Zeptol

Zeptol is an anticonvulsant.

Indications Zeptol

Indicated for the elimination of:

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

The drug is used both as monotherapy and in combination treatment.

It is used to eliminate acute stages of manic syndromes, and also as a supporting drug in the treatment of bipolar disorder (as a preventative measure against possible exacerbation or to reduce the severity of manifestations of an exacerbated disease). It is also prescribed for:

• withdrawal syndrome;
• idiopathic form of trigeminal neuralgia, as well as the same pathology, but against the background of multiple sclerosis (typical or atypical);
• idiopathic form of neuralgia in the region of the glossopharyngeal nerve.

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Release form

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

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Pharmacodynamics

When using carbamazepine as a monotherapeutic agent, epileptics (especially adolescents and children) develop a psychotropic effect of the drug. It has a partial positive effect on the manifestations of depression and anxiety, and in addition, it reduces 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 dosage size and at the same time it is either quite questionable or has a negative effect on the body. Other tests have shown that the drug has a positive effect on such indicators as learning ability, attentiveness, and the ability to remember.

As a neurotropic drug, carbamazepine is good for various neurological pathologies: for example, it relieves attacks of pain that occur with secondary or idiopathic trigeminal neuralgia. At the same time, carbamazepine is used to relieve neurogenic pain that develops with disorders such as post-traumatic paresthesia, spinal tabes, and the post-herpetic stage of neuralgia.

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

The effectiveness of the drug as a psychotropic agent in affective forms of disorders has been confirmed: elimination of acute stages of manic syndromes and a maintenance agent in bipolar disorder (manic-depressive type; both monotherapy and combination tactics with lithium drugs, antidepressants or neuroleptics are used). 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. However, the mechanism of action of the active component of the drug has not been fully elucidated.

Carbamazepine normalizes the membrane condition of overexcited nerve endings, slows down the recurrence of neuronal discharges and inhibits the synaptic movement of excitatory impulses. It has been revealed that the main mechanism of action of the drug is the prevention of the re-formation of potential-dependent sodium channels inside depolarized neurons, which is carried out by blocking sodium channels. The antiepileptic properties of the drug are mainly due to the slowing down of the release of the substance glutamate, as well as the stabilization of the state of neuronal membranes. But the antimanic effect is due to the suppression of the metabolism of norepinephrine, as well as dopamine.

Pharmacokinetics

After taking the drug, absorption of the substance is almost complete, but rather slow. With a single tablet, the peak plasma concentration occurs after 12 hours. As a result of a single oral dose of 400 mg, the average peak concentration is approximately 4.5 mcg/ml.

Food intake has no significant effect on the extent and rate of absorption.

Equilibrium plasma concentration is achieved within 1-2 weeks (the interval depends on the patient's metabolic parameters - autoinduction of the liver enzyme system by the active substance, as well as heteroinduction by other drugs used in combination with Zeptol; and also on the dosage size, duration of the treatment course and the patient's health). There are significant interindividual differences in the constant concentration parameters within the drug range: as a rule, they fluctuate within 4-12 μg/ml (or 17-50 μmol/l). The parameters of carbamazepine-10,11-epoxide (this is a pharmacologically active decay product) are approximately 30% compared to the carbamazepine level.

After complete absorption of the drug, the apparent distribution volume is 0.8-1.9 l/kg. The active component passes through the placenta. Synthesis of the substance with plasma protein is about 70-80%. The indicator of unchanged carbamazepine in the cerebrospinal fluid, and along with this saliva, corresponds to the part of the component not bound to plasma protein (approximately 20-30%). Breast milk contains approximately 25-60% of the substance (percentage relative to plasma indicators).

The active substance is metabolized in the liver, often via the epoxide pathway. The main decay products are formed in the process: 10,11-transdiol derivative with its conjugate and glucuronic acid. The main isoenzyme that promotes the biotransformation of the active ingredient into carbamazepine-10,11-epoxide is the hemoprotein type P450 ZA4. At the same time, metabolic reactions create a “minor” decay product: 9-hydroxy-methyl-10-carbamoyl acridan. As a result of a single oral administration of the drug, approximately 30% of carbamazepine is found in the urine in the form of final metabolites. Other main biotransformation pathways of the substance help to form various monohydroxylate derivatives, as well as carbamazepine N-glucuronide, which occurs with the help of the UGT2B7 element.

After a single oral administration, the average half-life of the unchanged substance is 36 hours, and with repeated use it decreases to an average of 16-24 hours (because autoinduction of the liver microsomal system occurs) in accordance with the duration of the course of administration. In people who simultaneously take Zeptol with other inducers of the same liver enzyme system (for example, phenytoin or phenobarbital), the half-life will be 9-10 hours.

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

With a single dose of 400 mg, 72% of the substance is excreted in the urine, and the remaining 28% is excreted in the feces. About 2% of the dose is excreted unchanged in the urine, and another 1% is excreted in the form of the pharmacoactive breakdown product 10,11-epoxide.

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Dosing and administration

Zeptol is prescribed for oral administration. The daily dosage is usually divided into 2-3 doses. The medicine may be taken with or after meals or in between meals (washed down with water).

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

In the process of treating epilepsy, it is necessary to start with a small daily dosage, which is gradually increased, taking into account the needs of the patient.

To select the required dose of the drug, it is necessary to first determine the plasma level of carbamazepine. This point is especially important in combination therapy.

The daily adult dosage is usually 100-200 mg (divided into 1-2 doses) at the beginning. Later, it is slowly increased until the optimal effectiveness is achieved - usually the size of such a dose is 800-1200 mg. Sometimes patients need a daily dosage that reaches 1600 or 2000 mg.

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

The standard daily dose is 10-20 mg/kg (to be taken in several doses).

Children aged 5-10 years: 400-600 mg (in 2-3 doses); children aged 10-15 years: 600-1000 mg (in 2-5 doses).

If possible, it is recommended to prescribe the drug for monotherapy, but when combined with other drugs, the same regimen of gradual increase in dosage is required (the dose of the additional drug does not need to be increased).

In acute forms of manic syndromes, as well as as a maintenance drug for bipolar disorder, the dosage is in the range of 400-1600 mg, and per day - 400-600 mg, which should be divided into 2-3 uses. In the case of an acute form of manic syndrome, it is recommended to quickly increase the dosage. But when ensuring the necessary tolerance in maintenance treatment for bipolar disorder, the dose should be increased gradually, in small quantities.

In case of withdrawal syndrome, the average daily dosage is 200 mg three times a day. In severe stages of the pathology, the dosage can be increased in the first few days (for example, up to 400 mg three times a day). In case of severe symptoms, therapy should be started by combining the drug with sedative-hypnotic drugs (such as clomethiazole or chlordiazepoxide), observing the above dosages. After the acute phase of the disease, the drug can be used as monotherapy.

For idiopathic trigeminal neuralgia (or neuralgia of the same area due to multiple sclerosis (typical or atypical)) or in the glossopharyngeal nerve area: the initial daily dosage is 200-400 mg (100 mg twice a day for the elderly). Then it is slowly increased until the pain goes away (usually at a dosage of 200 mg 3-4 times a day). Most people find this dosage regimen sufficient to maintain good health, but sometimes a dosage of 1600 mg per day may be required. After the pain has been eliminated, the dosage should be gradually reduced to the minimum necessary maintenance dosage.

Use Zeptol during pregnancy

Taking carbamazepine orally can cause some defects.

Children whose mothers suffer from epileptic seizures are prone to problems in the womb (including congenital malformations). There have been reports of an increased risk of such disorders due to carbamazepine intake, but there is no convincing evidence from controlled trials of monotherapy.

In addition, there is information about the use of the drug associated with intrauterine developmental disorders, as well as congenital defects - among them the spinal cleft and other congenital defects (problems with the development of the maxillofacial region, hypospadias, various cardiovascular anomalies, etc.).

When taking the medicine, pregnant women suffering from epilepsy require special caution. During the period of using the medicine, it is necessary to follow these rules:

• during pregnancy that occurs during the course of treatment; at the planning stage; or if there is a need to use the drug after pregnancy has already occurred - it is necessary to carefully assess the possible benefit for the woman and compare it with the potential negative impact on the fetus (especially during the 1st trimester);
• for women of reproductive age, the drug is prescribed as a monotherapeutic agent;
• it is necessary to prescribe the minimum effective dosages, as well as monitor the levels of the active component in the plasma;
• It is necessary to inform patients that the risk of congenital anomalies in the child increases, and also to provide the opportunity for antenatal screening;
• It is recommended not to cancel effective anticonvulsant treatment for pregnant women, because an exacerbation of the pathology will pose a threat to the health of both the mother and the fetus.

Contraindications

Among the contraindications of the drug:

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

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Side effects Zeptol

In the initial period or as a result of using an excess initial dosage of the drug, and in addition, in elderly people, some negative reactions may occur. Among such manifestations:

• CNS organs: development of headaches or dizziness, feeling of general weakness or drowsiness, development of diplopia or ataxia;
• gastrointestinal tract: vomiting with nausea;
• skin allergy.

Dose-related side effects generally disappear within a few days (either spontaneously or after a temporary reduction in the drug dosage).

There is also a possibility of developing such negative consequences:

• organs of the hematopoietic system: development of eosinophilia, leukopenia or thrombocytopenia; deficiency of folic acid, occurrence of lymphadenopathy, agranulocytosis or leukocytosis, anemia or its megaloblastic, hemolytic or aplastic forms, as well as pancytopenia. It is also possible to develop late cutaneous porphyria, acute stage of intermittent porphyria and mixed form of this pathology, as well as development of reticulocytosis or erythrocytic form of aplasia;
• Immune system organs: development of delayed-type multiorgan intolerance, accompanied by lymphadenopathy, vasculitis, fever and skin rash (in addition to symptoms similar to lymphoma, leukopenia, arthralgia, eosinophilia and hepatosplenomegaly, as well as disappearance of the bile ducts and changes in liver function tests (various combinations of the above symptoms are possible)). Possible occurrence of disorders of other organs (for example, the lungs, kidneys and liver or large intestine, myocardium and pancreas), development of the peripheral form of eosinophilia, aseptic form of meningitis, accompanied by myoclonus, and in addition Quincke's edema, anaphylaxis or hypogammaglobulinemia;
• endocrine system organs: weight gain, swelling, fluid retention, decreased plasma osmolarity due to an effect similar to that of vasopressin (this occasionally causes hyperhydration, which causes vomiting, lethargy, severe headaches, neurological problems, and confusion) and the development of hyponatremia. In addition, an increase in prolactin levels is observed in the blood (in this case, symptoms such as gynecomastia or galactorrhea may develop, as well as bone metabolism disorders - a decrease in calcium levels with 25-hydroxycholecalciferol in the blood plasma), resulting in osteoporosis / osteomalacia, and sometimes an increase in cholesterol levels (including triglycerides and high-density lipoprotein cholesterol);
• Digestive system and metabolism: folate deficiency, loss of appetite, acute porphyria (mixed form or acute stage of intermittent porphyria) or non-acute porphyria (late stage of cutaneous porphyria);
• mental disorders: development of auditory or visual hallucinations, depressive state, the appearance of a feeling of anxiety, overexcitement, aggressiveness, loss of appetite, exacerbation of psychosis, manifestation of confusion;
• organs of the nervous system: a feeling of general weakness or drowsiness, dizziness with headaches, development of ataxia or diplopia. Also, visual accommodation disorder (for example, blurred vision), involuntary movements of an abnormal nature (for example, fluttering and normal tremor, tic or dystonia), development of nystagmus. Disorder of the motor function of the eyes, orofacial dyskinesia, speech disorder (for example, slurred speech or dysarthria), development of peripheral neuropathy, choreoathetosis, paresthesia, muscle weakness, and paresis. Disorder of taste buds, malignant form of neuroleptic syndrome, as well as aseptic form of meningitis, accompanied by peripheral form of eosinophilia and myoclonus;
• visual organs: accommodation disorder (blurring), development of conjunctivitis, cataracts, as well as an increase in intraocular pressure;
• auditory organs: hearing problems (such as tinnitus), increased/decreased hearing sensitivity, problems with the perception of pitch;
• cardiovascular system organs: increase/decrease in blood pressure, cardiac conduction disorder, development of arrhythmia or bradycardia, in addition to blockade with fainting, thrombophlebitis or circulatory collapse, as well as thromboembolism (for example, pulmonary embolism) and congestive heart failure, as well as exacerbation of coronary heart disease;
• Respiratory system: increased pulmonary sensitivity, the symptoms of which are dyspnea, fever, pneumonia or pneumonitis;
• digestive tract: severe nausea, dry mouth, as well as vomiting, constipation or diarrhea, abdominal pain, pancreatitis, inflammation of the tongue or stomatitis;
• digestive system organs: increase in GGT levels (due to induction of liver enzyme), which often does not have a clinical effect on the body, as well as alkaline phosphatase levels in the blood and, along with this, the level of liver transaminases. In addition, the development of various types of hepatitis (cholestatic, as well as hepatocellular, granulomatous or mixed), liver failure or disappearance of the bile ducts;
• subcutaneous tissue together with the skin: development of urticaria (sometimes severe) or allergic dermatitis. Also the appearance of erythroderma or exfoliative dermatitis, itching, erythema multiforme or Stevens-Johnson syndrome, development of erythema multiforme and nodosa or photosensitivity, purpura or acne. In addition, increased sweating, skin pigmentation disorder, alopecia and hirsutism are observed;
• muscles and skeletal system: a feeling of weakness or pain in the muscles, the occurrence of muscle spasms, as well as arthralgia and bone metabolism disorders;
• organs of the urinary system: renal failure, renal dysfunction (such as hematuria with albuminuria or oliguria, as well as azotemia or increased urea levels), urinary retention or, conversely, increased frequency of this process, and, in addition, interstitial nephritis;
• reproductive system: development of impotence, as well as disorders of spermatogenesis (a decrease in sperm motility or quantity is observed);
• general: feeling of weakness;
• test results: changes in thyroid function – decreased L-thyroxine levels (such as T3 and T4, as well as FT4) and thyrotropin levels (often does not have a noticeable effect on the body).

Overdose

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

• CNS: CNS depression – development of disorientation, feelings of excitement or drowsiness, suppression of consciousness, deterioration of vision, appearance of hallucinations. In addition, comatose state, slurred speech, nystagmus and dysarthria, as well as dyskinesia and ataxia. Development of hyperreflexia (initially), and then hyporeflexia, psychomotor disorders and seizures, as well as hypothermia, myoclonus, and mydriasis are possible;
• respiratory system: pulmonary edema, suppression of respiratory function;
• cardiovascular system: development of tachycardia, increase/decrease in blood pressure, conduction disorder, in which the QRS complex additionally widens. In addition, loss of consciousness/fainting due to cardiac arrest;
• digestive tract area: food retention in the stomach, vomiting, and deterioration of the motility of the large intestine;
• Bone structure and muscles: there are reports of isolated cases of rhabdomyolysis, which occurs due to the toxic effects of carbamazepine;
• urinary organs: development of anuria or oliguria, fluid or urine retention. Hyperhydration may develop, which is associated with the effect of the active component of the drug on the body (similar to the effect of vasopressin);
• laboratory tests: development of hyponatremia; hyperglycemia or metabolic acidosis may also occur, and in addition, the muscle fraction of creatine kinase may increase.

There is no specific therapeutic antidote. Initial therapy depends on the person's condition and may require hospitalization. Plasma carbamazepine levels should be measured to confirm intoxication and to assess the severity of the overdose.

It is necessary to take activated carbon, induce vomiting, and wash out the stomach. In case of late evacuation of the stomach contents, delayed absorption and recurrence of signs of poisoning already at the stage of recovery are possible. It is also necessary to treat the symptoms with supportive methods in intensive care. In addition, cardiac function is monitored and the electrolyte balance is corrected.

In case of decreased blood pressure, dobutamine or dopamine should be administered. If cardiac arrhythmia is observed, individual treatment is selected. In case of seizures, benzodiazepines (for example, diazepam) or other anticonvulsants are administered - paraldehyde or phenobarbital (it is used with caution due to the high probability of respiratory function suppression). In case of hyponatremia, it is necessary to limit the supply of fluid to the body, use careful slow infusion of sodium chloride solution (0.9%). Such measures help prevent cerebral edema.

Hemosorption using carbon sorbents is also recommended. Peritoneal dialysis and forced diuresis do not bring results.

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Interactions with other drugs

Hemoprotein type P450 ZA4 (CYP3A4) is the main enzyme catalyst for the formation of the active decay product: carbamazepine-10,11-epoxide. When used in combination with inhibitors of the CYP3A4 element, it can increase plasma carbamazepine levels, which may cause negative effects.

Simultaneous use with CYP3A4 inducers can enhance the metabolism of the active component of Zeptol, resulting in a potential decrease in the serum concentration of the substance, as well as a weakening of its medicinal effect. Therefore, when stopping the use of the CYP3A4 inducer, the rate of carbamazepine metabolism may decrease, due to which its plasma value increases.

Carbamazepine is a strong inducer of the CYP3A4 element and other phase I and II enzyme systems in the liver. As a result, it can reduce the plasma levels of other drugs (those drugs whose metabolism is mainly carried out by induction of the CYP3A4 element).

Human microsomal epoxide hydrolase is an enzyme that promotes the formation of the 10,11-transdiol derivative of carbamazepine-10,11-epoxide. When combined with Zeptol, human microsomal epoxide hydrolase inhibitors may increase plasma levels of carbamazepine-10,11-epoxide.

Since the structure of the substance carbamazepine is similar to tricyclics, it is prohibited to combine Zeptol with MAO inhibitors. The use of the latter should be discontinued before starting treatment with Zeptol (do this at least 2 weeks in advance).

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Storage conditions

The medicine is kept in standard conditions for medicines, inaccessible to small children. The maximum temperature limit is 25°C.

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Shelf life

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