Carbamazepine ретард

General characteristics. Structure:

Active ingredient: 200 mg or 400 mg of carbamazepine;

Excipients: cellulose microcrystallic, silicon dioxide colloid anhydrous, кросповидон, magnesium stearate, polyacrylate dispersion.

Pharmacological properties:

Pharmacodynamics. Karbamazepin-FS 200 ретард and Karbamazepin-FS 400 ретард show antiepileptic, neurotropic and psychotropic activity.
As antiepileptic means it is active concerning partial convulsive attacks (simple and difficult), without or with secondary generalization; generalizirovanny toniko-clonic spasms, and also combination of these types of convulsive attacks.
The mechanism of effect of carbamazepine, active ingredient of drug, is found out only partially. Carbamazepine stabilizes membranes of hyperactive nervous cells, oppresses repeated categories of neurons, reduces synoptic distribution of exciting impulses. Perhaps, anticonvulsant effect of carbamazepine is connected with the prevention of repeated categories by blockade of natrium channels.
Anticonvulsant action can be connected with decrease in release of a glutamate and stabilization of neyronalny membranes also.
Warns attacks of an epileptiform neuralgia.
Antipsychotic effect of carbamazepine can be connected with oppression of a turnover of dopamine and noradrenaline in a brain.

Pharmacokinetics. After oral administration carbamazepine is soaked up almost completely, though rather slowly. After a single dose the maximum concentration in plasma (Cmax) of blood is reached in 24 hours.
Reception of food significantly does not influence the speed and extent of absorption of carbamazepine.
At use of a retardny form of tablets observed for 15% lower bioavailability in comparison with tablets of immediate release of active ingredient. Bioavailability fluctuates within 85-100%.
Equilibrium concentration of drug in plasma are reached within 1-2 weeks that depends on specific features of metabolism (an autoinduktion of fermental systems of a liver carbamazepine, heteroinduction by other medicines applied at the same time), and also on a condition of the patient, a dose of drug and duration of treatment. Essential interindividual distinctions of values of equilibrium concentration in the therapeutic range are observed: at most of patients these values fluctuate from 4 to 12 mkg/ml (17-50 µmol/l). Concentration of carbamazepine-10,11-epoxide (pharmacological an active metabolite) reaches about 30% of concentration of carbamazepine.
Linkng of carbamazepine with proteins of a blood plasma reaches 70-80%. Concentration of not changed carbamazepine in cerebrospinal fluid and saliva is proportional to a share of the active agent which is not connected with proteins (20-30%).
Gets into breast milk (25-60% of level of carbamazepine in a blood plasma) and through a placental barrier. The conditional volume of distribution makes 0,8-1,9 l/kg.
Carbamazepine is metabolized in a liver in preferential epoxy way with formation of several metabolites: 10,11-transdiolovy derivative and its conjugates with glucuronic acid, monohydroxylated derivatives, and also                            N-glucuronides. The main isoenzyme providing carbamazepine biotransformation in carbamazepine-10,11-epoxide is P450 3A4 cytochrome.
After a single dose of drug the elimination half-life (T1/2) of not changed carbamazepine averages about 36 hours, and after repeated administration of drug - on average 16-24 hours (owing to an autoinduktion of enzymes of metabolism) depending on treatment duration. At the patients accepting at the same time other drugs inducing the same fermental system of a liver (for example, Phenytoinum, phenobarbital), the elimination half-life of carbamazepine averages 9 - 10 hours.
The average elimination half-life of karbmazepin-10,11-epoxide after one-time reception makes about 6 hours of a blood plasma.
After a single dose in 400 mg of carbamazepine of 72% of the accepted dose also 28% - with a stake are removed with urine. About 2% of the accepted dose are removed with urine in the form of not changed carbamazepine, about 1% - in the form of pharmacological active          10,11-epoxy metabolite and about 30% - in the form of other metabolites.
At children owing to more bystry elimination of carbamazepine use of higher doses of drug at the rate on kilogram of body weight in comparison with adults can be required.
Are absent this, testimonial that the pharmacokinetics of carbamazepine changes at patients of advanced age (in comparison with adult persons of young age).
Data on carbamazepine pharmacokinetics at patients with renal failures or a liver are absent.

Indications to use:

- Epilepsy:
- difficult or simple partial convulsive attacks (with loss or without loss of consciousness) with secondary generalization or without it;
- generalizirovanny toniko-clonic convulsive attacks;
- the mixed forms of convulsive attacks.

To use drug as monotherapy, and as a part of a combination therapy.
· Acute maniacal states; a maintenance therapy of bipolar affective disorders for the purpose of prevention of aggravations or weakening of clinical manifestations of an aggravation.
· A syndrome of alcoholic abstinence (for prevention of convulsive attacks).
· Idiopathic epileptiform neuralgia.
· Idiopathic neuralgia of a glossopharyngeal nerve.

Route of administration and doses:

To accept drug orally; the daily dose is usually distributed on 2 receptions. Drug can be accepted in time either after food, or in intervals between reception of food together with a small amount of liquid.
Before an initiation of treatment the patients belonging to the Chinese ethnic group of Khan or patients of the Thai origin have to undergo, whenever possible, genetic inspection on existence of an allele of HLA-B*1502 as this allele can provoke development heavy carbamazepine - the associated Stephens-Johnson's syndrome.

Epilepsy. In cases when it is possible, Karbamazepin-FS ретард needs to appoint in the form of monotherapy.
Treatment should be begun with use of a low daily dose which should be raised further to achievement of optimum effect slowly.
For selection of an optimum dose of drug there can be useful a determination of level of active agent in a blood plasma. Therapeutic concentration of drug in a blood plasma has to make 4-12 mkg/ml. At purpose of the drug Karbamazepin-FS ретард in addition to the current antiepileptic therapy the dose of drug should be raised gradually, without changing a dose of current applied antiepileptic drug(s) or, if necessary, adjusting it.
Transfer of the patient from reception of tablets on reception of tablets ретард. Some patients at use of tablets ретард can have a need for increase in a dose of drug.
For adults the initial dose of drug makes 100-200 mg 1-2 times a day. Then slowly to raise a dose to achievement of optimum effect; usually it is reached at the dose of 800-1200 mg/days distributed on 2 receptions. Increase in a dose of the drug Karbamazepin-FS ретард to 1600 mg/days or even to 2000 mg/days can be necessary for some patients.
Patients of advanced age. Considering medicinal interactions and various pharmacokinetics of antiepileptic drugs, patients of advanced age of a dose of the drug Karbamazepin-FS 200 ретард or Karbamazepin-FS 400 ретард need to select with care.

Children. Gradual increase in an initial dose taking into account individual needs of the patient is recommended. The usual dose of carbamazepine for children averages 10-20 mg/kg of body weight a day (in stages).
Children of 5-10 years - 400-600 mg/days.
Children of 10-15 years - 600-1000 mg/days

Acute maniacal states and maintenance therapy at bipolar affective disorders.
Range of doses usually makes 400 to 1600 mg a day divided into 2 separate receptions. Usually therapy it is necessary to carry out in a dose 400-600 mg a day. At an acute maniacal state rather bystry increase in a dose to 800 mg/days while for the purpose of ensuring optimum tolerance within a maintenance therapy at bipolar disorders gradual increase by small doses is recommended is recommended.

Syndrome of alcoholic abstinence (for prevention of convulsive attacks).
Average dose - 600 mg a day, divided into 2 receptions. In hard cases during the first several days the dose can be raised (for example, to 1200 mg a day, divided into 2 receptions). At heavy manifestations of alcoholic abstinence treatment should be begun with a drug Karbamazepin-FS combination ретард with sedative and somnolent drugs (for example, with klometiazoly, chlordiazepoxide), adhering to the above-stated instructions concerning dosing. After end of an acute phase treatment by the drug Karbamazepin-FS ретард can be continued in the form of monotherapy.

Epileptiform neuralgia and glossopharyngeal nerve.
The initial dose of the drug Karbamazepin-FS ретард makes 200-400 mg a day. It should be raised slowly to disappearance of pain (usually to a dose             of 400-800 mg a day, divided into 1-2 receptions). Use of a daily dose of drug of 1600 mg can be in certain cases necessary. After the termination of pain gradually to reduce a dose to the minimum supporting. The recommended initial dose for patients of advanced age makes 200 mg a day, in 2 receptions.

Children.
Not to appoint drug in this dosage form to children up to 5 years.

Features of use:

Karbamazepin-FS 200 ретард and Kabamazepin-FS 400 ретард it is necessary to appoint only under medical observation and only after ratio assessment advantage/risk and on condition of careful monitoring of patients with cordial, hepatic or renal disturbances, side hematologic reactions to other drugs in the anamnesis, or patients with the interrupted therapy courses the drug Karbamazepin-FS 200 ретард or Kabamazepin-FS 400 ретард. Drug is usually inefficient at small attacks (petit mal, an absentia epileptica) and myoclonic attacks. Separate cases demonstrate that strengthening of attacks can arise at patients with atypical absentias epileptica.

Hematologic effects. Using carbamazepine connect development of an agranulocytosis and aplastic anemia; however because of excessively low frequency of cases of development of these states it is heavy to estimate significant risk at Carbamazepine administration of drug. It is known that the total risk of development of an agranulocytosis in the general population which did not receive treatment by carbamazepine reached 4,7 cases on 1 million population a year, and aplastichny anemia - 2 cases on 1 million population a year. Temporary or permanent decrease in quantity of thrombocytes or leukocytes in connection with carbamazepine reception is periodically or often noted. However for the majority of these cases their temporariness is confirmed, and they do not demonstrate development of aplastic anemia or an agranulocytosis. Prior to therapy and periodically during its carrying out it is necessary to perform blood test, including determination of quantity of thrombocytes (and also, perhaps, quantities of reticulocytes and level of hemoglobin).
In cases when during treatment the low level of quantity of leukocytes or thrombocytes (or the tendency to their decrease takes place) is noted, it is necessary to watch a condition of the patient and indicators of the developed clinical blood test attentively. At development of the expressed leukopenia progressing or with clinical manifestations like fever or a pharyngalgia drug needs to be cancelled. If signs of considerable oppression of marrow are revealed, drug needs also to be cancelled.
It is necessary to inform patients and their relatives of the precursory symptoms of toxicity inherent possible hematologic disturbance, and also of symptoms from integuments and a liver. The patient needs to be informed on need to see immediately a doctor in case of such undesirable reactions as fever, a pharyngalgia, rash on skin, ulcers in oral cavities, causeless developing of bruises, hemorrhages in the form of petechias or a purpura.

Heavy dermatological reactions. Heavy dermatological reactions which include a toxic epidermal necrolysis (TEN or a Lyell's disease) and the Stephens-Johnson's syndrome (SJS) at use of carbamazepine arise very seldom. Patients with heavy dermatological reactions can need hospitalization as these states can threaten life and have lethal character. The majority of cases of development of SSD/TEN are noted  within the first several months of treatment by carbamazepine. At development of signs and symptoms which demonstrate serious dermatological reactions (for example, SSD, a syndrome of Layella / TEN) administration of drug it is necessary to stop and appoint alternative therapy immediately.

Pharmacogenomics. There are more and more certificates on influence of various alleles of HLA on predisposition of the patient to emergence of the side reactions connected with immune system.
Communication with (HLA) - B*1502. Retrospective researches at Chinese patients of ethnic group of Khan showed the expressed correlation between the skin reactions of SSD or TEN connected with carbamazepine, and existence at these patients of human leukocytic antigen (HLA), an allele (HLA) - B*1502. Big frequency of messages on development of SSD (rather seldom, than very seldom) is characteristic of some countries of Asia (for example, Taiwan, Malaysia and Philippines) where among the population the allele (HLA) - B*1502 prevails.
At the patients considered per se that genetically belong to risk groups before an initiation of treatment of Karbamazepinom-FS 200 ретард or Karbamazepinom-FS 400 ретард it is necessary to hold testing for presence of an allele (HLA) - B*1502. If the analysis of the patient on presence of an allele (HLA) - B*1502 yields a positive take, then use of the drug Karbamazepin-FS 200 ретард or Karbamazepin-FS 400 ретард it is necessary to avoid if only advantages of such treatment do not exceed risks. The patients who underwent inspection and received a negative take on existence (HLA) - B*1502, have the low level of development of SSD though very much seldom such reactions can meet still.
The allele (HLA) - B*1502 can be risk factor of development of SSD or TEN in the Chinese patients receiving other antiepileptic means which can be connected with emergence of such syndromes. Thus, it is necessary to avoid use of other drugs which can be connected with emergence of SSD or TEN, for the patients having an allele (HLA) - B*1502 if it is possible to apply other, alternative therapy. Usually it is not recommended to carry out genetic screening of patients among nationalities with low coefficient of existence of an allele (HLA) - B*1502, and also at the persons who are already receiving Karbamazepin-FS 200 ретард or Karbamazepin-FS 400 ретард as the risk of emergence of SSD or TEN is considerably limited by the first several months irrespective of presence at genes of the patient of an allele (HLA) - B*1502.
Communication with (HLA) - A*3101. Leukocytic antigen of the person (HLA) - A*3101 can be risk factor of development of side reactions from skin, such as SSD, TEN, medicamentous rash with an eosinophilia and system symptoms (DRESS), acute generalized exanthematous пустулез, makulopapulezny rash. Therefore at detection of existence of an allele (HLA) - A*3101 should refrain from use of drug.

However results of genetic screening should not replace the corresponding clinical observation and management of treatment.
The role of other possible factors, such as dosing of antiepileptic means, observance of the mode of therapy, the accompanying therapy, influence of other diseases in emergence of these heavy side reactions from skin and monitoring of skin disturbances were not studied.

Other dermatological reactions. Development of the rapid and not menacing to health easy dermatological reactions, for example, of the isolated macular or makulopapulezny dieback is possible. Usually they disappear in several days or weeks both at constant dosing, and after a dose decline. At the same time, as can be very difficult to distinguish precursory symptoms of more serious dermatological reactions from moderate rapid reactions, the patient has to be under careful observation immediately to stop drug use if with its continuation reaction worsens.
Existence at the patient of an allele (HLA) - A*3101 is risk factor of emergence at it less serious skin reactions to carbamazepine, such as hypersensitivity syndrome to anticonvulsants or insignificant rash (makulopapulezny rash). However it was not established that existence at the patient of an allele (HLA) - B*1502 can be risk factor of emergence at it the above-stated skin reactions.

Hypersensitivity. Carbamazepine can provoke development of reactions of hypersensitivity, including multiple reactions of hypersensitivity, with localization in skin, a liver, the hemopoietic bodies and lymphatic system or other bodies, in total or separately, within system reaction (see the section "Side reactions").
Patients with reactions of hypersensitivity to carbamazepine have to be informed that about 25-30% of such patients can also have reactions of hypersensitivity on окскарбазепин.

At use of carbamazepine and Phenytoinum development of cross hypersensitivity is possible.
At emergence of the signs and symptoms indicating hypersensitivity, administration of drug of Karbamazepin-FS 200 ретард or Kabamazepin-FS 400 ретард it is necessary to stop immediately.

Attacks. Karbamazepin-FS 200 ретард or Kabamazepin-FS 400 ретард patients need to apply with care with the mixed attacks which include absentias epileptica (typical or atypical). Under such circumstances drug can provoke attacks. In case of provoking of attacks use of drug needs to be stopped immediately. Increase in frequency of attacks can take place during transition from peroral forms of drug to suppositories.

Function of a liver. At the beginning of therapy by drug and periodically throughout treatment it is necessary to carry out assessment of function of a liver, especially at patients with liver diseases in the anamnesis and at patients of advanced age. At an aggravation of abnormal liver functions or at patients with an active phase of a disease of a liver it is necessary to stop administration of drug immediately. Some indicators of laboratory analyses by means of which estimate a functional condition of a liver at patients who accept carbamazepine, can go beyond standard of values, in particular gamma glutaminetransferase (GGT). It probably happens because of induction of liver enzymes. Induction of enzymes can lead to moderate increase in level of an alkaline phosphatase also. Such increase in functional activity of hepatic metabolism is not an indicator for carbamazepine cancellation.
Heavy reactions from a liver because of use of carbamazepine happen very seldom. In case of signs and symptoms of hepatic dysfunction or an active disease of a liver it is necessary to inspect urgently the patient, and 200 ретард or Karbamazepinom-FS 400 ретард to suspend treatment of Karbamazepinom-FS before obtaining results of inspection.

Function of kidneys. It is recommended to carry out assessment of function of kidneys and determination of level of an urea nitrogen of blood at the beginning and periodically throughout a therapy course.

Hyponatremia. Cases of development of a hyponatremia at carbamazepine use are known. At patients with already existing renal failure or at patients with the accompanying use of the medicines reducing sodium level (for example, the diuretics, medicines associated with inadequate secretion of antidiuretic hormone), before treatment it is necessary to measure sodium level in blood. Further it is necessary to measure each two weeks, then at an interval of one month for the first three months of treatment or depending on clinical need. It concerns first of all patients of advanced age. It is necessary to limit amount of the used water in this case.

Anticholinergic effects. Carbamazepine shows moderate anticholinergic activity. Thus, patients with the increased intraocular pressure have to be under careful observation during therapy and exercise control of indicators of intraocular pressure.

Mental effects. It is necessary to remember probability of activation of latent psychosis, at patients of advanced age - confusion is consciousness or excitement.

The patients receiving antiepileptic drugs have separate data on development of suicide thoughts and behavior. Meta-analysis of randomized placebos - controlled researches of antiepileptic drugs showed small increase in risk of suicide thoughts and behavior. The origins of this risk are not known, and the available data do not exclude a possibility of the increased risk for carbamazepine. Therefore patients it is necessary to check for existence of suicide thoughts and behavior and, if necessary, to appoint the corresponding treatment. Patients (and to trustees of patients) should recommend to see a doctor at emergence of signs of suicide thoughts or behavior.

Endocrine effects. Cases of breakthrough bleedings at women who received carbamazepine in a combination with hormonal contraceptives were registered. As Karbamazepin-FS 200 ретард and Kabamazepin-FS 400 ретард can negatively influence efficiency of hormonal contraceptives, women of reproductive age need to advise to consider the possibility of use of alternative forms of contraception during drug use. As a result of induction of enzymes of a liver carbamazepine can become the reason of decrease in therapeutic effect of drugs of estrogen and/or progesterone (i.e. to interfere with effective contraception). The patients accepting carbamazepine and for which hormonal contraception is necessary have to receive the drug containing not less than 50 mkg of estrogen.

There are separate messages on disturbance of male fertility and/or disturbance of a spermatogenesis.
Hypothyroidism. Carbamazepine can reduce concentration of hormones of a thyroid gland, in this regard increase in a dose of replacement therapy by hormones of a thyroid gland at patients with a hypothyroidism is necessary.
Monitoring of level of drug in a blood plasma. In spite of the fact that correlation between dosing and level of carbamazepine in a blood plasma, and also between carbamazepine level in a blood plasma and clinical performance and portability is doubtful, monitoring of level of drug in a blood plasma can be reasonable in such cases: at sudden increase in frequency of attacks, check of a komplayns of the patient, at pregnancy, at treatment of children and teenagers; at suspicion on absorption disturbance, at the suspected toxicity and at use more than one drug.

Dose decline and drug withdrawal. Sudden drug withdrawal of Karbamazepin-FS 200 ретард or Kabamazepin-FS 400 ретард can provoke attacks therefore carbamazepine should be cancelled gradually for 6 months. In need of sudden cancellation of therapy by drug at patients transition to new antiepileptic drug has to happen to epilepsy during therapy by the corresponding medicine (for example, diazepam intravenously, rektalno or Phenytoinum intravenously).

Use during pregnancy or feeding by a breast.
Treatment of Karbamazepinom-FS 200 ретард and Karbamazepinom-FS 400 ретард the pregnant women sick with epilepsy, has to be performed with extra care.
For women of reproductive age drug should be used whenever possible in the monotherapy mode as the frequency of congenital anomalies of a fruit at women to whom carried out treatment by a combination of anti-epileptic means, above, than at those which received each of these means in the form of monotherapy.
If the woman receiving Karbamazepin-FS 200 ретард or Karbamazepin-FS 400 ретард became pregnant or if the question of purpose of drug arises during pregnancy, it is necessary to correlate attentively expected advantages of therapy and possible risks of a complication, especially in І a pregnancy trimester.
It is necessary to appoint a drug minimal effective dose. Regular control of level of active agent in a blood plasma is recommended.
During pregnancy it is not necessary to stop effective antiepileptic treatment because the exacerbation of a disease poses a threat for mother and a fruit.

It is known that the children born at mothers sick with epilepsy are more often than others are subject to disturbances of pre-natal development, including malformations. It was reported that carbamazepine, as well as all other antiepileptic means, increases risk of emergence of these disturbances though final confirmation is absent. There are single messages on cases of inborn diseases and malformations, including splitting of a backbone (spina bifida) and other anomalies of development, such as the kraniofatsialny defects, cardiovascular malformation, hypospadias and anomalies of development of various systems of an organism associated using carbamazepine.
Patients should be informed on a possibility of increase in risk of developing of malformations of a fruit and to give an opportunity to undergo antenatal diagnosis.

Observation and prevention. Antiepileptic means can increase deficit of folic acid. It can promote increase in frequency of inborn defects at the children who were born at women who accepted antiepileptic means. Therefore to and during pregnancy additional purpose of folic acid is recommended.

Newborns. For the purpose of prevention of the raised bleeding at newborns to women in recent weeks of pregnancy, and also the newborn recommends to appoint K1 vitamin.
Several cases of convulsive attacks and/or respiratory depressions, vomitings, diarrheas and/or a loss of appetite at newborns whose mothers accepted drugs of carbamazepine and other anticonvulsant drugs are described. These reactions can be withdrawal signs.

Feeding by a breast. Carbamazepine gets into breast milk, concentration in it make 25-60% of level in a blood plasma. Therefore it is necessary to compare advantages and possible undesirable effects of breastfeeding at therapy of Karbamazepinom-FS 200 ретард or Karbamazepinom-FS 400 ретард. Mothers accepting drug can nurse the children, but provided that for the child observation concerning development of possible side reactions will be established (for example, excessive drowsiness, allergic skin reactions).

Ability to influence speed of response at control of motor transport or work with other mechanisms.
Ability of the patient to bystry reaction, especially at the beginning of therapy or during selection of a dose, can be broken owing to developing of dizziness and drowsiness. Therefore during the driving or work with mechanisms the patient should be careful or to abstain from this type of activity.

Side effects:

Certain types of undesirable reactions, for example, from the central nervous system (CNS) (dizziness, a headache, an ataxy, drowsiness, the general weakness, a diplopia), the alimentary system (nausea, vomiting) or allergic skin reactions, arise very often or often, especially in an initiation of treatment carbamazepine, at use of too high initial dose or at treatment of patients of advanced age.
Dozozavisimy side reactions usually take place within several days as it is spontaneous, and after a temporary dose decline of carbamazepine. Development of side reactions from TsNS can be a consequence of relative overdose of drug or considerable fluctuations of concentration of active agent in a blood plasma. In such cases it is recommended to control the level of active agent in a blood plasma or to divide a daily dose into smaller (for example, on 3-4) separate doses.
From a nervous system: dizziness, an ataxy, sedation, drowsiness, the general weakness, a headache, a diplopia, sight accommodation disturbance (for example, sight opacification), the abnormal spontaneous movements (for example, a tremor, the "flitting" tremor, dystonia, a tic), a nystagmus, orofatsialny dyskinesia, disturbance of the movement of eyes, alalias (for example, a dysarthtia or the illegible speech), a memory impairment, choreoathetoid frustration, a peripheral neuropathy, paresthesias, muscular weakness and symptoms of paresis, disturbance of flavoring feelings, a malignant antipsychotic syndrome.
Mental disorders: hallucinations (visual or acoustical), depression, appetite loss, concern, agressive behavior, agitation, confusion of consciousness,  activation of psychosis.
From skin and hypodermic cellulose: allergic dermatitis, a small tortoiseshell, sometimes in a severe form, exfoliative dermatitis, an erythrosis, a system lupus erythematosus, an itch, Stephens-Johnson's syndrome, a toxic epidermal necrolysis, photosensitivity, a multiformny and nodular erythema, disturbance of a xanthopathy, purple, an acne, the increased perspiration, a hair loss, a hirsutism, acute generalized exanthematous пустулез, a lichenoid keratosis, онихомадезис.
From system of a hemopoiesis: insufficiency of marrow, a leukopenia, thrombocytopenia, an eosinophilia, a leukocytosis, a lymphadenopathy, deficit of folic acid, an agranulocytosis, aplastic anemia, a pancytopenia, a true erythrocyte aplasia, anemia, megaloblastny anemia, an acute intermittent porphyria, the mixed porphyria, a late porphyria of skin, a reticulocytosis and, perhaps, hemolitic anemia.
From gepatobiliarny system: increase in level gamma глутамилтрансферазы (owing to induction of this enzyme in a liver) that, as a rule, has no clinical value; increase in level of an alkaline phosphatase of blood, increase in level of transaminases, hepatitis cholestatic, the parenchymatous (hepatocellular) or mixed types, jaundice, granulematozny hepatitis, a liver failure.
From the alimentary system: nausea, vomiting, dryness in a mouth, diarrhea or a lock, an abdominal pain, a glossitis, stomatitis, pancreatitis, colitis.
From immune system: medicamentous rash with an eosinophilia and system symptoms (DRESS), multiorgan hypersensitivity of the slowed-down type with fever, skin rashes, a vasculitis, lymphadenopathy; with the signs reminding a lymphoma; arthralgias, a leukopenia, an eosinophilia, a gepatosplenomegaliya and the changed indicators of function of a liver and a syndrome of disappearance of bilious channels (destruction and disappearance of intra hepatic bilious channels) (the specified manifestations meet in different combinations). There can also be disturbances from other bodies (for example, lungs, kidneys, a pancreas, a myocardium, a large intestine) aseptic meningitis with a myoclonus and a peripheral eosinophilia, anaphylactic reaction, a Quincke's disease.
From cardiovascular system: disturbance of endocardiac conductivity, arterial hypertension or hypotension, bradycardia, arrhythmias, AV blockade with a loss of consciousness, a circulator collapse, congestive heart failure, an exacerbation of an ischemic disease, thrombophlebitis, a thrombembolia (for example, a vascular embolism of lungs).
From endocrine system and a metabolism: hypostases, a liquid delay, increase in body weight, a hyponatremia and decrease in osmolarity of plasma owing to effect, similar to effect of antidiuretic hormone that seldom leads to the overhydratation which is followed by a lethargy, vomiting, a headache, confusion of consciousness and neurologic disturbances, the increase in level of prolactin which is followed or not followed by such manifestations as a galactorrhoea, a gynecomastia; changes of indicators of function of a thyroid gland - decrease in level of L-thyroxine (FT4, T4, T3) and increase in level of tireostimuliruyushchy hormone that, as a rule, is not followed by clinical manifestations; disturbance of metabolism of a bone tissue (decrease in level of calcium and 25-IT-cholecalciferol in a blood plasma) that decrease in mineral density of a bone tissue leads to osteomalacy/osteoporosis; in some cases - increase in concentration of cholesterol, including cholesterol of lipoproteids of high density and triglycerides.
From urinogenital system: intersticial nephrite, a renal failure, a renal failure (for example, an albuminuria, a hamaturia, an oliguria, increase in level an urea/azotemia), a frequent urination, an ischuria, sexual dysfunction / impotence, disturbance of a spermatogenesis (with decrease in quantity/mobility of spermatozoa).
From organs of sight: cataract, conjunctivitis, increase in intraocular pressure.
From hearing and balance: disorders of hearing, including a noise/ring in ears, a hyperacusia, a gipoakuziya, change of perception of height of a sound. 
From a musculoskeletal system: arthralgias, muscular pain or spasms of muscles, changes.
From a respiratory organs: the reactions of hypersensitivity from lungs which are characterized by fever, an otdyshka, a pneumonitis or pneumonia.
Infections and invasions: reactivation of a virus of herpes of the person of the VI type.
General disturbances: fatigue.
Laboratory researches: hypogammaglobulinemia.

Interaction with other medicines:

P450 3A4 cytochrome (CYP 3A4) is the main enzyme providing formation of carbamazepine-10,11-epoxide. Simultaneous use with Karbamazepinom-FS 200 ретард or Karbamazepinom-FS 400 ретард CYP 3A4 inhibitors can lead to increase in concentration of carbamazepine in a blood plasma that, in turn, can cause emergence of side reactions. Combined use of the inductors CYP 3A4 can lead to acceleration of metabolism of Karbamazepina-FS 200 ретард and Karbamazepina-FS 400 ретард and, thus, to possible decrease in concentration of carbamazepine in a blood plasma and therefore - to possible reduction of expressiveness of therapeutic effect.
Similarly, phase-out of inductors of CYP 3A4 enzyme can lower a metabolic rate of carbamazepine and lead to increase in its concentration in a blood plasma.

Carbamazepine is the powerful inductor CYP 3A4 and other fermental systems of a phase І and phases II in a liver therefore can reduce concentration of other drugs in a blood plasma which are preferential metabolized by CYP 3A4 by induction of their metabolism.
Human microsomal epoxide-hydrolase represents the enzyme responsible for education 10,11 from carbamazepine-10,11-epoxide. Co-administration of inhibitors human microsomal can lead epoxide-hydrolase to increase in concentration of carbamazepine-10,11-epoxide in a blood plasma.

Drugs which can increase levels of carbamazepine and/or carbamazepine-10,11-epoxide in a blood plasma: an isoniazid, verapamil, diltiazem, an ibuprofen, dextropropoxyphene, it is possible - fluoxetine, флувоксамин; desipramine, нефазодон, вилоксазин, Trazodonum, пароксетин, Cimetidinum, омепразол; acetazoleamide, даназол, niacinamide (at adults - only in high doses); вигабатрин, стирипентол, makrolidny antibiotics (for example, erythromycin, кларитромицин, тролеандомицин, джозамицин), ципрофлакцин; azoles, for example, итраконазол, кетоконазол, флуконазол, вориконазол (to patients who receive treatment vorikonazoly or itrakonazoly alternative antiepileptic means), лоратадин, терфенадин, olanzapine, grapefruit juice, inhibitors of proteases for treatment of HIV infection (for example, ритонавир can be recommended), оксибутин, дантролен, тиклопидин.

It was reported about increase in concentration of an active metabolite of carbamazepine-10,11-epoxide under the influence of a loksapin, a kvetiapin, Primidonum, a progabid, valproic acid, a valnoktamid and a valpromid.

As increase in level of carbamazepine and/or carbamazepine-10,11-epoxide in a blood plasma can lead to emergence of side reactions (for example, to dizziness, drowsiness, an ataxy, a diplopia), it is necessary to adjust a dose of Karbamazepina-FS 200 ретард, 400 ретард and/or regularly to determine by Karbamazepina-FS carbamazepine levels in a blood plasma.

Drugs which can reduce carbamazepine levels in plasma: фелбамат, метсуксимид, phenobarbital, окскарбазепин, фенсуксимид, Phenytoinum (for avoidance of intoxication Phenytoinum and subtherapeutic concentration of carbamazepine it is recommended to correct concentration of Phenytoinum in a blood plasma to                      13 micrograms/ml before a carbamazepine initiation of treatment), фосфенитоин, Primidonum and clonazepam (though data on it are contradictory), theophylline, Aminophyllinum, rifampicin, Cisplatinum or doxorubicine.

Meflokhin can counteract anticonvulsant effect of carbamazepine. Therefore correction of doses of Karbamazepina-FS 200 ретард and Karbamazepina-FS 400 ретард can be necessary.

It was reported that изотретиноин changes bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide; in this case control of concentration of carbamazepine in a blood plasma is necessary.

Concentration of carbamazepine in a blood plasma can decrease at simultaneous use of a St. John's Wort of made a hole (Hipericum perforatum).  

Influence of Karbamazepina-FS 200 ретард and Karbamazepina-FS 400 ретард on concentration in a blood plasma of the drugs used as the accompanying therapy: carbamazepine can reduce concentration or reduce and even completely to level effects of some drugs. Correction of doses of such drugs can be required: left thyroxine, to klobaza, clonazepam, Ethosuximidum, фелбамат, ламотриджин, окскарбазепин, тиагабин, топирамат, Primidonum, valproic acid, зонисамид, to alprazola, midazolam, corticosteroids (for example, Prednisolonum, dexamethasone); cyclosporine, эверолимус, такролимус, сиролимус, doxycycline, рифабутин; dihydropyridine derivatives (for example, фелодипин and исрадипин); digoxin, quinidine, propranolol, симвастатин, аторвастатин, ловастатин, церивастатин, ивабрадин; protease inhibitors for treatment of HIV (for example, индинавир, саквинавир, ритонавир), methadone, paracetamol, phenazone (antipyrine), трамадол, the drugs containing estrogen and/or progesterona (selection of alternative methods of contraception, see the section "Features of Use"), theophylline, peroral anticoagulants (warfarin, фенпрокумон, дикумарол and ацетокумарол), бупропион is necessary, for tsitalopra, нефазодон, Trazodonum, tricyclic antidepressants (for example, Imipraminum, amitriptyline, нортриптиллин, кломипрамин), clozapine, a haloperidol, бромперидол, olanzapine, кветиапин, рисперидон, арипипразол, палиперидон, зипризидон, итраконазол, вориконазол, the aprepitant, a praziquantel, albendazole, tadalafit, buprenorphine, гестринон, тиболон, торемифен, миансерин, sertraline, иматиниб, cyclophosphamide, лапатиниб, терсиролимус.

There are messages that against the background of carbamazepine reception Phenytoinum level in a blood plasma can both increase, and to decrease, and Mephenytoinum level - to increase (in some cases).

Combinations which should be taken into account.
Simultaneous use of carbamazepine and levetiratsetam can lead to strengthening of toxicity of carbamazepine.
There are messages on strengthening of the hepatotoxic caused by an isoniazid in cases when it was accepted along with carbamazepine.
Prolonged use of carbamazepine with paracetamol (acetaminophen) can lead to development of a hepatotoxic.

The combined use of carbamazepine and lithium can lead to strengthening of a neurotoxicity in spite of the fact that lithium level in a blood plasma remains within therapeutic range. The combined use of carbamazepine and Metoclopramidum or neuroleptics (a haloperidol, thioridazine) can also lead to increase in frequency of undesirable neurologic reactions.

As Karbamazepin-FS 200 ретард and Karbamazepin-FS 400 ретард has structural similarity to tricyclic antidepressants, it is not necessary to appoint it in a combination with monoamine oxidase inhibitors (MAO); before purpose of drugs of carbamazepine MAO inhibitors need to be cancelled at least in 2 weeks or if the clinical situation, even allows earlier.

Simultaneous use of Karbamazepina-FS 200 ретард or Karbamazepina-FS 400 ретард with some diuretic means (a hydrochlorothiazide, furosemide) can lead to the hyponatremia which is followed by clinical manifestations.

Carbamazepine can counteract effects of not depolarizing muscular relaxants (for example, a pankuroniya). In case of use of such combination of medicines there can be a need for increase in a dose of the specified muscle relaxants; it is necessary to watch patients as perhaps more bystry, than was expected, cancellation of muscle relaxants attentively.

Karbamazepin-FS 200 ретард and Karbamazepin-FS 400 ретард, as well as other psychotropic drugs, can reduce portability of alcohol. In this regard the patient is recommended to refuse alcohol intake.

Influence on serological researches. Carbamazepine can yield false positive result of VEZhH of the analysis for definition of concentration of a perfenazon. Carbamazepine and carbamazepine-10,11-epoxide can yield false positive result of immunoassay by method of the polarized fluorescence for definition of concentration of tricyclic antidepressants.

Contraindications:

- Hypersensitivity to carbamazepine or to similar in the chemical relation of medicines (for example, tricyclic antidepressants), or to any other component of drug;
- atrioventricular block;
- existence in the anamnesis of episodes of oppression of function of a krovoobrazovaniye of marrow;
- a hepatic porphyria in the anamnesis (for example, the acute alternating porphyria, the mixed porphyria, a late porphyria of skin).

It is not necessary to appoint drug in a combination with igibitor of a monoaminooxidase (MAO) (see the section "Interaction with Other Medicines and Other Types of Interactions").

Overdose:

Symptoms. The symptoms and complaints arising at overdose usually reflect defeat central nervous, cardiovascular and respiratory systems.

Central nervous system: oppression of the TsNS functions; a disorientation, the suppressed consciousness level, drowsiness, excitement, hallucinations, a coma; sight opacification, illegible speech, dysarthtia, nystagmus, ataxy, dyskinesia, hyperreflexia (in the beginning), hyporeflexia (later); spasms, psychomotor frustration, myoclonus, hypothermia, mydriasis.

Respiratory system: respiratory depression, fluid lungs.

Cardiovascular system: tachycardia, arterial hypotension, sometimes - arterial hypertension, disturbance of conductivity with expansion of the QRS complex; the cardiac standstill which is followed by a loss of consciousness.

Alimentary system: vomiting, a delay of passing of food from a stomach, decrease in motility of a large intestine.

Skeletal and muscular system: it was reported about separate cases of the rabdomioliz connected with toxic influence of carbamazepine.

Urinary system: ischuria, oliguria or anury; liquid delay; intoxication of cultivation (hyponatremia) caused by effect of carbamazepine, similar to effect of antidiuretic hormone.

Changes from laboratory indicators: hyponatremia, possible metabolic acidosis, hyperglycemia, increase in muscular fraction of a kreatininfosfokinaza.

Treatment. The specific antidote is absent. In the beginning treatment has to be based on a clinical condition of the patient; hospitalization is shown. It is necessary to carry out definition of concentration of carbamazepine in a blood plasma for confirmation of poisoning with this means and assessment of extent of overdose. Evacuation of contents of a stomach, a gastric lavage, use of the drawn-up coal is carried out. Late evacuation of contents of a stomach can lead to the delayed absorption and repeated emergence of symptoms of intoxication during recovery. It is necessary to apply the symptomatic supporting treatment in intensive care unit, to carry out monitoring of functions of heart, correction of electrolytic frustration.

Special recommendations. At development of arterial hypotension intravenous administration of dopamine or Dobutaminum is shown; at development of disturbances of a heart rhythm to select treatment individually; at development of spasms - administration of benzodiazepines (for example, diazepam) or other anticonvulsants, for example, phenobarbital (with care, in connection with the increased risk of development of respiratory depression) or paraldehyde; at development of a hyponatremia (cultivation intoxication) - restriction of administration of liquid, slow, careful intravenous infusion of 0,9% of solution of sodium of chloride. These measures can be useful to the prevention of wet brain.

Carrying out hemosorption on coal sorbents is recommended. It was reported about inefficiency of an artificial diuresis, hemodialysis and peritoneal dialysis.

It is necessary to provide a possibility of repeated strengthening of symptoms of overdose for the 2nd and 3rd day after its beginning that is caused by the slowed-down drug absorption.

Storage conditions:

To store in original packaging at a temperature below 25 °C.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in the blister; on 1 or 5 blisters in a pack cardboard.