COMPOSITION:

Active substance:

Carbamazepin;

1 tablet contains carbamazepin 200 mg;

Additional ingredients:

Microcrystalline cellulose, hypromellose E5, sodium crosscarmellose, colloidal anhydrous silica, magnesium stearate.

INDICATIONS:

– Epilepsy and complex or simple partial seizure (with or without loss of consciousness) with secondary generalization or without it; generalized tonic-clonic convulsive attack.

Mixed forms of convulsive attack.

MEZACAR® can be used both as monotherapy and as combined therapy.

– Acute maniacal states and supporting therapy of bipolar affective disorders for prophylaxis of exacerbation or weakening of clinical manifestation of exacerbation.

– Alcohol abstinence syndrome.

– Idiopathic trigeminal neuralgia and trigeminal neuralgia in disseminated sclerosis (typical and atypical). Idiopathic glossopharyngeal neuralgia.

– Painful diabetic neuropathy.

– Diabetes insipidus of central genesis. Polyuria and polydipsia of neurohormonal origin.

Acute sinusitis, exacerbation of chronic bronchitis, pneumonia, complicated and non-complicated urinary tract infection (including pyelonephritis), chronic bacterial prostatitis, infections of skin and soft tissues, septicemia/bacteriemia, intraabdominal infections.

DOSAGE:

The preparation can be used during meal, after meal and between meals with a little water.

Epilepsy:

In case when it is possible MEZACAR® should be administered as monotherapy.

The treatment is started with the use of low-dose, which is slowly increased up to reaching of optimal effect.

For adjustment of optimal preparation dosage it may be useful determination of active substance level in plasma.

In MEZACAR® administration the dose is gradually increased as additional antiepileptic therapy, not changing the dose(s) of currently used antiepileptic drug(s) or, if necessary, adjusting it (them).

For adults initial dose of the preparation is 100 – 200 mg 1 – 2 times per day. Then the dose gradually increased up to reaching of optimal effect; it is usually reached in dose of 400 mg/day, which is divided on 2 – 3 single doses per day. Some patients may need the dose of MEZACAR® preparation of 1600 mg or even 2000 mg per day.

In children over 6 years old the treatment can be started with the use of 100 mg/day; the dose is gradually increased – every week by 100 mg.

Supporting doses:

10 – 20 mg/kg of body weight per day (in several intakes).

Acute maniacal states and supporting therapy of bipolar affective disorders:

Dose diapason:

Approximately from 400 to 1600 mg per day; usually – from 400 to 600 mg per day divided into 2 – 3 single intakes. In acute maniacal state it is recommended rather quick dose increase, whereas for optimal tolerance within the scope of supporting therapy of bipolar disorders it is recommended gradual increasing by small doses.

Alcohol abstinence syndrome:

Average daily dose is 200 mg 3 times per day. In severe cases this dose can be increased (for example, up to the dose of 400 mg 3 times per day) in the first days. In severe manifestations of alcohol abstinence the treatment is started by MEZACAR® preparation with sedative-hypnotic drugs (for example, with clomethiazole and chlordiazepoxide), following above mentioned instructions concerning dosage regimen. After the end of acute phase MEZACAR® treatment may be continued as monotherapy.

Trigeminal neuralgia:

Initial dose is 200 – 400 mg per day. It is gradually increased till pain disappearance (usually up to the dose of 200 mg 3 – 4 times per day). Then the dose is gradually lowered up to minimal supporting one. Recommended initial dose for elderly patients is 100 mg 2 times per day.

Diabetes insipidus of central genesis:

Average daily dose is 200 mg 2 – 3 times per day. In children the preparation dose should be lowered in accordance with child’s age and body weight.

Painful diabetic neuropathy:

Average daily dose of MEZACAR® preparation is 200 mg 2 – 4 times per day.

ADVERSE REACTIONS:

Certain adverse reactions of, for example, CNS (dizziness, headache, ataxia, drowsiness, general weakness and diplopia), gastro-intestinal tract (nausea and vomiting) or skin allergic reactions, occur Very often ((≥ 10%) or often (≥ 1%) – at the beginning of the treatment by MEZACAR® preparation, in usage of too big initial preparation dose, in the treatment of elderly patients.

Dose-depending adverse reactions usually disappear within several days both spontaneously and after temporarily preparation dose decreasing. Development of CNS adverse reactions can be a result of relative overdose of the preparation or significant fluctuation of active substance concentration in plasma. In such cases it is recommended to monitor active substance level in plasma.

In estimation of the rate of different adverse reactions occurrence it was used the following classification:

 10% – Very often, 1 % – < 10% – often,  0.1% – < 1% – not often,  0.01% up to < 0.1% – rarely, < 0.01% – Very rarely.

Central nervous system:

Very often – dizziness, ataxia, somnolence, general weakness; often – headache, diplopia, disturbance of accommodation of the eye (f. e., blurred vision); not often – abnormal involuntary movements (f. e., tremor, flapping tremor, dystonia, tic), nystagmus; rarely – orofacial dyskinesia, visual impairment, speech disturbance (f. e., dysarthria or indistinct speech), choreoathetosis, peripheral neuropathy, paresthesia, paresis; Very rarely – taste disorders, malignant neuroleptic syndrome.

Mental disorders:

Rarely – hallucination (visual or auditory), depression, loss of appetite, anxiety, aggressiveness, agitation, mental confusion; Very rarely – psychosis activation.

Skin and subcutaneous tissue:

Very often – allergic dermatitis, urticaria, sometimes severe: not often – exfoliative dermatitis, erythrodermatitis; rarely – lupous syndrome, itch; Very rarely – Stevens-Johnson syndrome, toxic epidermal necrolisis, photosensitivity, erythema multiforme and erythema nodosum, dermatodyschromia, purpura, acne, hyperhidrosis, over loss of hair, hirsutism.

Blood formation system:

Very often – leucopenia; often – thrombocytopenia, eosinophilia; rarely – leucocytosis, limphoadenopatia, folic acid deficiency; Very rarely – agranulocytosis, aplastic anemia, pancytopenia, red-cell aplasia, anemia, megaloblastic anemia, acute intermittent porphyria, mixed porphyria, late skin porphyria, reticulocytosis and, possibly, anemia.

Hepatobiliary system:

Very often – increased level of gamma-glutamyltransferase (due to liver enzyme induction), it usually does not have clinical meaning; often – increase of level of blood alkaline phosphatase; not often – increase of transaminase level; rarely – cholestatic, parenchymatous (hepatocellular]) or mixed hepatitis, urticaria; Very rarely – granulomatous hepatitis, hepatic insufficiency.

Gastro-intestinal tract:

Very often – nausea and vomiting; often – dry mouth; not often – diarrhea or constipation; rarely – abdominal pain; Very rarely – glossitis, stomatitis, pancreatitis.

Immune system:

Rarely – delayed multiorgan hypersensitivity with fever, skin rash, vasculitis, lymphadenopathy, signs like lymphoma, arthralgia, leucopenia, eosinophilia, hepatosplenomegalia and changed liver function indexes (mentioned signs are observed in different combinations). There can be disorders of other organs (for example, lungs, kidney, pancreas, myocard and large intestine); Very rarely – aseptic meningitis with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioneurotic edema.

Cardio-vascular system:

Rare – intracardiac conduction impairment; arterial hypertension or arterial hypotension; Very rarely – bradycardia, arrhythmia, atrioventricular blockade with syncope, circulatory collapse, congestive heart failure, acute condition of ischemic disease, thrombophlebitis and thromboembolism (for example, pulmonary embolism).

Endocrine system:

Often – edema, liquid retention, body weight increase, hyponatremia and decrease of plasma osmolarity due to effect similar to action of anti-diuretic hormone that causes dilution hyponatremia in isolated cases which is accompanied with lethargy, vomiting, headache, mental confusion and neural disorders; Very rarely – increase of blood prolactin level which is accompanied with such manifestations as galactorrhea, gynecomastia, change of indexes of thyroid gland function: decrease of L-thyroxin level (FT4, T4, T3) and increase of thyroid-stimulating hormone level, which is usually not accompanied with clinical manifestations; disorder of bone tissue metabolism (decrease of level of calcium and 25-OH-cholecalciferol in blood plasma) that causes osteomalacia/osteoporosis; in isolated cases – increase of cholesterol concentration, including high density lipoprotein cholesterol and triglyceride.

Kidney and urinary system:

Very rarely – interstitial nephritis, kidney insufficiency, kidney dysfunction (for example, albuminuria, hematuria, oliguria, increase of urea level in blood/azotemia), frequent urination, retention.

Reproductive system:

Very rarely – sexual dysfunction/impotence, spermatogenesis disorder (with decrease of spermatozoid number/motility).

Eyes:

Very rarely – lenticular opacity, conjunctivitis, increase of intraocular pressure.

Ear:

Very rarely – hearing disorders, for example, tinnitus, acoustic sensitivity increase, acoustic sensitivity decrease, pitch perception disorders.

Musculoskeletal system:

Very rarely – arthralgia, muscle pain, muscle spasm.

Respiratory system:

Very rarely – hypersensitivity reactions of lungs, which were accompanied with fever, dyspnea, pneumonitis and pneumonia.

Laboratory indexes:

Very rarely – hypogammaglobulinemia.

Drug interactions:

Cytochrome Р450 3А4 (CYP3A4) is a main metabolite that catalyzes formation of main metabolite of carbamazerin-10,11-epoxide. Concurrent administration of CYP3A4 inhibitors can cause increasing of carbamazerin concentration in blood, that by-turn can cause a development of adverse reactions. Concurrent administration of CYP3A4 inductors can enhance carbamazerin metabolism that causes potential decreasing of carbamazerin concentration in serum and therapeutic effect. Likewise discontinuation of CYP3A4 inductor can decrease carbamazerin metabolism that causes increasing of carbamazerin level in plasma.

Carbamazerin is a powerful inductor of CYP3A4 and other enzyme systems of I and II phases in liver, therefore it can decrease concentrations of other preparations in plasma, which are mainly metabolized by CYP3A4 via induction of their metabolism.

Human microsomal epoxide-hydrolase is an enzyme which is responsible for formation of 10.11-transdiol derivatives from carbamazepin-10,11-epoxide. Concurrent administration of inhibitors of human microsomal epoxide-hydrolase can cause increasing of carbamazepin-10,11-epoxide concentration in plasma.

Preparations increasing carbamazepin level in plasma:

As far as increasing of carbamazepin level in plasma can cause occurrence of unwanted reactions (for example, dizziness, somnolence, ataxia and diplopia), then it is necessary to adjust MEZACAR® doses and to control its levels in plasma in concomitant use with the following preparations:

Analgetics, anti-inflammatory preparations: dextropropoxiphen, ibuprofen.

Androgens:

Danazol.

Antibiotics:

Antibiotics-macrolides as (for example, erythromycin, troleandomycin, jozamicin, clarithromycin).

Antidepressants:

Possibly desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine.

Antiepileptic:

Stiripentol, vigabatrin.

Antifungal agents:

Azoles (for example, шекфсщтфящдуб ketoconazole, fluconazole, voriconazole.

Antihistamine drugs:

Loratadine, terfenadine.

Antipsychotics:

Olanzapine.

Antituberculous drugs:

Isoniazid.

Antiviral drugs:

Protease inhibitors for HIV (for example, ritonavir).

Carboanhydrase inhibitors:

Acetazolamide.

Cardiovascular drugs:

Diltiazem, verapamil.

Drugs for gastro-intestinal diseases treatment: possibly cimetidine, omeprazole.

Miorelaxants:

Oxybutinin, dantrolen.

Antiaggregants:

Ticlopidine.

Other substances:

Grapefruit juice, nicotinamide (in adults only in high doses).

Preparations increasing the level of active metabolite of carbamazepin-10,11-epoxide in plasma:

As far as increased level of active metabolite of carbamazepin-10,11-epoxide in plasma can cause a development of adverse reactions (for example, dizziness, somnolence, ataxia and diplopia), then it is necessary to adjust MEZACAR® doses and to control its levels in plasma in concomitant use with the following preparations: loxapine, primidone, progabide, valproic acid, valnoktamid and valpromide.

Preparations decreasing carbamazepin level in plasma:

It may be necessary an adjustment of MEZACAR® preparation in concurrent administration with the following preparations:

Antiepileptic drugs:

Felbamate, methsuximide, oxcarbazepine, fenobarbiton, phensuximide, phenytoin and phosphenytoin, primidone and clonazepam (though data concerning it is conflicting).

Antitumoral druds:

Cysplatin or doxorubicin.

Antituberculous drugs:

Rifampicin.

Bronchodilatators or antiasthmatic drugs: theophillin, aminophylline.

Dermatological preparations:

Isotretinoine.

Drugs interaction:

Herbal preparations, which contains Hypericum perforatum.

MEZACAR® preparation influence on the level of concurrently used preparations in plasma:

Carbamazepin can decrease the level of some preparations in plasma and reduce or level their effects. It may be necessary dosage adjustment of the following preparation in conformity with clinical requirements:

Analgetics, anti-inflammatory preparations:

methadone, paracetamol, phenazone (antipyrinum), tramadol.

Antibiotics:

Doxycyclin.

Anticoagulants:

Per oral anticoagulants (for example, warfarin, phenprocoumon, dicumarol and acenocoumarol).

Antidepressants:

Bupropion, cytalopram, nefazodone, trazodone, tricyclic antidepressants (for example, imipramine, amitriptiline, nortriptiline, clomipramine). It is not recommended to use MEZACAR® concurrently with inhibitors of monoaminooxidase (MAO); before the treatment beginning it is necessary to discontinue MAO inhibitor usage (at lest two weeks before or earlier, if there are clinical conditions).

Antiepileptic drugs:

Clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidom, tiagabin, topiramate, valproic acid, zonisamide. It was reported both about increase of phenytoin level in plasma as a result of carbamazepin action and about its decrease, and about single cases of increasing of mephenytoin level in plasma.

Antifungal drugs: itraconazole.

Anthelmintic drugs:

Praziquantel.

Antitumoral druds:

Imatinib.

Neuroleptic drugs:

Clozapine, galoperidol and bromperidol, olanzapine, quetiapine, risperidone, ziprazidone.

Antiviral drugs:

Protease inhibitors for HIV (for example, idinavir, ritonavir, saquinavir).

Anxiolytics:

Alprazolam, midazolam.

Bronchodilatators or antiasthmatic drugs: theophillin.

Contraceptives:

Hormonal contraceptives (it is necessary to consider a possibility of administration of alternative methods of contraception).

Cardiovascular drugs:

Calcium channel blockers (dihydropyridine group), for example, felodipine, digoxin.

Corticosteroids:

Corticosteroids (for example, prednizolone, dexametazone).

Immunosuppressants:

Cyclosporine, everolimus.

Thyroid drugs:

levothyroxine.

Drugs interaction:

preparations, which contains estrogen and/or progesterone.

Preparations combinations, which requires special examination:

Concurrent administration of carbamazepin and levetiracetam can cause carbamazepin toxicity enhancement.

Concurrent administration of carbamazepin and izoniazide can cause izoniazide hepatotoxicity enhancement.

Concurrent administration of carbamazepin and lithium or metoclopramide preparations as well as carbamazepin and neuroleptics (haloperidol, thioridazine) can cause side neurological effects enhancement (in case of the last combination – even in therapeutical levels in plasma). Combined therapy by MEZACAR® preparation and some diuretics (hydrochlortiazide, furosemide) can cause symptomatic hyponatremia occurrence.

Carbamazepin can antagonize effects of non-depolarizing muscle relaxants (for example, pancuronii). It may be a necessity of increasing of these preparations doses, and patients need a close monitoring because of possibility of faster, than expected, reversal of neuromuscular blockade.

Carbamazepin like other psychoactive drugs can reduce alcohol tolerance, therefore patients are recommended to refrain from drinking alcohol.

Pregnancy and lactation:

In animals per oral use of carbamazepin during organogenesis caused increasing of embryonic mortality in usage of daily doses, which were toxic for mother (over 200 mg/kg of body weight every day that is 10 – 20 times more than usual dose for human). It was also observed abortion in introduction a dose of 300 mg/kg of body weight. On the late stage of development it was observed fetation delay in usage of toxic dose of the preparation in mother. Reports about preparation teratogenicity in all 3 studied animal species are absent, but during one animal study carbamazepin in doses from 40 to 240 mg/kg of body weight per oral caused defects development (mainly it was cerebral ventricular dilatation) in 4.7% of fetus versus 1.3% in control group.

It was observed inclination to intrauterine developmental disorders, including congenital defect, in children, mothers of which suffered from epilepsy. It was reported about carbamazepin possibility to increase rate of these disorders like most anti-epileptic drugs, however valid evidence within controlled studies of carbamazepin monotherapy was absent. In addition, it was reported about congenital developmental defect, including fissure of vertebral column and other congenital anomaly, for example, maxillofacial defect, cardiovascular developmental defect, hypospadias and congenital abnormality of different systems of organism.

It is necessary to keep in mind the following data:

MEZACAR® administration in pregnant women with epilepsy requires special attention.

It is necessary to identify potential benefit of the preparation use and possible risk (especially in the first trimester of pregnancy) if a woman, who receives MEZACAR®, becomes pregnant, is planning to become pregnant or there is a necessity of MEZACAR® use during pregnancy.

For women of childbearing age, if it is possible, MEZACAR® should be administered as monotherapy, because rate of cases of congenital defect in children of those women who received combined antiepileptic therapy is higher than n women who received antiepileptic monotherapy.

It is recommended to administer minimal effective doses and monitor carbamazepin level in plasma.

Patients should be informed about possible increasing of congenital defect development and they should be given an opportunity of antenatal screening.

During pregnancy an effective antiepileptic therapy should not be discontinued because exacerbation may threaten both mother’s and child’s health.

Observation and prophylaxis:

It is known that during pregnancy it is possible a development of folic acid insufficiency. Antiepileptic drugs can increase folic acid insufficiency level. This insufficiency can cause increasing of rate of cases of congenital defect in children of those women who receive antiepileptic therapy. Therefore it is not recommended to administer folic acid before and during pregnancy.

Newborn:

For prophylaxis of blood coagulation disorder in newborn it is recommended K1 vitamin administration to mother during last weeks of pregnancy and to newborn.

There are known some cases of convulsions and/or respiratory depression in newborn which are related to usage of MEZACAR® preparation and other antiepileptic drugs by mother. It was reported about some cases of vomiting, diarrhea and/or poor appetite in newborn, which are related to usage of MEZACAR® by mother. These reactions can be put down to neonatal withdrawal syndrome.

Lactation:

Carbamazepin penetrates into breast milk (25-60% of concentration in plasma). It is necessary to thoroughly weight benefit of breast feeding with remote possibility of side effects development in newborn. Mothers who use MEZACAR® can suckle under the condition that baby is under supervision on development of possible side effects (for example, excessive drowsiness and skin allergic reactions).

Children:

In children versus adults it can be necessary usage of higher doses of carbamazepin, per kilogram of body weight, due to faster elimination of it. MEZACAR® tablets can be administered in children over 6 years old.

PRECAUTIONS:

MEZACAR® should be administered only under medical supervision. MEZACAR® should be administered after evaluation of benefit/risk ratio and in close monitoring of patients with cardiac, liver and kidney disorders, side hematologic reactions and other preparations in anamnesis or in patients with interrupted therapy courses by MEZACAR® preparation. The preparation is usually ineffective in small attacks (petit mal, absence) and myoclonic attacks.

Hematologic effects:

Development of agranulocytosis and aplastic anemia are related to the preparation use; but due to low rate of cases of these states development it is difficult to evaluate risk in MEZACAR® preparation use. General risk for human, who does not receive therapy, is 4.7 persons/1000000 per year for agranulocytosis development and 2 persons/1000000 per year for aplastic anemia development.

It is periodically observed temporal or steady decrease of thrombocyte number or white blood cell due to MEZACAR® usage. Nevertheless, for the most of theses cases it was proved their temporality and they are not evidence of development of agranulocytosis and aplastic anemia. Before therapy and periodically during therapy it is necessary to do a blood test, including determination of thrombocyte number (and also, probably, reticulocyte number and hemoglobin level).

If during therapy the number of leucocyte or thrombocyte is significantly decreased patient’s state should be carefully monitored and it must be constantly done blood tests. MEZACAR® preparation use should be discontinued in occurrence of signs of inhibition of bone marrow function.

Patients should be informed about early signs of toxicity and symptoms of possible hematologic disorders, and also about symptoms of dermatological and hepatic reactions. Patients should be warned that in case of appearance of such reactions as fever, angina, skin rash, oral cavity ulcer, easy bruising, petechial hemorrhage or hemorrhagic purpura they must immediately consult a doctor.

Severe dermatological reactions:

Severe dermatological reactions, including toxic epidermal necrolysis (TEN or Lyell’s syndrome) and Stevens-Johnson syndrome (SJS), during MEZACAR® preparation use occur Very rarely. Patients with severe dermatological reactions may need hospitalization, because these states can threaten their lives and may have a fatal nature. Most of cases of development of SJS/TEN are observed during the first months of MEZACAR® treatment. In development of signs and symptoms, which indicate severe dermatological reactions (for example, SJS, Lyell’s syndrome/TEN), MEZACAR® preparation usage should be immediately discontinued and alternative therapy should be administered.

If patient’s analysis of allele (HLA)-В*1502 presence is positive then MEZACAR® use should be avoided if benefit of this treatment significantly overweights risk. Allele (HLA)-В*1502 can be a risk factor of SJS/TEN development in patients-Japanese, who receive antiepileptic drugs, which can be related to SJS/TEN occurrence. Thereby, it is necessary to avoid use of other drugs related

to SJS/TEN occurrence in patients who have allele (HLA)-В*1502 if another alternative therapy may be used. Usually it is not recommended to screen genetically patients of nationalities with low allele (HLA)-В*1502. Usually it is not recommended to screen persons who have already taking MEZACAR® because risk of SJS/TEN occurrence is significantly limited during the first months in spite of allele (HLA)-В*1502 presence in patient’s genes.

Results of genetic screening never should change appropriate clinical supervision and treatment of patient. A lot of Asian patients who have allele (HLA)-В*1502 gene and have the treatment course by MEZACAR® preparation do not have SJS/TEN, and patients of any nationality who do not have allele (HLA)-В*1502 can get SJS/TEN. It has not been studied the role of other possible causative agents such as antiepileptic drug dosage level, complaence, concurrent drugs, influence of other diseases and monitoring level of skin disorders in development and disease incidence of SJS/TEN.

Other dermatological reactions:

It is possible a development of easy dermatological reactions both transient and not dangerous to health, for example, isolated macular and maculopapular exanthema. They usually pass in a few days or weeks both in regular dosage and after dose lowering. At the same time patient should be under close supervision for immediate discontinuation of the preparation use in case of reaction worsening during its continuation, because early signs of more serious dermatological reactions may be hardly differentiated from moderate transient reactions.

Allele (HLA)-В*1502 presence in patient is not a risk factor of less serious skin reactions on carbamazepin such as syndrome of hypersensitivity to anticonvulsive drugs or minor rash (maculopapular rash).

Hypersensitivity:

MEZACAR® can provoke hypersensitivity reactions development, including multiple hypersensitivity reactions with localization in skin, liver, blood-forming organ and lymphatic system or other organs, together or separately, within systemic reaction.

Patients with hypersensitivity reactions to carbamazepin should be informed that about 25 – 30% of those patients can have hypersensitivity reactions to carbamazepin (Trileptal®).

In MEZACAR® usage with phenytoin it is possible cross hypersensitivity development.

In general, in appearance of signs and symptoms, which indicate hypersensitivity, MEZACAR® preparation use should be immediately discontinuated.

Attacks:

MEZACAR® should be administered with caution in patients with mixed attacks, including absence (typical or non-typical). Under these circumstances the preparation can provoke attacks. In case of attacks provocation MEZACAR® preparation use should be immediately discontinued.

Increase of attack rate can be during change per oral forms of the preparation to suppository.

Liver function:

During preparation therapy it is necessary to evaluate liver function on initial level and periodical evaluate this function during therapy, especially in patients with hepatic disease in anamnesis and in elderly patients. In acute condition of hepatic dysfunction or in patients with active phase of hepatic disease it is necessary to discontinue the preparation use.

Kidney function:

It is recommended to evaluate kidney function and to determine urea nitrogen blood level at the beginning of and during therapy course.

Anticholinergic effects: MEZACAR® has a moderate anticholinergic activity. Thereby, patients with increased intraocular pressure should be under close supervision during therapy.

Psychic effects: It is necessary to remember about possibility of latent psychosis activation and mental constipation and agitation (in elderly patients).

Endocrine effects:

It was reported about cases of burst bleeding in women who took MEZACAR® in combination with hormonal contraceptives. As MEZACAR® can negatively influence on efficacy of hormonal contraceptives women of childbearing age should be recommended to use of alternative contraceptive forms during the preparation administration. Due to liver enzymes induction MEZACAR® can be a reason of therapeutical effect of estrogen and/or progesterone preparations (that is it can prevent effective contraception).

Monitoring of the preparation level in plasma: In spite of that a correlation between dosage and carbamazepin level in plasma and between carbamazepin level in plasma and clinical efficacy and tolerance is unreliable, then monitoring of the preparation level in plasma can be reasonable in the following cases: in sudden attacks rate increasing, in control of patient’s complaence, during pregnancy, in children and adolescent treatment; in suspicion of absorption disorder, in suspected toxicity and in usage of more than one drug.

Dosage lowering and preparation withdrawal:

Sudden MEZACAR® withdrawal can cause attacks. In case of sudden preparation withdrawal in patients with epilepsy a transfer into another antiepileptic drug should be against the background of the therapy by appropriate preparation (for example, diazepam intravenously, through rectum or phenytoin intravenously).

Patient’s transfer from tablets into retard tablets: Clinical experience shows that it can be a necessity of the preparation dose increasing in some patients in usage of retard tablets.

Taking into account drugs interaction and different pharmacokinetics of antiepileptic preparations it is necessary to adjust MEZACAR® doses with caution for elderly patients.

Overdose:

Symptoms:

Symptoms and complaints, which appear in overdose, reflex affection of central nervous, cardio-vascular and respiratory systems.

Central nervous system:

CNS function depression; disorientation, somnolence, excitement, hallucinations, coma; blurred vision, indistinct speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (at the beginning), hyporeflexia (later); convulsions, psychomotor disorders, myoclonus, hypothermia, mydriasis.

Respiratory system:

Respiratory depression, lungs edema.

Cardio-vascular system:

Tachycardia, arterial hypotension, sometimes – arterial hypertension, asequence with enlargement of QRS complex; cardiac arrest, which is accompanied with loss of consciousness.

Gastro-intestinal tract:

Vomiting, delay of gastric transit, decrease of colonic motility.

Urinary system:

Urinary retention, oliguria or anuria; liquid delay; dilution hyponatremia caused by effect of carbamezepin similar to action of antidiuretic hormone.

Laboratory indexes changes: hyponatremia, possible metabolic acidosis, hyperglycemia, increase of creatinphosphokinase muscular fraction.

Treatment:

Specific antidote is absent. Initially the treatment should be based on clinical state of patient; it is administered hospitalization. It is carried out determination of carbamazepin in plasma for confirmation of poisoning by this drug and estimation of overdose degree.

It is carried out gastric contents evacuation, gastric lavage, activated carbon use. Late gastric contents evacuation can cause delayed absorption re-occurence of intoxication symptoms during recovery period. It is used symptomatic supporting treatment in intensive care department, monitoring of cardiac function, thorough correction of electrolytic disorders.

Special recommendations:

In development of arterial hypotension it is administered intravenous introduction of dopamine and dobutamine; in development of cardiac rhythm disorders the treatment is adjusted individually; in development of convulsions – introduction of benzodiazepine (for example, diazepine) or other anticonvulsive drugs, for example, phenobarbital (with caution because of increased risk of development of respiratory depression) or paraldehyde; in hyponatremia development (water intoxication) – liquid introduction limitation, slow and cautious intravenous infusion of 0.9% solution of sodium chloride. These measures may be useful for brain edema prevention.

It is recommended hemosorption by carbon sorbates. It was reported about non-efficacy of forced diuresis, hemodialysis and peritoneal dialysis.

It is necessary to foresee a possibility of recurring enhancement of overdose symptoms on the 2nd and 3d day after its start, which is caused by slow preparation absorption.

Ability to influence reaction velocity while driving or operating any other mechanisms.

High responsiveness of patient who use MEZACAR® can be disturbed due to dizziness and somnolence appearance (especially at the beginning of the treatment or during dosage adjustment), therefore patient should be caution while driving motor transport or operating other mechanisms.

PHARMACOLOGICAL PROPERTIES:

Antiepileptic drugs. Code АТС N03A F01.

Pharmacodynamics:

As anticonvulsive drug MEZACAR® is effective in focal (partial) convulsive attacks (simple and complex), which are accompanied or not accompanied with secondary generalization, in generalized tonic-clonic convulsive attacks and also in combinations of these types of attacks.

In clinical studies during MEZACAR® preparation use as monotherapy in patients with epilepsy (especially in adolescences and children) it was observed a psychotropic action of the preparation, which was partly manifested in positive influence on symptoms of anxiety and depression, and through decreasing of irritation and aggression. According to data of some studies MEZACAR® influence on cognitive function and psychomotor parameters depended on dose and was uncertain or negative. In other studies it was reported about positive preparation influence on parameters of weight, learning ability and memorability.

As neurotropic drug MEZACAR® is effective in series of neurological diseases:

for example, it prevents pain attacks in idiopathic and secondary trigeminal neuralgia. In addition, MEZACAR® is used for relief of neurogenic pain in different states, including tabes dorsalis, posttraumatic paresthesia and postherpetic neuralgia. In alcohol abstinence syndrome MEZACAR® increases threshold of readiness for convulsions (which is decreased in this state) and reduces evidence of clinical syndrome manifestation such as excitability, tremor and gait disorder. In patients with diabetes insipidus of central genesis MEZACAR® decreases diuresis and sensation of thirst.

It is confirmed that as psychotropic drug MEZACAR® is effective in affective disorders, exactly for the treatment of acute manic states, for supporting treatment of bipolar affective (manic-depressive) disorders (both as monotherapy and in combination with neuroleptic drugs, antidepressants or litium preparations), in schizoaffective psychosis, in which it is used in combination with neuroleptics, and also in acute polymorphous schizophrenia (rapid cycling episodes). Mechanism of action of carbamazepin – active substance of MEZACAR® preparation – has been just partly cleared up. Carbamazepin stabilizes membranes of overexcited nerve fibers, inhibits appearance of repeated neuronal discharge and reduces synaptic excitation impulse conduction. It is established that the main mechanism of the preparation action is a preventing of repeated formation of sodium-dependent action potential in depolarized neuron via blockade of sodium channels. Anticonvulsive preparation action is generally caused by glutamate release and stabilization of neuron membrane, whereas anti-maniac effect can be caused by inhibiting of metabolism of dopamine and noradrenaline.

Pharmacokinetics:

After per oral usage carbamazepin is absorbed slowly and almost completely, though it is slowly absorbed. After single use maximal carbamazepin concentration in plasma (Cmax) in adults is reached in 12 hours. There are not observed clinically significant differences in degree of active substance absorption after administration of different medicine forms of the preparation for oral use. After single per oral use of the preparation tablet, which contains 400 mg of carbamazepin, average index of Cmax of unchanged active substance reaches approximately 4.5 mkg/ml.

Meal does not significantly influence on rate and degree of carbamazepin absorption.

Steady-stable preparation concentration in plasma is reached in 1-2 weeks that depends on individual peculiarities of metabolism (autoinduction of hepatic enzyme systems by carbamazepin, heteroinduction by other medicine preparations, which are concurrently used) and on patient’s state, preparation dose and treatment duration. There are observed significant interindividual differences of steady-stable concentration indexes in therapeutical diapason: in most patients these indexes are varied from 4 to 12 mkg/ml (17 – 50 micromole/l). Concentrations of carbamazerin-10,11-epoxide (pharmacologically active metabolite) are reached practically 30% versus carbamazepin concentrations.

Distribution:

On condition of full carbamazepin absorption an imaginary distribution volume is from 0.8 to 1.9 l/kg. Carbamazepin penetrates through placental barrier. Its binding with plasma proteins is 70-80%. Concentration of unchanged carbamazerin in cerebrospinal fluid and saliva is proportional to a part of active substance unbounded with proteins (20 – 30%). Carbamazepin concentration in breast milk is 25 – 60% of its level in plasma.

Metabolism:

Carbamazepin is metabolised in liver mainly through epoxy way, as a result of which main metabolites are formed – 10.11-trans-diol derivative and its conjugate with glucuronic acid. Main isoenzyme, which provides carbamazerin biotransformation into carbamazerin-10,11-epoxide, is P450 cytochrome. As a result of metabolic reactions it is also firmed 9-hydroxymethyl-10-carbamoilacridan “small” metabolite. After single per oral carbamazerin use approximately 30% of active substance is determined in urine like end product of epoxy metabolism. Other important carbamazerin biotransformation ways cause formation of different monohydroxilated derivatives and N-glucuronide of carbamazerin, which is formed with a help of uridil-diphosphate-glucuronyl transferase (UGT2B7).

Excretion:

After single per oral use of the preparation a half-life period of unchanged carbamazepin in average is 36 hours and after repeated use of the preparation – in average is 16 – 24 hours (due to autoinduction of hepatic monooxygenase system) depending on the treatment duration. In patients who concurrently use preparations, which induce hepatic enzyme system (for example, phenytoin and phenobarbital) a half-life period of carbamazepin in average is 9 – 10 hours.

Average half-life period of carbamazerin-10,11-epoxide metabolite from plasma is approximately 6 hours after single per oral epoxide use.

After single carbamazepin intake in dose of 400 mg 72% of used dose are excreted with urine and 28% – with faeces. Practically 2% of used dose is excreted with urine like unchanged preparation and about 1% – like pharmacologically active metabolite – 10.11-epoxide.

Pharmacokinetics peculiarities in individual groups of patients:

Elderly patients:

There is no data concerning changing of carbamazepin pharmacokinetics in elderly patients (versus young adults).

Patients with impaired hepatic and kidney functions:

There is no data concerning carbamazepin pharmacokinetics in patients with hepatic and kidney functions disorders.

PHARMACEUTICAL CHARACTERISTICS:

General physic-chemical properties:

White or nearly white round tablets with bevelled break-line on one side and “K” pressing on the other one.

Shelf-life:

3 years.

Storage:

Store in a dry, protected from sun light place at temperature not more 25° C.

Keep it out of reach of children.

Package:

There are 10 tablets in a blister; there are 5 blisters in a pack.

Conditions of supply:

By prescription.