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

Antiepileptic agent (dibenzazepine derivative), which also has a normotimic, antimanic, antidiuretic (in patients with diabetes insipidus) and analgesic (in patients with neuralgia).

The mechanism of action is associated with the blockade of potential-dependent Na +channels, which leads to the stabilization of the membrane of neurons, the inhibition of the occurrence of serial discharges of neurons, and the reduction of synaptic impulses. Prevents re-education Na +-dependent action potentials in depolarized neurons. Reduces the release of the excitatory neurotransmitter amino acid glutamate, increases the reduced convulsive threshold and thus reduces the risk of developing an epileptic attack. Increases the conductivity for K +, modulates the potential-dependent Ca²⁺channels, which can also cause an anticonvulsant effect of the drug.

Corrects the epileptic personality changes and ultimately enhances the communicability of patients, contributes to their social rehabilitation. Can be prescribed as the main therapeutic drug and in combination with other anticonvulsant drugs.

Effective in focal (partial) epileptic attacks (simple and complex), accompanied or not accompanied by secondary generalization, with generalized tonic-clonic epileptic seizures, and also with a combination of these types (usually ineffective in small seizures - petit mal, absences and myoclonic seizures) .

Patients with epilepsy (especially in children and adolescents) have a positive effect on the symptoms of anxiety and depression, as well as a decrease in irritability and aggressiveness. The effect on cognitive function and psychomotor parameters depends on the dose and is highly variable. The onset of an anticonvulsant effect varies from a few hours to several days (sometimes up to 1 month due to autoinduction of metabolism).

In the case of essential and secondary neuralgia of the trigeminal nerve, in most cases it prevents the occurrence of painful attacks.

Effective for alleviating neurogenic pain in the dry spinal cord, post-traumatic paresthesia and postherpetic neuralgia. Relaxation of pain in trigeminal neuralgia is noted after 8-72 hours.

With alcohol withdrawal syndrome, it increases the threshold of convulsive readiness (which is usually reduced in this condition) and reduces the severity of clinical manifestations of the syndrome (increased excitability, tremor, gait disturbance).

In patients with diabetes insipidus leads to rapid compensation of water balance, reduces diuresis and thirst.

Antipsychotic (antimanic) action develops after 7-10 days, may be due to oppression of the metabolism of dopamine and norepinephrine.

Pharmacokinetics:

Absorption - slow, but complete (eating does not significantly affect the speed and degree of absorption). After a single tablet intake, the maximum concentration in the blood plasma (Cmax) is reached after 12 hours. The time of onset is the equilibrium concentration (Css) in the plasma with daily use is achieved after 1-2 weeks (the rate of achievement depends on the individual characteristics of the metabolism: autoinduction of the liver enzyme systems, heteroinduction of other drugs used simultaneously), as well as the patient's condition, the dose of the drug and the duration of treatment. There are significant interindividual differences in the values Css in the therapeutic range: in most patients these values range from 4 to 12 μg / ml (17-50 μmol / l). The concentrations of carbamazepine-10,11-epoxide (pharmacologically active metabolite) are about 30% of the concentration of carbamazepine.

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

Metabolised in the liver, mainly along the epoxide route with the formation of the main metabolites: active - carbamazepine-10,11-epoxide and inactive conjugate with glucuronic acid. The main isoenzyme providing the metabolism of carbamazepine in carbamazepine-10,11-epoxide is cytochrome CYP3A4. As a result of these metabolic reactions, the low-activity metabolite 9-hydroxy-methyl-10-carbamoylacridan is also formed, can induce its own metabolism. Is the inducer of isoenzymes CYP3A4, CYP3A5 and CYP3A7 in the liver. Half-life (T1 / 2) after taking a single oral dose of 25-65 hours (an average of about 36 hours), after repeated administration, depending on the duration of treatment - 12-24 hours (due to autoinduction of the monooxygenase system of the liver).

In patients receiving additionally other anticonvulsant drugs (inducers of the monooxygenase system - phenytoin, phenobarbital), T1 / 2 - an average of 9-10 hours.

After taking 400 mg of carbamazepine once inside, 72% of the dose is taken with 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 10,11-epoxide metabolite.

Children due to faster elimination of carbamazepine may require the use of higher doses of the drug at a rate of 1 kg of body weight compared with adults.

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

Data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function are not yet available.

Indications:

Epilepsy (monotherapy or as part of complex therapy):

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

- generalized tonic-clonic epileptic seizures;

- mixed forms of epileptic seizures.

Acute manic conditions and maintenance therapy of bipolar affective disorders in order to prevent exacerbations or reduce the severity of clinical manifestations.

In complex therapy of alcohol withdrawal syndrome.

Neuralgia of the trigeminal nerve (idiopathic, with multiple sclerosis), idiopathic neuralgia of the glossopharyngeal nerve.

Contraindications:

Hypersensitivity to any of the components of the drug or to chemically similar medicinal products (tricyclic antidepressants).

Inhibition of bone marrow hematopoiesis.

Hepatic porphyria.

Atrioventricular block.

Simultaneous administration of monoamine oxidase inhibitors (MAO) and a period of two weeks after their withdrawal.

Children up to 4 years.

Breastfeeding period.

Carefully:With caution should be used at low levels of white blood cells or platelets; mixed forms of epileptic seizures, including absences; in old age; with cardiac, hepatic or renal insufficiency; increased intraocular pressure; hyponatremia of breeding, hypothyroidism; hyperplasia of the prostate.

Pregnancy and lactation:

Carbamazepine and its active metabolite quickly penetrate the placenta. The concentration of carbamazepine in the liver and kidneys of the fetus is increased. At the onset of pregnancy (when deciding on the appointment of 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. Treatment of pregnant women with epilepsy should be carried out with extreme caution. It is known that children born to mothers with epilepsy, predisposed to violations of intrauterine development, including malformations. Carbamazepine, like all other antiepileptic drugs, is capable of increasing the risk of these disorders. There are isolated reports of cases of congenital diseases and malformations, including the absence of spinal bifida spines and other congenital anomalies: defects in the development of craniofacial structures, cardiovascular and other organ systems, hypospadias.

With sufficient clinical efficacy for women of childbearing age, the drug should be prescribed as a monotherapy, as the incidence of congenital fetal anomalies with combined antiepileptic therapy is higher than when the drugs are prescribed as 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.The drug should be given in the lowest effective dose. It is recommended to regularly monitor the concentration of active substance in the blood plasma and conduct electroencephalography. 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.

Carbamazepine can reduce the therapeutic effect of oral contraceptive drugs (alternative methods of contraception are needed).

During pregnancy, effective antiepileptic treatment should not be interrupted, as the progression of the disease can have a negative effect on the mother and on the fetus.Antiepileptic drugs increase the deficiency of folic acid, often observed during pregnancy, which can contribute to an increase in the frequency of birth defects in children (before and during pregnancy an additional folic acid supplement is recommended). In order to prevent increased bleeding in newborns in the last weeks of pregnancy, as well as newborns, it is recommended to prescribe vitamin K1. Several cases of epileptic seizures and / or respiratory depression, vomiting, diarrhea and / or hypotrophy in newborns whose mothers have been taken carbamazepine concomitantly with other anticonvulsant drugs (perhaps these reactions are manifestations of the "withdrawal syndrome" in newborns).

Carbamazepine penetrates into breast milk, the concentration of carbamazepine in it is 25-60% of the concentration in the blood plasma. Therefore, one should compare the benefits and possible undesirable effects of breastfeeding in conditions of continuing therapy. When continuing breastfeeding with carbamazepine, the observation of the child should be made in connection withthe possibility of the development of adverse reactions (eg, pronounced drowsiness, allergic skin reactions). In children who received carbamazepine antenatal or with breast milk, cases of cholestatic hepatitis are described, and therefore monitoring of such children should be carried out in order to diagnose side effects from the hepato-biliary system.

Dosing and Administration:

The drug should be taken orally, regardless of food intake, along with a small amount of liquid.

Given the drug interactions with other drugs and the pharmacokinetics of antiepileptic drugs, elderly patients should be selected carefully with carbamazepine.

Epilepsy

If possible, carbamazepine should be administered as a monotherapy. Treatment begins with a small daily dose, which is then slowly increased until an optimal effect is achieved. The recommended therapeutic concentration of carbamazepine in blood plasma is 4-12 μg / ml (17-50 μmol / l). The addition of carbamazepine to already conducted antiepileptic therapy should be carried out gradually, if necessary, appropriate correction of the doses taken.

If the patient forgot to take the next dose of the drug in a timely manner, you should take the missed dose as soon as the omission became noticed, and you can not take a double dose of the drug.

For adults, the initial dose 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 or glossopharyngeal nerves

The initial dose is 200-400 mg / day, the dose is gradually increased by no more than 200 mg / day until the pain ceases (usually up to a dose of 200 mg 3-4 times a day). The maximum daily dose is 1200 mg. After achieving clinical improvement, the dose is reduced (treatment can continue with a lower maintenance dose of 400 mg / day, divided into 2 doses). In the treatment of elderly patients and patients with hypersensitivity, the initial dose is -100 mg 2 times a day.

Alcohol withdrawal syndrome

The average dose is 200 mg 3 times a day; in severe cases during the first few days the dose can be increased to 400 mg 3 times a day.At the beginning of treatment with severe manifestations of alcohol withdrawal, treatment is recommended in combination with drugs that have sedative and hypnotic effects (for example, clomethiazole, chlordiazepoxide). After resolving the acute phase, treatment with the drug can be continued as a monotherapy.

Acute manic conditions and maintenance therapy of bipolar affective disorders

The daily dose is 400-1600 mg. The average daily dose is 400-600 mg (2-3 times taken). 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.

The length of the course of treatment depends on the indications, the effectiveness of the treatment, the patient's response to therapy.

Discontinuation of the drug

A sudden discontinuation of the drug may trigger epileptic seizures, so carbamazepine should be lifted gradually over 6 months or more. If it is necessary to cancel the 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.

Use in children

The main indication for the use of carbamazepine in children is epilepsy. This drug form of the drug should be used to treat the same as in adults, forms of epilepsy in children older than 4 years. Treatment can be started with a dose of 100 mg / day; dose increase gradually, no more than 100 mg per week.

Children aged 4 years and under are recommended to take carbamazepine in the form of other dosage forms (syrup), the initial dose for children aged 4 years and younger is 20-60 mg / day with a gradual increase of 20-60 mg / day every other day.

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

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

Maximum doses: for children <6 years 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 do not 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 values indicated in dosage table.

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 CNM 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 "-> 1/10000 - <1/1000," very rarely "- <1/10000, including individual messages.

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

Impaired 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, urticaria, 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 from 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 agranulocytosis in the general population not receiving treatment is 4.7 cases per million population per 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.

Disorders 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 disorders: rarely - multi-organ hypersensitivity of delayed type with fever, skin rashes, vasculitis, lymphadenopathy, signs resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered parameters of liver function and destruction of intrahepatic bile ducts with a decrease in their number (these manifestations occur in various 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, bradycardia, arrhythmia, 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 system: often swelling, fluid retention, weight gain, hyponatremia and decreased blood osmolarity due to an effect similar to that of antidiuretic hormone, which in rare cases leads to water intoxication (hyponatremia), accompanied by lethargy, vomiting, headache, disorientation and neurologic impairment ; 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 of the urinary tract: very rarely tubulointerstitial nephritis, renal failure, impaired renal function (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 mobility) .

Disorders from the side of the organ of vision: often - a violation of accommodation (including blurred vision); very rarely - clouding of the lens, conjunctivitis.

Hearing disorders and labyrinthine disturbances: very rarely - hearing disorders, including tinnitus, hyperacusia, hypoacusia, changes in perception of the height of sound.

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

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

Undesirable phenomena according to postmarketing observations (frequency unknown):

Infectious and parasitic diseases: reactivation of the herpes simplex virus type 6.

Violations of the blood and lymphatic system: bone marrow failure.

Disturbances from the nervous system: 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, onychomadezis.

Laboratory and instrumental data: decreased bone density.

Overdose:

Overdose is usually manifested by symptoms from the side of the central nervous system, cardiovascular and respiratory systems, as well as the phenomena indicated in the "side effect" section. In case of an overdose, the following symptoms and complaints are possible:

Central nervous system: oppression of the central nervous system; 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, increase or decrease in blood pressure, conduction disorders with expansion of the QRS complex; 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: retention of urine, 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, increased activity of muscle fraction, 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 reinforce the symptoms of overdose on the 2nd and 3rd day after its onset, which is due to the slow absorption of carbamazepine.

Interaction:

Isozyme cytochrome P4503A4 (CYP3A4) is the main enzyme providing the formation of carbamazepine-10,11-epoxide (active metabolite). Simultaneous use of carbamazepine with inhibitors of the isoenzyme CYP3A4 can lead to an increase in its concentration in the plasma, which, in turn, can cause side reactions. The combined use of CYP3A4 isoenzyme inducers can lead to an acceleration of the metabolism of carbamazepine and, thus, to a possible decrease in its plasma concentration and, consequently, to a possible decrease in the severity of the therapeutic effect. The cancellation of simultaneously taken inducers of the isoenzyme CYP3A4 can reduce the rate of biotransformation of carbamazepine and, as a consequence, lead to an increase in its concentration in the blood plasma. Carbamazepine is a strong inducer of the isoenzyme CYP3A4 and enzyme hepatic systems of the first and second phase and, when used simultaneously with drugs metabolized by the isoenzyme CYP3A4, can cause induction of metabolism and a decrease in their concentration in the plasma.Since the conversion of carbamazepine-10,11-epoxide into carbamazepine-10,11-trans-diol takes place with the microsomal enzyme of epoxide hydrolase, the use of the drug together with epoxyhydrolase inhibitors can lead to an increase in the blood plasma concentrations 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 (androgens): danazol; macrolide antibiotics: erythromycin, troleandomycin, josamycin, clarithromycin; antidepressants: possible desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine; antiepileptic drugs: styipentol, vigabatrin; antifungal agents: azole derivatives (eg, itraconazole, ketoconazole, fluconazole, voriconazole); blockers of H1-histamine receptors: loratadine, terfenadine; antipsychotic drugs (antipsychotics): olanzapine; anti-tuberculosis drugs: isoniazid; antiviral agents: HIV protease inhibitors for the treatment of HIV infection (eg, ritonavir); antiglaucoma agents (inhibitors of carbonic anhydrase): acetazolamide; antihypertensive agents (blockers of "slow" calcium channels): verapamil, diltiazem; antiulcer agents (proton pump inhibitors, H2-histamine receptor blockers): omeprazole, cimetidine; muscle relaxants: oxybutynin, dantrolene; antiplatelet agents: ticlopidine; other medicines and nutritional supplements: grapefruit juice, nicotinamide (in adults, only in high doses).

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

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 level of carbamazepine-10,11-epoxide in blood plasma can lead to the occurrence of adverse reactions (for example, dizziness, drowsiness, ataxia,diplopia), in these situations, the dosage of the drug should be corrected and / or the carbamazepine-10,11-epoxide concentration in the blood plasma regularly determined.

Drugs that can reduce the concentration of carbamazepine in blood plasma: antiepileptic agents: felbamate, mezuximide, oxcarbazepine, phenobarbital, fensuximide, phenytoin and fosphenytoin, primidon and, possibly, also clonazepam; antineoplastic agents: cisplatin or doxorubicin; anti-tuberculosis drugs: rifampicin; bronchodilating

facilities: theophylline, aminophylline; remedy for acne (retinoids): isotretinoin; other medicines and nutritional supplements: 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

When combined with carbamazepine, a decrease in plasma concentration, a decrease or even a complete cessation of action of certain drugs is possible.When used simultaneously with carbamazepine, dosage adjustments for the following drugs may be required: analgesic and non-steroidal anti-inflammatory drugs: buprenorphine, methadone, paracetamol, phenazone, tramadol; antibiotics of the tetracycline group: doxycycline; oral anticoagulants: warfarin, fenprokumone, dicoumarol and acenocoumarol; antidepressants: bupropion, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (imipramine, amitriptyline, nortriptyline, clomipramine); antiepileptic drugs: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidon, tiagabine, topiramate, valproic acid, zonisamide; antifungal agents: itraconazole; anthelmintic means: praziquantel; antineoplastic agents: imatinib; antipsychotic drugs (antipsychotics): clozapine, haloperidol, bromperidol, olanzapine, quetiapine, risperidone, ziprasidone; antiviral agents: HIV protease inhibitors used in HIV therapy (indinavir, ritonavir, saquinavir); anxiolytic means: alprazolam, midazom; bronchodilating agents: theophylline; contraceptive means: oral contraceptive means (alternative methods of contraception are needed); antihypertensive agents (blockers of "slow" calcium channels of the dihydropyridines group): felodipine; cardiac glycosides: digoxin; glucocorticosteroids: prednisolone, dexamethasone; immunosuppressive means: ciclosporin, everolimus; funds for the treatment of thyroid diseases: levothyroxine; other medicines and food products: preparations containing estrogens and / or progesterone.

Women may experience bleeding in the period between menstruation in cases when oral contraceptives were used simultaneously. The drug may reduce the therapeutic effect of oral contraceptive preparations due to the induction of microsomal effects.

There are reports that, when taking carbamazepine, the concentration of phenytoin in the plasma can both increase and decrease, and the concentration of mephenitoin increases (in rare cases).

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.

Combinations that should be taken into account

It is possible to increase the hepatotoxicity caused by isoniazid, in case of simultaneous application with carbamazepine.

In case of simultaneous application with levetiracetam, the toxic effect of carbamazepine may be increased. 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).

Carbamazepine, when used concomitantly with paracetamol, increases the risk of its toxic effect on the liver and reduces therapeutic effectiveness (acceleration of the metabolism of paracetamol).

Simultaneous use of carbamazepine with phenothiazine derivatives, pimozide, thioxanthene derivatives, molindone, haloperidol,maprotilinom, clozapine and tricyclic antidepressants leads to an increase in the inhibitory effect on the central nervous system and the weakening of the anticonvulsant effect of carbamazepine.

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

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

Carbamazepine can exhibit antagonism to the action of nondepolarizing muscle relaxants (for example, pancuronium bromide). If such a combination is used, it may be necessary to increase the dose of muscle relaxants, and careful monitoring of the patients is necessary, since a faster cessation of their effect is possible).

Reduces the tolerance of ethanol.

Accelerates the metabolism of indirect anticoagulants, hormonal contraceptive drugs, folic acid, praziquantel, can enhance the elimination of thyroid hormones.

Accelerates the metabolism of the drug for general anesthesia (enflurane, halothane, ftorotan) with an increased risk of hepatotoxic effects; enhances the formation of nephrotoxic metabolites of methoxyflurane.

Interaction with serological reactions

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

Special instructions:

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

The drug is 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, the drug 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 the beginning of treatment, and also periodically during the treatment, it is necessary to conduct clinical blood tests, including counting the number of platelets and, possibly, reticulocytes, as well as 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 immediately consult a doctor in case of the appearance of such undesirable reactions as fever, sore throat, rash, oral ulcers, unjustified bruising, hemorrhages in the form of petechiae or purpura.

In those cases when a low white blood cell or platelet count is observed during treatment (or a tendency to decrease them), you should carefully monitor the patient's condition and the indicators of the developed clinicalblood test. If signs of significant bone marrow suppression are revealed, the drug should be canceled.

Dermatological reactions

Severe dermatological reactions with carbamazepine, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), developed in approximately 1-6 cases per 100,000 first-time carbamazepine in countries with predominantly Caucasoid populations. The drug should be immediately withdrawn if signs and symptoms suggestive of the development of Stevens-Johnson syndrome or Lyell syndrome are noted.

With the development of severe (in some cases life-threatening patient) skin reactions, the patient must be hospitalized in a hospital. In most cases, Stevens-Johnson syndrome and Lyell's syndrome developed during the first months of therapy with the drug.

Retrospective analysis data from patients of Japanese nationality and inhabitants of Northern Europe demonstrated a link between severe skin lesions (Stevens-Johnson syndrome, Lyell syndrome, drug rash with eosinophilia and systemic manifestations,acute generalized exanthematous pustulosis and patchy-nodular rash) in carriers of the HLA-A * 3101 allele 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 (HLA) gene may differ for different ethnic groups. The allele frequency is less than 5% in the population of Europe, Australia, Asia, Africa and North America, exceptions are from 5% up 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 Spoke tribes, Sanori in Mexico), South India (Tamil Nadu), and 10-15% among others native inhabitants of these regions.

When prescribing carbamazepine, it is recommended that the HLA-A * 3101 allele carriers (for example, Japanese patients, Caucasians, Native Americans, Hispanics, people of southern India and Arabs) be genotyped with this allele. Prescribe the drug carriers of this allele should be only if the benefit of therapy exceeds the possible risk.

Patients already receiving carbamazepine, it is not recommended to carry out genotyping on this allele, since severe skin reactions in most cases were observed 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 Chinese patients, 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.

When carbamazepine was used in patients in the countries of the Asian region (Thailand, Malaysia, Philippines), where the prevalence of the HLA-B * 1502 allele was noted, an increase in the frequency of development (from "very rare" (<1/10000) to "rarely" (> 1/10000 - <1/1000)) of severe dermatological reactions, including Stevens-Johnson syndrome and Lyell's syndrome. The frequency of distribution of the HLA-B * 1502 allele is more than 15% in the Philippines, Thailand, Hong Kong and Malaysia, 10% in Taiwan, 4% in Northern China, 2-4% in South Asia (including India) in Japan and Korea - less than 1%. The prevalence of this allele in Caucasians, Negroid and Americanoid (Latino and Indian) races is insignificant.

When prescribing carbamazepine, it is recommended that carriers of the HLA-B * 1502 allele (for example, Chinese nationals) be genotyped according to this allele. Prescribe the drug carriers of this allele should be only if the benefit of therapy exceeds the possible risk. In the face of the Caucasoid, Negroid and Americanic races, genotyping along the HLA-B * 1502 allele before prescribing carbamazepine is not necessary.

Patients who are already receiving carbamazepine therapy are not recommended to carry out genotyping for this allele, since severe skin reactions were mostly observed in the first months of application (regardless of the presence of the HLA-B * 1502 allele). It has been shown that the identification of patients with the presence of the HLA-B * 1502 allele and the absence of the prescription 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.Also in many cases, patients with positive HLA-B * 1502 and HLA-A * 3101 alleles did not develop severe skin syndrome with carbamazepine.

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

Slightly expressed skin reactions, for example, isolated macular or maculopapular exanthema, in most cases are transient and mild, usually occur for several days or weeks with continued treatment or after a reduction in the dose of the drug. Nevertheless, since differential diagnosis between early manifestations of severe skin reactions and mild skin transient eruptions 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 the drug therapy 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 reactions to anticonvulsants or mildly exaggerated maculate), for the HLA-B * 1502 allele such a relationship is not established.

Hypersensitivity reactions

With the development of hypersensitivity to the drug in patients can be observed as separate lesions of the skin, liver, blood and lymphatic systems or other organs, and their combination, which should be regarded as a systemic reaction.

In case of development of symptoms and symptoms of hypersensitivity to the drug, it should be immediately canceled.

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 of hypersensitivity is also found between carbamazepine and phenytoin.

Hyponatremia

The development of hyponatremia is associated with the use of carbamazepine. In patients with pre-existing renal damage associated with low serum sodium levels,(eg, diuretics, drugs that affect the secretion of an antidiuretic hormone), serum sodium should be determined before the initiation of carbamazepine therapy. 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 the appointment of the drug and during the treatment it is necessary to study the liver function, especially in patients,in the anamnesis of which there is information about the liver disease, as well as in elderly patients. In case of strengthening of already existing violations of the liver function or when there is an active liver disease, the drug should be immediately canceled.

Violations of the function of the nights

Before starting treatment with the drug and periodically during therapy, a general urine and urea test in the blood is recommended.

M-holinoblocking activity The drug has a weak anticholinergic 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

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

Suicidal behavior or intentions

Treatment with antiepileptic drugs, including carbamazepine, may be accompanied by the appearance of suicidal attempts / suicidal intentions. Patients (and attendants) should be warned about the need to monitor the occurrence ofsuicidal attempts / suicidal intentions and, in the event of symptoms, seek medical help immediately.

Endocrinological disorders

There are some reports of violations of male fertility and / or violations of spermatogenesis. However, the causal relationship between these disorders and carbamazepine has not been proven to date. 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.

Determination of carbamazepine plasma concentration

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 cases: 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 drug absorption abnormalities; atsuspicion of the development of toxic reactions in case the patient takes several medicines.

Translation into carbamazepine from another antiepileptic drug

When transferring the patient to carbamazepine should gradually reduce the dose of the previously prescribed antiepileptic drug until its complete cancellation.

Joint reception with alcohol

For the duration of therapy, it is necessary to refrain from drinking alcohol, since carbamazepine enhances the depressant effect of alcohol on the central nervous system.

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

During the treatment period, care should be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions (the reaction rate may be disturbed due to dizziness, drowsiness, visual impairment, especially at the beginning of treatment or during the dose selection period) . Patients should be warned about possible hazards in the management of vehicles and working with mechanisms.

Form release / dosage:

Tablets 200 mg.

Packaging:For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

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

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:P N001329 / 01

Date of registration:23.07.2008

The owner of the registration certificate:VALENTA PHARM, PAO VALENTA PHARM, PAO Russia

Manufacturer: & nbsp

VALENTA PHARMACEUTICS, JSC Russia

Representation: & nbspVALENTA PHARM, PAO VALENTA PHARM, PAO Russia

Information update date: & nbsp07.12.2017

Illustrated instructions

Instructions

Carbamazepine (Carbamazepine)