin reactions. The highest risk of developing SJS and TEN occurs in the first months of treatment.

If symptoms or signs of SJS or TEN occur (e.g. progressive skin rash often with blistering or mucosal lesions) treatment with Tegretol should be discontinued.

The best results in the management of SJS and TEN are obtained with an early diagnosis and immediate discontinuation of therapy with any suspect drug. Early discontinuation is associated with a better prognosis.

If the patient has developed SJS or TEN with the use of Tegretol, Tegretol should no longer be used in this patient.

Patients experiencing serious dermatological reactions may require hospitalization as these conditions can be life threatening and can be fatal.

Pharmacogenomics

The role of different HLA alleles in predisposition to immune-mediated adverse reactions is increasingly evident in these patients (see section 4.2).

Association with the HLA-B * 1502 allele - in the Chinese population of Han ethnicity, Thai and other Asian populations

In individuals of Chinese origin of Han ethnicity and of Thai origin, positivity to the allele HLA-B * 1502 (allelle of the human leukocyte antigen, Human Leukocyte Antigen, HLA) has been shown to be strongly associated with the risk of developing severe skin reactions such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) during treatment with carbamazepine. The prevalence of the HLA-B * 1502 allele is about 10% in Han Chinese and Thai populations.

Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine (see section 4.2 and "Information for healthcare professionals"). If these patients test positive, carbamazepine treatment should not be initiated unless there is no other therapeutic alternative. Patients tested who have tested negative for HLA-B * 1502 are at low risk of developing Stevens-Johnson (SJS), although this reaction may still occur although very rarely.

Some data suggest an increased risk of carbamazepine-associated severe reactions such as SJS / TEN in other Asian populations. Due to the prevalence of this allele in other Asian populations (eg above 15% in the Philippines and Malaysia), testing in genetically at risk populations for the presence of the HLA-B * 1502 allele can be considered.

The prevalence of the HLA-B * 1502 allele is negligible, for example in populations of European origin, African, in a Hispanic population sample, in Japanese and Koreans (

The allele frequencies described here represent the percentage of chromosomes in that specific population that carry the affected allele, which means that the percentage of patients carrying a copy of the allele on at least one of their two chromosomes (ie the "carrier frequency" ") is approximately twice the allele frequency. Therefore the percentage of patients at risk is approximately twice the allele frequency.

The presence of the HLA-B * 1502 allele may be a risk factor for the development of SJS / TEN in Chinese patients taking other antiepileptic drugs that can cause SJS / TEN. Therefore, in patients positive for the HLA-B allele * 1502, care should be taken to avoid the use of other drugs that can cause SJS / TEN if equally acceptable alternative therapies are available.

Screening is generally not recommended in patients from populations where the prevalence of the HLA-B * 1502 allele is low or in patients who are already taking Tegretol, as the risk of developing SJS / TEN is generally limited to the first few months. of therapy, regardless of the presence of the HLA-B * 1502 allele.

Identifying individuals expressing the HLA-B * 1502 allele and avoiding carbamazepine therapy in these individuals have been shown to decrease the incidence of carbamazepine-induced SJS / TEN.

Association with the HLA-A * 3101 allele - in the population of European descent and in the Japanese population

Some data suggest that HLA-A * 3101 is associated with an increased risk of carbamazepine-induced severe skin adverse reactions including (SJS, and TEN, rash with eosinophilia (DRESS), or acute generalized exanthematous pustulosis (AGEP) less severe and maculopapular rash (see section 4.8) in persons of European and Japanese descent.

The frequency of the HLA-A * 3101 allele varies widely among ethnic populations. The HLA-A * 3101 allele has a prevalence of 2 to 5% in European populations and approximately 10% in the Japanese population.

The presence of the HLA-A * 3101 allele may increase the risk of carbamazepine-induced skin reactions (mostly severe) from 5.0% in the general population to 26% among subjects of European origin, while its absence can reduce the risk from 5.0% to 3.8%.

The allele frequencies described here represent the percentage of chromosomes of

that specific population carrying the affected allele, which means that the percentage of patients carrying a copy of the allele on at least one of their two chromosomes (ie the "carrier frequency") is approximately twice the allele frequency. Therefore the percentage of patients at risk is approximately twice the allele frequency.

There are insufficient data to support a recommendation for screening for HLA-A * 3101 before starting treatment with carbamazepine.

If patients of European or Japanese descent are found to be positive for the HLA-A * 3101 allele, the use of carbamazepine may only be considered if the expected benefits outweigh the risks.

Limitations of genetic screening

Genetic screening should never replace adequate clinical observation and patient management. Many Asian patients HLA-B * 1502 positive and treated with Tegretol will not develop SJS / TEN and in HLA- negative patients. B * 1502 of any ethnicity, however, episodes of SJS / TEN may occur. Similarly, many patients who are positive for the HLA-A * 3101 allele and treated with Tegretol will not develop SJS, TEN, DRESS, AGEP or maculopapular rash, and in patients with any ethnicity negative for the HLA-A * 3101 allele, however, these severe skin adverse reactions may arise. The role of other factors that may be involved in the development, and morbidity, of these severe skin adverse reactions, such as dose, has not been studied. of antiepileptic drugs, adherence to treatment (compliance), concomitant therapies, co-morbidities and the level of dermatological control.

Information for healthcare professionals

If testing for the presence of the "HLA-B * 1502 or HLA-A * 3101 allele is to be performed, it is recommended to use the" HLA-B * 1502 genotype "or" HLA-A * 3101 genotype "test respectively with high Resolution The test is positive if one or two HLA-B * 1502 or HLA-A * 3101 alleles are detected, negative if no HLA-B * 1502 or HLA-A * 3101 alleles are detected.

Other dermatological reactions

Mild skin reactions may also occur (for example, isolated episodes of macular or maculopapular exanthematous reactions), which are generally transient and not dangerous; these usually disappear within a few days or weeks, either by continuing treatment or by reducing the doses. However, as it may be difficult to distinguish the first signs of more serious skin reactions from those of mild and transient reactions, patients should be closely monitored during therapy taking care to discontinue therapy immediately if, during administration of the medicinal product, it is observed. worsening of symptoms.

Positivity for the HLA-A * 3101 allele was associated with less severe carbamazepine skin reactions and may predict the risk of developing reactions such as anticonvulsant hypersensitivity syndrome or non-severe rash following treatment with carbamazepine. (maculopapular rash).

Hypersensitivity

Tegretol can trigger hypersensitivity reactions, including drug-induced rash with eosinophilia and systemic symptoms (DRESS), a delayed multi-organ hypersensitivity reaction that can occur in different combinations, such as fever, rash, vasculitis, lymphadenopathy, pseudo-lymphoma , arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests and evanescent bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts). Other organs may also be affected, such as lungs, kidneys, pancreas, myocardium, colon (see section 4.8).

Positivity for the HLA-A * 3101 allele was associated with the onset of hypersensitivity syndrome, including maculopapular rash.

Patients who have experienced episodes of hypersensitivity reactions to carbamazepine should be advised that hypersensitivity reactions to oxcarbazepine (Tolep) may occur in approximately 25-30% of these cases.

Cross-hypersensitivity can also occur between carbamazepine and phenytoin.

In general, if signs and symptoms of hypersensitivity reactions occur, Tegretol therapy should be discontinued immediately.

Seizures

Tegretol should be used with caution in patients with mixed seizures, which include typical or atypical absences. In these cases, Tegretol can exacerbate the attacks. If attacks worsen, Tegretol therapy should be discontinued.

Liver function

Especially in patients with liver disorders and the elderly, liver function checks should be performed at the beginning and during treatment. The administration of Tegretol should be discontinued immediately in case of worsening of hepatic dysfunction or active liver disease.

Renal function

It is recommended that a complete analysis of urine and blood urea nitrogen be performed periodically.

Hyponatremia

Hyponatremia is known to occur with carbamazepine. In patients with conditions

kidney associated with low sodium levels or in patients treated concomitantly with drugs that lower sodium levels (e.g. diuretics, drugs associated with abnormal ADH secretion), serum sodium levels should be measured before initiating therapy with carbamazepine. Serum sodium levels should therefore be measured after approximately two weeks and at monthly intervals thereafter during the first three months of therapy, or as needed clinically. These risk factors can mainly affect elderly patients. If hyponatremia is observed, reducing the fluid intake may represent an "important countermeasure, where clinically indicated.

Hypothyroidism

Carbamazepine can reduce serum concentrations of thyroid hormones by enzyme induction. It is suggested to monitor thyroid function; in patients with hypothyroidism, dose adjustments of thyroid replacement therapy may be necessary.

Anticholinergic effects

Tegretol showed weak anticholinergic activity; therefore, patients with elevated ocular pressure and urinary retention should be closely monitored during therapy (see section 4.8).

Psychiatric Effects

We must not forget the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation.

Suicidal ideation and behavior

Cases of suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs in their various indications. A meta-analysis of randomized clinical trials versus placebo also highlighted the presence of a modest increase in the risk of suicidal ideation and behavior.

The mechanism of this risk has not been established and the available data do not exclude the possibility of an increased risk with Tegretol.

Therefore, patients should be monitored for signs of suicidal ideation and behavior and appropriate treatment should be considered if so. Patients (and caregivers) should be instructed to notify their treating physician if signs of suicidal ideation or behavior emerge.

Endocrinological effects

Blood loss has been reported in women taking oral contraceptives concomitantly with Tegretol; the safety of oral contraceptives may be compromised by the use of Tegretol. It is therefore recommended for women of childbearing age in

treatment with Tegretol to use alternative methods of contraception. The enzyme induction determined by Tegretol can in fact cancel the therapeutic effect of drugs containing estrogen and / or progesterone.

Monitoring of plasma levels

Although the correlation between carbamazepine dose, plasma levels and clinical efficacy-tolerability is rather weak, the control of plasma levels can be useful in the following conditions: significant increase in the frequency of attacks (verification of compliance), in pregnancy, in the treatment of children and adolescents, in cases of suspected abnormal absorption, in cases of suspected toxicity when multiple drugs are being administered (see section 4.5).

Hypericum perforatum preparations should not be taken concomitantly with carbamazepine containing medicinal products due to the risk of decreased plasma levels and decreased therapeutic efficacy of carbamazepine (see section 4.5).

Reduction of doses and effects upon discontinuation of treatment

Abrupt discontinuation of Tegretol treatment can trigger epileptic fits: carbamazepine therapy should therefore be gradually discontinued over at least 6 months. If treatment with Tegretol is to be abruptly stopped in an epileptic patient, the switch to a new antiepileptic preparation should be made using "adequate drug coverage.

Interactions

Co-administration of carbamazepine and CYP3A4 inhibitors or epoxide hydrolase enzyme inhibitors may result in adverse reactions (increased plasma concentrations of carbamazepine or carbamazepine-10,11-epoxide, respectively). Tegretol dosage should be adjusted accordingly and / or plasma levels monitored.

Co-administration of carbamazepine and CYP3A4 inducers may result in decreased plasma carbamazepine concentrations and its therapeutic effect, while discontinuation of a CYP3A4 inducer may result in increased plasma carbamazepine concentrations. The dosage of Tegretol may need to be adjusted

Carbamazepine is a potent inducer of CYP3A4 and other phase I and II liver enzyme systems, and therefore may decrease the plasma concentrations of co-administered medicinal products metabolised predominantly by CYP3A4 by inducing their metabolism (see section 4.5).

Patients of childbearing potential should be advised that concomitant use of Tegretol and hormonal contraceptives may cancel the effect of the latter (see sections 4.5 and 4.6). It is recommended that alternative non-hormonal methods of contraception be used during Tegretol therapy.

Important information about some of the excipients

TEGRETOL 100 mg chewable tablets contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose / galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicine.

TEGRETOL Children 20 mg / ml Syrup contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

TEGRETOL Children 20 mg / ml Syrup contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. They can cause allergic reactions (even delayed).

TEGRETOL 200 mg modified-release tablets contain hydrogenated polyhydric castor oil. It can cause stomach upset and diarrhea.

TEGRETOL 400 mg modified-release tablets contain hydrogenated polyhydric castor oil. It can cause stomach upset and diarrhea.

04.5 Interactions with other medicinal products and other forms of interaction

Cytochrome P450 3A4 (CYP 3A4) is the main enzyme that catalyzes the formation of the active metabolite carbamazepine-10,11-epoxide. Co-administration of substances with inhibitory activity on the CYP 3A4 enzyme may lead to an increase in plasma carbamazepine levels with consequent occurrence of adverse events. Co-administration of CYP 3A4 inducers has the potential to increase the metabolism of carbamazepine, reducing so are the serum levels of carbamazepine and the therapeutic effect. Similarly, discontinuation of the administration of a CYP 3A4 inducer may reduce the metabolism of carbamazepine, thus resulting in an increase in plasma carbamazepine levels.

Carbamazepine is a potent inducer of CYP 3A4 and other phase I and II hepatic enzyme systems, and may therefore, by inducing their metabolism, reduce the plasma concentrations of co-administered medicinal products that are primarily metabolised by CYP 3A4.

The human microsomal enzyme epoxide hydrolase has been identified as being responsible for the formation of the 10,11-transdiol derivative of carbamazepine-10,11-epoxide. Co-administration of human microsomal epoxide-hydrolase enzyme inhibitors may result in an increase in plasma concentrations of carbamazepine-10,11-epoxide.

Interactions that determine a contraindication to use

The use of Tegretol is contraindicated in combination with monoamine oxidase inhibitors (MAOIs). MAOIs should be discontinued for at least 2 weeks before using Tegretol or longer if the clinical condition permits (see section 4.3).

Drugs that can raise carbamazepine plasma levels

Since increased carbamazepine plasma levels can cause side effects (e.g. dizziness, somnolence, ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and / or the plasma levels monitored if the following drugs are administered concomitantly.

Analgesics, anti-inflammatories: dextropropoxyphene, ibuprofen.

Androgens: donazole.

Antibiotics: macrolide antibiotics (e.g. erythromycin, troleandomycin, iosamycin, clarithromycin, ciprofloxacin).

Antidepressants: probably desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine.

Antiepileptics: stiripentol, vigabatrin.

Antifungals: azoles (e.g. itraconazole, ketoconazole, fluconazole), voriconazole.

Antihistamines: loratidine, terfenadine.

Antipsychotics: olanzapine.

Antituberculotics: isoniazid.

Antivirals: HIV protease inhibitors (eg ritonavir).

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular drugs: verapamil, diltiazem.

Gastrointestinal drugs: probably cimetidine, omeprazole.

Muscle relaxants: oxybutynin, dantrolene.

Inhibitors of platelet aggregation: ticlopidine.

Other interactions: grapefruit juice, nicotinamide (in adults only in high doses).

Drugs that may raise plasma levels of the carbamazepine-10,11-epoxide metabolite

Since elevated plasma levels of carbamazepine-10,11-epoxide may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and / or plasma levels monitored when Tegretol is administered concomitantly. with the substances listed below:

Loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.

Drugs that can reduce carbamazepine plasma levels

The dosage of Tegretol may need to be adjusted when they come

simultaneously administered the drugs described below.

Antiepileptics: felbamate, mesuximide, oxcarbazepine, phenobarbital, fensuximide, phenytoin (to avoid phenytoin intoxication and sub-therapeutic carbamazepine concentrations, it is recommended to adjust the plasma concentration of phenytoin to 13 mcg / ml before adding carbamazepine to treatment) and fosphenytoin, primidone and, although the data are partially contradictory, also clonazepam.

Antineoplastics: cisplatin, doxorubicin.

Antituberculosis: rifampicin.

Bronchodilators or anti-asthmatics: theophylline, aminophylline.

Dermatological drugs: isotretinoin.

Other interactions: Serum carbamazepine levels may be reduced by concomitant administration of Hypericum perforatum preparations. This is due to the induction of the enzymes responsible for drug metabolism by preparations based on Hypericum perforatum which, therefore, should not be administered concomitantly with carbamazepine. The induction effect may persist for at least 2 weeks after discontinuation. treatment with Hypericum perforatum products. If a patient is taking Hypericum perforatum products at the same time, carbamazepine blood levels should be monitored and therapy with Hypericum perforatum products discontinued. Carbamazepine blood levels may be discontinued. increase with stopping Hypericum perforatum. The dosage of carbamazepine may need to be adjusted.

Effect of Tegretol on plasma levels of concomitant drugs

Carbamazepine can cause a decrease in the plasma levels of certain drugs, and can also lead to a decrease or even cancellation of their activity. The dosage of the following drugs may need to be adjusted according to specific clinical needs:

Analgesics, anti-inflammatories: buprenorphine, methadone, paracetamol (long-term administration of carbamazepine and paracetamol (acetaminophen) may be associated with hepatotoxicity), phenazone (antipyrine), tramadol.

Antibiotics: doxycycline, rifabutin.

Anticoagulants: oral anticoagulants (warfarin, phenprocoumon, dicumarol and acenocoumarol).

Antidepressants: bupropion, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine).

Antiemetics: aprepitant.

Antiepileptics: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine,

oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. To avoid phenytoin intoxication and sub-therapeutic concentrations of carbamazepine, it is recommended to adjust the plasma concentration of phenytoin to 13 mcg / ml before adding carbamazepine). Carbamazepine has rarely raised the plasma levels of mephenytoin.

Antifungals: itraconazole, voriconazole.

Pesticides: praziquantel, albendazole.

Antineoplastics: imatinib, cyclophosphamide, lapatinib, temsirolimus.

Antipsychotics: clozapine, haloperidol and bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone.

Antivirals: HIV protease inhibitors (eg indinavir, ritonavir, saquinavir).

Anxiolytics: alprazolam, midazolam.

Bronchodilators or antiasthmatics: theophylline.

Contraceptives: hormonal contraceptives (the use of alternative methods is recommended).

Cardiovascular drugs: calcium channel blockers (dihydropyridine derivatives) eg. felodipine, digoxin, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.

Corticosteroids: corticosteroids (e.g. prednisolone, dexamethasone).

Drugs used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.

Thyroid preparations: levothyroxine.

Other drug interactions: products containing estrogen and / or progesterone.

Concurrent treatments to be carefully evaluated

Concomitant administration of carbamazepine and levetiracetam increases the toxicity induced by carbamazepine.

Concomitant administration of carbamazepine and isoniazid increases the hepatotoxicity induced by isoniazid.

The administration of carbamazepine and lithium or metoclopramide, or carbamazepine and neuroleptics (haloperidol, thioridazine) can cause an increase in neurological side effects (with the second combination, even in the presence of therapeutic plasma levels).

Concomitant administration of Tegretol with some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia.

Carbamazepine may antagonize the effect of non-depolarising muscle relaxants (eg pancuronium); their dosage should be increased and patients closely monitored to avoid resolution of neuromuscular block occurring too rapidly.

Carbamazepine, like other psychoactive drugs, can reduce alcohol tolerability; it is therefore advisable for the patient to refrain from alcohol consumption.

Interference with serological tests

Carbamazepine can give false positives on HPLC analysis for perphenazine concentrations due to interference with the latter.

Carbamazepine and the metabolite 10,11-epoxide can give false positives with the immunological method based on polarized fluorescence measurements regarding the concentrations of tricyclic antidepressants.

04.6 Pregnancy and breastfeeding

Pregnancy

Children of epileptic mothers are known to be more prone to developmental disorders, including possible malformations. There have been reports of developmental disturbances and malformations, including spina bifida, as well as other congenital anomalies (eg craniofacial defects, cardiovascular malformations, hypospadias and anomalies affecting other systems) in association with the use of Tegretol. data from a North American pregnancy registry, the frequency of major congenital malformations (defined as a structural abnormality of surgical, medical or cosmetic significance), diagnosed within the first 12 weeks of birth, was 3.0% (CI 95 % 2.1-4.2%) among mothers exposed to carbamazepine administered alone in the first trimester, and 1.1% (95% CI 0.35-2.5%) among mothers who had not taken any antiepileptic drug in pregnancy (relative risk 2.7; 95% CI 1.1-7.0%).

Consider the following:

• Patients with epilepsy should be treated with great caution during pregnancy.

• If pregnancy is planned or verified during therapy with Tegretol, or if there is a need to take Tegretol during pregnancy, the expected benefits should be carefully weighed together with the possible risks, particularly in the first 3 months of pregnancy.

• In women of childbearing potential, Tegretol should be prescribed as monotherapy whenever possible, as the incidence of congenital abnormalities in children of women treated with combinations of antiepileptic drugs is higher than in mothers treated alone. The risk of malformations later on. Exposure to carbamazepine administered in polytherapy may vary depending on the antiepileptic drugs used and may be greater in the case of polytherapies that include valproate.

• It is recommended that the lowest effective dose be administered and plasma levels monitored. Plasma concentrations can be maintained at the lower level of the therapeutic range of 4-12 mcg / ml provided that the

seizure control. There is evidence to suggest that the risk of malformations with carbamazepine may be dose-dependent, i.e. at doses below 400 mg / day the frequency of malformations was less than with higher doses of carbamazepine.

• Patients should be informed of the possibility of an increased risk of malformations and should be advised to undertake an antenatal diagnosis.

• Effective antiepileptic therapy should not be interrupted during pregnancy, as worsening of the disease is harmful to both the mother and the fetus.

Monitoring and prevention

Folic acid deficiency is known to occur during pregnancy. Antiepileptic drugs have been shown to aggravate this situation. Folic acid deficiency may be one of the causes of the increased incidence of malformations in children of treated epileptic mothers. Therefore, additional folic acid treatment is recommended before and during pregnancy.

Newborn

To prevent excessive blood loss, it is also recommended that vitamin K1 be administered to both the mother during the last weeks of pregnancy and the newborn.

There have been some episodes of seizures and / or respiratory depression in infants whose mothers were treated with Tegretol and concomitantly with other anticonvulsant drugs; in some cases, vomiting, diarrhea and / or decreased food intake in the newborn have also been reported. These reactions could signal a neonatal withdrawal syndrome.

Women of childbearing age and contraceptive measures

Due to enzyme induction, the use of Tegretol may negate the therapeutic effect of oral contraceptives containing estrogen and / or progesterone.Patients of childbearing potential should be advised to use alternative methods of contraception during therapy with Tegretol.

Feeding time

Carbamazepine passes through breast milk (approximately 25-60% of the plasma concentration). The benefit of breastfeeding must be carefully weighed against the risk, albeit remote, of possible side effects on the newborn. Mothers treated with Tegretol can breastfeed as long as the newborn is followed carefully to assess the onset of any reactions adverse (e.g. excessive sleepiness, allergic skin reactions). There have been some reports of colostatic hepatitis in infants exposed to carbamazepine in the prenatal period or during lactation. Infants of carbamazepine-treated and breast-fed mothers should be carefully monitored for the occurrence of hepatobiliary adverse events.

Fertility

Very rare cases of impaired male fertility and / or abnormalities in spermatogenesis have been reported.

04.7 Effects on ability to drive and use machines

Patients' ability to react may be impaired by the underlying disease (seizures) and adverse reactions including somnolence, dizziness, ataxia, diplopia, accommodation disturbances and blurred vision reported with Tegretol, especially at the start of treatment or when adjust the doses. Therefore, patients should take appropriate precautions when driving or using machines.

04.8 Undesirable effects

Summary of the safety profile

Particularly at the beginning of treatment with Tegretol, or if the starting dose is too high or in elderly patients, some adverse reactions may occur very frequently or frequently, for example in the CNS (dizziness, headache, ataxia, somnolence, fatigue, diplopia ), gastrointestinal tract (nausea, vomiting) and allergic skin reactions.

Dose-related adverse reactions usually disappear within a few days, either spontaneously or after temporary dose reduction. CNS adverse reactions may be the expression of overdose or significant fluctuations in plasma levels. In these cases it is suggested to check the plasma levels.

Tabular summary of adverse reactions from clinical trials and spontaneous reports

Undesirable effects from clinical trials (Table 1) are listed below by system organ class and frequency. Frequencies are defined as: very common (> 1/10), common (> 1/100 to 1/1000 to 1/10000 to

Table 1

Disorders of the blood and lymphatic system

Very common: leukopenia.

common: thrombocytopenia, eosinophilia.

Rare: leukocytosis, lymphadenopathy.

Very rare: agranulocytosis, aplastic anemia, pancytopenia, pure red cell aplasia, anemia, megaloblastic anemia, reticulocytosis, haemolytic anemia.

Disorders of the immune system

Rare: multiple delayed hypersensitivity response affecting multiple organs with disorders, which can occur in different combinations, such as fever, rash, vasculitis, lymphadenopathy, pseudo-lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal function tests hepatic and evanescent bile duct syndrome (destruction and disappearance of intrahepatic bile ducts). Other organs may also be affected, such as lungs, kidneys, pancreas, myocardium, colon.

Very rare: anaphylactic reactions, angioedema, hypogammaglobulinemia.

Endocrine pathologies

common: edema, water retention, weight gain, hyponatremia and reduction of blood osmolarity due to an "action similar to" ADH, which can in rare cases lead to water intoxication accompanied by vomiting, lethargy, headache, confusion, disturbances neurological.

Very rare: galactorrhea, gynecomastia.

Metabolism and nutrition disorders

Rare: folic acid deficiency, decreased appetite.

Very rare: acute porphyria (acute intermittent porphyria and variegated porphyria), non-acute porphyria (porphyria cutanea tarda).

Psychiatric disorders

Rare: hallucinations (visual or auditory), depression, aggression, agitation, restlessness, confusion.

Very rare: activation of psychosis.

Nervous system disorders

Very common: ataxia, dizziness, somnolence.

Common: diplopia, headache.

Uncommon: involuntary abnormal movements (e.g. tremor, asterypsis, dystonia, tics), nystagmus.

Rare: dyskinesia, ocular motility disorders, speech disorders (dysarthria, indistinct speech), choreoathetosis,

peripheral neuropathies, paraesthesia, and paresis.

Very rare: neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

Eye disorders

Common: disturbances of accommodation (eg blurred vision).

Very rare: opacity of the lens, conjunctivitis.

Ear and labyrinth disorders

Very rare: hearing disorders (eg tinnitus, hyperacusis, hypoacusis, altered perception of tone).

Cardiac pathologies

Rare: cardiac conduction disturbances.

Very rare: arrhythmia, atrioventricular block with syncope, bradycardia, congestive heart failure, aggravation of coronary artery disease.

Vascular pathologies

Rare: hypertension or hypotension.

Very rare: circulatory collapse, embolism (e.g. pulmonary embolism), thrombophlebitis.

Respiratory, thoracic and mediastinal disorders

Very rare: pulmonary hypersensitivity characterized for example by fever, dyspnoea, pneumonia.

Gastrointestinal disorders

Very common: vomiting, nausea.

common: dry mouth.

Uncommon: diarrhea, constipation.

Rare: abdominal pain.

Very rare: pancreatitis, glossitis, stomatitis.

Hepatobiliary disorders

Rare: cholestatic, parenchymal (hepatocellular) or mixed liver disease, evanescent bile duct syndrome, jaundice.

Very rare: liver failure, granulomatous hepatitis.

Skin and subcutaneous tissue disorders

Very common: urticaria which can be severe, allergic dermatitis.

Uncommon: exfoliative dermatitis.

Rare: systemic lupus erythematosus, pruritus.

Very rare: severe cutaneous adverse reactions (SCARs) such as the syndrome

Steven-Johnson's (*) (SJS), toxic epidermal necrolysis (TEN), photosensitivity reactions, erythema multiforme, erythema nodosum, skin pigmentation alteration, purpura, acne, hyperhidrosis, alopecia, hirsutism.

Musculoskeletal and connective tissue disorders

Rare: muscle weakness.

Very rare: disturbances of bone metabolism (decrease in plasma calcium concentrations and blood concentrations of 25-hydroxy-cholecalciferol) leading to osteomalacia / osteoporosis, arthralgia, myalgia, muscle spasms. The mechanism by which Tegretol affects bone metabolism has not been identified.

Renal and urinary disorders

Very rare: tubulointerstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria, increased blood urea / azotemia levels), urinary retention, pollakiuria.

Diseases of the reproductive system and breast

Very rare: sexual dysfunction / erectile dysfunction, abnormalities in spermatogenesis (with decreased sperm count and / or motility).

General disorders and administration site conditions

Very common: fatigue.

Diagnostic tests

Very common: elevation of gamma-GT (due to induction of liver enzymes), usually not clinically relevant.

common: increase in blood concentrations of alkaline phosphatase.

Uncommon: elevation of transaminases.

Very rare: increased intraocular pressure, increased blood levels of cholesterol, high-density lipoprotein, and triglycerides. Alteration of the functional parameters of the thyroid: decrease in L-Thyroxine (free thyroxine, thyroxine, triiodothyroxine) and increase in blood concentrations of thyroid stimulating hormone, usually without clinical manifestations, increase in blood levels of prolactin.

(*) In some Asian countries the frequency is "rare". See also section 4.4.

Additional adverse reactions from spontaneous reporting (frequency not known)

The following adverse reactions derive from post-marketing experience with Tegretol and refer to spontaneous reports and cases described in the literature. As these reactions arise spontaneously from a population of uncertain size, it is not possible to estimate with certainty the frequency which is therefore indicated. as “not known.” Adverse reactions are listed by MedDRA system organ class. Within each class, adverse reactions are listed in order of decreasing severity.

Infections and infestations

Reactivation of Human Herpesvirus Infections 6.

Disorders of the blood and lymphatic system

Medullary depression.

Nervous system disorders

Sedation, memory disturbances.

Gastrointestinal disorders

Colitis.

Disorders of the immune system

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

Skin and subcutaneous tissue disorders

Acute Generalized Exanthematous Pustulosis (AGEP), lichenoid keratosis, onychomadesis.

Musculoskeletal and connective tissue disorders

Fractures.

Diagnostic tests

Decrease in bone density.

There is growing evidence regarding the association of genetic markers and the occurrence of cutaneous adverse reactions such as SJS, TEN, DRESS, AGEP and maculopapular rash. In Japanese and European patients these reactions are reported in association with the use of carbamazepine and the presence of the HLA-A * 3101 allele. Another marker, HLA-A * 1502, has been shown to be strongly associated with SJS and syndromes. TEN among individuals of Chinese descent of Han ethnicity, Thai and some other Asian descent (see sections 4.2 and 4.4 for further information).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after

Authorization of the medicine is important, as it allows continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at: www.agenziafarmaco.gov.it / it / responsible.

04.9 Overdose

Signs and symptoms

The presenting signs and symptoms of overdose usually involve the central nervous, cardiovascular and respiratory systems and include the adverse reactions described in section 4.8.

Central nervous system

Central nervous system depression, disorientation, decreased level of consciousness, somnolence, agitation, hallucination, coma, blurred vision, dysarthria, indistinct speech, nystagmus, ataxia, dyskinesia, hyperreflexia followed by hyporeflexia, convulsions, psychomotor disorders, myoclonus, hypothermia, mydriasis.

Respiratory System

Respiratory depression, pulmonary edema.

Cardiovascular system

Tachycardia, hypotension, sometimes hypertension, cardiac conduction disturbances with widening of the QRS complex; syncope associated with cardiac arrest.

Gastrointestinal system

Vomiting, delayed gastric emptying, impaired intestinal motility.

Musculoskeletal system

There have been some reports of rhabdomyolysis in association with carbamazepine toxicity.

Renal function

Urinary retention, oliguria, anuria, fluid retention, water intoxication due to the ADH-like effect of carbamazepine.

Laboratory parameters

Hyponatremia, possible metabolic acidosis, possible hyperglycaemia, increase in muscle creatine phosphokinase.

Treatment

There is no specific antidote.

Initial treatment should be conducted on the basis of the patient's condition, who should be hospitalized. The plasma concentration of carbamazepine should be measured in order to confirm poisoning and the amount of dose taken.

Empty the stomach, do a gastric lavage and administer activated charcoal. Delayed stomach emptying can result in delayed absorption resulting in flare-ups during the recovery phase from intoxication.

It is important to support vital functions in intensive care units with cardiac monitoring and correct blood electrolyte values.

Special recommendations

A "coal hemoperfusion" is recommended. Hemodialysis is the effective treatment for managing carbamazepine overdose.

In the 2-3 days following the intoxication it is necessary to prevent the exacerbation and the aggravation of the symptoms due to the delayed absorption.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, carboxamide derivatives (ATC code: N03 AF01).

Tegretol belongs to the Dibenzazepine family.

As an antiepileptic drug, its spectrum of action includes partial seizures (simple or complex) with or without secondary generalization; generalized tonic-clonic seizures, as well as combinations of these types of seizures.

It is reported in clinical studies that Tegretol, administered alone, to epileptic patients - especially children and adolescents - exerts a psychotropic action with improvement of the symptoms of anxiety and depression and a decrease in irritability and aggression. cognitive and psychomotor effects, some studies report negative or unclear effects, also in relation to the doses administered, while other studies show a positive effect on attention, cognitive functions and memory.

As a neurotropic drug, Tegretol prevents the onset of painful paroxysms of essential and secondary trigeminal neuralgia and is also useful for reducing neurogenic pain in various conditions, such as backbone, post-traumatic paraesthesia, post-herpetic neuralgia; in alcohol withdrawal syndrome increases the seizure threshold, reduced by alcohol abuse, and improves withdrawal symptoms (eg. hyperexcitability, tremor, altered gait); in central diabetes insipidus, Tegretol reduces urinary volume and the sensation of thirst .

As a psychotropic drug Tegretol is effective in affective disorders, eg. in the treatment of acute mania, as well as in the maintenance therapy of bipolar affective (manic-depressive) disorders, both when prescribed alone and in combination with neuroleptics, antidepressants or lithium. Tegretol is effective in schizo-affective disorders and in excitatory mania in combination with other neuroleptics, as well as in episodes that occur rapidly in short-cycle forms.

The mechanism of action of carbamazepine has been only partially elucidated. Carbamazepine stabilizes over-excited nerve membranes, inhibits discharges

neuronal repeated and reduces the synaptic propagation of excitatory impulses. It is reasonable to think that the main mechanism of action of carbamazepine is the prevention of repetitive firing of sodium-dependent action potentials in depolarized neurons through use- and voltage-dependent blockade of sodium channels.

While the decrease in glutamate release and the stabilization of neuronal membranes could explain the antiepileptic effects, the inhibiting effect on dopamine and noradrenaline turnover could explain the antimanic properties of carbamazepine.

05.2 Pharmacokinetic properties

Absorption

Carbamazepine is absorbed almost completely but relatively slowly from the tablets. Conventional tablets and chewable tablets reach the peak plasma concentration of unchanged substance after 12 and 6 hours, respectively, after a single oral dose. With the syrup, the maximum plasma concentration is reached within 2 hours. With respect to the amount of active substance absorbed, there is no relevant difference between the oral forms. After a single oral dose of 400 mg carbamazepine (tablets) the peak plasma concentration of unchanged substance is approximately 4.5 mcg / ml.

When modified-release tablets are administered in single or repeated doses, they achieve approximately 25% of the lowest peak plasma concentration of active substance compared to conventional tablets. The peaks are reached within 24 hours. Modified-release tablets produce a statistically significant decrease in the fluctuation index, but not a significant decrease in steady-state Cmin. With a twice daily dose the fluctuation in plasma concentrations is very low. The bioavailability of the tablets modified-release is approximately 15% lower than that of other oral forms.

Steady-state plasma carbamazepine concentrations are achieved within 1-2 weeks, depending on individual characteristics in terms of carbamazepine self-induction, hetero-induction by other inducing drugs, pre-treatment situation, dosage, treatment duration .

At steady-state, plasma concentrations of carbamazepine considered as the therapeutic range vary greatly from individual to individual: a range of 4-12 mcg / ml corresponding to 17-50 mcmol / l has been reported in most patients. The concentration of 10.11-epoxide (the active metabolite of carbamazepine) is approximately 30% of the levels of the active substance.

Ingestion of food does not affect the rate or extent of absorption, regardless of the formulation of Tegretol administered.

Distribution

Assuming complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.9 l / kg.

Carbamazepine crosses the placenta.

Carbamazepine is 70-80% bound to plasma proteins. The concentration of unchanged substance in the cerebrospinal fluid and saliva mirrors the portion not bound to plasma proteins (20-30%). Concentrations in breast milk are 25-60% of the corresponding plasma levels.

Metabolism

Carbamazepine is metabolised in the liver, the most important route of elimination of which is epoxidation; thus the derivative 10,11-trans-diol and its glucuronide are obtained as the main metabolites. Cytochrome P450 3A4 has been identified as the main isoform responsible for the transformation of carbamazepine into the metabolite 10,11-epoxide. The human microsomal enzyme epoxide-hydrolase has been identified as being responsible for the formation of 10,11-transdiol, derivative of carbamazepine-10,11-epoxide. 9-hydroxy-methyl-10-carbamoyl acridane is the least frequent metabolite of this pathway. After a single oral dose of carbamazepine, approximately 30% appears in the urine as the end product of metabolism. Another important carbamazepine biotransformation pathway leads to various monohydroxylated compounds, as well as the carbamazepine N-glucuronide produced by UGT2B7.

Elimination

The elimination half-life of unchanged substance is approximately around 36 hours after a single oral dose, while after repeated administration it is around 16-24 hours (self-induction of the hepatic mono-oxygenase system), depending on the duration of therapy. patients concomitantly treated with other hepatic enzyme inducing drugs (eg phenytoin, phenobarbital) the half-life values ​​were found to be around 9-10 hours. The plasma elimination half-life of 10,11-epoxide is approximately 6 hours later single oral doses of the epoxide itself.

Following administration of a single oral dose of 400 mg carbamazepine, 72% is excreted in the urine and 28% in the faeces. In the urine, approximately 2% of the dose is in the form of unchanged substance and approximately 1% in the form of the active metabolite 10,11-epoxide.

Special populations

Children

Given the greater elimination of carbamazepine, children may require higher doses than adults (in mg / kg).

Senior citizens

There is no indication of an "altered carbamazepine pharmacokinetics in elderly patients compared with young adults."

Patients with renal or hepatic insufficiency

There are no data on the pharmacokinetics of carbamazepine in patients with renal or hepatic impairment.

05.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential. However, animal studies are not sufficient to rule out a teratogenic effect of carbamazepine.

Carcinogenicity

In rats treated with carbamazepine for 2 years, an increase in the incidence of hepatocellular tumors in females and benign testicular tumors in males was observed. The significance of these data for the therapeutic use of carbamazepine in humans is currently unknown. .

Genotoxicity

Carbamazepine was not genotoxic in several standard mutagenicity studies in bacteria and mammals.

Reproductive toxicity

In animal studies conducted in mice, rats and rabbits, oral administration of carbamazepine during organogenesis resulted in increased embryo-fetal mortality and fetal growth retardation at daily doses associated with maternal toxicity (greater than 200 mg / kg / day). Carbamazepine has been shown to be teratogenic in several animal studies, especially in mice, however it has no or only minimal teratogenic potential at doses relevant to humans. reduced weight growth at maternal doses of 192 mg / kg / day.

Fertility

Testicular atrophy and dose-related aspermatogenesis were observed in rats treated with carbamazepine in chronic toxicity studies. The safety margin for this effect is unknown.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Tablets 200 mg and 400 mg

Microcrystalline cellulose; carmellose sodium; anhydrous colloidal silica; magnesium stearate.

Syrup children

Polyethylene glycol stearate; microcrystalline cellulose / carmellose sodium; 70% sorbitol (not crystallizable); methyl parahydroxybenzoate; propyl parahydroxybenzoate; sodium saccharin; hydroxyethylcellulose; sorbic acid; propylene glycol; caramel flavor; purified water.

Modified-release tablets of 200 mg and 400 mg

Anhydrous colloidal silica; aqueous dispersion of ethyl cellulose; microcrystalline cellulose; polyacrylate dispersion 30%; magnesium stearate; croscarmellose sodium; talc; hypromellose; hydrogenated polyhydric castor oil; red iron oxide; yellow iron oxide; titanium dioxide.

Chewable tablets of 100 mg

Anhydrous colloidal silica; mint-cherry flavor; erythrosine; jelly; glycerol; magnesium stearate; cornstarch; sodium starch carboxymethyl A; stearic acid; sucrose by compression.

06.2 Incompatibility

Not relevant.

06.3 Period of validity

Tablets: 2 years

Modified-release tablets: 1 year

Chewable tablets: 3 years

Syrup: 3 years

06.4 Special precautions for storage

Syrup: protect from heat and light.

Conventional tablets: protect from moisture.

Modified release tablets: protect from moisture - Store at a temperature not exceeding 25 ° C.

Chewable tablets: store at a temperature not exceeding 25 ° C.

06.5 Nature of the immediate packaging and contents of the package

Tegretol 200 mg tablets: PVC / PE / PVDC blister, 50 tablets

Tegretol 400 mg tablets: PVC / PE / PVDC blister, 30 tablets

Tegretol 200 mg modified release tablets: PVC / PCTFE and PVC / PE / PVDC blisters, 30 tablets

Tegretol 400 mg modified release tablets: PVC / PCTFE and PVC / PE / PVDC blisters, 30 tablets

Tegretol 100 mg chewable tablets: PVC and PVC / PCTFE blisters, 28 tablets

Tegretol 20 mg / ml Syrup: 250 ml dark glass bottle

06.6 Instructions for use and handling

No special instructions for disposal.

07.0 MARKETING AUTHORIZATION HOLDER

Novartis Farma S.p.A.

Largo Umberto Boccioni, 1 - 21040 Origgio (VA)

08.0 MARKETING AUTHORIZATION NUMBER

TEGRETOL 200 mg tablets AIC n. 020602013

TEGRETOL 400 mg tablets AIC n. 020602025

TEGRETOL 200 mg modified release tablets AIC n. 020602049

TEGRETOL 400 mg modified release tablets AIC n. 020602052

TEGRETOL Children 20 mg / ml Syrup AIC n. 020602037

TEGRETOL 100 mg chewable tablets AIC n. 020602064

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

TEGRETOL 200 mg tablets

Authorization: 19.02.1966 Renewal: 01.06.2010

TEGRETOL 400 mg tablets

Authorization: 16.03.1983 Renewal: 01.06.2010

TEGRETOL 200 mg modified release tablets

Authorization: 01.09.1989 Renewal: 01.06.2010

TEGRETOL 400 mg modified release tablets

Authorization: 01.09.1989 Renewal: 01.06.2010

TEGRETOL Children 20 mg / ml Syrup

Authorization: 13.06.1979 Renewal: 01.06.2010

TEGRETOL 100 mg chewable tablets

Authorization: 31.07.1998 Renewal: 01.06.2010

10.0 DATE OF REVISION OF THE TEXT

05/2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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