Zeptol - instructions for use, doses, side effects, contraindications

Excipients: ethylcellulose M50 - 11.50 mg / 45.00 mg, microcrystalline cellulose - 33.75 mg / 27.50 mg, hypromellose 2208 (Methocel K4M) 25.00 mg (for tablets 400 mg), corn starch 1.80 mg / 10.00 mg, talc purified - 10.50 mg / 20.00 mg, silicon dioxide colloid - 2.50 mg / 5.00 mg, croscarmellose sodium - 2.50 mg / 10.00 mg, magnesium stearate - 2.50 mg / 5.00 mg;

shell composition: butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer [1: 2: 1] (Eudragit E-100) - 2.50 mg / 3.00 mg, talc purified 2.15 mg / 4.30 mg, macrogol-6000 (polyethylene glycol 6000) - 0.50 mg / 1.00 mg, titanium dioxide 2.0 mg / 4.0 mg, magnesium stearate 1.00 mg / 2.00 mg, iron oxide red oxide 0.10 mg / 0.20 mg, iron-oxide oxide yellow - 0.25 mg / 0.50 mg.

Description:

Round biconvex tablets of light brown color, covered with a film membrane, with a risk on one side.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.F.01 Carbamazepine

Pharmacodynamics:

The derivative of iminostilbene, which has a pronounced anticonvulsant (antiepileptic) effect, and also to a moderate degree antipsychotic, antidepressant (timoanaleptic) and normotimicheskim action. In addition, it has an analgesic effect, especially in trigeminal neuralgia. The mechanism of action has been studied in part.

Presumably, anticonvulsant action is associated with a decrease in the ability of neurons, maintain a high frequency of development of repeated action potentials through inactivation of sodium channels. In addition, it seems that inhibition of the release of neurotransmitters by blocking the presynaptic sodium channels and the development of action potentials, which in turn reduces the synaptic transmission, is important.

The mechanisms of action may involve gamma-aminobutyric acid (GABA) receptors, which can be linked to calcium channels; Also, apparently, the effect of carbamazepine on the systems of neurotransmitter modulators is important.The antidiuretic effect of carbamazepine may be related to the hypothalamic effect on osmoreceptors, which is mediated through the secretion of the antidiuretic hormone, and is also due to direct action on the renal tubules.

Effective with 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 of attacks (usually ineffective in small attacks - petit mal, absences and myoclonic seizures).

In patients with epilepsy (especially in children and adolescents) a positive effect on symptoms of anxiety and depression, as well as reduced irritability and aggressiveness. Influence on cognitive function and psychomotor parameters depends on the dose. The onset of anticonvulsant effect varies from several 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.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). Antipsychotic (antimanic) action develops after 7-10 days, may be due to the 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 when taken 1-2 times a day.

Pharmacokinetics:

Absorption is 72-96%. The maximum concentration in the blood plasma is achieved after 6-24 hours. Binding to plasma proteins is about 75%. The half-life is from 30 to 40 hours. 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. A low-active metabolite of 9-hydroxymethyl-10 carbamoylacridan is also formed. The concentration of carbamazepine-10,11-epoxide is 30% of the concentration of carbamazepine.In the cerebrospinal fluid (further CSF) and saliva, concentrations are created in proportion to the amount of the active substance unbound with proteins (20-30%). Penetrates through the placental barrier. Concentration in breast milk is 25-60% of that in plasma. It is excreted as inactive metabolites with urine (70%) and feces (30%).

It is an inducer of hepatic enzymes and stimulates its own metabolism. There is no evidence that the pharmacokinetics of carbamazepine change in elderly patients.

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

Indications:

- Epilepsy: 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;

- trigeminal neuralgia and neurogenic pain syndrome;

- Pain in the defeat of peripheral nerves in diabetes mellitus, pain in diabetic neuropathy, polyuria and polydipsia of neurohormonal nature in diabetes insipidus of central genesis;

- idiopathic neuralgia of the trigeminal nerve and trigeminal neuralgia with multiple sclerosis (typical and atypical); idiopathic neuralgia of the glossopharyngeal nerve;

- alcohol withdrawal syndrome;

- acute manic conditions and maintenance therapy of bipolar affective disorders with the purpose of preventing exacerbations or alleviating clinical manifestations of exacerbation.

Contraindications:

- Hypersensitivity to carbamazepine and other components of the drug, as well as to substances with a carbamazepine-like structure (eg, tricyclic antidepressants);

- Children under 4 years (for children under 4 years old carbamazepine preferably in the form of a syrup - due to the difficulties of using solid dosage forms in this age group);

- Mr.ossification of bone marrow hematopoiesis (anemia, leukopenia);

- Mr.A history of episodes of suppression of bone marrow hematopoiesis or all varieties of porphyria;

- atrioventricular blockade;

- aboutsimultaneous administration of lithium preparations and MAO inhibitors.

Carefully:

Decompensated chronic heart failure,hyponatremia of dilution (ADH hypersecretion syndrome, hypopituitarism, hypothyroidism, adrenal cortex insufficiency), liver and kidney function deficiency, elderly age, active alcoholism (CNS depression is increased, carbamazepine metabolism is increased), oppression of bone marrow hemopoiesis against medications (in anamnesis), hyperplasia prostate cancer, increased intraocular pressure, in combination with sedative-hypnotics.

Pregnancy and lactation:

Zepthol treatment of epilepsy during pregnancy should be carried out with extreme caution.

In women of childbearing age, Zeptol should, if possible, be used as a monotherapy, since the incidence of congenital anomalies in fetuses born to women treated with a combination of antiepileptic drugs is higher than those who received each of these agents as monotherapy. The minimum effective dose of Zeptol should be given.

It is recommended that the concentration of carbamazepine in the blood plasma be monitored regularly.

When pregnancy occurs in a woman receiving Zepthol, or in the event that she is pregnant,if there is a question about the appointment of Zeptol in pregnancy, it is necessary to carefully compare the expected benefits of therapy and its possible complications, especially in the first trimester of pregnancy.

It is known that children born to mothers with epilepsy are more likely to be predisposed to violations of intrauterine development, including malformations. It was reported that carbamazepine, like all major antiepileptic drugs, is capable of increasing the risk of these disorders, although there is no final confirmation that would have been obtained through controlled trials using Zepthol as monotherapy. There are reports of cases of congenital diseases and malformations, including spina bifida and other congenital anomalies (including craniofacial and cardiovascular system) that have been observed in patients taking Zaptol. Patients should be provided with information on the possibility of increasing the risk of malformations and the possibility of undergoing antenatal diagnosis. It is known that when pregnancy develops a deficiency of folic acid, it was reported that antiepileptic drugs enhance 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, it is recommended to prescribe vitamin K₁.

Carbamazepine is excreted in breast milk, the concentration in it is 25-60% of the level in the blood plasma. Therefore, the benefits and possible undesirable effects of breastfeeding should be compared with the ongoing therapy with Zeptol. Mothers taking Zeptol may continue breastfeeding, but on condition that a child is observed to develop possible side effects (eg, severe drowsiness, allergic skin reactions).

It is recommended that the concentration of carbamazepine in breast milk be monitored regularly.

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 vomiting, diarrhea, and / or reduced diets in neonates whose mothers received Zepthol have also been reported. Perhaps these reactions are manifestations in newborn withdrawal syndrome.

Women of childbearing age during the treatment with carbamazepine are recommended to use non-hormonal contraceptives.

Dosing and Administration:

Inside. The drug can be taken during, after meals or in between meals 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 swallowed whole, without chewing, squeezed with a small amount of liquid, tk. the active substance is released from the tablets of prolonged action slowly and gradually, they are prescribed 2 times / day. Given that Zeptol is prescribed 2 times / day, the optimal scheme of therapy is determined by the doctor on the basis of the recommendations given.

When transferring a patient from taking conventional tablets to taking prolonged-action tablets,that at some patients at application of tablets of the prolonged action there can be a necessity in increase of a dose of a preparation.

Epilepsy: complex or simple partial epileptic seizures (with or without loss of consciousness) with or without secondary generalization: generalized tonic-tonic epileptic seizures: mixed fseizures of epileptic seizures: If possible, Zeptol should be given as monotherapy. Treatment begins with a small daily dose, which is then slowly increased until an optimal effect is achieved. To determine the optimal dose of the drug, it is recommended to determine the concentration of the active substance in the blood plasma. Joining Zepthol to already conducted antiepileptic therapy should be carried out gradually, while the doses of the drugs used do not change or, if necessary, carry out appropriate correction of the doses of the drugs 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 this omission became noticed, while you can not take a double dose of the drug.

For adults the initial dose of 100-200 mg 1-2 times a day. Then the dose is slowly increased to 400-600 mg 2 times a day. The maximum daily dose is 1600-2000 mg.

For children at the age of over 4 years treatment can be started with the use of the drug at a dose of 100 mg / day; The dose is increased gradually - every week by 100 mg.

For children under 4 years carbamazepine is preferably administered in the form of a syrup due to the difficulties in using solid dosage forms in this age group.

Supportive doses for children are 10-20 mg / kg / day (in several steps):

Age of child	Daily dose
4-5 years	200-400 mg
6-10 years	400-600 mg
11-15 years old	600-1000 mg

With neuralgia of the trigeminal nerve and neurogenic pain syndrome: 100-200 mg twice a day, then gradually increase the dose by no more than 200 mg per day until the pain ceases (on average 600-800 mg), then reduced to the lowest effective dose. The effect usually occurs 1 to 3 days after the start of treatment. Assign the drug for a long time; with the premature cancellation of the drug pain can resume. In the treatment of elderly patients, the initial dose is 100 mg 2 times a day.

Pain in the defeat of peripheral nerves in diabetes mellitus, pain in diabetic neuropathy: 200-300 mg 2 times a day.

Polyuria and polydipsia neurohormonal of nature in diabetes insipidus central genesis: the average dose for adults is 200 mg 2 times a day. In children, the dose of the drug should be reduced in accordance with the age and body weight of the child.

Idiopathic neuralgia of the trigeminal nerve and trigeminal neuralgia in multiple sclerosis; idiopathic neuralgia of the glossopharyngeal nerve: the average daily dose is 200-400 mg twice a day.

Alcohol abstinence syndrome: the average dose is 200 mg twice a day. In severe cases, in the first days the dose can be increased to 600 mg 2 times a day. At the beginning of treatment, severe abstinence is prescribed in combination with detoxification therapy and sedative-hypnotic drugs (for example, clomethiazole, chlordiazepoxide). After resolving the acute phase, Zeptol treatment can be continued as a monotherapy.

Acute manic conditions and maintenance therapy of bipolar affective disorders: in the first week the daily dose of 200 - 400 mg. Subsequently, the dose is increased by 200 mg per week, bringing it to 1 g / day. The daily dose is evenly divided into 2 doses.

The transition to carbamazepine treatment should be gradual, with a decrease in the dose of the previous drug. Stop treatment should be gradual.The duration of treatment is determined by the doctor.

Side effects:

When assessing the frequency of occurrence of various adverse reactions, the following grades are used: very often 10% or more; often - 1-10%; infrequently, 0.1-1%; rarely - 0,01-0,1%; very rarely - less than 0.01%.

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

From the central nervous system (further CNS): very often - dizziness, ataxia, drowsiness, fatigue; often - headache, diplopia, impaired vision accommodation (eg, blurred vision); infrequently - abnormal involuntary movements (eg, tremor, "fluttering" tremor - asterixis, dystonia, tics); nystagmus; rarely - orofacial dyskinesia, oculomotor disorders, speech disorders (eg, dysarthria), choreoathetosis, peripheral neuropathy, paresthesia, paresis; very rarely - taste disorders, malignant neuroleptic syndrome.The role of the carbamazepine as the drug causing or contributing to the development of neuroleptic malignant syndrome, especially when it is administered in conjunction with antipsychotics, remains unclear.

From the psychic sphere: rarely - hallucinations (visual or auditory), depression, anorexia, anxiety, aggression, agitation, disorientation; very rarely - activation of psychosis.

Allergic reactions: very often - allergic dermatitis, hives, which can be very pronounced; infrequently - exfoliative dermatitis, erythroderma; rarely - systemic lupus erythematosus, itching; very rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity reactions, erythema multiforme and nodosum, skin pigmentation disorders, purpura, acne, sweating, hair loss. There have been reports of rare cases of hirsutism, but the cause-and-effect relationship of this complication with taking the drug remains unclear.

Hypersensitivity reactions: 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 - aseptic meningitis with myoclonus and peripheral eosinophilia, anaphylactic reaction, angioedema. If the above-mentioned allergic reactions occur, the drug should be discontinued.

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

From the digestive system (further GASTROINTESTINAL TRACT): very often - a nausea, vomiting; often - dry mouth; infrequently - diarrhea, constipation; rarely - abdominal pain; very rarely - glossitis, stomatitis, pancreatitis.

From the side of the liver: very often - increasing the activity of gamma-glutamyl transferase (due to the induction of this enzyme in the liver), which usually has clinical significance; often - increased activity of alkaline phosphatase of the blood; infrequently - increased activity of transaminases; rarely - hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, destruction of intrahepatic bile ducts with a decrease in their number, jaundice; very rarely - granulomatous hepatitis, hepatic insufficiency.

From the side of the cardiovascular system (further SSS): rarely - violations intracardiac conduction; decrease or increase in blood pressure (BP); very rarely - bradycardia, arrhythmias, atrio-ventricular blockade with syncope, collapse, chronic heart failure, exacerbation of coronary heart disease, thrombophlebitis, thromboembolism (eg, pulmonary embolism).

From the endocrine system and metabolismFrequently - edema, fluid retention, weight gain, and decreased blood hyponatremia osmolarity due to an effect similar to the action of antidiuretic hormone,which in rare cases leads to water intoxication (hyponatremia of breeding), accompanied by lethargy, vomiting, headache, disorientation and neurologic disorders; very rarely - an increase in the concentration of blood prolactin, accompanied or not accompanied by such manifestations as galactorrhea, gynecomastia; changes in the function of the thyroid gland - reduced concentration L-tiroxine (free thyroxine, thyroxine, triiodothyronine) and an increase in the thyroid-stimulating hormone (TSH) concentration, which is usually not accompanied by clinical manifestations; metabolic disorders of bone tissue (decrease in calcium and 25-hydroxycholecalciferol in the blood), which leads to osteomalacia / osteoporosis; increased cholesterol concentrations, including high-density lipoprotein cholesterol, and triglycerides.

From the genitourinary system: very rarely - interstitial nephritis, renal insufficiency, renal dysfunction (eg, albuminuria, hematuria, oliguria, urea / azotemia increase), frequent urination, urinary retention, sexual function / impotence disorders, spermatogenesis disorders (decrease in the number of spermatozoa and their mobility) .

From the side of the musculoskeletal system: rarely - muscle weakness; very rarely - arthralgia, muscle pain or cramps.

From the sense organs: very rarely - a violation of taste, clouding of the lens, conjunctivitis, increased intraocular pressure; Hearing impairment, incl. noise in the ears, hyperacusia, hypoacusia, changes in perception of the height of sound.

Overdose:

Symptoms: usually reflect abnormalities from the CNS, SSS and respiratory system. From the side of the central nervous system and sensory organs - oppression of CNS functions, 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).

On the part of the CAS: tachycardia, decreased blood pressure, sometimes increased blood pressure, intraventricular conduction disorders with expansion of the complex QRS; fainting, cardiac arrest.

On the part of the respiratory system: respiratory depression, pulmonary edema.

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

From the urinary system: retention of urine, oliguria or anuria; fluid retention; hyponatremia.

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

Treatment: there is no specific antidote. Treatment is based on the clinical condition of the patient; (for confirmation of poisoning with this drug and assessment of the degree of overdose), gastric lavage, the appointment of activated charcoal (late evacuation of gastric contents can lead to delayed absorption on days 2 and 3 and the re-emergence of symptoms of intoxication during the recovery period) . Intense diuresis, hemodialysis and peritoneal dialysis are ineffective (dialysis is indicated by a combination of severe poisoning and kidney failure). In young children, there may be a need for exchange blood transfusion. Symptomatic supportive treatment in the intensive care unit, monitoring of heart function, body temperature, corneal reflexes, kidney and bladder function, correction of electrolyte disorders.

With a decrease in blood pressure: the position with the lowered head end, plasma substitutes, with ineffectiveness - in / in dopamine or dobutamine; at heart rhythm disturbances - treatment is selected individually; with convulsions - the introduction of benzodiazepines (eg, diazepam), with caution (because of the possible increase in respiratory depression), the introduction ofof the anticonvulsant drugs (eg, phenobarbital).

With the development of hyponatremia of dilution (water intoxication) - restriction of the introduction of fluids and slow intravenous infusion of 0.9% solution NaCl (can help prevent the development of brain edema). It is recommended to carry out hemosorption on carbon sorbents.

Interaction:

Cytochrome P4503A4 (CYP3A4) is the main enzyme providing formation of carbamazepine-10,11-epoxide (active metabolite). Simultaneous application of Zeptol with inhibitors of the isoenzyme CYP3A4 can lead to an increase in the concentration of carbamazepine in the plasma and 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 of the drug.The cancellation of simultaneously taken inducers of the isoenzyme CYP3A4 can 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 isoenzyme CYP3A4 and other enzyme hepatic systems of the first and second phases of the metabolism of drugs and with simultaneous use with drugs metabolized by isoenzyme CYP3A4, can induce induction of metabolism and a decrease in their concentration in plasma.

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

Preparations, which can increase the concentration of carbamazepine in blood plasma:

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

- antineoplastic agents (androgen): danazol;

- macrolide antibiotics: erythromycin, josamycin, clarithromycin, troleandomycin;

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

- antiepileptic drugs: styipentol, vigabatrin;

- antifungal agents: azole derivatives (itraconazole, ketoconazole, fluconazole, voriconazole);

- blockers H₁-gistaminovyh receptors: terfenadine, loratadine;

- antipsychotic drugs (antipsychotics): olanzapine;

- anti-tuberculosis drugs: isoniazid;

- antiviral agents: HIV protease inhibitors (e.g., ritonavir);

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

- drugs that reduce blood pressure (blockers of "slow" calcium channels): verapamil, diltiazem;

- antiulcer agents (proton pump inhibitors, histamine H blockers₂-receptors): omeprazole, cimetidine;

- muscle relaxants: oxybutynin, dantrolene;

- antiplatelet agents: ticlopidine;

- other medicines and food products: grapefruit juice, nicotinamide (y - adults, 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 it is necessary to correct the dose of the drug and / or regularly determine the concentration of carbamazepine in the blood plasma.

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 the blood plasma can lead to side reactions (for example, dizziness, drowsiness, ataxia, diplopia), in these situations, the dose of Zeptol 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:

- antiepileptic means: felbamate, oxcarbazepine, phenobarbital, phenytoin, phosphenytoin, primidon, mezuximide, fensuximide, and although the data are partially contradictory, it is also possible clonazepam;

- antineoplastic agents: cisplatin or doxorubicin;

- anti-tuberculosis drugs: rifampicin;

- bronchodilating agents: theophylline, aminophylline;

- remedy for acne (retinoids): isotretinoin;

- other medicines and food products: vegetative preparations containing St. John's wortHypericum perforatum).

With simultaneous use with the above drugs may require dose adjustment of Zepthol.

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.

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, phenazone, tramadol;

- antibiotics of the tetracycline group: doxycycline;

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

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

- antiepileptic means: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidon, tiagabine, topiramate, valproic acid, zonisamide.

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

- antifungal agents: itraconazole;

- anthelmintic means: praziquantel;

- antineoplastic agents: imatinib;

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

- 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, lowering blood pressure (blockers of "slow" calcium channels of the dihydropyridines group): felodipine;

- cardiac glycosides: digoxin;

- glucocorticosteroids: prednisolone, dexamethosone;

- immunosuppressive means: ciclosporin, everolimus;

- 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 and 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,need for an increase in the dose of these 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 therapeutic effect of hormonal contraceptive preparations 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.

Special instructions:

The drug is usually ineffective at 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 the possible intensification of seizures). In the case of increased seizures, Zeptol should be withdrawn.

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 immediately consult a doctor if there are undesirable reactions such as fever, sore throat, rash, ulceration of the oral mucosa, unreasonable occurrence of hemorrhages, haemorrhages 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 there are signs of significant bone marrow suppression, Zeptol should be withdrawn.

When Zeptol was used, very severe dermatological reactions were very rare, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). Zepthol should be immediately withdrawn 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 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.

The influence of 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 incidence of severe skin reactions (and mortality in patients with Stevens-Johnson syndrome and Lyell's syndrome) is not established.

Slightly expressed skin reactions (isolated macular or maculopapular exanthema) in most cases are transient and non-severe andusually pass for several days or weeks, even with continued treatment or after a reduction in the dose of the drug.

However, since the differential diagnosis between early signs of severe skin reactions and mild transient skin rash may be difficult, in the development of any skin reactions, the patient should be under medical supervision (with a view to the timely termination of drug therapy in case of deterioration of the patient's condition).

According to a retrospective analysis of the drug in patients Hoa there is a correlation between the frequency of severe dermatological reactions and the presence of the allele in the genome of the patient HLA-B*1502 the human leukocyte antigen gene (HLA).

When carbamazepine is used in patients in countries of the Asian region (Thailand, Malaysia, Philippines), where the prevalence of the allele is noted HLA-BM502, found an increase in the incidence (from gradation "very rarely" to "rarely") severe dermatological reactions, including Stevens-Johnson syndrome and Lyell's syndrome. Allele spreading frequency HLA-B* 1502 is: in the Philippines, Thailand, Hong Kong and Malaysia - more than 15%, in Taiwan - 10%, in North China - 4%, in South Asia, including India - 2-4%, 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, possible carriers of the allele HLA-B* 1502 (for example, people of Chinese nationality) it is recommended to carry out genotyping on this allele. Prescribe the drug carriers of this allele should be only if the benefit of therapy exceeds the possible risk. In the face of the Caucasoid, Negroid and Americanic races, genotyping along the allele HLA-B* 1502 before prescribing Zepthol is optional.

Patients already receiving Zepthol 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 HLA-B* 1502 alleles).

However, the results of genotyping by allele HLA-B* 1502 should not influence the degree of control over the patient's condition and the doctor's caution regarding severe skin reactions.The development of Stevens-Johnson and Lyell syndromes is possible in patients with a negative allele HLA-B1502. Also in many cases, people of Chinese nationality are positive for the allele HLA-B* 1502 when Zeptol was used, there was no development of Stevens-Johnson and Lyell syndromes.

The influence of other factors, such as the dose of anticonvulsant drugs, patient compliance, simultaneous therapy with other drugs, concomitant diseases or the level of control of dermatological reactions, the incidence of severe skin reactions (and mortality in patients with Stevens-Johnson syndrome and Lyell's syndrome) is not established .

Slightly expressed skin reactions (isolated macular or maculopapular exanthema) in most cases are transient and non-severe and usually take place for several days or weeks, even with continued treatment or after a reduction in the dose of the drug.

However, since differential diagnosis between early manifestations of severe skin reactions and mild to moderate transient skin eruptions can be difficult,in the development of any skin reactions, the patient should be under medical supervision (with a view to the timely termination of drug therapy in case of deterioration of the patient's condition).

The relationship between the presence of an allele in the genome HLA-B* 1502 and the development of non-severe skin reactions (such as hypersensitivity reactions, isolated macular or maculopapular exanthema) has not been established.

With the development of hypersensitivity to Zeptolu patients may be observed as separate skin lesions, liver (including intrahepatic bile duct disease), blood and lymphatic system, or other organs, and a combination thereof that should be considered as a systemic reaction. In the case of development of symptoms and symptoms of hypersensitivity to Zeptol, the drug should be immediately discontinued.

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

Cross-reactive hypersensitivity reactions can also occur between carbamazepine and phenytoin.

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. Before the appointment of carbamazepine and in the process of treatment, it is necessary to study the liver function, especially in patients whose history includes information on liver diseases, as well as in elderly patients. In case of strengthening of already existing violations of the liver function or when there is an active liver disease, the drug should be immediately canceled.

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

To date, there have been individual reports of male fertility impairment and / or spermatogenesis disorders (the relationship of these disorders to carbamazepine has not yet been proven).

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.

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

Since the use of the drug may exacerbate latent mental disorders, care should be taken to monitor elderly patients with symptomatic problems such as confusion and psychomotor agitation.

In some cases, treatment with antiepileptic drugs was accompanied by the appearance of suicidal attempts / suicidal intentions.This was also confirmed by a meta-analysis of randomized, placebo-controlled trials using antiepileptic drugs. Since the mechanism of occurrence of suicidal attempts with the use of antiepileptic drugs is not known, we can not exclude their occurrence and treatment of patients with Zeptol. Patients and attendants should be warned about the need to monitor the occurrence of suicidal thoughts / suicidal behavior and, in the event of symptoms, seek medical help immediately.

A sudden discontinuation of carbamazepine may provoke epileptic seizures. If it is necessary to abruptly terminate the treatment, the patient should be transferred to another antiepileptic agent under the cover of the drug shown in such cases (for example, diazepam administered intravenously or rectally, orphenytoin administered intravenously).

Prior to the appointment of the drug, MAO inhibitors should be withdrawn at least 2 weeks or, if the clinical situation permits, even for a longer period.

During the treatment period, do not drink alcohol.

Effect on the ability to drive transp. cf. and fur:The ability of the patient taking Zeptol to respond quickly, especially at the beginning of therapy or during the dose selection period, may be impaired due to the occurrence of dizziness and drowsiness. Therefore, when driving a car or controlling mechanisms, the patient should be cautious.

Form release / dosage:

Tablets of prolonged action, film-coated, 200 mg, 400 mg.

Packaging:

For 10 tablets in a strip of aluminum foil.

By 3 strips with instructions for use in a cardboard bundle.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N011348 / 02

Date of registration:11.04.2012

Expiration Date:Unlimited

The owner of the registration certificate:San Pharmaceutical Industries Co., Ltd.San Pharmaceutical Industries Co., Ltd. India

Manufacturer: & nbsp

Sun Pharmaceutical Industries, Ltd. India

Representation: & nbspSAN PHARMACEUTICAL INDUSTRIES LTD. SAN PHARMACEUTICAL INDUSTRIES LTD. India

Information update date: & nbsp11.10.2017

Illustrated instructions

Instructions

Zeptol (Zeptol)