Carbamazepine

General characteristics. Structure:

Active ingredient: 200 mg of carbamazepine.

Excipients: potato starch, silicon dioxide colloid (aerosil), talc, magnesium stearate, povidone (polyvinylpirrolidone), polysorbate (twin-80).

The anticonvulsant applied at epilepsy. Has the expressed anticonvulsant effect, positively influences a condition of patients with epilepsy. It is also capable to have moderate antidepressive effect, to stabilize mood at patients with various mental disorders, being including psychotropic drug. Has moderate anti-maniacal effect.

At appointment as the patient with epilepsy allows not only to cope with an attack, but also reduces probability of emergence and intensity of new attacks. At the same time – also eliminates feeling of alarm, fear of society, irritability and aggression.

Raises a convulsive threshold in cases if it is lower than norm. Eliminates or reduces pains at neuralgia. And also prevents development of painful attacks. It can be used also for anesthesia after injuries.

At alcoholics in hard cases of a condition of a hangover carbamazepine reduces manifestations of neurologic and mental character, eliminates reexcitement, a lack of coordination of movements, trembling of extremities.

Reducing education and release of urine, carbamazepine helps a sick not diabetes mellitus, reducing feeling of thirst and normalizing a water balance.

Carbamazepine can be appointed as the main medicine, and to be combined with other anticonvulsant and anesthetics.

Pharmacological properties:

Pharmacodynamics. Carbamazepine is derivative dipetrolazepine and possesses antiepileptic, neurotropic, psychotropic and antidiuretic action.

As antiepileptic means, stabilizes membranes of the overexcited neurons, suppresses serial categories of neurons and reduces synoptic transfer of exciting impulses. This action is reached, presumably, due to blockade of natrium channels therefore repeated emergence in the depolarized neurons sodium - dependent action potentials is prevented. Reduces release of a neurotransmitter of a glutamate. Psychotropic effect of carbamazepine, apparently, is caused by oppression of exchange of dopamine and noradrenaline.

Reduces the frequency of attacks, alarm, a depression, irritability and aggression at patients with epilepsy. Influence on cognitive functions at patients with epilepsy is variable. Prevents emergence of paroxysmal pains at neuralgia. At a syndrome of alcoholic abstinence raises a threshold of convulsive readiness, reduces the increased nervous irritability, a tremor, gait disturbances. It is used for treatment of affective frustration as antipsychotic and normotimichesky means. At not diabetes mellitus reduces a diuresis and feeling of thirst.

Pharmacokinetics. Absorption - slow, but rather full (meal significantly does not influence the speed and extent of absorption). After a single dose, the maximum concentration in plasma krovidostigatsya in 12 hours. Equilibrium concentration of drug in plasma are reached in 1-2 weeks. Among patients essential individual distinctions of value of equilibrium concentration in the therapeutic range are observed. Communication with proteins of a blood plasma makes 70 – 80%. Concentration of not changed carbamazepine in cerebrospinal fluid and saliva is proportional to amount of active agent, untied with proteins (20 – 30%). Concentration in breast milk makes 25 – 60% of that in plasma. Gets through a placental barrier.

It is metabolized in a liver, it is preferential on an epoxy way with formation of metabolites: active - carbamazepine-10,11-epoxide and low-active - 9-hydroxy-methyl-10 карбамоилакридан. The main isoenzyme providing carbamazepine biotransformation in carbamazepine-10,11-epoxide is the isoenzyme of P450 3A4 cytochrome. Content of carbamazepine-10,11-epoxide makes about 30% of carbamazepine level in plasma. Biotransformation of carbamazepine-10,11-epoxide in a carbamazepine-10,11-transdiol occurs by means of microsomal enzyme hydrolase epoxide. Other way of metabolism of carbamazepine – formation of various monohydroxylated derivatives, and also N-glucuronides. The elimination half-life after one-time reception averages about 36 hours (from 25 to 65 hours fluctuate), after repeated reception - 16-24 h. At the patients receiving in addition other antiepileptic drugs inducing liver enzymes, on average 9-10 h. It is removed preferential in the form of inactive metabolites with urine (about 70%) and a stake (about 30%). About 2% are removed with urine in the form of not changed carbamazepine and 1% in the form of carbamazepine-10,11-epoxide.

At children owing to more bystry removal of carbamazepine use of higher doses of drug at the rate on kilogram of body weight in comparison with adults can be required.

There are no data that the pharmacokinetics of carbamazepine changes at patients of advanced age. Patients with renal failures or a liver have no data on carbamazepine pharmacokinetics.

Indications to use:

• Epilepsy (monotherapy or as a part of complex therapy):
  - difficult and simple partial attacks (with loss or without loss of consciousness) with secondary generalization or without it;

  - generalized toniko-clonic attacks. The mixed forms of epileptic seizures.

• Acute maniacal states and a maintenance therapy of bipolar affective disorders for the purpose of prevention of aggravations or decrease in expressiveness of clinical manifestations.
• In complex therapy of a syndrome of alcoholic abstinence.
• An epileptiform neuralgia (idiopathic, at multiple sclerosis), idiopathic neuralgia of a glossopharyngeal nerve.
• A pain syndrome at diabetic neuropathy.
• A polyuria and a polydipsia of the neurohormonal nature at not diabetes mellitus.

Route of administration and doses:

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

Epilepsy: whenever possible, it is necessary to appoint carbamazepine in the form of monotherapy. Treatment is begun with 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.

For adults an initial dose of 100-200 mg 1-2 times a day. Then the dose is slowly raised to 400 mg by 2-3 times a day. Maximum daily dose of 2000 mg.

For children under 5 years an initial dose of 20-60 mg a day with increase on 20-60 mg each two days. At children from 5 years the initial dose makes 100 mg/day, with the subsequent increase on 100 mg a week. The maintenance dose for children makes 10-20 mg/kg of body weight a day for 2-3 receptions. For ensuring exact dosing, at children up to 5 years, it is necessary to use liquid peroral dosage forms of carbamazepine.

Neuralgia of trigeminal or glossopalatine nerves: an initial dose of 200-400 mg/day, then the dose is gradually raised no more than on 200 mg a day up to the termination of pains (on average, to 600 - 800 mg), then reduced to a minimal effective dose. At treatment of patients of advanced age an initial dose of 100 mg 2 times a day.

Alcoholic abstinence syndrome: an average dose - 200 mg 3 times a day. In hard cases, in the first days, a dose it is possible to raise to 400 mg 3 times a day. In an initiation of treatment at the heavy phenomena of abstinence it is appointed in combination with disintoxication therapy, sedative and somnolent drugs.

Polyuria and polydipsia at not diabetes mellitus: an average dose for adults - 200 mg 2 – 3 times a day. At children the dose is selected taking into account the body weight and age.

Pain syndrome at diabetic neuropathy: 200 mg 2 – 4 times a day.

Acute maniacal states and maintenance therapy of bipolar affective disorders: a daily dose of 400-1600 mg (an average daily dose of 200-600 mg) for 2-3 receptions a day. In acute cases the dose is raised quickly enough. At a maintenance therapy increase in a dose has to be gradual and small.

Features of use:

Before an initiation of treatment, and also periodically in the course of treatment it is necessary to carry out clinical blood tests (including calculation of number of thrombocytes, reticulocytes, and also concentration of iron in blood serum), the general analyses of urine and determination of level of urea to blood. Drug has weak anticholinergic activity. Therefore in case of use of drug for patients with the increased intraocular pressure constant control of this indicator is necessary.

Periodic definition of concentration of carbamazepine in a blood plasma in cases of increase in frequency of emergence of epileptic attacks is recommended, at treatment of children, at pregnant women, in case of its use as a part of complex therapy, development of the expressed side effects.

There are separate messages on disturbances of male fertility and/or disturbances of a spermatogenesis. However the causal interrelation of these disturbances with administration of drug is so far not proved.

Cross-reactions of hypersensitivity can arise between carbamazepine and Phenytoinum or okskarbazepiny.

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.

For the period of therapy it is necessary to refuse alcohol intake as carbamazepine strengthens the oppressing effect of alcohol on the central nervous system.

Side effects:

Disturbances from a nervous system: dizziness, ataxy, drowsiness, feeling of fatigue, headache, diplopia, accommodation disturbances, tremor, muscular dystonia, tics, nystagmus, orofatsialny dyskinesia, oculomotor disturbances, dysarthtia, choreoathetoid frustration, peripheral neuropathy, paresthesias, paresis, taste disturbances, malignant antipsychotic syndrome.

Disturbances from mentality: hallucinations (visual or acoustical), depression, anorexia, concern, agressive behavior, agitation, disorientation, strengthening of psychosis.

From skin and its appendages: allergic dermatitis, small tortoiseshell, exfoliative dermatitis, erythrosis, system lupus erythematosus, itch, Stephens-Johnson's syndrome, toxic epidermal necrolysis, reactions of a photosensitization, multiformny and knotty erythema, disturbances of a xanthopathy, purple, acne, perspiration, hair loss. It was reported about exceptional cases of a hirsutism, however the causal interrelation of this complication with administration of drug remains not clear.

From system of a hemopoiesis: a leukopenia, thrombocytopenia, an eosinophilia, a leukocytosis, a limfoadenopatiya, deficit of folic acid, an agranulocytosis, aplastic anemia, a pancytopenia, anemia, a true erythrocyte aplasia, megaloblastny anemia, a variyegatny porphyria, a late skin porphyria, the acute alternating porphyria, a reticulocytosis, hemolitic anemia.

From gepatobiliarny system: increase in indicators of gamma glutaminetransferase, alkaline phosphatase, transaminases; hepatitis (cholestatic, the parenchymatous (hepatocellular) or mixed type), jaundice, granulematozny hepatitis, a liver failure.

From digestive tract: nausea, vomiting, dryness in a mouth, diarrhea, a lock, abdominal pains, a glossitis, stomatitis, pancreatitis.

Hypersensitivity reactions: multiorgan hypersensitivity of the slowed-down type with fever, skin rashes, a vasculitis, limfoadenopatiya, arthralgia, leukopenia, an eosinophilia, a gepatosplenomegaliya and the changed indicators of function of a liver (the specified manifestations meet in various combinations). Also other bodies (lungs, kidneys, a pancreas, a myocardium, a large intestine) can be involved. Aseptic meningitis with a myoclonus and an eosinophilia; anaphylactic reaction, Quincke's disease.

From cardiovascular system: disturbances of endocardiac conductivity; decrease or increase in arterial pressure, bradycardia, arrhythmia, an atrioventricular block with faints, a collapse, congestive heart failure, deterioration in a course of coronary heart disease, thrombophlebitis, a thrombembolia.

From endocrine system and a metabolism: hypostases, a liquid delay, increase in body weight, a hyponatremia and decrease in osmolarity of plasma owing to the effect similar to effect of antidiuretic hormone that in rare instances leads to water intoxication (a cultivation hyponatremia) which is followed by a lethargy, vomiting, a headache, a disorientation and neurologic disturbances; the increase in level of prolactin which is followed or not followed by a galactorrhoea, a gynecomastia; decrease in concentration of triiodothyronine and thyroxine, increase in concentration of thyritropic hormone that usually is not followed by clinical manifestations; disturbances of metabolism of a bone tissue (decrease in concentration of calcium and a 25-gidroksikolekaltsiferol in a blood plasma) that leads to osteomalacy; increase in concentration of cholesterol, including cholesterol of lipoproteids of high density and triglycerides.

From urinogenital system: intersticial nephrite, a renal failure, an albuminuria, a hamaturia, an oliguria, an azotemia, the speeded-up urination, an ischuria, disorders of sexual function, disturbance of a spermatogenesis.

From sense bodys: disturbances of flavoring feelings, phacoscotasmus, increase in intraocular pressure, conjunctivitis; disorders of hearing.

From a skeletal and muscular sistemy:artralgiya, muscular pains, muscular weakness, spasms.

From respiratory system: the hypersensitivity reactions which are characterized by fever, short wind, a pneumonitis or pneumonia.

Change of results of laboratory researches: hypogammaglobulinemia.

Interaction with other medicines:

Simultaneous use with inhibitors of an isoenzyme CYP3A4 can lead to increase in concentration of carbamazepine in plasma. Combined use of inductors of an isoenzyme of CYP3A4 can lead to acceleration of metabolism of carbamazepine and to possible decrease in its concentration in plasma. Cancellation of at the same time accepted inductors of an isoenzyme CYP3A4 can reduce the speed of biotransformation of carbamazepine and lead to increase in level of carbamazepine in a blood plasma. At simultaneous use with the drugs which are metabolized CYP3A4 isoenzyme induction of metabolism and decrease in their concentration in plasma is possible.

Drugs which can increase concentration of carbamazepine or carbamazepine-10,11-epoxide in plasma: dextropropoxyphene, an ibuprofen, даназол, makrolidny antibiotics (for example, erythromycin, тролеандомицин, джозамицин, кларитромицин), fluoxetine, флувоксамин, нефазодон, пароксетин, Trazodonum, вилоксазин, стирипентол, вигабатрин, azoles (for example, итраконазол, кетоконазол, флуконазол, вориконазол), лоратадин, терфенадин, локсапин, olanzapine, кветиапин, an isoniazid, inhibitors of virus protease for therapy of HIV infection (for example, ритонавир), acetazoleamide, verapamil, diltiazem, омепразол, оксибутинин, дантролен, тиклопидин, niacinamide (at adults, only in high doses), it is possible – Cimetidinum, desipramine, Primidonum, valproic acid.

Drugs which can reduce concentration of carbamazepine in plasma: фелбамат, метсуксимид, окскарбазепин, phenobarbital, фенсуксимид, Phenytoinum, фосфенитоин, Primidonum, прогабид, theophylline, Aminophyllinum, изотретиноин, rifampicin, Cisplatinum, doxorubicine; the vegetable drugs containing the St. John's Wort which is made a hole and though data are contradictory, perhaps also clonazepam, valproic acid or вальпромид.

Influence of carbamazepine on concentration in plasma of the drugs used as the accompanying therapy: Carbamazepine can reduce concentration in plasma or reduce or even completely to level effects of the following drugs: methadone, paracetamol, antipyrine, трамадол, doxycycline, peroral anticoagulants (warfarin, фенпрокумон, дикумарол, аценокумарол), бупропион, to tsitalopra, Trazodonum, tricyclic antidepressants (Imipraminum, amitriptyline, нортриптилин, кломипрамин), to klobaza, clonazepam, an Ethosuximidum, фелбамат, ламотриджин, окскарбазепин, Primidonum, тиагабин, топирамат, valproic acid, зонизамид, итраконазол, a praziquantel, иматиниб, clozapine, a haloperidol, бромперидол, olanzapine, кветиапин, рисперидон, зипрасидон, applied at therapy of HIV infection (индинавир, ритонавир, саквинавир), to alprazola; midazolam, theophylline, blockers of calcium channels of group of dihydropyridines (for example, фелодипин), digoxin, peroral contraceptive means (selection of alternative methods of contraception), glucocorticosteroids (for example, Prednisolonum, dexamethasone is necessary); cyclosporine, эверолимус, sodium left thyroxine, estrogen and/or progesterone. 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 rare instances).

Combinations which should be taken into account: Strengthening of the hepatotoxic caused by an isoniazid in case of simultaneous use with carbamazepine is possible.

In case of joint appointment with levetiratsetamy, strengthening of toxic effect of carbamazepine is possible.

The combined use of carbamazepine and lithium or Metoclopramidum, and also carbamazepine and neuroleptics (haloperidol, thioridazine) can lead to increase in frequency of undesirable neurologic reactions (in case of the last combination - even at therapeutic concentration of active agents in a blood plasma).

Simultaneous use of carbamazepine with some diuretic means (a hydrochlorothiazide, furosemide) can lead to the hyponatremia which is followed by clinical manifestations.

Carbamazepine can show antagonism to action of not depolarizing muscle relaxants (for example, a pankuroniya bromide). 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 carry out attentive observation of patients as perhaps more bystry, than was expected, cancellation of muscle relaxants.

Joint reception with grapefruit juice can increase carbamazepine level in plasma.

Contraindications:

· Hypersensitivity to any of components of drug or similar medicines (tricyclic antidepressants) in the chemical relation,

· atrioventricular block,

· oppression of a marrowy hemopoiesis in the anamnesis,

· hepatic porphyrias,

· a concomitant use of monoamine oxidase inhibitors (further MAO inhibitors) and within 2 weeks after their cancellation,

· breastfeeding period.

With care to apply at: low level of leukocytes or thrombocytes; the mixed forms of the epileptic attacks including an absentia epileptica; at advanced age; at a heart, liver or renal failure; the increased intraocular pressure; cultivation hyponatremias; hypothyroidism; prostate hyperplasia; pregnancies (the increased risk of development of disturbances of pre-natal development, including malformations).

Overdose:

Symptoms:

- central nervous system: oppression of functions of the central nervous system up to a coma, a disorientation, drowsiness, agitation, hallucinations, feeling of "fog" before eyes, a dysarthtia, a nystagmus, the ataxy, dyskinesia, a hyperreflexia which is replaced with a hyporeflexia, spasms, psychomotor frustration, a myoclonus a hypothermia, a mydriasis;

- respiratory system: respiratory depression, fluid lungs;

- cardiovascular system: tachycardia, decrease or increase in arterial pressure, disturbance of conductivity of heart with expansion of the QRS complex, a cardiac standstill;

- alimentary system: vomiting, a delay of evacuation of food from a stomach, decrease in motility of a large intestine;

- urinary system: ischuria, oliguria or anury, liquid delay, cultivation hyponatremia;

- laboratory indicators: metabolic acidosis, hyperglycemia, increase in muscular fraction of a kreatinfosfokinaza, hyponatremia.

Treatment: the specific antidote is absent. A gastric lavage, purpose of absorbent carbon (late evacuation of gastric contents can lead to the delayed absorption for 2-3 days and to repeated emergence of symptoms of intoxication), hospitalization, symptomatic therapy. The artificial diuresis, a hemodialysis and peritoneal dialysis are inefficient (dialysis is shown at a combination of a serious poisoning and renal failure). Carrying out hemosorption on coal sorbents is recommended.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in a blister strip packaging. On 1,2,3,4 or 5 blister strip packagings with the application instruction in a pack cardboard.

On 500, 600, 1000, 1200 tablets in bank polymeric (for hospitals). To bank together with the application instruction in a pack from a cardboard.