Zeptol

Zeptol is an anticonvulsant.

Indications Zeptol

Indicated for elimination:

• simple or complex focal seizures of epilepsy (with or without loss of consciousness) with a secondary form of generalization or without;
• generalized form of tonic-clonic seizures;
• seizures of mixed types.

The drug is used both under the form of monotherapy, and with combined treatment.

It is used to eliminate acute stages of manic syndromes, and also as a supporting drug in the treatment of BAP (as prevention of possible exacerbation or to reduce the intensity of manifestations of exacerbated disease). Also assigned when:

• abstinence syndrome;
• idiopathic form of trigeminal neuralgia, as well as the same pathology, but against the backdrop of disseminated sclerosis (typical or atypical);
• idiopathic form of neuralgia in the glossopharyngeal nerve area.

[1], [2]

Release form

Available in tablet form, 10 pieces per blister. One package contains 10 blister plates.

[3], [4]

Pharmacodynamics

When carbamazepine is used as a monotherapeutic agent, the psychotropic effect of drugs develops in epileptics (especially in adolescents and children). It has a partial positive effect on the manifestations of depression and feelings of anxiety, and besides it reduces the aggression and irritability of the patient. There are studies that have demonstrated that the effectiveness of carbamazepine in relation to psychomotor data and cognitive function is manifested in accordance with the size of the dosage and while it is either rather questionable or generally has a negative effect on the body. Other tests showed that the drug has a positive effect on such indicators as learning, attentiveness, and also the ability to memorize.

As a neurotropic drug, carbamazepine works well for various neurological pathologies: for example, it relieves pain attacks that occur in the secondary or idiopathic form of trigeminal neuralgia. At the same time, carbamazepine is used to relieve neurogenic pains that develop in disorders such as post-traumatic paresthesia, spinal cord, and post-herpetic neuralgia.

During the abstinence syndrome, the drug helps to increase the threshold of convulsive readiness (it is lower in a person in this state), and also weakens the clinical symptoms of the pathology - tremor, increased excitability, and gait disorder. In people with a central diabetes (unsugar type), carbamazepine reduces the feeling of thirst, as well as diuresis.

The effectiveness of drugs in the form of psychotropic in affective forms of disorders has been confirmed: the elimination of acute stages of manic syndromes and a supportive agent for BAP (manic-depressive type, monotherapy and combination therapy with lithium drugs, antidepressants or antipsychotics). In addition, Zeptol is effective in cases of manic or schizoaffective forms of psychosis (combination with neuroleptic drugs) and the acute stage of the polymorphic form of schizophrenia. At the same time, the mechanism of the impact of the active drug component was not fully understood.

Carbamazepine normalizes the state of the membranes of overexcited nerve endings, slows the re-emergence of neuronal discharges, and inhibits the synaptic movement of the exciting impulses. It was revealed that the main mechanism of drug exposure is the prevention of the re-formation of potential-dependent sodium canals within depolarized neurons, which is performed by blocking sodium channels. Antiepileptic properties of drugs mainly due to a slow release of glutamate, as well as stabilization of the state of neuronal membranes. But the anti-manic effect is due to the suppression of the metabolism of norepinephrine, as well as dopamine.

Pharmacokinetics

After the use of drugs, the absorption of the substance is almost complete, but it is rather slow. With a one-time tablet use, the peak plasma concentration occurs after 12 hours. As a result of a single oral intake of 400 mg, the average peak concentration is about 4.5 μg / ml.

The consumption of food does not have a noticeable effect on the strength and speed of the absorption that is being carried out.

The equilibrium plasma concentration occurs over a period of 1-2 weeks (the interval depends on the patient's metabolic rate-the autoinduction of the active substance of the liver enzyme system, and also the heteroinduction of other drugs used in conjunction with Zeptol, and in addition to the size of the dosage, the duration of the treatment course and the state of health of the patient). There are noticeable interindividual differences in the indices of constant concentrations within the drug range: as a rule, they range from 4-12 μg / ml (or 17-50 μmol / l). The carbamazepine-10,11-epoxide (this pharmacologically active decay product) is about 30% compared to the carbamazepine level.

After full absorption of the drug, the apparent distribution volume is 0.8-1.9 l / kg. The active component passes through the placenta. Synthesis of a substance with a plasma protein is about 70-80%. The index of unchanged carbamazepine inside the liquor, and along with it the saliva corresponds to the part of the component unrelated to the plasma protein (approximately 20-30%). Inside the breast milk contains approximately 25-60% of the substance (percentage relative to the plasma parameters).

Metabolism of the active substance occurs inside the liver, often epoxy. In the process, the main decay products are formed - 10,11-trans-diol derivative with its conjugate and glucuronic acid. The main isoenzyme that promotes the biotransformation of the active ingredient in carbamazepine-10,11-epoxide is a hemoprotein of the P450 type. Along with this, metabolic reactions create a "small" decay product: 9-hydroxy-methyl-10-carbamoyl acridane. As a result of a one-time oral drug use, approximately 30% of carbamazepine is found inside the urine in the form of final metabolites. The other main biotransformation pathways of the substance help form a variety of monohydroxylate derivatives, and in addition, carbamazepine N-glucuronide, which occurs with the UGT2B7 element.

After a one-time oral intake, the average half-life of the unchanged substance is 36 hours, and with repeated use, it decreases on average to 16-24 hours (because of the autoinduction of the microsomal hepatic system) in accordance with the duration of the course of admission. In humans, concomitantly with Zeptol taking other inducers of the same system of hepatic enzymes (eg, phenytoin or phenobarbital), the half-life will be 9-10 hours.

The plasma half-life of the decay product of 10,11-epoxide is approximately 6 hours after a single oral use of the epoxide.

With a single use of drugs at a dosage of 400 mg, 72% of the substance is excreted together with urine, and the remaining 28% is excreted with feces. About 2% of the dosage is excreted from the body with urine unchanged, and about 1% - in the form of a pharmacoactive decay product 10,11-epoxide.

[5], [6], [7]

Dosing and administration

Zeptol is prescribed for ingestion. Basically, the daily dosage is divided into 2-3 uses. The medicine is allowed to be taken with food either after it or at intervals between meals (drink with water).

Prior to the beginning of the treatment course, patients who are potential carriers of the HLA-A * 3101 allele should, if possible, be screened for their presence, since in such people, the drug can cause severe side effects.

In the treatment of epilepsy, you need to start with a small daily dosage, which is gradually increased, taking into account the needs of the patient.

To find the right dose of drugs, you must first determine the plasma index of carbamazepine. This point is especially important in combination therapy.

The daily adult dosage in the beginning, as a rule, is equal to 100-200 mg (divided by 1-2 doses). Later, it is slowly increased until optimal efficacy is achieved - in general, the size of this dose is 800-1200 mg. Sometimes patients need a daily dosage that goes up to 1600 or 2000 mg.

For children, treatment starts with a daily dosage of 100 mg, which is increased weekly by 100 mg.

The standard size of the daily dose is 10-20 mg / kg (should be used in several receptions).

Children 5-10 years of 400-600 mg (for 2-3 uses); children 10-15 years old - 600-1000 mg (for 2-5 uses).

If possible, it is recommended to prescribe medicines for monotherapy, but when combined with other medicines, the same regimen of a gradual increase in dosage is required (the dose of an additional drug should not be increased at the same time).

In acute forms of manic syndromes, and also as a supporting drug for BAP, the dosage is in the range of 400-1600 mg, and at the same time 400-600 mg, which need to be divided into 2-3 uses. In the case of an acute form of manic syndrome, it is recommended to rapidly increase the dosage. But with the maintenance of the necessary tolerance with maintenance treatment in the BAP should increase the dose gradually, in small amounts.

With an abstinence syndrome, the average daily dosage is 200 mg three times a day. With a severe stage of the pathology, you can increase the dose in the first few days (eg, to 400 mg three times a day). For severe symptoms, therapy should be started by combining the drug with sedative-hypnotic drugs (such as clomethiazole or chlordiazepoxide), with the above dosages. After the end of the acute phase of the disease, the drug is allowed to be used as a monotherapy.

In the idiopathic form of trigeminal neuralgia (or neuralgia of the same site against multiple sclerosis (typical or atypical)) or in the glossopharyngeal nerve: the initial size of the daily dosage is 200-400 mg (twice a day for 100 mg for the elderly). Further, it slowly increases until pain passes (usually at a dosage of 200 mg in 3-4 doses per day). Most people have this kind of dosing regimen to maintain their well-being, but sometimes a dosage of 1600 mg per day may be required. After elimination of pain, dosage should be gradually reduced, bringing to the minimum necessary support.

Use Zeptol during pregnancy

The use of carbamazepine inside provokes the development of certain defects.

In children whose mothers suffer from epileptic seizures, there is a propensity for problems in prenatal development (among them congenital malformations in development). There were reports of a risk of an increase in the incidence of such abnormalities due to carbamazepine, but there are no convincing facts confirmed by controlled trials of drug monotherapy.

In addition, there is information about drug-related disorders in prenatal development, as well as congenital malformations, including vertebral fissure and other birth defects (problems with the development of the maxillofacial region, hypospadias, various cardiovascular anomalies, etc.).

When taking medicine by pregnant women suffering from epilepsy, special care is required. During the period of use of the medicine, it is necessary to observe the following rules:

• during pregnancy, which occurred during the course of treatment; at the planning stage; or if there is a need for drugs even after pregnancy, it is necessary to carefully evaluate the possible benefits for the woman and compare it with the potential negative impact on the fetus (especially at the time of the 1st trimester);
• women who are in reproductive age, the drug is prescribed as a monotherapeutic agent;
• it is required to prescribe the lowest effective dosages, and also to monitor the indices of the active component inside the plasma;
• it is necessary to inform patients that the risk of congenital anomalies in a child is increased, and also provide an opportunity for antenatal screening;
• it is recommended not to abolish effective anticonvulsant treatment for pregnant women, because an exacerbation of pathology will become a threat to the health of both mother and fetus.

Contraindications

Among the contraindications of drugs:

• established intolerance of carbamazepine or similar in chemical properties of drugs (tricyclics), and in addition other components of the drug;
• presence of AV blockade;
• history of functional bone marrow suppression;
• the presence of porphyria of the liver type in the anamnesis (for example, the late stage of cutaneous porphyria, the acute stage of intermittent porphyria, and in addition the mixed form of porphyria);
• children under the age of 5;
• combination with drugs-inhibitors MAO.

[8]

Side effects Zeptol

In the initial period, or as a result of consuming an excess initial dosage of drugs, and in addition, some negative reactions may appear in the elderly. Among such manifestations are:

• CNS organs: development of headaches or dizziness, a feeling of general weakness or drowsiness, development of diplopia or ataxia;
• Gastrointestinal organs: vomiting with nausea;
• an allergy on the skin.

Dependent side effects mostly disappear after a few days (either spontaneously or after a temporary reduction in the dosage of the drug).

There is also a possibility of developing such negative consequences:

• organs of the hematopoiesis system: development of eosinophilia, leuko- or thrombocytopenia; lack of folic acid, the emergence of lymphadenopathy, agranulocytosis or leukocytosis, anemia or megaloblastic, hemolytic or aplastic forms of it, and in addition pancytopenia. It is also possible the appearance of late cutaneous porphyria, the acute stage of intermittent porphyria and the mixed form of this pathology, and in addition the development of reticulocytosis or erythrocyte form of aplasia;
• organs of the immune system: the development of multi-organ slow-motion intolerance, which is accompanied by lymphadenopathy, vasculitis, febrile condition and skin rash (in addition to symptoms similar to lymphoma, leukopenia, arthralgia, eosinophilia and hepatosplenomegaly, and disappearance of bile ducts and changes in hepatic parameters different combinations of the above symptoms are possible)). Perhaps the appearance of disorders of other organs (for example, lungs, kidneys and liver or large intestine, myocardium and pancreas), the development of a pre-feric form of eosinophilia, an aseptic form of meningitis accompanied by myoclonus, and in addition Quincke edema, anaphylaxis or hypogammaglobulinemia;
• organs of the endocrine system: weight gain, the appearance of edemas, fluid retention, lowering of plasma osmolarity due to the effect similar to that of vasopressin (this occasionally causes hyperhydration, against which vomiting, lethargic state, severe headaches, neurological problems, and besides addition confusion) and the development of hyponatremia. In addition, there is an increase in prolactin levels in the blood (symptoms such as gynecomastia or galactorrhea, as well as disorders of bone metabolism - a decrease in calcium with 25-hydroxycolecalciferol in the blood plasma), which leads to osteoporosis / osteomalacia, and sometimes - increased cholesterol (including triglycerides and high-density lipoprotein cholesterol);
• organs of the digestive system and metabolism: folate deficiency, appetite impairment, acute porphyria (mixed form or acute stage of intermittent porphyria) or porphyria (late stage of cutaneous porphyria);
• mental disorders: the development of auditory or visual hallucinations, a depressed state, the emergence of a feeling of anxiety, overexcitation, aggression, loss of appetite, exacerbation of psychosis, manifested confusion;
• organs of the National Assembly: a feeling of general weakness or drowsiness, dizziness with headaches, development of ataxia or diplopia. Also, the disorder of visual accommodation (for example, blurred vision), the performance of involuntary movements of anomalous nature (eg, fluttering and ordinary tremor, tick or dystonia), the development of nystagmus. An impairment of the motor function of the eyes, an orofacial form of dyskinesia, a speech disorder (for example, slurred speech or dysarthria), the development of peripheral forms of neuropathy, choreoathetosis, paresthesias, muscle weakness, and paresis. Disorder of taste buds, malignant form of neuroleptic syndrome, as well as an aseptic form of meningitis, accompanied by a peripheral form of eosinophilia and myoclonus;
• visual organs: disorder of accommodation (blurred vision), development of conjunctivitis, cataracts, as well as increased intraocular pressure;
• auditory organs: hearing problems (such as ringing in the ears), increased / decreased hearing sensitivity, problems with perception of the sound altitude;
• cardiovascular system: increase / decrease in blood pressure, cardiac conduction disorder, arrhythmia or bradycardia, in addition to blockade with syncope, thrombophlebitis or circulatory collapse, and in addition thromboembolism (eg pulmonary embolism) and congestive heart failure, as well as exacerbation IHD;
• organs of the respiratory system: increased pulmonary sensitivity, the symptoms of which are dyspnea, febrile condition, pneumonia or pneumonitis;
• the digestive tract: severe nausea, dryness in the mouth, as well as vomiting, constipation or diarrhea, abdominal pain, pancreatitis, inflammation of the tongue or stomatitis;
• organs of the digestive system: an increase in GGT (due to the induction of the liver enzyme), which often does not have a clinical effect on the body, as well as the parameters of alkaline phosphatase inside the blood and, at the same time, the level of hepatic transaminases. In addition, the development of hepatitis of various types (cholestatic, and in addition hepatocellular, granulomatous or mixed), liver failure or disappearance of the biliary tract;
• subcutaneous tissue together with the skin: development of urticaria (sometimes severe) or allergic form of dermatitis. Also the appearance of erythroderma or exfoliative form of dermatitis, pruritus, spp, Lyell syndrome or Stevens-Johnson, the development of polyform and nodose erythema or photosensitivity, purpura or acne. In addition, there is increased sweating, a disorder of skin pigmentation, alopecia and hirsutism;
• musculature and bone system: sensation of weakness or pain in the muscles, the development of muscle spasms, as well as arthralgia and bone metabolism disorder;
• organs of the urinary system: kidney failure, kidney disorders (such as hematuria with albuminuria or oliguria, as well as azotemia or an increase in urea), urinary retention or, on the contrary, an increase in this process, and in addition, the interstitial form of nephritis;
• reproductive system: the development of impotence, as well as disorders of spermatogenesis (there is a decrease in motility or the number of spermatozoa);
• general: a sense of weakness;
• Indicators of analysis: a change in the thyroid function - a decrease in L-thyroxine (such as T3 and T4, as well as FT4) and thyrotropin indices (often does not have a noticeable effect on the body).

Overdose

Among the main signs that develop as a result of drug overdose are the defeat of the respiratory system, the central nervous system and the cardiovascular system:

• CNS: suppression of the central nervous system - the development of disorientation, feelings of excitement or drowsiness, suppression of consciousness, visual impairment, the appearance of hallucinations. In addition, a coma, insensibility of speech, nystagmus and dysarthria, as well as dyskinesia and ataxia. Perhaps the development of hyperreflexia (at first), and then hyporeflexia, psychomotor disorders and seizures, and in addition to hypothermia, myoclonia, and mydriasis;
• respiratory system: pulmonary swelling, suppression of respiratory function;
• Cardiovascular system: development of tachycardia, increase / decrease in blood pressure, conduction disorder, in which the QRS complex is further expanded. In addition, loss of consciousness / fainting due to cardiac arrest;
• the area of the digestive tract: the delay of food in the stomach, the appearance of vomiting, and the deterioration of the motility of the large intestine;
• bone structure and muscles: there is information about single cases of development of rhabdomyolysis, which arises from the toxic effects of carbamazepine;
• urinary organs: development of anuria or oliguria, fluid retention or urine retention. Hyperhydration may develop, which is associated with the effect on the body of an active drug component (similar to that of vasopressin);
• laboratory tests: development of hyponatremia; may also occur hyperglycemia or metabolic acidosis, and in addition to increase the muscle fraction of creatine kinase.

There is no specific therapeutic antidote. At the initial stage, therapy depends on the state of the person, and in addition, hospitalization is required. It is necessary to determine the plasma indices of carbamazepine to confirm intoxication, as well as to assess the force of the overdose.

It is required to take activated charcoal, induce vomiting, and wash the stomach. In the case of late evacuation of the contents of the stomach, delayed absorption and the re-emergence of signs of poisoning are possible at the stage of recovery. It is also necessary to treat the symptoms with supportive methods on intensive care. In addition, the cardiac function is monitored and the electrolyte balance is adjusted.

In the case of a decrease in blood pressure indicators, it is required to administer dobutamine or dopamine. If there are disorders of the heart rhythm, individual treatment is selected. When convulsions are introduced benzodiazepines (eg, diazepam) or other anticonvulsants - paraldehyde or phenobarbital (it is used with caution because of the high probability of suppression of respiratory function). In hyponatremia, the flow of fluid into the body should be limited, using a cautious slow infusion with sodium chloride solution (0.9%). Such measures help prevent cerebral edema.

Also recommended is hemosorption using coal sorbents. Peritoneal dialysis, as well as forced diuresis do not bring results.

[9]

Interactions with other drugs

Hemoprotein type P450 ZA4 (CYP3A4) is the main enzyme catalyst for the formation of the active degradation product: carbamazepine-10,11-epoxide. When combined with inhibitors of the element, CYP3A4 is able to increase the plasma indices of carbamazepine, and this can cause negative effects.

Simultaneous use of the element CYP3A4 with inductors can enhance the metabolism of the active component of Zepthol, which results in a potential decrease in serum concentration of the substance, and in addition, the weakening of its drug effect. Therefore, when the use of the inducer of the element CYP3A4 ceases, the rate of carbamazepine metabolism may decrease, which causes its plasma value to increase.

Carbamazepine is a strong inducer of the element CYP3A4, as well as other systems of enzymes I and II phases inside the liver. Because of this, it is able to reduce the indices of other drugs inside the plasma (those whose metabolism is mainly carried out by the induction of element CYP3A4).

Human microsomal epoxide hydrolase is an enzyme that promotes the formation of 10,11-transdiol derivatives of carbamazepine-10,11-epoxide. With the combined use of microsomal epoxyhydrolase inhibitors with Zeptol, an increase in the plasma indices of carbamazepine-10,11-epoxide is possible.

Since the structure of carbamazepine is similar to tricyclics, it is forbidden to combine Zeptol with MAO inhibitors. It is necessary to interrupt the use of the latter before treatment with Zeptol (do this in at least 2 weeks).

[10], [11], [12]

Storage conditions

The drug is contained in standard conditions for medicines, inaccessible to young children. The maximum temperature limit is 25 ° C.

[13]

Shelf life

Zeptol is suitable for use for 5 years from the date of its release.