Zeptol

Cytochrome P4503A4 (CYP3A4) is the main enzyme responsible for the formation of carbamazepine-10,11-epoxide (the active metabolite). Concomitant use of Zeptol with inhibitors of the CYP3A4 isoenzyme may lead to increased plasma concentrations of carbamazepine and cause adverse reactions. The combined 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 plasma and, consequently, to a possible decrease in the severity of the therapeutic effect of the drug. Cancellation of concomitantly taken inducers of the CYP3A4 isoenzyme may reduce the rate of biotransformation of carbamazepine and lead to an increase in its concentration in the blood plasma.

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

Since the conversion of carbamazepine-10,11-epoxide to carbamazepine-10,11-transdiol occurs with the help of microsomal epoxide hydrolase, the use of Zeptol together with inhibitors of microsomal epoxide hydrolase may lead to an increase in the plasma concentration of carbamazepine-10,11-epoxide.

Drugs that may increase plasma concentrations of carbamazepine: verapamil, diltiazem, omeprazole, oxybutynin, dantrolene, ticlopidine, felodipine, dextropropoxyphene, viloxazine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine, stiripentol, vigabatrin, acetazolamide, ibu profen, danazol , nicotinamide (in adults, only in high doses); macrolide antibiotics (erythromycin, josamycin, clarithromycin, troleandomycin); azoles (itraconazole, ketoconazole, fluconazole, voriconazole), terfenadine, loratadine, olanzapine, isoniazid, HIV viral protease inhibitors (for example, ritonavir), possibly cimetidine, desipramine.

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

Drugs that may increase plasma concentrations of carbamazepine 10,11-epoxide: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.

Since an increase in the level of carbamazepine-10,11-epoxide in the blood plasma can lead to adverse reactions (for example, dizziness, somnolence, ataxia, diplopia), in these situations the dose of Zeptol should be adjusted and/or the concentration of carbamazepine-10,11 should be regularly determined -epoxide in blood plasma.

Preparations that can reduce the concentration of carbamazepine in blood plasma: felbamat, oxcarbazepine, phenobarbital, phenytoine, phosphenitoin, primidone, mesuximide, phenesuximide, theophylline, aminophylline, isotinin, rifampicin, cimpiclatin or - doxorubicin, plant preparations containing plants containing the surgery. rowal (Hypericum Perforatum) , and although the evidence is partly conflicting, clonazepam may also be.

When used simultaneously with the above drugs, a dose adjustment of Zeptol may be required.

Effect of carbamazepine on plasma concentrations of drugs used as concomitant therapy

When used together with carbamazepine, a decrease in plasma concentration, a decrease or even a complete cessation of the effect of some drugs is possible.

When used simultaneously with carbamazepine, dose adjustment of the following drugs may be required: methadone, paracetamol, phenazone (antipyrine), tramadol, doxycycline, oral anticoagulants (warfarin, phenprocoumon, dicumarol and acenocoumarol), bupropion, citalopram, trazodone, tricyclic antidepressants (imipramine, amitriptyline, nortriptyline, clomipramine), clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide, itraconazole, praziquantel, imatinib, clozapine, haloperidol, bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, used for HIV therapies (indinavir, ritonavir, saquinavir), alprazolam, midazolam, theophylline, calcium channel blockers of the dihydropyridine group (for example, felodipine), digoxin, oral contraceptives (selection of alternative methods of contraception is necessary), glucocorticosteroids (for example, prednisolone, dexamethosone) , cyclosporine, everolimus; levothyroxine, drugs containing estrogens and/or progesterone.

There are reports that while taking carbamazepine, the level of phenytoin in the blood plasma may either increase or decrease, and the level of mephenytoin may increase (in rare cases).

Combinations to Consider

When carbamazepine was prescribed together with levetiracetam, an increase in the toxic effect of carbamazepine was observed in some cases.

There are reports of increased hepatotoxicity caused by isoniazid in cases where it was used concomitantly with carbamazepine.

The combined use of carbamazepine and lithium or metoclopramide, as well as carbamazepine and antipsychotic drugs (haloperidol, thioridazine) can lead to an increase in the frequency of adverse neurological reactions (in the case of the latter combination, even with therapeutic concentrations of active substances in the blood plasma. Concomitant use of carbamazepine with certain diuretics (hydrochlorothiazide, furosemide) can lead to hyponatremia, accompanied by clinical manifestations.

Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (eg, pancuronium bromide). In the case of using such combinations of drugs, it may be necessary to increase the dose of these muscle relaxants; Patients should be closely monitored as the effects of muscle relaxants may cease more quickly than expected.

Bleeding has been reported in women between menstrual periods when oral contraceptives were used at the same time. The drug may reduce the therapeutic effect of oral contraceptives due to the induction of microsomal enzymes.

Carbamazepine, like other psychotropic drugs, can reduce alcohol tolerance. In this regard, the patient is advised to stop drinking alcohol.

Coadministration with grapefruit juice may increase plasma levels of carbamazepine.

Zeptol, 30 pcs., 200 mg, extended-release film-coated tablets

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

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

From the side of the central nervous system: often - dizziness, ataxia, drowsiness, general weakness, headache, accommodation paresis; sometimes - abnormal involuntary movements (for example, tremor, “fluttering” tremor - asterixis, dystonia, tics); nystagmus; rarely - hallucinations (visual or auditory), depression, loss of appetite, anxiety, aggressive behavior, psychomotor agitation, disorientation, activation of psychosis, orofacial dyskinesia, oculomotor disorders, speech disorders (for example, dysarthria or slurred speech), choreoathetoid disorders, peripheral neuritis, paresthesia, muscle weakness and symptoms of paresis. The role of the drug in the development of neuroleptic malignant syndrome, especially in combination with antipsychotics, remains unclear.

Allergic reactions: often - urticaria; sometimes - erythroderma, multiorgan delayed-type hypersensitivity reactions with fever, skin rashes, vasculitis (including erythema nodosum as a manifestation of cutaneous vasculitis), lymphadenopathy, signs resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered liver function tests (these manifestations occur in various combinations). Other organs may also be involved (eg, lung, kidney, pancreas, myocardium, colon), aseptic meningitis with myoclonus and peripheral eosinophilia, anaphylactoid reaction, angioedema, hypersensitivity pneumonitis, or eosinophilic pneumonia. If the above allergic reactions occur, the use of the drug should be discontinued, rare - lupus-like syndrome, skin itching, erythema multiforme exudative (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), photosensitivity.

From the hematopoietic organs: often - leukopenia, thrombocytopenia, eosinophilia; rarely - leukocytosis, lymphadenopathy, folic acid deficiency, agranulocytosis, aplastic anemia, true erythrocyte aplasia, metal regional anemia, acute intermittent porphyria, reticulocytosis, hemolytic anemia, splenomegaly.

From the digestive system: often - nausea, vomiting, dry mouth, increased activity of gamma-glutamyl transferase (due to the induction of this enzyme in the liver), which usually has no clinical significance, increased activity of alkaline phosphatase; sometimes - increased activity of liver transaminases, diarrhea or constipation, abdominal pain; rarely - glossitis, gingivitis, stomatitis, pancreatitis, cholestatic, parenchymal (hepatocellular) type hepatitis, jaundice, granulomatous hepatitis, liver failure.

From the cardiovascular system: rarely - intracardiac conduction disorders; decrease or increase in blood pressure, bradycardia, arrhythmias, atrioventricular block with fainting, collapse, worsening or development of chronic heart failure, exacerbation of coronary heart disease (including the appearance or increased frequency of angina attacks), thrombophlebitis, thromboembolic syndrome.

From the endocrine system and metabolism: often - edema, fluid retention, weight gain, hyponatremia (decrease in plasma osmolarity due to an effect similar to the action of antidiuretic hormone, which in rare cases leads to dilution hyponatremia, accompanied by lethargy, vomiting, headache, disorientation and neurological disorders); rarely - increased concentration of prolactin (may be accompanied by galactorrhea and gynecomastia); a decrease in the concentration of L-thyroxine and an increase in the concentration of thyroid-stimulating hormone (usually not accompanied by clinical manifestations); disorders of calcium-phosphorus metabolism in bone tissue (decrease in the concentration of Ca2+ and 25-OH-cholecalciferol in the blood plasma): osteomalacia, hypercholesterolemia (including high-density lipoprotein cholesterol), hypertriglyceridemia and enlarged lymph nodes, hirsutism.

From the genitourinary system: rarely - interstitial nephritis, renal failure, impaired renal function (for example, albuminuria, hematuria, oliguria, increased urea/azotemia), frequent urination, urinary retention, decreased potency.

From the musculoskeletal system: rarely - arthralgia, myalgia or convulsions.

From the senses: rarely - taste disturbances, increased intraocular pressure; clouding of the lens, conjunctivitis; hearing impairment, incl. tinnitus, hyperacusis, hypoacusia, changes in the perception of pitch.

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

What is the research used for?

A blood test of carbamazepine is prescribed to determine the effective concentration of the drug and its dosage regimen for each patient individually, as well as to prevent the toxic effect of the dosage form used.

When is the study scheduled?

Publications in the media

Pharmgruppa is an antiepileptic drug.

Pharmaceutical action. An antiepileptic drug (dibenzazepine derivative), which also has a normothimic, antimanic, antidiuretic (in patients with diabetes insipidus) and analgesic (in patients with neuralgia) effect. The mechanism of action is associated with the blockade of voltage-gated Na+ channels, which leads to stabilization of the neuronal membrane, inhibition of the occurrence of serial neuronal discharges and a decrease in synaptic conduction of impulses. Prevents the repeated formation of Na+-dependent action potentials in depolarized neurons. Reduces the release of the excitatory neurotransmitter amino acid glutamate, increases the reduced seizure threshold, etc. reduces the risk of developing an epileptic attack. Increases conductivity for K+, modulates voltage-dependent Ca2+ channels, which can also determine the anticonvulsant effect of the drug. Corrects epileptic personality changes and ultimately increases the sociability of patients and promotes their social rehabilitation. It can be prescribed as the main therapeutic drug and in combination with other anticonvulsant drugs. Effective for focal (partial) epileptic seizures (simple and complex), accompanied or not accompanied by secondary generalization, for generalized tonic-clonic epileptic seizures, as well as a combination of these types (usually ineffective for small seizures - petit mal, absence seizures and myoclonic seizures) . In patients with epilepsy (especially children and adolescents), a positive effect on symptoms of anxiety and depression, as well as a decrease in irritability and aggressiveness, was noted. The effect on cognitive function and psychomotor performance is dose dependent and highly variable. The onset of the anticonvulsant effect varies from several hours to several days (sometimes up to 1 month due to autoinduction of metabolism). In case of essential and secondary neuralgia of the trigeminal nerve, in most cases it prevents the occurrence of painful attacks. Effective for relieving neurogenic pain from tabes spinal cord, post-traumatic paresthesia and postherpetic neuralgia. Relief of pain in trigeminal neuralgia is observed after 8-72 hours. In alcohol withdrawal syndrome, it increases the threshold of convulsive readiness (which is usually reduced in this condition) and reduces the severity of the clinical manifestations of the syndrome (increased excitability, tremor, gait disturbances). In patients with diabetes insipidus, it leads to rapid compensation of water balance, reduces diuresis and the feeling of thirst. The antipsychotic (antimanic) effect develops after 7-10 days and may be due to inhibition of the metabolism of dopamine and norepinephrine. The prolonged dosage form ensures the maintenance of a more stable concentration of carbamazepine in the blood without “peaks” and “troughs”, which makes it possible to reduce the frequency and severity of possible complications of therapy and increase the effectiveness of therapy even when using relatively low doses. Dr. An important advantage of the prolonged form is the possibility of taking it 1-2 times a day.

Pharmacokinetics. Absorption is slow but complete (food intake does not significantly affect the speed and extent of absorption). After a single dose of a regular tablet, Cmax is achieved after 12 hours. There are no clinically significant differences in the degree of absorption of the drug after using its various oral dosage forms (bioavailability when taking retard tablets is 15% lower than when taking other dosage forms). After a single oral dose of a tablet containing 400 mg of carbamazepine, the average Cmax of the unchanged active substance is about 4.5 mcg/ml (25% lower when taking the retard form). TCmax - 1.5 hours when taking a suspension continuously, 4-5 hours when taking tablets, for a prolonged dosage form in the form of capsules - 5-9 hours, for tablets with a slow release - 3-12 hours. The retard form allows you to reduce daily fluctuations in plasma levels , while no significant decrease in the minimum Css value is observed. Css in plasma are achieved in 1-2 weeks (the speed of achievement depends on the individual characteristics of metabolism: autoinduction of liver enzyme systems, heteroinduction of others, simultaneously used drugs), as well as on the condition of the patient, the dose of the drug and the duration of treatment. There are significant interindividual differences in Css values in the therapeutic range: in most patients these values range from 4 to 12 μg/ml (17-50 μmol/l). Concentrations of carbamazepine-10,11-epoxide (a pharmacologically active metabolite) are approximately 30% of those of carbamazepine. Communication with plasma proteins in children is 55-59%, in adults - 70-80%. The apparent volume of distribution is 0.8-1.9 l/kg. Concentrations are created in the CSF and saliva in proportion to the amount of drug not bound to proteins (20-30%). Penetrates through the placental barrier. The concentration in breast milk is 25-60% of that in plasma. Metabolized in the liver, mainly along the epoxide pathway with the formation of the main metabolites: active - carbamazepine-10,11-epoxide and inactive conjugate with glucuronic acid. The main isoenzyme that ensures the metabolism of carbamazepine into carbamazepine-10,11-epoxide is cytochrome CYP3A4. As a result of these metabolic reactions, a low-active metabolite, 9-hydroxy-methyl-10-carbamoylacridan, is also formed. Can induce its own metabolism. It is an inducer of CYP3A4, CYP3A5 and CYP3A7 isoenzymes in the liver. T1/2 after taking a single oral dose is 25-65 hours (on average about 36 hours), after repeated doses, depending on the duration of treatment - 12-24 hours (due to autoinduction of the liver monooxygenase system). In patients receiving additional anticonvulsants (inducers of the monooxygenase system - phenytoin, phenobarbital), T1/2 is on average 9-10 hours. After a single oral dose of 400 mg of carbamazepine, 72% of the dose taken is excreted in the urine and 28% in feces . About 2% of the dose taken is excreted in the urine as unchanged carbamazepine, about 1% as the 10,11-epoxide metabolite. In children, due to the faster elimination of carbamazepine, it may be necessary to use higher doses of the drug per 1 kg of body weight compared to adults. There is no evidence that the pharmacokinetics of carbamazepine changes in elderly patients (compared to young adults). Data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function are not yet available.

Indications. Epilepsy (excluding absence seizures, myoclonic or flaccid seizures) - partial seizures with complex and simple symptoms, primary and secondary generalized forms of seizures with tonic-clonic seizures, mixed forms of seizures (monotherapy or in combination with other anticonvulsants). Idiopathic trigeminal neuralgia, trigeminal neuralgia in multiple sclerosis (typical and atypical), idiopathic glossopharyngeal neuralgia. Acute manic states (monotherapy and in combination with Li+ drugs and other antipsychotic drugs). Phasonic affective disorders (including bipolar) prevention of exacerbations, weakening of clinical manifestations during exacerbation. Alcohol withdrawal syndrome (anxiety, convulsions, hyperexcitability, sleep disturbances). Diabetic neuropathy with pain syndrome. Diabetes insipidus of central origin. Polyuria and polydipsia of neurohormonal nature. It is also possible to use (indications are based on clinical experience, no controlled studies have been conducted): - for psychotic disorders (affective and schizoaffective disorders, psychoses, panic disorders, treatment-resistant schizophrenia, dysfunction of the limbic system), - for aggressive behavior of patients with organic brain damage, depression, chorea; - for anxiety, dysphoria, somatization, tinnitus, senile dementia, Klüver-Bucy syndrome (bilateral destruction of the amygdala complex), obsessive-compulsive disorders, benzodiazepine and cocaine withdrawal; — for pain syndrome of neurogenic origin: with tabes dorsalis, multiple sclerosis, acute idiopathic neuritis (Guillain-Barre syndrome), diabetic polyneuropathy, phantom pain, “tired legs” syndrome (Ekbom syndrome), hemifacial spasm, post-traumatic neuropathy and neuralgia, postherpetic neuralgia ; - for the prevention of migraine.

Contraindications. Hypersensitivity to carbamazepine or chemically similar drugs (for example, tricyclic antidepressants) or to any other component of the drug; disorders of bone marrow hematopoiesis (anemia, leukopenia), acute “intermittent” porphyria (including history), AV block, simultaneous use of MAO inhibitors. Carefully. Decompensated CHF, dilution hyponatremia (ADH hypersecretion syndrome, hypopituitarism, hypothyroidism, adrenal insufficiency), old age, active alcoholism (increased central nervous system depression, increased carbamazepine metabolism), suppression of bone marrow hematopoiesis while taking drugs (in history); liver failure, chronic renal failure; prostatic hyperplasia, increased intraocular pressure.

Dosing. Inside, regardless of food intake, along with a small amount of liquid. Retard tablets (a whole tablet or half) should be swallowed whole, without chewing, with a small amount of liquid, 2 times a day. In some patients, when using retard tablets, it may be necessary to increase the dose of the drug. Epilepsy. Where possible, carbamazepine should be prescribed as monotherapy. Treatment begins with a small daily dose, which is subsequently slowly increased until the optimal effect is achieved. The addition of carbamazepine to already ongoing antiepileptic therapy should be carried out gradually, while the doses of the drugs used are not changed or, if necessary, adjusted. For adults, the initial dose is 100-200 mg 1-2 times a day. Then the dose is slowly increased until the optimal therapeutic effect is achieved (usually 400 mg 2-3 times a day, maximum 1.6-2 g/day). Children under 4 years old - at an initial dose of 20-60 mg/day, gradually increasing by 20-60 mg every other day. In children over 4 years of age, the initial dose is 100 mg/day, the dose is increased gradually, every week by 100 mg. Maintenance doses: 10-20 mg/kg per day (in several doses): for 4-5 years - 200-400 mg (in 1-2 doses), 6-10 years - 400-600 mg (in 2-3 doses ), for 11-15 years - 600-1000 mg (in 2-3 doses). For trigeminal neuralgia, 200-400 mg/day is prescribed on the first day, gradually increased by no more than 200 mg/day until the pain stops (on average 400-800 mg/day), and then reduced to the minimum effective dose. For pain syndrome of neurogenic origin, the initial dose is 100 mg 2 times a day on the first day, then the dose is increased by no more than 200 mg/day, if necessary increasing it by 100 mg every 12 hours until the pain subsides. Maintenance dose - 200-1200 mg/day in several doses. When treating elderly patients and patients with hypersensitivity, the initial dose is 100 mg 2 times a day. Alcohol withdrawal syndrome: average dose - 200 mg 3 times a day; in severe cases, the dose can be increased to 400 mg 3 times a day during the first few days. At the beginning of treatment for severe withdrawal symptoms, it is recommended to prescribe it in combination with sedative-hypnotic drugs (clomethiazole, chlordiazepoxide). Diabetes insipidus: the average dose for adults is 200 mg 2-3 times a day. In children, the dose should be reduced according to the age and body weight of the child. Diabetic neuropathy accompanied by pain: average dose - 200 mg 2-4 times a day. For the prevention of relapses of affective and schizoaffective psychoses - 600 mg/day in 3-4 doses. For acute manic states and affective (bipolar) disorders, daily doses are 400-1600 mg. The average daily dose is 400-600 mg (in 2-3 doses). In acute manic states, the dose is increased quickly; for maintenance treatment of affective disorders, the dose is increased gradually (to improve tolerability).

Side effect. When assessing the frequency of occurrence of various adverse reactions, the following gradations were used: very often - 10% and more often; often - 1-10%; sometimes - 0.1-1%; rarely - 0.01-0.1%; very rarely - less than 0.01%. Dose-dependent adverse reactions usually resolve within a few days, either spontaneously or after a temporary dose reduction. The development of adverse reactions from the central nervous system may be a consequence of a relative overdose of the drug or significant fluctuations in the concentrations of the active substance in plasma. In such cases, it is recommended to monitor the concentration of drugs in plasma. From the side of the central nervous system: very often - dizziness, ataxia, drowsiness, asthenia; often - headache, accommodation paresis; sometimes - abnormal involuntary movements (for example, tremor, “fluttering” tremor - asterixis, dystonia, tics); nystagmus; rarely - orofacial dyskinesia, oculomotor disorders, speech disorders (eg dysarthria), choreoathetoid disorders, peripheral neuritis, paresthesia, myasthenia gravis and symptoms of paresis. The role of carbamazepine as a drug that causes or contributes to the development of neuroleptic malignant syndrome, especially when it is prescribed together with antipsychotics, remains unclear. From the mental sphere: rarely - hallucinations (visual or auditory), depression, loss of appetite, anxiety, aggressive behavior, agitation, disorientation; very rarely - activation of psychosis. Allergic reactions: often - urticaria; sometimes - erythroderma; rarely - lupus-like syndrome, skin itching; very rarely - exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), photosensitivity. Rarely - multiorgan delayed-type hypersensitivity reactions with fever, skin rash, vasculitis (including erythema nodosum as a manifestation of cutaneous vasculitis), lymphadenopathy, signs resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered liver function tests (these manifestations found in various combinations). Other organs (eg, lungs, kidneys, pancreas, myocardium, colon) may also be involved. Very rarely - aseptic meningitis with myoclonus and peripheral eosinophilia, anaphylactoid reaction, angioedema, allergic pneumonitis or eosinophilic pneumonia. If the above allergic reactions occur, use of the drug should be discontinued. From the hematopoietic organs: very often - leukopenia; often - thrombocytopenia, eosinophilia; rarely - leukocytosis, lymphadenopathy, folic acid deficiency; very rarely - agranulocytosis, aplastic anemia, true erythrocyte aplasia, megaloblastic anemia, acute “intermittent” porphyria, variegated porphyria, porphyria cutanea tarda, reticulocytosis, hemolytic anemia. From the digestive system: very often - nausea, vomiting; often - dry mouth; sometimes - diarrhea or constipation, abdominal pain; very rarely - glossitis, stomatitis, pancreatitis. From the liver: very often - increased GGT activity (due to the induction of this enzyme in the liver), which usually does not matter; often - increased alkaline phosphatase activity; sometimes - increased activity of “liver” transaminases; rarely - hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, jaundice; very rarely - granulomatous hepatitis, liver failure. From the cardiovascular system: rarely - intracardiac conduction disorders; decrease or increase in blood pressure; very rarely - bradycardia, arrhythmias, AV block with fainting, collapse, worsening or development of CHF, exacerbation of coronary heart disease (including the appearance or increase in angina attacks), thrombophlebitis, thromboembolic syndrome. From the endocrine system and metabolism: often - edema, fluid retention, weight gain, hyponatremia (decrease in plasma osmolarity due to an effect similar to the effect of ADH, which in rare cases leads to dilution hyponatremia, accompanied by lethargy, vomiting, headache, disorientation and neurological disorders); very rarely - hyperprolactinemia (may be accompanied by galactorrhea and gynecomastia); a decrease in the concentration of L-thyroxine (free T4, T4, T3) and an increase in the concentration of TSH (usually not accompanied by clinical manifestations); disorders of calcium-phosphorus metabolism in bone tissue (decrease in the concentration of Ca2+ and 25-OH-colecalciferol in plasma): osteomalacia, osteoporosis; hypercholesterolemia (including HDL cholesterol) and hypertriglyceridemia. From the genitourinary system: very rarely - interstitial nephritis, renal failure, renal dysfunction (for example, albuminuria, hematuria, oliguria, increased urea/azotemia), frequent urination, urinary retention, decreased potency, spermatogenesis disorders (decreased sperm count and motility) . From the musculoskeletal system: very rarely - arthralgia, myalgia or convulsions. From the senses: very rarely - disturbances in taste, lens clouding, conjunctivitis, increased intraocular pressure; hearing impairment, incl. tinnitus, hyperacusis, hypoacusia, changes in the perception of pitch. Other: skin pigmentation disorders, purpura, acne, increased sweating, alopecia. Rare cases of hirsutism have been reported, but the causal relationship of this complication to carbamazepine remains unclear.

Overdose. Symptoms: usually reflect disorders of the central nervous system, cardiovascular system and respiratory system. From the side of the central nervous system and sensory organs - depression of central nervous system functions, disorientation, drowsiness, agitation, hallucinations, fainting, coma; visual disturbances (“fog” before the eyes), dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (initially), hyporeflexia (later); convulsions, psychomotor disorders, myoclonus, hypothermia, mydriasis). From the cardiovascular system: tachycardia, decreased blood pressure, sometimes increased blood pressure, intraventricular conduction disturbances with widening of the QRS complex; heart failure. From the respiratory system: respiratory depression, pulmonary edema. From the digestive system: nausea and vomiting, delayed evacuation of food from the stomach, decreased colonic motility. From the urinary system: urinary retention, oliguria or anuria; fluid retention; dilution hyponatremia. Laboratory indicators: leukocytosis or leukopenia, hyponatremia, metabolic acidosis, hyperglycemia and glycosuria, increased CPK muscle fraction.

Treatment: there is no specific antidote. Treatment is based on the patient's clinical condition; hospitalization, determination of the concentration of carbamazepine in plasma (to confirm poisoning with this drug and assess the degree of overdose), gastric lavage, administration of activated charcoal are indicated (late evacuation of gastric contents can lead to delayed absorption for 2 and 3 days and the reappearance of symptoms of intoxication during the recovery period) . Forced diuresis, hemodialysis and peritoneal dialysis are ineffective (dialysis is indicated for a combination of severe poisoning and renal failure). Young children may require exchange transfusions. Symptomatic supportive treatment in the intensive care unit, monitoring of cardiac function, body temperature, corneal reflexes, renal and bladder function, correction of electrolyte disorders. When blood pressure decreases: position with the head end down, plasma expanders, if ineffective - intravenous dopamine or dobutamine; for heart rhythm disturbances, treatment is selected individually; for convulsions - administration of benzodiazepines (for example diazepam), with caution (due to a possible increase in respiratory depression) administration of other anticonvulsants (for example phenobarbital). With the development of dilution hyponatremia (water intoxication), limit the administration of fluids and slow intravenous infusion of a 0.9% NaCl solution (can help prevent the development of cerebral edema). It is recommended to carry out hemosorption on carbon sorbents.

Interaction. Cytochrome CYP3A4 is the main enzyme responsible for the metabolism of carbamazepine. Co-administration of carbamazepine with CYP3A4 inhibitors may lead to an increase in its plasma concentration and cause adverse reactions. The combined use of CYP3A4 inducers can lead to an acceleration of the metabolism of carbamazepine, a decrease in the concentration of carbamazepine in plasma and a decrease in the therapeutic effect; on the contrary, their withdrawal can reduce the rate of metabolism of carbamazepine and lead to an increase in its concentration. Increase the concentration of carbamazepine in plasma: verapamil, diltiazem, felodipine, dextropropoxyphene, viloxazine, fluoxetine, fluvoxamine, cimetidine, acetazolamide, danazol, desipramine, nicotinamide (in adults, only in high doses); macrolides (erythromycin, josamycin, clarithromycin, troleandomycin); azoles (itraconazole, ketoconazole, fluconazole), terfenadine, loratadine, isoniazid, propoxyphene, grapefruit juice, viral protease inhibitors used in the treatment of HIV infection (for example, ritonavir) - dosage adjustment or monitoring of carbamazepine plasma concentrations is required. Felbamate reduces the plasma concentration of carbamazepine and increases the concentration of carbamazepine-10,11-epoxide, and a simultaneous decrease in the serum concentration of felbamate is possible. The concentration of carbamazepine is reduced by phenobarbital, phenytoin, primidone, methsuximide, fensuximide, theophylline, rifampicin, cisplatin, doxorubicin, possibly clonazepam, valpromide, valproic acid, oxcarbazepine and herbal drugs containing St. John's wort (Hypericum perforatum). There are reports of the possibility of displacement of carbamazepine by valproic acid and primidone from binding to plasma proteins and an increase in the concentration of the pharmacologically active metabolite (carbamazepine-10,11-epoxide). Isotretinoin alters the bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide (monitoring of carbamazepine plasma concentrations is necessary). Carbamazepine may reduce plasma concentrations (reduce or even completely neutralize the effects) and require dose adjustment of the following drugs: clobazam, clonazepam, ethosuximide, primidone, valproic acid, alprazolam, GCS (prednisolone, dexamethasone), cyclosporine, doxycycline, haloperidol, methadone, oral Medicines containing estrogens and/or progesterone (selection of alternative methods of contraception is necessary), theophylline, oral anticoagulants (warfarin, phenprocoumon, dicumarol), lamotrigine, topiramate, tricyclic antidepressants (imipramine, amitriptyline, nortriptyline, clomipramine), clozapine, felbamate, tiagabine, oxcarbazepine, protease inhibitors used in the treatment of HIV infection (indinavir, ritonavir, saquinovir), BMCC (a group of dihydropyridones, for example felodipine), itraconazole, levothyroxine, midazolam, olazapine, praziquantel, risperidone, tramadol, ciprasidone. There are reports that while taking carbamazepine, plasma levels of phenytoin may either increase or decrease, and mephenytoin levels may increase (in rare cases). Carbamazepine, when used together with paracetamol, increases the risk of its toxic effect on the liver and reduces therapeutic effectiveness (acceleration of paracetamol metabolism). The simultaneous administration of carbamazepine with phenothiazine, pimozide, thioxanthenes, molindone, haloperidol, maprotiline, clozapine and tricyclic antidepressants leads to an increased inhibitory effect on the central nervous system and a weakening of the anticonvulsant effect of carbamazepine. MAO inhibitors increase the risk of developing hyperpyretic crises, hypertensive crises, convulsions, and death (before prescribing carbamazepine, MAO inhibitors should be discontinued at least 2 weeks in advance or, if the clinical situation allows, even longer). Concomitant administration with diuretics (hydrochlorothiazide, furosemide) can lead to hyponatremia, accompanied by clinical manifestations. Weakens the effects of non-depolarizing muscle relaxants (pancuronium). If this combination is used, it may be necessary to increase the dose of muscle relaxants, and patients should be closely monitored as their effects may wear off more quickly). Reduces ethanol tolerance. Accelerates the metabolism of indirect anticoagulants, hormonal contraceptive drugs, folic acid; praziquantel may enhance the elimination of thyroid hormones. Accelerates the metabolism of drugs for general anesthesia (enflurane, halothane, fluorothane) with an increased risk of hepatotoxic effects; enhances the formation of nephrotoxic metabolites of methoxyflurane. Strengthens the hepatotoxic effect of isoniazid. Myelotoxic drugs increase the manifestations of hematotoxicity of the drug. Special instructions. Monotherapy for epilepsy begins with the prescription of small doses, individually increasing them until the desired therapeutic effect is achieved. It is advisable to determine plasma concentrations in order to select the optimal dose, especially in combination therapy. When transferring a patient to carbamazepine, the dose of the previously prescribed antiepileptic drug should be gradually reduced until it is completely discontinued. Sudden cessation of carbamazepine may trigger epileptic seizures. If it is necessary to abruptly interrupt treatment, the patient should be transferred to another antiepileptic drug under the cover of the drug indicated in such cases (for example, diazepam administered intravenously or rectally, or phenytoin administered intravenously). Several cases of vomiting, diarrhea and/or decreased nutrition, convulsions and/or respiratory depression have been described in newborns whose mothers took carbamazepine simultaneously with other anticonvulsants (possibly these reactions represent manifestations of the “bruising” syndrome in newborns, hemorrhages in the form of petechiae or purpura. In most cases, a transient or persistent decrease in the number of platelets and/or leukocytes is not a precursor to the onset of aplastic anemia or agranulocytosis. However, clinical blood tests, including platelet count and, possibly reticulocytes, as well as determine the concentration of Fe in the blood serum. Non-progressive asymptomatic leukopenia does not require discontinuation, however, treatment should be discontinued if progressive leukopenia or leukopenia accompanied by clinical symptoms of an infectious disease occurs. Before starting treatment, it is recommended to conduct an ophthalmological examination, including a slit fundus examination lamp and, if necessary, measure intraocular pressure. If the drug is prescribed to patients with increased intraocular pressure, constant monitoring of this indicator is required. It is recommended to stop drinking ethanol. The drug in a prolonged form can be taken once, at night. The need to increase the dose when switching to retard tablets occurs extremely rarely. Although the relationship between the dose of carbamazepine, its concentration and clinical efficacy or tolerability is very small, regular determination of carbamazepine concentrations may be useful in the following situations: with a sharp increase in the frequency of attacks; to check whether the patient is taking the drug properly; during pregnancy; when treating children or adolescents; if there is a suspicion of impaired absorption of the drug; if toxic reactions are suspected if the patient is taking several drugs. In women of reproductive age, carbamazepine should be used as monotherapy whenever possible (using the minimum effective dose) - the incidence of congenital anomalies in newborns born to women who received combined antiepileptic treatment is higher than in those who received each of these drugs as monotherapy. When pregnancy occurs (when deciding whether to prescribe carbamazepine during pregnancy), it is necessary to carefully compare the expected benefits of therapy and its possible complications, especially in the first 3 months of pregnancy. It is known that children born to mothers with epilepsy are predisposed to disorders of intrauterine development, including malformations. Carbamazepine, like all other antiepileptic drugs, can increase the risk of these disorders. There are isolated reports of cases of congenital diseases and malformations, including spina bifida and hypospadias. Patients should be provided with information about the possibility of an increased risk of malformations and the opportunity to undergo antenatal diagnosis. Antiepileptic drugs increase folic acid deficiency, which is often observed during pregnancy, which may increase the incidence of birth defects in children (additional folic acid intake is recommended before and during pregnancy). In order to prevent increased bleeding in newborns, it is recommended that women in the last weeks of pregnancy, as well as newborns, be prescribed vitamin K1. Carbamazepine passes into breast milk; the benefits and possible undesirable effects of breastfeeding should be weighed against ongoing therapy. Mothers taking carbamazepine may breastfeed their infants, provided that the infant is monitored for possible adverse reactions (eg, severe drowsiness, allergic skin reactions). During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.