Carbamazepine retard-Akrihin - instructions for use, dose, side effects, contraindications

Excipients: carbomer 65 mg, microcrystalline cellulose 374.65 mg, silicon dioxide colloid 3.2 mg, magnesium stearate 6.5 mg, carboxymethyl starch sodium 0.65 mg.

1 tablet 400 mg contains:

active substance: carbamazepine in terms of 100% substance 400 mg;

Excipients: Carbomer 110 mg, microcrystalline cellulose 572.4 mg, silicon dioxide colloid 5.5 mg, magnesium stearate 11 mg, carboxymethyl starch sodium 1.1 mg.

Description:

Tablets are white or white with a grayish or creamy hue of color and the presence of white impregnations. Tablets with a dosage of 200 mg are planocylindrical, with a facet and a risk. Tablets with a dosage of 400 mg of oval form, biconvex.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.F.01 Carbamazepine

Pharmacodynamics:

Antiepileptic agent, a derivative of dibenzazepine.Along with antiepileptic, the drug also has neurotropic and psychotropic effects.

The mechanism of action of carbamazepine is currently only partially explained. Carbamazepine stabilizes membranes of overexcited neurons, suppresses serial discharges of neurons and reduces the synaptic transmission of exciting impulses. Probably, the main mechanism of action of carbamazepine is the prevention of repeated occurrence in the depolarized neurons of sodium-dependent action potentials due to blockade of open voltage-dependent sodium channels.

When used as a monotherapy in patients with epilepsy (especially in children and adolescents), the psychotropic effect of the drug was noted, which included a positive effect on anxiety and depression symptoms, as well as a decrease in irritability and aggression. There is no unambiguous data on the effect of the drug on cognitive and psychomotor functions: in some studies, a double or negative effect was shown that depended on the dose of the drug, in other studies, the positive effect of the drug on attention and memory was revealed.

how neurotropic The preparation is effective for a number of neurological diseases. So, for example, with idiopathic and secondary neuralgia of the trigeminal nerve, he prevents the occurrence of paroxysmal pain attacks.

With the alcohol withdrawal syndrome, the drug raises the threshold of convulsive readiness, which in this condition is usually reduced, and reduces the severity of clinical manifestations of the syndrome, such as increased excitability, tremor, gait disturbance.

In patients with diabetes insipidus, the drug reduces diuresis and thirst.

how psychotropic the drug is effective in affective disorders, namely, in the treatment of acute manic conditions, with the supportive treatment of bipolar affective (manic-depressive) disorders (either as monotherapy or in combination with antipsychotics, antidepressants or lithium preparations), in schizoaffective psychosis, with manic attacks, where it is used in combination with neuroleptics, as well as with manic-depressive psychosis with fast cycles.

The ability of the drug to suppress manic manifestations can be due tooppression of dopamine and norepinephrine.

Pharmacokinetics:

Absorption

After oral administration carbamazepine Absorbed almost completely, absorption is relatively slow (eating does not significantly affect the speed and degree of absorption). After oral administration (single or repeated) of prolonged action tablets, the maximum concentration in the blood plasma (C_max) is reached within 24 hours, its value is approximately 25% less than in the case of a conventional tablet. When taking prolonged-action tablets, the carbamazepine concentration in plasma is significantly less, and there is no significant decrease in the minimum value of equilibrium concentration. When taking the drug in the form of long-acting tablets 2 times a day, the fluctuations in the concentration of the active substance in the plasma are very small. Bioavailability of the active substance from the long-acting tablets is approximately 15% lower than that of other carbamazepine dosage forms for oral administration.

Equilibrium concentrations of carbamazepine in plasma are achieved after 1-2 weeks.The time to achieve individual and depends on the degree of auto-induction of liver enzyme systems carbamazepine, geteroinduktsii other simultaneously applicable medicaments as well as the patient's condition to the purpose of therapy, the dose and duration of treatment. There are substantial interindividual differences equilibrium concentrations in the therapeutic range of values: in most patients, these values range from 4 to 12 micrograms / ml (17-50 micromol / L).

RAssignment

Binding to blood plasma proteins in children is 55-59%, in adults 70-80%. The apparent volume of distribution is 0.8-1.9 l / kg. In the cerebrospinal fluid and saliva, concentrations proportional to the amount of the active substance unbound with proteins (20-30%) are created. Penetrates through the placental barrier. Concentration in breast milk is 25-60% of that in plasma.

Given the complete absorption of carbamazepine, the apparent volume of distribution is 0.8-1.9 l / kg.

Metabolism

Carbamazepine is metabolized in the liver. The main pathway of biotransformation is the epoxyldiol route, as a result of which the main metabolites are formed: 10,11 -transdiol derivative and its conjugate with glucuronic acid.The transformation of carbamazepine-10,11-epoxide into carbamazepine-10,11-trans-diol in the human body takes place using a microsomal enzyme of epoxide hydrolase.

The concentration of carbamazepine-10,11-epoxide (pharmacologically active metabolite) is about 30% of the concentration of carbamazepine in plasma.

The main isoenzyme, providing biotransformation of carbamazepine in carbamazepine-10,11-epoxide, is cytochrome P450 ZA4. As a result of these metabolic reactions, a small amount of another metabolite, 9-hydroxymethyl-10-carbamoylacridan, is also formed.

Another important way of carbamazepine metabolism is formation under the influence of isoenzyme UGT2B7 different monohydroxylated derivatives, and N-glucuronides.

Excretion

The half-life of unchanged carbamazepine after a single oral intake is an average of 36 hours, and after repeated administration of the drug - an average of 16-24 hours, depending on the duration of treatment (due to autoinduction enzyme systems of the liver). In patients taking concurrently other drugs that induce liver enzymes (for example, phenytoin, phenobarbital), the half-life of carbamazepine averages 9-10 hours. After taking 400 mg of carbamazepine once inside, 72% of the accepted dose is excreted by the kidneys and 28% by the intestine; while about 2% of the dose taken is excreted by the kidneys in the form of unchanged carbamazepine, about 1% - in the form of a pharmacologically active 10,11-epoxide metabolite. After a single oral intake, 30% of carbamazepine is excreted in the urine in the form of the end products of the epoxidiol pathway of metabolism.

Peculiarities of pharmacokinetics in individual patient groups

Children, due to faster elimination of carbamazepine, may require the use of higher doses of the drug per kilogram of body weight, compared with adults.

Data showing that the pharmacokinetics of carbamazepine varies in elderly patients (compared to older adults) is not. Data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function have not been reported to date.

Indications:

Epilepsy:

- complex or simple partial epileptic seizures (with or without loss of consciousness) with secondary generalization or without it;

- generalized tonic-clonic epileptic seizures;

- Mixed forms of epileptic seizures.

Carbamazepine, as a rule, is not effective in absences and myoclonus-epilepsy.

Acute manic conditions and maintenance therapy of bipolar affective disorders with the aim of preventing exacerbations or alleviating clinical manifestations of exacerbation.

Alcohol withdrawal syndrome.

Idiopathic neuralgia of the trigeminal nerve and trigeminal neuralgia in multiple sclerosis (typical and atypical).

Idiopathic neuralgia of the glossopharyngeal nerve.

Contraindications:

- Hypersensitivity to carbamazepine and other components of the drug, as well as to tricyclic antidepressants;

- disorders of bone marrow hematopoiesis (anemia, leukopenia);

- hepatic porphyria (for example, acute intermittent porphyria, late cutaneous porphyria, variegate porphyria);

- atrioventricular block;

- simultaneous administration of lithium preparations and monoamine oxidase inhibitors (MAO);

- Children's age up to 4 years.

Carefully:

Decompensated chronic heart failure;

- hyponatremia of dilution (ADH hypersecretion syndrome, hypopituitarism, hypothyroidism, insufficiency of the adrenal cortex);

- Insufficiency of liver and kidney function;

- elderly age;

- oppression of bone marrow hemopoiesis against the background of medication (in history);

- hyperplasia of the prostate;

- increased intraocular pressure;

- mixed forms of epileptic seizures, including absences, typical or atypical, and myoclonic seizures (taking into account the possible increase in seizures).

Pregnancy and lactation:

To women of reproductive age carbamazepine if possible, it is administered as a monotherapy in a minimally effective dose, since the incidence of congenital anomalies in newborns from mothers taking combined antiepileptic treatment is higher than in monotherapy. Depending on the drugs that make up the combination therapy, the risk of congenital malformations may increase, especially when added to the therapy of valproate.

Carbamazepine quickly penetrates the placenta and creates an increased concentration in the liver and kidneys of the fetus. It is recommended to regularly monitor the concentration of active substance in the blood plasma, conduct EEG.

At the onset of pregnancy, the expected benefit of therapy and possible complications should be compared, especially in the first trimester of pregnancy.

It is known that children of mothers with epilepsy are predisposed to violations of intrauterine development, including developmental defects. Carbamazepine can increase the risk of these violations. There are isolated reports of cases of congenital diseases and malformations, including non-vertebral arches (spina bifida) and other congenital anomalies: defects in the development of craniofacial structures, cardiovascular and other organ systems, hypospadias.

According to the North American Pregnancy Registry, the frequency of gross developmental malformations related to structural abnormalities requiring surgical, pharmacological or cosmetic correction diagnosed within 12 weeks after birth was 3.0% among pregnant women taking the first trimester carbamazepine as a monotherapy, and 1.1% among pregnant women who did not take any antiepileptic drugs.

Treatment with drug Carbamazepine retard-acrychin pregnant women with epilepsy should be carried out with extreme caution. You should use the drug Carbamazepine retard-Akrihin in the minimum effective dose.It is recommended to regularly monitor the concentration of active substance in the blood plasma. In the case of effective anticonvulsant control, a minimum concentration of carbamazepine in the blood plasma should be maintained in a pregnant woman (therapeutic range 4-12 μg / ml), since there are reports of the possibility of dose-dependence of the risk of congenital malformations (eg, mg per day was lower than with higher doses).

Patients should be informed about the possibility of increasing the risk of developmental malformations and the need, in connection with this, for antenatal diagnosis.

During pregnancy, effective antiepileptic treatment should not be interrupted, as the progression of the disease can have a negative effect on the mother and on the fetus.

Antiepileptic drugs increase the deficiency of folic acid, often observed during pregnancy, which can contribute to an increase in the frequency of birth defects in children, so folic acid intake is recommended before the planned pregnancy and during pregnancy.In order to prevent hemorrhagic complications in newborns, women in the last weeks of pregnancy, as well as newborns are recommended to prescribe vitamin K.

Several cases of epileptic seizures and / or respiratory depression in newborns whose mothers were taken concomitantly with other anticonvulsants have been described. In addition, several cases of emesis, diarrhea, and / or hypotrophy in newborns, whose mothers were receiving carbamazepine. Perhaps these reactions are manifestations in newborn withdrawal syndrome. Carbamazepine penetrates into breast milk, the concentration in it is 25-60% of the concentration in the blood plasma, therefore, one should compare the benefits and possible undesirable consequences of breastfeeding in conditions of continuing therapy. With the continuation of breastfeeding on the background of taking the drug should be established observation of the child due to the possibility of developing adverse reactions (eg, pronounced drowsiness, allergic skin reactions). In children who received carbamazepine antenatal or with breast milk, cases of cholestatic hepatitis are described, and therefore monitoring of such children should be carried out in order to diagnose side effects from the hepato-biliary system.

Patients of childbearing age should be warned about a decrease in the effectiveness of oral contraceptives when used with carbamazepine.

Dosing and Administration:

Inside, during or after a meal, with plenty of liquid.

For ease of use, the tablet (as well as its half or quarter) can be pre-dissolved in water or in juice, since the prolonged release of the active ingredient after dissolution of the tablet in the liquid is maintained. The range of doses used is 400-1200 mg per day, which is divided into 1-2 doses per day. The maximum daily dose should not exceed 1600 mg.

Given the drug interaction with other drugs and the pharmacokinetics features of antiepileptic drugs, elderly patients should receive their dose with caution.

Epilepsy

Wherever possible, Carbamazepine retard-acrichine should be administered as a monotherapy. Treatment begins with the application of a small daily dose, which is then slowly increased until an optimal effect is achieved.

To determine the optimal dose of the drug, it is recommended to determine the concentration of the active substance in the blood plasma. In the treatment of epilepsy, a dose of carbamazepine is required, corresponding to a total carbamazepine concentration in the blood plasma at a level of 4-12 μg / ml (17-50 μmol / L).

Accession of the drug Carbamazepine retard-Akrihin to already conducted antiepileptic therapy should be carried out gradually, while the doses of the drugs used do not change or, if necessary, correct. If the patient forgot to take the next dose of the drug in a timely manner, you should take the missed dose as soon as this omission became noticed, while you can not take a double dose of the drug.

Adults. Initial dose - 200-400 mg per day, then the dose is gradually increased to achieve the optimal effect. Supportive dose - 800-1200 mg per day, which is divided into 1-2 doses per day.

Children. Initial dose for children from 4 to 15 years - 200 mg per day, then gradually increase the dose by 100 mg per day until the optimal effect is achieved.

Maintenance doses for children 4-10 years - 400-600 mg per day (in 2 divided doses); for children 11-15 years -600-1000 mg per day (in 2 divided doses).

The following dosing schedule is recommended:

Adults: initial dose - 200-300 mg in the evening, maintenance dose - 200-600 mg in the morning, 400-600 mg in the evening.

Children from 4 to 10 years: initial dose - 200 mg in the evening, maintenance dose - 200 mg in the morning, 200-400 mg in the evening; children from 11 to 15 years: initial dose - on 200 mg in the evening, maintenance dose - 200-400 mg in the morning, 400-600 mg in the evening.

Children from 15 to 18 years old: dosing regimen 800-1200 mg / day, maximum daily dose - 1200 mg / day.

The duration of application depends on the indication and individual response of the patient to treatment. The decision to transfer the patient to Carbamazepine retard-Akrikhin, the duration of its use and the cancellation of treatment is taken by the doctor individually. The possibility of reducing the dose of the drug or discontinuing treatment is considered after a 2-3-year period of complete absence of seizures.

Treatment is stopped, gradually reducing the dose of the drug for 1-2 years, under the control of the EEG. Children with a decrease in the daily dose of the drug should take into account the increase in body weight with age.

Neuralgia of the trigeminal nerve, idiopathic neuralgia of the glossopharyngeal nerve

The initial dose is 200-400 mg per day, which is divided into 2 doses.The initial dose is increased until the pain disappears completely, on average, to 400-800 mg per day. After this, in a certain part of patients, treatment can be continued with a lower maintenance dose of 400 mg.

The maximum recommended dose is 1200 mg / day, with the achievement of clinical improvement, you should gradually reduce the dose of the drug before the onset of the next pain attack.

The elderly patient and the patient, sensitive to carbamazepine, Carbamazepine retard-Akrihin is prescribed in an initial dose of 100 mg twice a day, then the dose is slowly increased until the pain syndrome is resolved, which is usually achieved with a dose of 200 mg 3-4 times a day. Then gradually reduce the dose to the minimum maintenance.

With trigeminal neuralgia in this category of patients, the maximum recommended dose is 1200 mg / day. When resolving the pain syndrome, you should gradually stop therapy with the drug before the next pain attack occurs.

Treatment of alcohol abstinence in a hospital

The average daily dose is 600 mg (200 mg in the morning and 400 mg in the evening).In severe cases, in the early days, the dose can be increased to 1200 mg per day, which is divided into 2 divided doses. If necessary Carbamazepine retard-Akrihin can be combined with other substances used to treat alcohol withdrawal, except for sedatives and hypnotics. During the treatment, the content of carbamazepine in the blood plasma must be regularly monitored. In connection with the possible development of side effects from the central and autonomic nervous system, patients are carefully monitored in a hospital.

Acute manic conditions and maintenance treatment of affective (bipolar) disorders

The daily dose is 400-1600 mg. The average daily dose is 400-600 mg (in 2-3 doses). In acute manic state, the dose should be increased rather quickly. With maintenance therapy for bipolar disorders, in order to ensure optimal tolerability, each next dose increase should be small, the daily dose increases gradually.

Discontinuation of the drug

A sudden discontinuation of the drug may trigger epileptic seizures.If it is necessary to cancel the drug in a patient with epilepsy, the transition to another antiepileptic agent should be done under the cover of the drug shown in such cases (for example, diazepam administered intravenously or rectally or phenytoin administered intravenously).

Side effects:

Certain types of unwanted reactions, for example, from the central nervous system (dizziness, headache, ataxia, drowsiness, fatigue, diplopia), from the digestive system (nausea, vomiting), as well as allergic skin reactions, occur very often or often, especially at the beginning of treatment with the drug, or with an excessively high initial dose of the drug or in the treatment of elderly patients.

Dose-dependent adverse reactions usually occur within a few days, both spontaneously and after a temporary dose reduction. The development of adverse reactions from the central nervous system may be due to a relative overdose of the drug or significant fluctuations in the concentration of the active substance in the blood plasma.In such cases it is recommended to monitor the concentration of active substance in the blood plasma.

When assessing the incidence of various adverse reactions, the following grades were used: very often 10% or more, often 1-10%, sometimes 0.1-1%, rarely 0.01-1.1%, very rarely less 0.01%.

The development of adverse reactions from the central nervous system may be due to a relative overdose of the drug or significant fluctuations in the concentration of carbamazepine in the blood plasma.

From the central nervous system: often - dizziness, ataxia, drowsiness, general weakness, headache, paresis of accommodation; sometimes - abnormal involuntary movements (eg, tremor, "fluttering" tremor - asterixis, dystonia, tics); nystagmus; rarely hallucinations (visual or auditory), depression, loss of appetite, anxiety, aggressive behavior, psychomotor agitation, disorientation, psychosis activation, orofacial dyskinesia, oculomotor disorders, speech disorders (eg, dysarthria or slurred speech), choreoathetoid disorders, peripheral neuritis, paresthesia, muscle weakness and symptoms of paresis; very rarely - taste disorders, malignant neuroleptic syndrome, dysgeusia.

Allergic reactions: very often - allergic dermatitis; often - hives; sometimes exfoliative dermatitis, erythroderma, multiorgan hypersensitivity reactions of delayed type with fever, skin rashes, vasculitis (including erythema nodosum, manifestation of cutaneous vasculitis), lymphadenopathy, signs resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered indicators of liver function (these manifestations occur in various combinations). Other organs (for example, lungs, kidneys, pancreas, myocardium, large intestine), aseptic meningitis with myoclonus and peripheral eosinophilia, anaphylactoid reaction, angioedema, allergic pneumonitis, or eosinophilic pneumonia may also be involved. If the above-mentioned allergic reactions occur, the drug should be discontinued, rarely - lupus-like syndrome, skin itching, exudative erythema multiforme (including Stevens-Johnson syndrome), erythema nodosum, toxic epidermal necrolysis (Lyell's syndrome), photosensitivity.

On the part of the organs of hematopoiesis: often - leukopenia, thrombocytopenia, eosinophilia; rarely - leukocytosis, lymphadenopathy, folic acid deficiency, agranulocytosis, aplastic anemia, true erythrocyte aplasia, megaloblastic anemia, acute "intermittent" porphyria, reticulocytosis, hemolytic anemia, splenomegaly; very rarely - pancytopenia, late cutaneous porphyria, variegate porphyria.

From the digestive system: often - nausea, vomiting, dry mouth, increased activity of gamma-glutamyltransferase (due to the induction of this enzyme in the liver), which usually has no clinical significance, increased activity of alkaline phosphatase; sometimes - higherwactivity of "hepatic" transaminases, diarrhea or constipation, abdominal pain; rarely glossitis, gingivitis, stomatitis, pancreatitis, hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, jaundice, granulomatous hepatitis, hepatic insufficiency, destruction of intrahepatic bile ducts with a decrease in their number.

From the side of the cardiovascular system: rarely - violations of intracardiac conduction, a decrease or increase in blood pressure, bradycardia, arrhythmias,atrioventricular blockade with syncope, collapse, aggravation or development of chronic heart failure, exacerbation of coronary heart disease (including the appearance or increasing episodes of angina pectoris), thrombophlebitis, thromboembolic syndrome.

From the endocrine system and metabolism: often - swelling, fluid retention, weight gain, hyponatremia (decreased plasma osmolarity due to an effect similar to that of an antidiuretic hormone, which in rare cases leads to hyponatremia of the dilution, accompanied by lethargy, vomiting, headache, disorientation and neurologic disorders); rarely - an increase in the concentration of prolactin (may be accompanied by galactorrhea and gynecomastia); decrease in concentration L-tiroxine and increasing the concentration of thyroid-stimulating hormone (usually not accompanied by clinical manifestations); disturbance of calcium-phosphorus metabolism in bone tissue (decrease in calcium concentration and 25-OH-cholecalciferol in blood plasma): osteomalacia, osteoporosis, hypercholesterolemia (including high-density lipoprotein cholesterol), hypertriglyceridemia and enlarged lymph nodes, hirsutism.

From the genitourinary system: rarely interstitial nephritis, renal insufficiency, renal dysfunction (eg, albuminuria, hematuria, oliguria, urea / azotemia increase), frequent urination, urinary retention, decreased potency, impaired spermatogenesis (decreased sperm count and motility).

From the side of the musculoskeletal system: very often - fatigue, rarely - muscle weakness, arthralgia, myalgia or convulsions.

From the sense organs: often - disruption of accommodation (including blurred vision), rarely - a violation of taste, increased intraocular pressure, clouding of the lens, conjunctivitis; hearing impairment, and so on. noise in the ears, hyperacusia, hypoacusia, changes in perception of the height of sound.

Disturbances from the respiratory system, chest and mediastinal organs: very rarely - hypersensitivity reactions characterized by fever, dyspnea, pneumonitis, or pneumonia.

Laboratory and instrumental data: very rarely - hypogammaglobulinemia.

Other: disorders of skin pigmentation, purpura, acne, sweating, alopecia.

Undesirable phenomena according to postmarketing observations (frequency unknown)

Immune system disorders: drug rash with eosinophilia and systemic manifestations.

Disturbances from the skin and subcutaneous tissues: acute generalized eczematous pustulosis, lichenoid keratosis, onychomadesis.

Infectious and parasitic diseases: reactivation of the herpes simplex virus type 6. Violations of the blood and lymphatic system: bone marrow failure.

Disturbances from the nervous system: memory impairment.

Disorders from the gastrointestinal tract: colitis.

Disturbances from musculoskeletal and connective tissue: fractures.

Overdose:

Symptoms usually reflect violations of the central nervous system, cardiovascular and respiratory system.

Central nervous system and sense organs: oppression of central nervous system functions, impaired consciousness, disorientation, drowsiness, agitation, hallucinations, coma, blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (at first), hyporeflexia (later), convulsions, psychomotor disorders, myoclonus, hypothermia, mydriasis).

The cardiovascular system: tachycardia, lowering blood pressure, sometimes increasing blood pressure, violations of intraventricular conduction with expansion of the complex QRS; fainting, cardiac arrest.

Respiratory system: respiratory depression, pulmonary edema.

Digestive system: nausea and vomiting, delayed evacuation of food from the stomach, decreased motility of the colon.

urinary system: urinary retention, oliguria or anuria; fluid retention, hyponatremia.

Musculoskeletal system: there are reports of rhabdomyolysis associated with the use of carbamazepine.

Laboratory indicators: leukocytosis or leukopenia, hyponatremia, metabolic acidosis is possible, hyperglycemia and glucosuria are possible, muscle fraction of creatine phosphokinase is increased.

Treatment: there is no specific antidote. It requires symptomatic supportive treatment in the intensive care unit, monitoring of heart function, body temperature, corneal reflexes, kidney and bladder function, correction of electrolyte disorders. It is necessary to determine the concentration of carbamazepine in the plasma to confirm poisoning with this drug and assess the degree of overdose, gastric lavage, the appointment of activated charcoal.

With a decrease in blood pressure, IV administration of dopamine or dobutamine is indicated; when heart rhythm disturbances develop, treatment is selected individually; with the development of seizures - the introduction of benzodiazepines, for example, diazepam or other anticonvulsants, such as phenobarbital (with caution due to increased respiratory depression); with the development of hyponatremia (water intoxication) - limiting the introduction of fluid and careful intravenous injection of 0.9% sodium chloride solution, which can help prevent the development of brain damage.

It is recommended to carry out hemosorption on carbon sorbents. Hemodialysis is an effective method of treatment with an overdose of carbamazepine.

Late evacuation of gastric contents can lead to delayed absorption on days 2 and 3 and the re-emergence of symptoms of intoxication during recovery.

Interaction:

Simultaneous administration of carbamazepine with inhibitors CYP3A4 can lead to an increase in its concentration in the blood plasma and the development of adverse reactions. Joint application of inducers CYP3A4 can lead to an acceleration of the metabolism of carbamazepine,reduce its concentration in the blood plasma and reduce the therapeutic effect; on the contrary, their cancellation can reduce the rate of biotransformation of carbamazepine and lead to an increase in its concentration.

Increase the concentration of carbamazepine in the blood plasma verapamil, diltiazem, felodipine, dextropropoxyphene, viloxazine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, olanzapine, cimetidine, omeprazole, acetazolamide, danazol, desipramine, nicotinamide (in adults, only in high doses); macrolides (erythromycin, josamycin, clarithromycin, troleandomycin); ciprofloxacin, styipentol, vigabatrin, azoles (itraconazole, ketoconazole, fluconazole, voriconazole), terfenadine, loratadine, isoniazid, propoxyphene, oxybutynin, dantrolene, ticlopidine, grapefruit juice, viral protease inhibitors used in the treatment of HIV infection (for example, ritonavir) - correction of the dosing regimen or monitoring of carbamazepine concentration in plasma is required.

Felbamate reduces the concentration of carbamazepine in plasma and increases the concentration of carbamazepine-10,11-epoxide, while a simultaneous decrease in serum felbamate concentration is possible.

Drugs that can increase the concentration of carbamazepine-10,11-epoxide in blood plasma: loxapine, quetiapine, primidon, progabide, valproic acid, valnoktamide and valpromid.

Since an increase in the concentration of carbamazepine-10,11-epoxide in blood plasma can lead to side reactions (for example, dizziness, drowsiness, ataxia, diplopia), in these situations, the dosage of the drug should be corrected and / or the carbamazepine concentration 10,11 -epoxide in the blood plasma.

The concentration of carbamazepine is reduced phenobarbital, phenytoin (in order to avoid intoxication with phenytoin and the appearance of subtherapeutic concentrations of carbamazepine, the recommended plasma concentration of phenytoin should be no more than 13 μg / ml before addition to carbamazepine therapy), phosphenytoin, primidon, metsuksimide, fensuksimid, theophylline, aminophylline, rifampicin, cisplatin, doxorubicin, perhaps: clonazepam, valpromid, valproic acid, oxcarbazepine and herbal preparations containing St. John's wort perfumed (Hypericum perforatum).

With simultaneous use with the above drugs, you may need to adjust the dose of carbamazepine.

It is possible to displace valproic acid, primidone carbamazepine and of its association with plasma proteins and enhance the concentration of a pharmacologically active metabolite (carbamazepine-10,11-epoxide). With the combined use of carbamazepine with valproic acid, in exceptional cases, coma and confusion may occur. Isotretinoin changes the bioavailability and / or clearance of carbamazepine and carbamazepine-10,11-epoxide (carbamazepine concentration in the plasma is monitored).

Carbamazepine can reduce concentration in plasma (reduce or even completely neutralize the effects) and require dose adjustments following drugs: klobazama, clonazepam, digoxin, ethosuximide, primidone, zonisamide, valproate, alprazolam, corticosteroids (prednisone, dexamethasone), cyclosporine, tetracyclines (doxycycline), bromperidol, methadone, oral preparations containing estrogens and / or progesterone (Requires selection of alternative methods of contraception), theophylline, oral anticoagulants (warfarin, phenprocoumon, dicumarol, acenocoumarol), lamotrigine, topiramate,tricyclic antidepressants (imipramine, amitriptyline, nortriptyline, clomipramine), bupropion, citalopram, mianserin, sertraline, clozapine, felbamate, tiagabine, oxcarbazepine, protease inhibitors used in HIV therapy (indinavir, ritonavir, saquinovir), drugs for treating cardiovascular diseases -sosudistoy system (blockers "slow" calcium channel blockers (dihydropyridines group, e.g., felodipine); simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine), itraconazole, levothyroxine, midazolam, olanzapine, ziprasidone, aripiprazole, paliperidone, praziquantel, risperidone, tramadol, ziprasidone, buprenorphine, phenazone, aprepitant, albendazole, imatinib, cyclophosphamide, lapatinib, everolimus, tacrolimus, sirolimus, tamsirolimus, tadalafil.

There is the possibility of increasing or reducing the level of phenytoin in the blood plasma against the background of carbamazepine and increasing the level of mephenytoin.

With simultaneous application of carbamazepine and lithium or metoclopramide formulations may increase the neurotoxic effect of both active substances.

Tetracyclines can weaken the therapeutic effect of carbamazepine.

When combined with paracetamol, the risk of its toxic effect on the liver increases and therapeutic effectiveness decreases (acceleration of the metabolism of paracetamol).

Simultaneous administration of carbamazepine with phenothiazine, pimozide, thioxanthenes, molindone, haloperidol, maprotiline, clozapine and tricyclic antidepressants leads to an intensifying inhibitory effect on the central nervous system and a weakening of the anticonvulsant effect of carbamazepine.

Monoamine oxidase inhibitors increase the risk of developing hyperpyretic crises, hypertensive crises, seizures, and death (prior to prescribing carbamazepine, monoamine oxidase inhibitors should be withdrawn at least 2 weeks or, if the clinical situation permits, even over a longer period).

Simultaneous administration with diuretics (hydrochlorothiazide, furosemide) can lead to hyponatremia, accompanied by clinical manifestations.

Weakens the effects of nondepolarizing muscle relaxants (pancuronium).If such a combination is used, it may be necessary to increase the dose of muscle relaxants, and careful monitoring of the patient's condition is necessary in connection with the possibility of a faster cessation of the muscle relaxants.

With the simultaneous use of carbamazepine along with levetiracetam, in some cases, the toxic effect of carbamazepine has been noted. Carbamazepine reduces the tolerance of ethanol.

Myelotoxic drugs increase manifestations of hematotoxicity of the drug.

Accelerates the metabolism of indirect anticoagulants, hormonal contraceptives, folic acid; prazikvantela, can enhance the elimination of thyroid hormones.

Accelerates the metabolism of drugs for anesthesia (enflurane, halothane, ftorotana) and increases the risk of hepatotoxic effects; enhances the formation of nephrotoxic metabolites of methoxyflurane. Enhances the hepatotoxic effect of isoniazid.

Interaction with serological reactions

Carbamazepine can lead to a false positive result of determining the concentration of perphenazine by high-performance liquid chromatography. Carbamazepine and 10,11-carbamazepine epoxide can lead to a false-positive result of the determination of the concentration of a tricyclic antidepressant by the method of polarization fluorescent immunoassay.

Special instructions:

Monotherapy for epilepsy begins with the appointment of a low initial dose, gradually increasing it to achieve the desired therapeutic effect.

When choosing the optimal dose, it is advisable to determine the concentration of carbamazepine in the blood plasma, especially when combined therapy. In some cases, the optimal dose may deviate significantly from the recommended initial and maintenance dose, for example, due to the induction of microsomal liver enzymes or due to interactions in combination therapy. Carbamazepine It should not be combined with sedative-hypnotic means. If necessary, it can be combined with other substances used to treat alcohol withdrawal. During the treatment, the content of carbamazepine in the blood plasma must be regularly monitored. In connection with the development of side effects from the central and autonomic nervous system, patients are carefully monitored in a hospital. When transferring a patient to carbamazepine should gradually reduce the dose of the previously prescribed antiepileptic agent until its complete cancellation. A sudden discontinuation of carbamazepine may provoke epileptic seizures.

If it is necessary to abruptly terminate treatment, the patient should be transferred to another antiepileptic agent under the cover of the drug shown in such cases (for example, diazepam administered intravenously or rectally, or phenytoin administered intravenously).

Several cases of vomiting, diarrhea, and / or hypotrophy, seizures and / or respiratory depression in newborns whose mothers have been taken carbamazepine concomitantly with other anticonvulsants (perhaps these reactions are manifestations in newborn withdrawal syndrome). Before the appointment of carbamazepine and in the process of treatment, it is necessary to study the liver function, especially in patients whose history includes information on liver diseases, as well as in elderly patients. In case of strengthening of already existing violations of the liver function or when there is an active liver disease the drug should be immediately canceled.Before starting treatment, it is necessary to conduct a blood test (including platelet count, reticulocyte count), serum iron level, total urine test, blood urea level, electroencephalogram, determination of serum electrolyte concentration (and periodically during treatment, t. possibly the development of hyponatremia). Subsequently, these indicators should be monitored during the first month of treatment on a weekly basis, and then on a monthly basis.

In most cases, a transient or persistent decrease in the number of platelets and / or leukocytes is not a harbinger of the onset of aplastic anemia or agranulocytosis. Nevertheless, before the start of treatment, and also periodically during the treatment, clinical blood tests should be performed, including counting the number of platelets and, possibly, reticulocytes, as well as determining the level of iron in the blood serum. Non-progressive asymptomatic leukopenia does not require withdrawal, however, treatment should be discontinued if progressive leukopenia or leukopenia occurs, accompanied by clinical symptoms of an infectious disease.

With the use of carbamazepine, very severe dermatological reactions were very rare, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome).

Carbamazepine should be immediately withdrawn when hypersensitivity reactions or symptoms, presumably indicative of the development of Stevens-Johnson syndrome or Lyell syndrome, appear.

With the development of severe (in some cases life-threatening patient) skin reactions, the patient must be hospitalized in a hospital. In most cases, Stevens-Johnson syndrome and Lyell's syndrome developed during the first months of therapy with the drug. These reactions developed in approximately 1-6 cases per 10,000 first-time drug users in countries with predominantly Caucasoid populations.

Retrospective analysis data from patients of Japanese nationality and inhabitants of Northern Europe demonstrated the relationship between severe skin lesions (Stevens-Johnson syndrome, Lyell syndrome, drug rash with eosinophilia and systemic manifestations, acute generalized exenthematous pustulosis and spotty-nasal rash) in the carriers of the allele HLA-A* 3101 gene of human leukocyte antigen (HLA) and the use of carbamazepine. Frequency of the allele HLA-A* 3101 gene of human leukocyte antigen (HLA) may differ for different ethnic groups: about 2-5 % the population of Europe, about 10% - from the Japanese. The allele frequency is less than 5% in the population of Australia, Asia, Africa and North America, exceptions range from 5% to 12%. The frequency of more than 15% is found in some ethnic groups of South America (Argentina and Brazil), indigenous peoples of North America (Navajo and Siocs, Sanora Seri in Mexico), South India (Tamil Nadu) and 10-15% among other indigenous people regions.

When prescribing carbamazepine, possible carriers of the allele EGLA-A* 3101 (for example, patients of Japanese nationality, Caucasians, Native Americans, Latinos, people of southern India and Arabs) are recommended to carry out genotyping on this allele.

Prescribe the drug carriers of this allele should be only if the benefit of therapy exceeds the possible risk.

Patients already receiving carbamazepine therapy are not recommended to carry out genotyping on this allele, since severe skin reactions in most cases were noted in the first months of the drug (regardless of the presence HLA-A*3101).

According to a retrospective analysis, the use of the drug in patients of Chinese and Thai nationalities has a correlation between the incidence of Stevens-Johnson syndrome and Lyell's syndrome and the presence of an allele in the patient's genome HLA-A* 1502 gene of human leukocyte antigen (HLA). The frequency of occurrence of this allele in patients of Chinese nationality is 2-12%, in Thai - about 8%. The use of carbamazepine in patients in countries of the Asian region (Taiwan, Malaysia, Philippines), where there is a high prevalence of the allele HLA-A* 1502, there was an increase in the incidence of development (from gradation "very rare" to "rarely") of Stevens-Johnson syndrome. Allele spreading frequency HLA-A* 1502 is: in the Philippines and among some groups of the population of Malaysia - more than 15%. Allele spreading frequency HLA-AM 502 in Korea and India is 2% and 6%, respectively. The prevalence of this allele in Caucasians, Negroid races, Latinos, Indians and Japanese is insignificant (<1%).

The frequencies of these alleles represent the percentage of chromosomes in certain population populations that carry the allele.This means that the percentage of patients carrying a copy of the allele in at least one of their two chromosomes is almost twice as high as the frequency of the allele. Thus, the percentage of patients who may be at risk is almost twice as likely to be alleles.

When using carbamazepine in possible carriers of the allele HLA-A* 1502 it is recommended to carry out genotyping on this allele. Use the drug in carriers of this allele should be only if the benefit of therapy exceeds the possible risk. It is not recommended to carry out genotyping in representatives of nationalities in which the frequency of occurrence of this allele is low.

Patients already receiving drug therapy Carbamazepine retard-Akrihin, it is not recommended to perform genotyping on this allele, since severe skin reactions in most cases were observed in the first months of the drug (regardless of the presence HLA-A*1502).

It was shown that the identification of patients with an allele HLA-A* 1502 and the absence of carbamazepine in such patients reduces the incidence of carbamazepine-induced Stevens-Johnson syndrome or Lyell's syndrome.

However, the results of genotyping should not affect the degree of control over the patient's condition and the doctor's caution regarding severe skin reactions. The development of severe skin lesions is possible in patients who are negative for these alleles. Also in many cases, patients who are positive for alleles HLA-A* 1502 or HLA- A * 3101, when the drug is used Carbamazepine retard-Akrihin, there was no development of severe skin syndromes.

The influence of other factors, such as the dose of anticonvulsant drugs, patient compliance, simultaneous therapy with other drugs, concomitant diseases or the level of control over dermatological reactions, the incidence and prevalence of severe skin reactions has not been established.

Slightly expressed skin reactions (isolated macular or maculopapular exanthema) usually pass for several days or weeks, even with continued treatment or after a decrease in the dose of the drug (the patient at this time should be under close medical supervision).

There is a correlation between the presence of an allele in the genome HLA-A* 3101 and the development of less severe skin reactions (such as a hypersensitivity syndrome to anticonvulsants or a mildly muculopapular exanthema), for an allele HLA-B* 1502 this relationship is not established.

It should take into account the possibility of activation of latent psychoses, and in elderly patients - the possibility of development of disorientation or psychomotor agitation.

With the development of hypersensitivity to carbamazepine, patients may have separate lesions of the skin, liver (including damage to the intrahepatic bile ducts) of the circulatory and lymphatic systems or other organs, and their combination, which should be considered as a systemic reaction. In the case of development of symptoms and symptoms of hypersensitivity to carbamazepine, the drug should be immediately discontinued.

Patients with known hypersensitivity to carbamazepine should be informed about the possibility of 25-30% of cases of development of hypersensitivity reactions to oxcarbazepine.

Cross-reacting hypersensitivity, is also found between carbamazepine and phenytoin.

There are male fertility disorders and / or disorders of spermatogenesis, but the relationship between these disorders with carbamazepine has not been established. There may be intermenstrual bleeding with the simultaneous use of oral contraceptives. Carbamazepine can adversely affect the reliability of oral contraceptives, so women of reproductive age should be treated with alternative methods of protection during pregnancy. Carbamazepine should be used only under medical supervision. It is necessary to inform patients about the early signs of toxicity, as well as the symptoms of the skin and liver. The patient is informed of the need to immediately consult a doctor if there are undesirable reactions such as fever, sore throat, rash, ulceration of the oral mucosa, unjustified bruising, hemorrhage in the form of petechiae or purpura.

Before the beginning of treatment it is recommended to conduct an ophthalmological examination, including examination of the fundus and measurement of intraocular pressure.In the case of prescribing, patients with increased intraocular pressure require constant monitoring of this indicator.

Patients with severe cardiovascular diseases, liver and kidney damage, as well as elderly people are prescribed lower doses of the drug. Although the relationship between the dose of carbamazepine, its concentration and clinical efficacy or tolerability is very low, nevertheless, regular determination of the level of carbamazepine can be useful in the following situations: with a sharp increase in the frequency of seizures; to check whether the patient is taking the drug properly; during pregnancy; when treating children or adolescents; with suspected drug absorption abnormalities; if there is a suspicion of the development of toxic reactions in the event that the patient takes several medicines. During treatment with the drug Carbamazepine retard-Akrihin is recommended to refrain from drinking alcohol.

In some cases, treatment with antiepileptic drugs was accompanied by the appearance of suicidal intentions.This was also confirmed by a meta-analysis of randomized clinical trials using antiepileptic drugs. As the mechanism of occurrence of suicidal attempts at use of antiepileptic preparations is not known, it is impossible to exclude their occurrence and at treatment of patients with a preparation Carbamazepine retard-Akrihin. Patients (and attendants) should be warned about the need to monitor the occurrence of suicidal ideation / suicidal behavior, and immediately seek medical help if symptoms occur.

Effect on the ability to drive transp. cf. and fur:

The ability of the patient taking the drug to respond quickly, especially at the beginning of therapy or during the dose selection period, can be compromised due to both the disease itself (eg seizures) and the occurrence of side effects such as dizziness and drowsiness, ataxia, diplopia, violation of accommodation and visual impairment. During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets with prolonged action of 200 mg and 400 mg.

Packaging:

For 10 tablets with a dosage of 200 mg in a planar cell package.

For 50 tablets with a dosage of 400 mg in a can of polypropylene (polyethylene).

Each bank or 5 contour mesh packages together with instructions for use in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:P N003829 / 01

Date of registration:10.12.2009 / 09.01.2017

Expiration Date:Unlimited

The owner of the registration certificate:AKRIKHIN HFK, JSC AKRIKHIN HFK, JSC Russia

Manufacturer: & nbsp

AKRIKHIN HFK, JSC Russia

Representation: & nbspAKRIKHIN OJSC AKRIKHIN OJSC Russia

Information update date: & nbsp08.12.2017

Illustrated instructions

Instructions

Carbamazepine retard-Akrihin (Carbamazepine retard-Akrichin)