Tegretol CR - instructions for use, dose, side effects, contraindications

core: cellulose microcrystalline 30.0 mg, 60.0 mg; carmellose sodium 25.0 mg, 50.0 mg; polyacrylate dispersion 30% 15.0 mg, 30.0 mg; ethylcellulose aqueous dispersion 10.0 mg, 20.0 mg; talc 10.0 mg, 20.0 mg; silicon dioxide colloidal anhydrous 3.5 mg, 7.0 mg; magnesium stearate 1.5 mg, 3.0 mg;

shell: hypromellose 4.71 mg, 9.43 mg; talc 4.19 mg, 8.37 mg; titanium dioxide 0.66 mg, 1.32 mg; castor oil (macrogol glycerylricinoleate) 0.22 mg, 0.44 mg; iron oxide red 0.02 mg, 0.13 mg; iron oxide yellow 0.20 mg, 0.31 mg.

Description:

Tablets of prolonged action coated with 200 mg: brick-orange, oval, slightly biconvex tablets, coated, with a risk on each side. On one side is marked "N / C" on the other - "CG".

Tablets of the prolonged action covered with a cover 400 mg: brownish orange, oval, slightly biconvex tablets, coated, with a risk on each side.On one side is marked "ENE/ENE" another - "CG/CG".

Pharmacotherapeutic group:antiepileptic agent

ATX: & nbsp

N.03.A.F.01 Carbamazepine

Pharmacodynamics:

Carbamazepine, the active substance of the preparation Tegretol® CR, is a derivative of dibenzoazepine. 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 the re-emergence in the depolarized neurons of sodium-dependent potentials of action due to blockade of open potential-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 aggressiveness.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 neurotrophic agent the drug is effective in 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 is usually reduced in this condition, and reduces the severity of clinical manifestations of the syndrome, such as increased excitability, tremor, violation of gait.

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

how psychotropic drug 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 (both as monotherapy and in combination with neuroleptic drugs,antidepressants or lithium preparations), with attacks of schizoaffective psychosis, with manic attacks, where it is used in combination with neuroleptics, as well as with manic-depressive psychosis with fast cycles. Although a decrease in the release of glutamate and stabilization of the neuronal membrane can explain the antiepileptic effect, the ability of the drug to suppress manic manifestations may be due to the inhibition of the metabolism of dopamine and norepinephrine.

Pharmacokinetics:

Suction

After oral administration carbamazepine absorbed almost completely, when taking a tablet form, absorption is relatively slow.

After oral administration (single or repeated) of long-acting C_max is reached within 24 hours, its value is approximately 25% less than in the case of taking 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 ingredient from long-acting tablets is approximately 15% lower than that of other oral dosage forms.

The intake of food does not significantly affect the speed and degree of absorption of carbamazepine.

Equilibrium concentrations of carbamazepine in plasma are achieved within 1-2 weeks. The time of its achievement is individual and depends on the degree of autoinduction of the enzyme systems of the liver carbamazepine, heteroinduction of other, concurrently used drugs, as well as on the condition of the patient prior to the appointment of therapy, the dose of the drug and the duration of treatment. There are significant interindividual differences in the values of equilibrium concentrations in the therapeutic range: in most patients these values range from 4 to 12 μg / ml (17-50 μmol / l).

Distribution and binding to blood plasma proteins

The binding of carbamazepine to plasma proteins is 70-80%. Concentration of unchanged carbamazepine in the cerebrospinal fluid and saliva is proportional to the proportion of the active substance not associated with plasma proteins (20-30%). The concentration of carbamazepine in breast milk is 25-60% of its concentration in the blood plasma. Carbamazepine penetrates the placental barrier.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 epoxidiol 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 content of carbamazepine-10,11-epoxide (active metabolite) is about 30% of the concentration of carbamazepine in plasma. The main isoenzyme providing biotransformation carbamazepine in carbamazepine-10,11-epoxide, is the cytochrome P4503A4. As a result of these metabolic reactions, a small amount of another metabolite, 9-hydroxy-methyl-10-carbamoylacridan, is also formed. Other important ways metabolism of carbamazepine - the formation under the influence of the isoenzyme UGT2B7 of various monohydroxylated derivatives, as well as N-glucuronides.

Excretion

The half-life of unchanged carbamazepine after a single oral intake is on average about 36 hours,and after repeated administration of the drug - an average of 16-24 hours, depending on the duration of treatment (due to autoinduction of the monooxygenase system of the liver). It was shown that in patients taking simultaneously other drugs inducing liver enzymes (for example, phenytoin, phenobarbital), the half-life of carbamazepine averages 9-10 hours. When carbamazepine-10,11-epoxide is ingested, the average half-life of it is about 6 hours.

After a single oral intake of 400 mg of carbamazepine, 72% of the dose taken is excreted in the urine and 28% with feces. About 2% of the dose is taken with urine in the form of unchanged carbamazepine, about 1% - in the form of a pharmacologically active 10,11-epoxide metabolite. After a single oral intake of 30% of carbamazepine is excreted in the urine in the form of the end products of the epoxy-diadole pathway of metabolism.

Peculiarities of pharmacokinetics in individual patient groups

In children, due to the more rapid elimination of carbamazepine, It is necessary to use higher doses of the drug per kg body weight, in comparison with adults.

There is no evidence to suggest that the pharmacokinetics of carbamazepine change in elderly patients (compared to older adults).

Data on the pharmacokinetics of carbamazepine in patients with renal or hepatic impairment attaching.

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.

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.

Pain syndrome with diabetic neuropathy.

Polyuria and polydipsia of neurohormonal nature in diabetes insipidus of central genesis.

Contraindications:

Hypersensitivity to carbamazepine or chemically similar medicinal products (eg, tricyclic antidepressants) or to any other component of the drug.

Atrioventricular block.

Presence in the anamnesis of episodes of oppression of bone marrow hematopoiesis or information about acute intermittent porphyria.

Combination with monoamine oxidase inhibitors (structural similarity with tricyclic antidepressants).

Carefully:

Patients who have a history of heart disease (including decompensated chronic heart failure), liver (including liver failure), kidney (including renal failure), adverse hematologic reactions to other drugs, or cancellation of previous treatment with Tegretol®, a drug should be prescribed only after a careful analysis of the relationship between the expected effect of treatment and the possible risk of therapy, and by ensuring a thorough and regular ntrolya the patient's condition.

Caution is advised to prescribe the drug:

- patients with hyponatremia of dilution, hypothyroidism;

- elderly patients (taking into account the possibility of drug interactions and the different pharmacokinetics of antiepileptic drugs);

- patients with mixed forms of epileptic seizures, including absences, typical or atypical, taking into account the possible intensification of seizures;

- patients with increased intraocular pressure should take Tegretol® CR under the supervision of a doctor, given the m-cholinoblocking activity of carbamazepine.

Pregnancy and lactation:

Carbamazepine rapidly penetrates the hematoplacental barrier, and is found in high concentrations in the fetal tissues, especially in the liver and kidneys.

Children of patients with epilepsy are more likely than others to develop developmental disorders, including congenital malformations. At present, there is no definitive data on the presence of a cause-and-effect relationship of these disorders with the use of carbamazepine in mothers as monotherapy.

There are reports of cases of congenital diseases and malformations, including the absence of vertebral arches (spina bifida) and other congenital anomalies: defects in 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. Caution should be used Tegretol® CR in pregnant women with epilepsy.

If it is necessary to use the drug in pregnant women, and also if the pregnancy is diagnosed during the use of the drug, or the patient plans a pregnancy, the ratio of expected benefits and possible risks, especially in the first trimester of pregnancy, should be carefully evaluated.

With sufficient clinical efficacy in women of childbearing age, Tegretol® CR should be used as a monotherapy, as the incidence of congenital fetal anomalies with combined antiepileptic therapy is higher than with 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.

Use Tegretol® CR in the lowest 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.

It is known that a deficiency of folic acid develops during pregnancy. It has been reported that antiepileptic drugs increase this deficit. This can contribute to an increase in the frequency of birth defects in children born to women taking antiepileptic drugs. Therefore, before and during pregnancy, an additional intake of folic acid is recommended.

In order to prevent increased bleeding in newborns, in the last weeks of pregnancy, as well as newborns, vitamin K1 is recommended.

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 received Tegretol® CR, were also reported. Perhaps these reactions are manifestations of the newborn "withdrawal" syndrome.

Carbamazepine penetrates into breast milk, where its concentration is 25-60% of the concentration in the blood plasma. In connection with the above, if you need to use the drug during breastfeeding, you should carefully evaluate the ratio of the expected benefits of natural feeding to the possible risk of developing side effects of the drug. It is necessary to monitor children receiving breast milk with the aim of diagnosing side effects as early as possible (for example, severe 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. The drug can be taken during meals, after meals or in between meals. Tablets should be taken with a small amount of liquid.

The drug can be used as a monotherapy or as part of a combination therapy.

Tablets of prolonged action (whole tablet or half if prescribed by a doctor) should be taken without chewing, squeezed small amount of liquid. Since the active substance is released from the long-acting tablets slowly and gradually, they are taken 2 times a day.

Transfer of the patient from the drug Tegretol® CR in the form of regular tablets for taking Tegretol® CR tablets of prolonged action: clinical experience shows that in some patients When using long-acting tablets, it may be necessary to increase the dose of the drug.

Given the drug interactions and features of the pharmacokinetics of antiepileptic drugs, elderly patients dose of the drug should be selected with caution.

Epilepsy

If possible, the drug should be used as a monotherapy.

The drug is not used for small seizures (petit mal, absance) and myoclonic seizures.

Treatment begins with a small daily dose, which is then slowly increased until an optimal effect is achieved.

The dose of carbamazepine is selected individually to achieve adequate control of convulsions. 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).

When the preparation Tegretol® CR is added to other antiepileptic drugs, the dose of Tegretol® CR is increased gradually.If necessary, appropriate correction of the doses taken.

For adults and children older than 16 years, the initial dose of carbamazepine is 100-200 mg 1 or 2 times a day. Then the dose is slowly increased until the optimal therapeutic effect is achieved; it is usually achieved at a dose of 400 mg 2-3 times a day. Some patients may require an increase in the daily dose to 1600 mg or 2000 mg.

Neuralgia of the trigeminal nerve

Initial dose for adults is 200-400 mg per day. It is slowly increased until the pain disappears (usually up to a dose of 200 mg 3-4 times a day). Then the dose is gradually reduced to the minimum maintenance level.

The maximum recommended dose for adults is 1200 mg / day. When resolving the pain syndrome, you should gradually stop therapy with the drug before the next pain attack occurs.

Recommended initial dose for elderly patients is 100 mg 2 times a day, then the dose is slowly increased to resolve the pain syndrome, which is usually achieved with a dose of 200 mg 3-4 times a day.

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.

Alcohol withdrawal syndrome

The average dose is 200 mg 3 times a day. In severe cases, during the first few days the dose may be increased (for example, to a dose of 400 mg 3 times per day).

In severe manifestations of alcohol abstinence treatment begins with the use of the drug in combination with drugs that have sedative and hypnotic effects (eg, clomethiazole, chlordiazepoxide). After resolving the acute phase, treatment with the drug can be continued as a monotherapy.

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.

Use in children

The main indication for the use of Tegretol® CR in children is epilepsy.

Children aged 4 years and younger are recommended to take Tegretol ® in the form of other medicinal forms (syrup), with treatment recommended starting at a dose of 20-60 mg per day, the dose can be increased every other day by 20-60 mg.

Maintenance doses: for children set at the rate of 10-20 mg / kg body weight per day (in several receptions).

Age of child	Daily dose
4-5 years	200-400 mg per day
6-10 years	400-600 mg per day
11-15 years old	600-1000 mg per day
> 15 years	800-1200 mg per day (as for adults)

Maximum doses: for children <6 years of age is 35 mg / kg / day, 6-15 years - 1000 mg / day,> 15 years - 1200 mg / day.

As for the use of the drug for other indications, the children have sufficient reliable information, the dosage regimen of the drug is recommended to be selected in accordance with the age and weight of the child, not exceeding the dosages indicated in the table.

Discontinuation of the drug

Sudden discontinuation may cause epileptic seizures, so carbamazepine should be lifted gradually over 6 months or more. If it is necessary to quickly cancel a drug in a patient with epilepsy, the transition to another antiepileptic agent should be carried out under the cover of the drug shown in such cases.

Side effects:

Certain types of unwanted reactions, for example, from the side of the CNS (dizziness, headache, ataxia, drowsiness, fatigue, diplopia), from the digestive system (nausea, vomiting), as well as allergic skin reactions, occur very often or often, especially in 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 CNS 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 are used: "very often" -> 1/10, "often" -> 1/100 - <1/10, "infrequently" -> 1/1000 - <1/100 "rarely "-> 1/10 000 - <1/1000," very rarely "- <1/10 000, including individual messages.

Disorders of the psyche: rarely - hallucinations (visual or auditory), depression, anxiety, aggression, agitation, disorientation; very rarely - activation of psychosis.

Disturbances from the nervous system: very often - dizziness, ataxia, drowsiness; often - headache, diplopia; infrequent - abnormal involuntary movements (eg, tremor, "fluttering" tremor / asterixis /, muscular dystonia, tics), nystagmus; rarely - dyskinesia, oculomotor disorders, speech disorders (eg, dysarthria), choreoathetosis, peripheral neuropathy, paresthesia, paresis; very rarely - malignant neuroleptic syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

Disturbances from the skin and subcutaneous tissues: very often - allergic dermatitis, hives, which can be very pronounced; infrequently exfoliative dermatitis; rarely - systemic lupus erythematosus, itching; very rarely - Stevens-Johnson syndrome (in some countries of Asia is classified as "rarely"), toxic epidermal necrolysis, photosensitivity reactions, erythema multiforme, erythema nodosum, skin pigmentation disorders, purpura, acne, sweating, alopecia, hirsutism.

Violations of the blood and lymphatic system: very often - leukopenia; often thrombocytopenia,eosinophilia; rarely - leukocytosis, lymphadenopathy; very rarely agranulocytosis, aplastic anemia, pancytopenia, anemia, true erythrocyte aplasia, megaloblastic anemia, reticulocytosis, hemolytic anemia.

During the administration of the drug, agranulocytosis and aplastic anemia can develop. However, due to the fact that these conditions occur very rarely, it is difficult to quantify the risk of their occurrence. It is known that the total risk of developing agranulocytosis in the general population not receiving treatment is 4.7 cases per million people a year, and aplastic anemia - 2.0 cases per million population per year.

Disorders from the digestive system: very often - nausea, vomiting; often - dry mouth; infrequently - diarrhea, constipation; rarely - abdominal pain; very rarely - glossitis, stomatitis, pancreatitis.

Disturbances from the liver and bile ducts: rarely - hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, destruction of intrahepatic bile ducts with a decrease in their number, jaundice; very rarely - granulomatous liver damage, liver failure.

Immune system disordersSeldom - multiorgan delayed type hypersensitivity with fever, skin rashes, vasculitis, lymphadenopathy, symptoms resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered liver function, and destruction of the intrahepatic bile ducts with a reduction in their number (as shown manifestations occur in different combinations ). Other organs may also be involved (eg, lungs, kidneys, pancreas, myocardium, large intestine); very rarely - anaphylactic reaction, angioedema, hypogammaglobulinemia.

If the above-mentioned hypersensitivity reactions occur, the drug should be discontinued.

Heart Disease: rarely - violations of intracardiac conduction; very rarely - bradycardia, arrhythmias, AV blockade with syncope, chronic heart failure, exacerbation of ischemic heart disease.

Vascular disorders: rarely - increase or decrease in blood pressure; very rarely - collapse, thrombophlebitis, thromboembolism (eg, pulmonary embolism).

Disorders from the endocrine systemFrequently - edema, fluid retention, weight gain, hyponatremia and reduced blood osmolarity due to an effect similar to the action of antidiuretic hormone, which rarely leads to water intoxication (hyponatremia dilution), accompanied by lethargy, vomiting, headache, disorientation and neurologic violations; very rarely - galactorrhea, gynecomastia.

Disorders from the metabolism and nutrition: rarely - deficiency of folic acid, decreased appetite; very rarely - acute porphyria (acute intermittent porphyria and mixed porphyria), acute porphyria (late cutaneous porphyria).

Disorders from the kidneys and urinary tract: very rarely tubulointerstitial nephritis, renal insufficiency, renal dysfunction (eg, albuminuria, hematuria, oliguria, urea / azotemia increase), frequent urination, urinary retention, sexual function disorders / erectile dysfunction, spermatogenesis disorders (decrease in the number of spermatozoa and their motility) .

Disturbances on the part of the organ of sight: often - violation of accommodation (incl.blurred vision); very rarely - clouding of the lens, conjunctivitis.

Hearing disorders and labyrinthine disorders: very rarely - hearing disorders, incl. noise in the ears, hyperacusia, hypoacusia, changes in perception of the height of sound.

Disturbances from musculoskeletal and connective tissue: rarely - muscle weakness; very rarely - a violation of bone metabolism (a decrease in blood plasma levels of calcium and 25-hydroxy-cholecalciferol, leading to osteomalacia / osteoporosis), arthralgia, myalgia and muscle spasms.

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

General disorders and disorders at the site of administration: very often fatigue.

Laboratory and instrumental data: very often - increased activity of gamma-glutamyltransferase (due to the induction of this enzyme in the liver), which usually has no clinical significance; often an increase in the activity of alkaline phosphatase of the blood; infrequently - increased activity of transaminases; very rarely - increased intraocular pressure,increase in cholesterol concentration, including high-density lipoprotein cholesterol, and triglycerides, changes in thyroid function indices-decreasing the concentration of thyroxine (free and bound fraction) and triiodothyronine and increasing the thyroid-stimulating hormone concentration, which is usually not accompanied by clinical manifestations, and an increase in prolactin concentration in serum.

Undesirable phenomena according to postmarketing observations (frequency unknown):

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

Disturbances from the nervous system: sedation, memory impairment.

Disorders from the gastrointestinal tract: colitis.

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

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

Disturbances from musculoskeletal and connective tissue: fractures.

Laboratory and instrumental data: decreased bone density.

Overdose:

Overdose manifests itself usually symptoms from the side of the central nervous system, cardiovascular and respiratory systems, as well as the phenomena indicated in the section "Side effect."

In case of overdose, the following are possible Symptoms and complaints:

central nervous system: depression of CNS functions; impairment of consciousness, disorientation, drowsiness, agitation, hallucinations, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (at the beginning), hyporeflexia (later); convulsions, psychomotor disorders, myoclonus, hypothermia, mydriasis.

Respiratory system: respiratory depression, pulmonary edema.

The cardiovascular system: tachycardia, decrease and increase of arterial pressure, conduction disorders with QRS complex expansion; heart failure and fainting caused by cardiac arrest.

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

urinary system: urinary retention, oliguria or anuria; fluid retention; water intoxication (hyponatremia of dilution), caused by the effect of carbamazepine, similar to the action of antidiuretic hormone.

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

Changes in laboratory indicators: hyponatremia, metabolic acidosis is possible, hyperglycaemia is possible, increased activity of the muscle fraction of creatine phosphokinase.

Treatment

There is no specific antidote.

Initially, treatment should be based on the clinical state of the patient; hospitalization is indicated.

The concentration of carbamazepine in the plasma is determined to confirm the poisoning of this agent and to assess the degree of overdose.

Evacuation of the stomach contents, gastric lavage, the use of activated charcoal are carried out. Late evacuation of gastric contents can lead to delayed absorption and re-emergence of symptoms of intoxication during recovery. Symptomatic supportive treatment is used in the intensive care unit, monitoring of heart functions, careful correction of water-electrolyte balance disorders.

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

It is possible to re-increase the symptoms of overdose on the 2nd and 3rd day after its onset, which is due to the slow absorption of carbamazepine.

Interaction:

Carbamazepine is not recommended for use simultaneously with monoamine oxidase (MAO) inhibitors. Before using the drug, MAO inhibitors should be withdrawn at least 2 weeks or, if the clinical situation permits, even for a longer period.

Cytochrome P4503A4 (CYP3A4) is the main isoenzyme providing the formation of carbamazepine-10,11-epoxide (active metabolite). Simultaneous use of an inhibitor of the isoenzyme CYP3A4 with the preparation can lead to an increase in the concentration of carbamazepine in the plasma, which, in turn, can cause side reactions. Simultaneous use of inducers of the CYP3A4 isoenzyme may lead to an acceleration of the metabolism of carbamazepine and, thus, to a possible decrease in its concentration in the plasma and, consequently, to a possible decrease in the severity of the therapeutic effect of the drug. The cancellation of simultaneously taken inducers of the isoenzyme CYP3A4 can reduce the rate of biotransformation of carbamazepine, and, as a result, lead to an increase in the concentration of carbamazepine in the blood plasma.

Carbamazepine is a potent inducer of the isoenzyme CYP3A4 and other enzyme hepatic systems of the first and second phases of drug metabolism and, when used simultaneously with drugs metabolized by the CYP3A4 isoenzyme, can induce metabolism induction and a decrease in their concentration in the plasma.

Since the conversion of carbamazepine-10,11-epoxide to carbamazepine-10,11-trans-diol occurs with the aid of microsomal epoxide hydrolase, the use of carbamazepine simultaneously with the inhibitors of microsomal epoxide hydrolase can lead to an increase in the plasma concentration of carbamazepine-10,11-epoxide.

Drugs that can increase the concentration of carbamazepine in blood plasma:

- analgesic and non-steroidal anti-inflammatory drugs: dextropropoxyphene, ibuprofen;

- antineoplastic agents (androgen): danazol;

-antibiotics: macrolide (for example, erythromycin, troleandomycin, josamycin, clarithromycin), ciprofloxacin;

- antidepressants: possibly, desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine;

- antiepileptic drugs: styipentol, vigabatrin;

- antifungal agents: azole derivatives (for example, itraconazole, ketoconazole, fluconazole, voriconazole). Alternative anticonvulsants may be recommended to patients receiving voriconazole or itraconazole;

- blockers of histamine H2 receptors: loratadine, terfenadine;

- antipsychotic drugs (antipsychotics): olanzapine;

- anti-tuberculosis drugs: isoniazid;

- antiviral agents: HIV protease inhibitors (eg, ritonavir);

- antiglaucoma agents (inhibitors of carbonic anhydrase): acetazolamide;

- antihypertensive drugs (blockers of "slow" calcium channels): verapamil, diltiazem;

- antiulcer drugs (proton pump inhibitors, histamine H2 receptor blockers): omeprazole, perhaps, cimetidine;

- muscle relaxants: oxybutynin, dantrolene;

- antiplatelet agents: ticlopidine;

- other medicines and food products: grapefruit juice, nicotinamide (only in high doses).

Since an increase in the concentration of carbamazepine in the blood plasma can lead to the occurrence of adverse reactions (eg, dizziness, drowsiness, ataxia, diplopia),in these situations, the dose of the drug should be corrected and / or the concentration of carbamazepine in the blood plasma regularly determined.

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.

Drugs that can reduce the concentration of carbamazepine in blood plasma:

- antiepileptics: felbamate, mezuximide, oxcarbazepine, phenobarbital, fensuximide, 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) and phosphenytoin, primidon, and although the data is partially contradictory, it is also possible that clonazepam;

- antineoplastic agents: cisplatin or doxorubicin;

- anti-tuberculosis drugs: rifampicin;

- bronchodilating agents: theophylline, aminophylline;

- remedy for acne (retinoids): isotretinoin;

- other medicines and food products: herbal preparations containing St. John's wort.

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

The effect of carbamazepine on the plasma concentration of drugs used as concomitant therapy

With simultaneous use with carbamazepine, a decrease in plasma concentration, a decrease or even a complete cessation of action of certain drugs is possible.

With simultaneous use with carbamazepine, you may need to adjust the doses of the following drugs:

- analgesic and non-steroidal anti-inflammatory drugs: buprenorphine, methadone, paracetamol (long-term use of carbamazepine and paracetamol (acetaminophen) may lead to the development of hepatotoxic effects), phenazone, tramadol;

- antibiotics: doxycycline, rifabutin;

- indirect anticoagulants: warfarin, fenprokumone, dicoumarol and acenocoumarol;

- antidepressants: bupropion, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (imipramine, amitriptyline, nortriptyline, clomipramine);

- antiemetics: aprepitant;

- antiepileptic drugs: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidon, tiagabine, topiramate, valproic acid, zonisamide. To avoid intoxication with phenytoin and the occurrence of subtherapeutic concentrations of carbamazepine, the recommended plasma concentration of phenytoin should be no more than 13 μg / ml before addition to carbamazepine. There are reports that, when taking carbamazepine, the concentration of mephenytoin in the blood plasma may increase (in rare cases);

- antifungal agents: itraconazole, voriconazole.

Alternative anticonvulsants may be recommended to patients receiving voriconazole or itraconazole;

- anthelmintic agents: praziquantel, albendazole;

- antineoplastic agents: imatinib, cyclophosphamide, lapatinib, tessirolimus;

- antipsychotic drugs (antipsychotics): clozapine, haloperidol, bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone;

- antiviral agents: HIV protease inhibitors (indinavir, ritonavir saquinavir);

- anxiolytic means: alprazolam, midazolam;

- bronchodilating agents: theophylline;

- Contraceptive means: hormonal contraceptives (alternative methods of contraception are necessary);

- drugs for the treatment of cardiovascular diseases systems: blockers "slow" calcium channels of the dihydropyridine group (felodipine), simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine;

- cardiac glycosides: digoxin;

- glucocorticosteroids: prednisolone, dexamethasone;

- funds for the treatment of erectile dysfunction: tadalafil;

- immunosuppressive agents: ciclosporin, everolimus, tacrolimus, sirolimus;

- funds for the treatment of thyroid diseases: levothyroxine;

- Other medicines and food products: preparations containing estrogens and / or progesterone.

Combinations that should be taken into account

With the simultaneous use of carbamazepine with levetiracetam in some cases, increased toxic effects of carbamazepine. There are reports of increased hepatotoxicity caused by isoniazid, when it was used concomitantly with carbamazepine. The combined use of carbamazepine and lithium or metoclopramide, as well as carbamazepine and neuroleptics (haloperidol, thioridazine) may lead to an increase in the incidence of unwanted neurologic reactions (in the case of the latter combination, even with therapeutic concentrations of active substances in the blood plasma).

The simultaneous use of carbamazepine with certain diuretic drugs (hydrochlorothiazide, furosemide) can lead to hyponatremia, accompanied by clinical manifestations.

Carbamazepine may exhibit antagonism to the action of nondepolarizing muscle relaxants (for example, pancuronium bromide). If such a combination of drugs is used, it may be necessary to increase the dose of these muscle relaxants; careful monitoring of patients should be carried out, as possible a faster, than expected, cessation of muscle relaxants.

Reported the occurrence of bleeding in women between menstruation in cases when hormonal contraceptives were used simultaneously. The drug may reduce the effect of hormonal contraceptives due to the induction of microsomal enzymes.

Carbamazepine, as well as other psychotropic drugs, can reduce the tolerance of alcohol. In this regard, the patient is recommended to abandon the use of alcohol.

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 false-positive results in the determination of the concentration of tricyclic antidepressants by the method of polarization fluorescent immunoassay.

Special instructions:

The drug should be taken only with medical supervision.

Patients with mixed forms of epileptic seizures, including absence and myoclonic seizures

The drug is usually ineffective in absences (petit mal) and myoclonic seizures.In patients with mixed forms of epileptic seizures, the drug should be used with caution and only on condition that regular medical supervision is provided (due to possible increased seizures). In case of increased seizures, Tegretol® CR should be discarded.

Decrease in the number of platelets and leukocytes

During the application of the drug at different frequencies, there is a transient or persistent decrease in the number of platelets or leukocytes. However, in most cases, these phenomena are transient and usually do not precede the onset of aplastic anemia or agranulocytosis.

Before starting 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 concentration of iron in the blood serum.

It is necessary to inform patients about the early signs of toxicity inherent in probable hematologic disorders, as well as symptoms from the skin and liver. The patient is informed of the need to consult a doctor immediately if there are undesirable reactions such as fever, sore throat, rash,ulcers in the oral cavity, causeless occurrence of hemorrhages, hemorrhages in the form of petechiae or purpura.

In those cases when the low content of leukocytes or platelets (or the tendency to decrease them) during the treatment, it is necessary to closely monitor the patient's condition and the parameters of the developed clinical blood test. If signs of significant bone marrow depression are detected, Tegretol® CR should be withdrawn.

Dermatological reactions

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

The drug Tegretol® CR should be immediately discontinued and alternative therapy should be selected if signs and symptoms are suspected to be indicative of the development of severe dermatological reactions - for example, Stevens-Johnson syndrome or Lyell syndrome. With the development of severe (in some cases life-threatening patient) skin reactions, the patient should 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 exanthematous pustulosis and spotty-nasal rash) in carriers of the HLA-A allele * 3101 of the human leukocyte antigen (HLA) gene and the use of carbamazepine.

The frequency of the HLA-A * 3101 allele of the human leukocyte antigen (E1LA) may differ in different ethnic groups: about 2-5% in the European population, about 10% in 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), the indigenous peoples of North America (the Navajo and Siocs, Sanora Seri in Mexico), South India (Tamil Nadu), and 10-15% among other indigenous people these regions.

When carbamazepine is used, it is recommended to carry out genotyping with this allele in possible carriers of the HLA-A * 3101 allele (for example, patients of Japanese nationality, Caucasians, Native Americans, Hispanics, people of southern India and Arabs). Use the drug in carriers of this allele should be only if the benefit of therapy exceeds the possible risk.

Patients who are already receiving therapy with Tegretol® CR do not recommend genotyping for this allele, since severe skin reactions in most cases were noted in the first months of application (regardless of the presence of HLA-A * 3101).

According to a retrospective analysis of the use of the drug in patients of Chinese and Thai nationalities, there is a correlation between the incidence of Stevens-Johnson syndrome and Lyell syndrome and the presence of the HLA-B * 1502 human leukocyte antigen (HLA) gene in the patient's genome. The frequency of occurrence of this allele in patients of Chinese nationality is 2-12%, in Thai - about 8%.

When carbamazepine is used in patients in countries of the Asian region (Taiwan, Malaysia, Philippines),where there is a high prevalence of the HLA-B * 1502 allele, an increase in the frequency of development (from the gradation "very rare" to "rarely") of Stevens-Johnson syndrome was revealed. The frequency of distribution of the HLA-B * 1502 allele is more than 15% in the Philippines and among some population groups in Malaysia. The frequency of distribution of the HLA-BM502 allele 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 high as the allele frequency.

When carbamazepine is used, it is recommended to carry out genotyping using this allele in possible carriers of the HLA-B * 1502 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 who are already receiving therapy with Tegretol® CR do not recommend genotyping for this allele, since severe skin reactions were mostly observed in the first months of application (regardless of the presence of HLA-B * 1502.

It has been shown that the detection of patients with the presence of the HLA-B * 1502 allele and the absence of carbamazepine in such patients reduces the incidence of carbamazepine-induced Stevens-Johnson syndrome or Lyell syndrome.

However, the results of genotyping should not affect the degree of control over the patient's condition and the doctor's vigilance regarding severe skin reactions. The development of severe skin lesions is possible in patients who are negative for these alleles. In many cases, patients with positive HLA-B * 1502 or HLA-A * 3101 alleles did not develop severe skin syndromes when using Tegretol® CR.

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 of dermatological reactions, the frequency of development and the prevalence of severe skin reactions have not been established.

Slightly expressed skin reactions, for example, isolated macular or maculopapular exanthema, in most cases are transient and non-severe, usually occur for several days or weeks with continued treatment or after a reduction in the dose of the drug. Nevertheless, since differential diagnostics between early manifestations of severe skin reactions and mild transient skin rashes can be difficult, with the development of any skin reactions the patient should be under the supervision of a doctor (in order to timely stop therapy with the drug in case of deterioration of the patient's condition).

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

Hypersensitivity reactions

With the development of hypersensitivity to the drug Tegretol® RA patients may experience a variety of reactions, including drug rash with eosinophilia and systemic symptoms, delayed poliorgannnye manifestations of hypersensitivity to the development of fever, rashes, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, changes in indicators liver function and the syndrome of destruction of the bile ducts with a decrease in their number, which can occur in any combination. Also it may result in other internal organs (r. H. The lung, kidney, pancreas, myocardium, colon).

In case of development of symptoms and symptoms of hypersensitivity to the drug Tegretol® CR, 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-reactivity hypersensitivity is also found between carbamazepine and phenytoin.

Hyponatremia

The development of hyponatremia is associated with the use of carbamazepine.Patients with pre-existing kidney lesions associated with low serum sodium levels, or in patients receiving concomitant sodium-reducing drugs (eg, diuretics, drugs that affect the secretion of antidiuretic hormone) should determine the serum sodium content before initiation of therapy with carbamazepine. After that, the sodium content should be determined after about two weeks, and then monthly during the first three months of therapy, or according to clinical need. These risk factors are especially common in elderly patients. If hyponatremia is observed, water restriction is an important criterion for determining the condition in the presence of clinical indications.

Hypothyroidism

Carbamazepine can reduce serum concentrations of thyroid hormones by inducing enzymes, which requires an increase in the dose of drugs used for substitution therapy in patients with hypothyroidism. This category of patients needs to monitor the function of the thyroid gland to select a dose of substitution therapy.

Dysfunction of the liver

Before using Tegretol® CR and during the treatment it is necessary to carry out a study of 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, Tegretol® should be immediately discontinued.

Renal impairment

Before starting treatment with the drug and periodically during the therapy, it is recommended to study the general urine test and determine the concentration of urea in the blood.

M-holinoblocking activity

The drug has a weak m-cholinoblocking activity. Therefore, in the case of using the drug in patients with increased intraocular pressure and urinary retention, continuous monitoring of this indicator is necessary.

Mental disorders

Since the use of the drug may exacerbate latent mental disorders, care should be taken to monitor elderly patients for the purpose of identifying such symptoms as confusion and psychomotor agitation.

Suicidal behavior or intentions

In patients who received anticonvulsants for a number of indications, there were cases of suicidal behavior or intentions. The results of a meta-analysis of randomized placebo-controlled trials showed a slight increase in the risk of suicidal behavior in patients receiving anticonvulsant drugs. The mechanism of strengthening suicidal behavior in this category of patients is not established. Therefore, it is necessary to carefully monitor the symptoms of suicidal behavior and intentions and to decide on the appropriate treatment. Patients (caregivers) should be urged to seek help from a doctor in case of symptoms of suicidal behavior or intentions.

Endocrinological disorders

The drug may reduce the effectiveness of medications containing estrogens and / or progesterone, therefore women of childbearing age should be treated with alternative methods of protection from pregnancy during treatment with the drug.

To date, very rare reports of male fertility impairment and / or spermatogenesis disorders have been recorded.

Determination of the concentration of carbamazepine in the blood plasma

Although the relationship between the dose of the drug, the concentration of carbamazepine in the blood plasma, its clinical efficacy or tolerability is very low, nevertheless, a regular determination of the carbamazepine concentration may be appropriate in the following situations: with a sharp increase in the frequency of seizures, in order to check whether the patient the drug is properly administered; during pregnancy; when treating children or adolescents; with suspected carbamazepine absorption abnormalities; if there is a suspicion of the development of toxic reactions in the event that the patient takes several medicines.

Effect on the ability to drive transp. cf. and fur:The ability of a patient taking Tegretol® CR preparation to a rapid reaction, 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, drowsiness, ataxia, diplopia, disruption of accommodation and visual impairment. Patientsmust be warned of the possible dangers and the need to be cautious when driving vehicles and working with machinery.

Form release / dosage:

Tablets of prolonged action, coated with a coating, 200 mg and 400 mg.

Packaging:

Tablets 200 mg and 400 mg of 10 pcs in the blister.

5 blisters with 200 mg tablets with instructions for use in a cardboard pack.

3 blisters with 400 mg tablets with instructions for use in a cardboard bundle.

Storage conditions:

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

The drug should be stored out of the reach of children.

Shelf life:

3 years.

The drug should not be used after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N012082 / 01

Date of registration:28.11.2007

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA, S.A. France

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp23.01.2015

Illustrated instructions

Instructions

Tegretol® CR (Tegretol® CR)