Карбалепсин® ретард

General characteristics. Structure:

Active ingredient: 200 mg or 400 mg carbamazepine.

Excipients: carbomer, cellulose microcrystallic, silicon dioxide colloid (aerosil), magnesium stearate, sodium carboxymethylstarch (примогель).

Pharmacological properties:

Pharmacodynamics. The antiepileptic means derivative of dibenzazepine rendering also normotimichesky, antipsychotic and analgetic action. Activates the central brake GAMK-ergichesky system. Blocks potentsialzavisimy natrium channels of membranes of nervous cells that leads to functional stabilization of neurons, reduces activity of exciting neuromediator acids (a glutamate, aspartame), interacts with the central adenosine receptors (adenylatecyclase activation suppression). Raises a convulsive threshold, reduces risk of development of an epileptic attack. It is possible to appoint both as the main therapeutic means, and in combination with other anticonvulsant drugs.

Adjusts epileptic changes of the personality, leads to increase in skill to communicate of patients and their social rehabilitation. At an essential epileptiform neuralgia prevents emergence of paroxysmal pains. At an alcoholic abstinence syndrome raises a reduced convulsive threshold and, thus, reduces development of a convulsive attack, also reduces expressiveness of clinical manifestations of a syndrome (a hyperexcitability, a tremor, affective frustration). At not diabetes mellitus reduces a diuresis and feeling of thirst (due to antidiuretic effect).

Pharmacokinetics. Adsorption is slow, but rather full (meal significantly does not influence the speed and extent of absorption). After a single dose the maximum concentration (is 25% less, than after reception of a usual tablet) is reached within 24 h. Equilibrium concentration of drug in plasma are reached in 1-2 weeks (speed of achievement depends on specific features of metabolism: an autoinduktion of fermental systems of a liver, heteroinduction by others, at the same time applied, medicines, and also from a condition of the patient, a dose of drug and duration of treatment). The Retardny form allows to reduce daily fluctuations of plasma level of drug. Essential interindividual distinctions of values of equilibrium concentration in the therapeutic range are observed: at most of patients of value from 4 to 12 mkg/ml fluctuate. Communication with proteins of plasma children — 55-59%, at adults have 70-80%. The seeming distribution volume — 0,8-1,9 l/kg. Gets through a placental barrier. Concentration in breast milk makes 25-60% of that in plasma. It is metabolized in a liver with the participation of P450 cytochrome (CYP 3A4), it is preferential on an epoxy way with formation of the main metabolites: active — carbamazepine-10,11-epoxide and an inactive conjugate with glucuronic acid.

Can induce own metabolism. Concentration of carbamazepine-10,11-epoxide makes 30% of concentration of carbamazepine. The elimination half-life after reception of a single peroral dose makes 25-65 h (on average about 36 h), after repeated reception depending on treatment duration — 8-29 h (owing to an autoinduktion of monooksigenazny system of a liver). It is removed in the form of inactive metabolites with urine (70%) and a stake (30%). At children, owing to more bystry elimination of carbamazepine, use of higher doses of drug at the rate on body weight kg can be required. There are no data testimonial of the fact that the pharmacokinetics of carbamazepine changes at patients of advanced age.

Indications to use:

• Epilepsy (excepting absentias epileptica, myoclonic or sluggish attacks) — partial attacks with difficult and simple symptomatology, initially and for the second time generalized forms of attacks with tonikoklonichesky spasms, the mixed forms of attacks (monotherapy or in combination with other anticonvulsant drugs).
• An idiopathic epileptiform neuralgia, an epileptiform neuralgia at multiple sclerosis (typical and atypical), idiopathic neuralgia of a glossopharyngeal nerve.
• Acute maniacal states (monotherapy and in combination with lithium drugs, etc. antipsychotic drugs).
• Alcoholic abstinence syndrome (uneasiness, spasms, hyper excitability, sleep disorders).
• Faznoprotekayushchy affective frustration (maniac-depressive psychosis, schizoaffective disorders, etc.): prevention of aggravations, weakening of clinical manifestations at an aggravation.
• Diabetic neuropathy with a pain syndrome, not diabetes mellitus of the central genesis. Polyuria and polydipsia of the neurohormonal nature.

Route of administration and doses:

Inside, irrespective of meal, with a small amount of liquid.

Epilepsy: When it is possible, it is necessary to appoint carbamazepine in the form of monotherapy. Treatment is begun with use of a small daily dose which in the subsequent is slowly raised to achievement of optimum effect.

Accession of carbamazepine to already carried out antiepileptic therapy should be carried out gradually, at the same time doses of the used drugs do not change or, if necessary, korrigirut.

For adults the initial dose makes 100-200 mg 1-2 times a day. Then the dose is slowly raised, to achievement of optimum medical effect (as much as possible — 800-1200 mg/days).

At children 4 years — in initial to a dose of 100 mg/days are more senior, doses raise gradually — every week on 100 mg. Maintenance doses: for 4-5 years — 200-400 mg (in 1-2 receptions), 6-10 years — 400-600 mg in 2-3 receptions), 11-15 years — 600-1000 mg (in 2-3 receptions).

Epileptiform neuralgia: in the first day appoint 200-400 mg/days, gradually increase no more than on 200 mg/days up to the termination of pains (on average 400-800 mg/days), and then reduce to a minimal effective dose. Appoint it is long, sharp drug withdrawal can lead to resuming of pains.

Alcoholic abstinence syndrome: an average dose — 200 mg 3 times a day; in hard cases during the first several days it is possible to raise a dose to 400 mg 3 times a day. In an initiation of treatment at the heavy phenomena of abstinence it is recommended to appoint in combination with sedative and somnolent drugs (клометиазол, chlordiazepoxide).

Not diabetes mellitus: an average dose for adults — 200 mg 2-3 times a day. At children of doses it has to be reduced according to age and body weight of the child.

Pain syndrome of neurogenic genesis: an initial dose — 100 mg 2 times a day in the first day, then a dose increase no more than on 200 mg/days, if necessary raising it on 100 mg each 12 h to easing of pains. A maintenance dose — 200-1200 mg/days in stages. At treatment of patients of advanced age and patients with hypersensitivity an initial dose — 100 mg 2 times a day.

The diabetic neuropathy which is followed by pains: an average dose — 200 mg 2-4 times a day.

Prevention of a recurrence of affective and schizoaffective psychoses: 600 mg/days in 3-4 receptions.

Acute maniacal states and affective (bipolar) frustration: daily doses — 400-1600 mg. An average daily dose — 400-600 mg (in 2-3 receptions). At an acute maniacal state the dose is raised quickly, at a maintenance therapy affective frustration — gradually (for portability improvement).

Features of use:

Monotherapy of epilepsy is begun with purpose of small doses, individually raising them to achievement of desirable therapeutic effect. It is reasonable to define concentration in plasma for the purpose of selection of an optimum dose, in particular at a combination therapy.

At transfer of the patient into carbamazepine it is necessary to reduce gradually a dose of earlier appointed antiepileptic means up to its full cancellation. The sudden termination of reception of carbamazepine can provoke epileptic attacks. If it is necessary to interrupt sharply treatment, it is necessary to transfer the patient to other antiepileptic means under cover of the drug shown in such cases (for example, the diazepam entered intravenously or rektalno or Phenytoinum entered intravenously).

Before purpose of carbamazepine and in the course of treatment the research of function of a liver, especially at patients in whose anamnesis there are data on liver diseases, and also for patients of advanced age is necessary. In case of strengthening of already available abnormal liver functions or at emergence of an active disease of a liver, drug should be cancelled immediately.

Also before an initiation of treatment it is necessary to conduct a research of a picture of blood, iron level in blood serum, urea level in blood, definition of concentration of electrolytes in blood serum, an electroencephalography, the general analysis of urine. Afterwards these indicators should be controlled within the first month of treatment weekly, and then - monthly. Before an initiation of treatment it is recommended to conduct ophthalmologic examination, including a research of an eyeground and measurement in need of intraocular pressure.

Carbamazepine has to be immediately cancelled at the emergence of reactions of hypersensitivity or symptoms presumably testimonial of development of a syndrome of Stephens-Johnson or a Lyell's disease. Poorly expressed skin reactions (the isolated macular or makulopapulezny dieback) usually take place within several days or weeks even at continuation of treatment or after a drug dose decline (the patient has to be under fixed observation of the doctor at this time). Not progressing symptomless leukopenia does not demand cancellation, however, treatment should be stopped at emergence of the progressing leukopenia or the leukopenia which is followed by clinical symptoms of an infectious disease. It is necessary to take into account a possibility of activation latentno of the proceeding psychoses, and patients of advanced age have a possibility of development of a disorientation or excitement.

Carbamazepine can negatively affect reliability of oral contraceptive drugs therefore women of reproductive age during treatment should apply alternative methods of protection from pregnancy.

Carbamazepine has to be applied only under medical observation. It is necessary to inform patients information on the precursory symptoms of toxicity inherent to probable hematologic disturbances, and also on symptoms from integuments and a liver. It is necessary to see immediately a doctor in case of such undesirable reactions as: fever, pharyngalgias, rash, an ulceration of a mucous oral cavity, causeless developing of bruises, hemorrhages in the form of petechias or a purpura. In case of purpose of drug patients with increase in intraocular pressure need constant control of this indicator.

During treatment it is necessary to abstain from occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

It is recommended to refuse alcohol intake.

Use at pregnancy and in the period of a lactation. At women of reproductive age carbamazepine has to be applied, whenever possible, in the form of monotherapy (using minimum effective dose) — the frequency of congenital anomalies of the newborns born by women to whom the combined antiepileptic treatment, above, than at those who received each of these means in the form of monotherapy was carried out. At approach of pregnancy it is necessary to compare carefully expected advantages of therapy and its possible complications, especially in the first trimester.

Antiepileptic means increase the deficit of folic acid which is often observed during pregnancy therefore during pregnancy additional reception of folic acid is recommended. 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.

Carbamazepine gets into breast milk, it is necessary to compare advantages and possible undesirable effects of breastfeeding in the conditions of the continuing therapy. Mothers accepting carbamazepine can nurse the children provided that for the child observation concerning development of possible side reactions will be established (for example, the expressed drowsiness, skin allergic reactions).

Side effects:

Development of side reactions is observed, as a rule, in an initiation of treatment and can be a consequence of relative overdose of drug or considerable fluctuations of concentration of active agent in a blood plasma. Dozozavisimy side reactions usually take place within several days as it is spontaneous, and after a temporary dose decline of drug. Most often, especially at the beginning of therapy are observed: dizziness, drowsiness, disturbance of the movement, nausea and vomiting.

Also in practice of use of carbamazepine other side reactions are registered:
- from the central nervous system: headache, ataxy, general weakness, accommodation paresis, nystagmus, orofatsialny dyskinesia, choreoathetoid frustration, peripheral neuritis, paresthesias, paresis;
- from the mental sphere: hallucinations (visual or acoustical), a depression, a loss of appetite, concern, an agressive behavior, excitement, a disorientation, in exceptional cases — activation of psychosis;
- allergic reactions: a small tortoiseshell, an erythrosis, a lupoid and similar syndrome, an itch, a multiformny exudative erythema (including Stephens-Johnson's syndrome), a scalded skin syndrome, photosensitivity, multiorgan reactions of hypersensitivity of the slowed-down type with fever, skin rashes, a vasculitis (including a knotty erythema as manifestation of a skin vasculitis), the lymphadenopathy, signs reminding a lymphoma, arthralgias, a leukopenia, an eosinophilia, a gepatosplenomegaliya and the changed indicators of function of a liver (the specified manifestations meet in various combinations), can be also involved, etc. bodies (for example, lungs, kidneys, a pancreas, a myocardium, a large intestine); aseptic meningitis with a myoclonus and a peripheral eosinophilia, anaphylactoid reaction, a Quincke's disease, an allergic pneumonitis or eosinophilic pneumonia.
- from bodies of a hemopoiesis: a leukopenia, thrombocytopenia, an eosinophilia, a leukocytosis, a limfoadenopatiya, deficit of folic acid, an agranulocytosis, aplastic anemia, a true erythrocyte aplasia, megaloblastny anemia, the acute "alternating" porphyria, a reticulocytosis, hemolitic anemia;
- from the alimentary system: dryness in a mouth, diarrhea or a lock, abdominal pains, a glossitis, stomatitis, pancreatitis;
- from a liver: clinically not significant increase in activity gamma глутамилтрансферазы, alkaline phosphatase and "hepatic" transaminases; hepatitis cholestatic, the parenchymatous (hepatocellular) or mixed type, jaundice, granulematozny hepatitis, a liver failure;
- from cardiovascular system: disturbances of endocardiac conductivity, decrease or increase in the ABP, bradycardia, arrhythmias, an atrioventricular block with faints, a collapse, aggravation or development of chronic heart failure, an exacerbation of coronary heart disease (including emergence or increase of attacks of stenocardia), thrombophlebitis, a thromboembolic syndrome;
- from endocrine system and exchange of substance: hypostases, a liquid delay, increase in body weight, a hyponatremia (decrease in osmolarity of plasma owing to the effect similar to effect of antidiuretic hormone that in rare instances leads to the hyponatremia of cultivation which is followed by a lethargy, vomiting, a headache, a disorientation and neurologic disturbances), increase in level of prolactin (can be followed by a galactorrhoea and a gynecomastia); decrease in level of L-thyroxine (free T4, T4, T3) and increase in level of thyritropic hormone (usually is not followed by clinical manifestations); disturbances of calcium-phosphorus exchange in a bone tissue (decrease in concentration of calcium ions and 25-ON-kolekaltsiferola in a blood plasma): osteomalacy, a hypercholesterolemia (including cholesterol and lipoproteins of high density), a gipertriglitseridemiya;
- from molepolovy system: intersticial nephrite, a renal failure, a renal failure (for example, an albuminuria, a hamaturia, an oliguria, increase an urea/azotemia), the speeded-up urination, an ischuria, decrease in a potentiality;
- from a musculoskeletal system: arthralgia, mialgiya, spasms;
- from sense bodys: disturbances of flavoring feelings, cataract, conjunctivitis, hearing disorder, including sonitus, hyperacusia, gipoakuziya, changes of perception of height of a sound;
- others: disturbances of a xanthopathy, purple, acne, perspiration, alopecia.

Interaction with other medicines:

Carbamazepine increases activity of microsomal enzymes of a liver and can reduce effect of the separate drugs which are metabolized in a liver (peroral anticoagulants, etc.).

P4503A4 cytochrome (CYP 3A4) is the main enzyme providing carbamazepine metabolism. Co-administration of carbamazepine with CYP 3A4 inhibitors can lead to increase in its concentration in a blood plasma and cause side reactions. Combined use of the inductors CYP 3A4 can lead to carbamazepine metabolism acceleration, decrease in concentration of carbamazepine in a blood plasma and to reduction of therapeutic effect, on the contrary, their cancellation can reduce the speed of biotransformation of carbamazepine and lead to increase in its concentration.

Increase concentration of carbamazepine in plasma: verapamil, diltiazem, фелодипин, dextropropoxyphene, вилоксазин, fluoxetine, флувоксамин, Cimetidinum, acetazoleamide, даназол, desipramine, niacinamide (at adults, only in high doses); macroleads (erythromycin, джозамицин, кларитромицин, тролеандомицин); azoles (итраконазол, кетоконазол, флуконазол), терфенадин, лоратадин, the isoniazid, the propoxyhair dryer, grapefruit juice, inhibitors of virus protease used at therapy of HIV infection (for example, ритонавир) - is required correction of the mode of dosing or monitoring of concentration of carbamazepine in plasma.

Concentration of carbamazepine is reduced by phenobarbital, Phenytoinum, Primidonum, метсуксимид, фенсуксимид, theophylline, rifampicin, Cisplatinum, doxorubicine, it is possible: clonazepam, вальпромид, valproic acid, окскарбазепин and the vegetable drugs containing a St. John's Wort made a hole (Hypericum perforatum). There are messages on a possibility of replacement by valproic acid and Primidonum of carbamazepine from communication with proteins of plasma and increase in concentration pharmacological of an active metabolite (carbamazepine-10,11-epoxide). Felbamat reduces concentration of carbamazepine in plasma and increases concentration of carbamazepine-10,11-epoxide, at the same time perhaps simultaneous decrease in concentration in serum of a felbamat.

Izotretinoin changes bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide (monitoring of concentration of carbamazepine in plasma is necessary).

Carbamazepine can reduce concentration in plasma (to reduce or even completely to level effects) and to demand correction of doses of the following drugs: klobazama, clonazepam, an Ethosuximidum, Primidonum, valproic acid, an alprazolam, GKS (Prednisolonum, dexamethasone), cyclosporine, doxycycline, a haloperidol, methadone, peroral drugs containing estrogen and/or progesterone (selection of alternative methods of contraception), theophylline, peroral anticoagulants (warfarin, a fenprokumon, a dikumarol), a lamotridzhina, a topiramata, tricyclic antidepressants (Imipraminum, amitriptyline, a nortriptilin, a klomipramin), clozapine, a felbamat, a tiagabin, an okskarbazepin, inhibitors of the proteases applied at therapy of HIV infection (an indinavir, a ritonavir, a sakvinovir), blockers of slow calcium channels (group of digidropiridon, for example, фелодипин is necessary), an itrakonazola, left thyroxine, midazolam, an olazapin, a prazikvantel, a risperidon, a tramadol, a tsiprazidon.
There are messages that against the background of carbamazepine reception Phenytoinum level in a blood plasma can both increase, and to decrease, and the level of Mephenytoinum to increase (in rare instances).

Carbamazepine at combined use with paracetamol increases risk of its toxic influence on a liver and reduces a therapeutic effectiveness (paracetamol metabolism acceleration).

Co-administration of carbamazepine with fenotiaziny, Pimozidum, thioxanthenes, molindony, a haloperidol, Maprotilinum, clozapine and tricyclic antidepressants leads to strengthening of the oppressing action on the central nervous system and to easing of anticonvulsant effect of carbamazepine.

MAO inhibitors increase risk of development of hyperpyrexial crises, hypertensive crises, spasms, death (before purpose of carbamazepine MAO inhibitors have to be cancelled, at least, for 2 weeks or if the clinical situation, even for bigger term allows).

Co-administration with diuretics (Hydrochlorthiazidum, furosemide) can lead to the hyponatremia which is followed by clinical manifestations.

Carbamazepine weakens effects of not depolarizing muscle relaxants (pankuroniya). In case of use of such combination there can be a need of increase in a dose of muscle relaxants, at the same time it is necessary to carry out attentive observation of patients as perhaps more bystry termination of their action.

Reduces portability of ethanol.

Accelerates metabolism of indirect anticoagulants, hormonal contraceptive drugs, folic acid; prazikvantet, can strengthen elimination of hormones of a thyroid gland.

Accelerates metabolism of anesthetics (an enfluran, a halothane, Ftorotanum) with increase in risk of gepatotoksichny effects; strengthens formation of nefrotoksichny metabolites of a metoksifluran.

Strengthens a hepatotoxic action of an isoniazid.

Contraindications:

Hypersensitivity to carbamazepine or similar medicines in the chemical relation (for example, to tricyclic antidepressants) or to any other component of drug, the acute alternating porphyria (including in the anamnesis), an atrioventricular block, a concomitant use of monoamine oxidase inhibitors (MAO), disturbances of a marrowy hemopoiesis (anemia, a leukopenia), children's age (up to 4 years).

With care: a cultivation hyponatremia (a syndrome of hypersecretion of antidiuretic hormone, a hypopituitarism, a hypothyroidism, insufficiency of bark of adrenal glands), oppression of a marrowy hemopoiesis against the background of reception of medicines (in the anamnesis), a prostate hyperplasia, increase in intraocular pressure, heavy heart failure, a liver failure, a chronic renal failure.

Overdose:

Symptoms:

- from the central nervous system and sense bodys: oppression of functions of the central nervous system, disorientation, drowsiness, excitement, hallucinations, sight misting, muffled speech, dysarthtia, nystagmus, ataxy, dyskinesia, hyperreflexia (in the beginning), hyporeflexia (later), spasms, myoclonus, hypothermia, mydriasis, coma;
- from cardiovascular system: tachycardia, decrease in the ABP, sometimes increase in the ABP, disturbance of intra ventricular conductivity with expansion of the QRS complex; faints, cardiac standstill;
- from respiratory system: respiratory depression, fluid lungs;
- from digestive tract: nausea, vomiting, a delay of evacuation of food from a stomach, decrease in motility of a large intestine;
from an urinary system: ischuria, oliguria or anury; liquid delay, cultivation hyponatremia;
- laboratory and tool data: the leukocytosis or a leukopenia, a hyponatremia, is possible a metabolic acidosis, the hyperglycemia and a glucosuria, increase in muscular fraction of a kreatinifosfokinaza is possible.

Treatment: The specific antidote is absent. Treatment is based on a clinical condition of the patient; hospitalization, definition of concentration of carbamazepine in plasma, evacuation of contents of a stomach, a gastric lavage, purpose of absorbent carbon is shown (late evacuation of gastric contents can lead to the delayed absorption for 2 both 3 days and to repeated emergence of symptoms of intoxication during recovery).

Are inefficient: an artificial diuresis, a hemodialysis and peritoneal dialysis (dialysis is shown at a combination of a serious poisoning and renal failure). Small children can have a need for exchange hemotransfusion. The symptomatic supporting treatment in intensive care unit, monitoring of functions of heart, body temperature, corneal reflexes, functions of kidneys and a bladder, correction of electrolytic frustration. Carrying out hemosorption on coal filters is recommended.

Storage conditions:

List B. In dry, protected from light and the place, unavailable to children, at a temperature not over 25 to the °sena to use drug after a period of validity. A period of validity - 2 years.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets with a dosage of 200 mg or on 6 tablets with a dosage of 400 mg in a blister strip packaging. On 10, 20, 30, 50 or 100 tablets in bank of orange glass or in bank from polypropylene or polyethylene. Each can or on 1, 2, 3, 5 or 10 blister strip packagings together with the application instruction is placed in a pack from a cardboard.