Exalieff

Exalieff is an anti-epileptic drug.

Indications Exalieff

It is indicated for the elimination of local seizures of epilepsy (with secondary stage of generalization or without it) in adults (as an auxiliary medicine).

Release form

It is produced in tablet form (the volume of one tablet is 800 mg). One blister contains 10 tablets. One package contains 2, 3 and 6 or 9 blister plates.

Pharmacodynamics

There is no known exact mechanism of action of eslacarbazepine acetate, but electrophysiological tests conducted in vitro have shown that the active component and its decay products allow stabilizing the potential-dependent sodium channels in the inactivation state. This prevents the possibility of their activation, allowing to maintain periodic neuronal excitability.

Acetate eslikarbazepine with its active decay products prevents the occurrence of seizures in pre-clinical models, making it possible to predict the delivery of an anticonvulsant effect on humans. In this case, its pharmacological properties are manifested in humans mainly through the active product of the decay of this substance - eslikarbazepine.

Pharmacokinetics

The active ingredient through metabolism is converted to eslikarbazepine. With oral administration of the drug, the plasma concentration of the active substance is usually kept below the quantitative determination. The peak concentration of eslikarbazepine is observed 2-3 hours after the use of the tablet. Bioavailability of drugs is considered high, since the number of decay products observed in urine is equal to more than 90% of the accepted dosage of the active ingredient.

The synthesis of a metabolite with a plasma protein is rather low (<40%), it does not depend on the concentration of the substance. In vitro tests show that the presence of diazepam with warfarin, phenytoin, and digoxin with tolbutamide weakly affects the synthesis of the substance with the protein - the same is observed in the opposite direction.

The active component after the 1 st hepatic passage by hydrolysis is intensively and very quickly converted into its main active degradation product - eslikarbazepine.

Peak plasma concentrations it reaches 2-3 hours after the use of drugs, and the steady-state concentration is observed after 4-5 days of taking tablets 1 time per day. This corresponds to the indicators of an effective half-life - about 20-24 hours. When tested on healthy volunteers and adults suffering from epilepsy, the apparent half-life was 10-20 and 13-20 hours, respectively.

A small part of the following degradation products is observed inside the plasma: oxcarbazepine, as well as R-lycarbazepine (have pharmacological properties), and besides this, conjugates of the active substance with the product of decomposition, and besides R-lycarbazepine along with oxcarbazepine and glucuronic acid.

The active component of the tablets has no effect on its own coefficient of purification and metabolism.

Experimental testing on fresh human hepatocytes has shown that eslikarbazepine is able to weakly induce isoenic activity of UGT1A1, which is a participant in glucuronation processes.

The removal of the decay products of the drug is carried out, mainly, through the kidneys (unchanged, as well as in the form of conjugates together with glucuronic acid). In this case, together with its glucuronide, eslikarbazepine is more than 90% excreted with urine decay products (approximately 2/3 excreted in the form of eslikarbazepine, and another 1/3 - in the guise of glucuronide).

Dosing and administration

Oral reception, regardless of eating. The drug is an auxiliary drug during the course of anticonvulsant treatment. The tablet is allowed to be divided into equal halves.

The initial daily dosage is 400 mg per day (once). After 1-2 weeks of treatment, it can be increased to 800 mg. Taking into account the patient's individual reaction to therapy, it is allowed to increase the daily dose to 1200 mg of a single dose.

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Use Exalieff during pregnancy

There is no information on the use of the drug in pregnant women. Testing in animals has shown that the drug has reproductive toxicity.

It is required to re-evaluate the appropriateness of using the medicine if during the course of treatment it is planned or has already become pregnant. In this case, you should appoint Eksalef in minimally effective dosages, and in addition, if possible, even at the first trimester, use monotherapy.

Patients should be warned that the use of drugs increases the risk of congenital malformations in the fetus, and in addition, it is possible to perform prenatal screening procedures.

Contraindications

Among the contraindications of drugs:

• intolerance of the active ingredient of the drug, as well as other derivatives of the carboxamide (such as carbamazepine or oxcarbazepine) or auxiliary elements;
• AV blockade (II or III degree);
• severe form of kidney failure (insufficient information about the use of drugs in this group of patients);
• severe form of liver failure (this group of patients did not study the pharmacokinetics of the active ingredient of Exalief);
• children under the age of 18 years (as there is no data on the efficacy and safety of this remedy in the above group of patients).

Care should be taken:

• elderly patients (65+ years of age) (as there is insufficient information on the safety of drugs in this group);
• if there is a low level of thyroxine in the blood;
• in disorders of cardiac conduction or in combination with drugs that extend the range of PR;
• with a moderate or mild degree of kidney failure (in such a case, the dosage correction is performed according to the indices of the creatinine cleansing factor) or the liver (in this case, care must be taken because the clinical information regarding this category of patients is limited);
• with hyponatremia.

Side effects Exalieff

Side effects, as a rule, were moderate or weak, and manifested, mainly, in the early stages of treatment.

Side effects, as a rule, depend on the dosage of the drug, and are associated with the fact that it is part of the carboxamide group. Most often in the process of studying patients suffering from epilepsy, there were such manifestations as the development of nausea and severe headaches with dizziness, and also a feeling of drowsiness. In addition, the following symptoms were observed:

• lymphatic and hematopoietic system: anemia rarely develops, even less often thrombocyto- or leukopenia;
• organs of the immune system: occasionally there were signs of increased sensitivity;
• organs of the endocrine system: occasionally hypothyroidism develops;
• nutrition and metabolism: there is rarely a decrease or an increase in appetite, and in addition obesity, an electrolyte balance disorder and hyponatremia. Dehydration of the body or cachexia is also rare;
• mental disorders: occasionally there is a state of depression, apathy, nervousness, irritability, agitation. Possible insomnia, confusion, tearfulness, unstable mood, the development of ADHD, and in addition, the inhibition of psychomotor reactions, the emergence of psychotic disorders and the development of stress;
• organs of the National Assembly: most often there is a feeling of drowsiness or dizziness; Headaches, tremors, attention disorders or motor coordination are often also observed. More rarely there is amnesia or memory impairment, a balance disorder, severe drowsiness, develops dysesthesia, a sedative effect, or aphasia. Possible manifestations such as lethargy, dystonia, a sense of smell, a violation of the balance of the autonomic NA, a cerebellar form of ataxia or a cerebellar syndrome. In addition, nystagmus, speech disorders and sleep phases, a large epileptic fit, a nerve neuropathy, a burning sensation, a dysarthria, an agestia and hypoesthesia can develop;
• visual organs: most often defocusing of vision or diplopia; Occasionally - oscilloscopy, a disorder of vision or friendly movements of eyeballs, redness of the eye mucosa, saccadic movements or pain in the eyes;
• the organs of hearing together with labyrinthine disorders: most often the vertego is manifested; Occasionally - hearing impairment, noise or pain in the ears;
• cardiovascular system: occasionally there is a bradycardia or a sinus form of it, but also a feeling of a heart rhythm. In addition, occasionally hypo- or hypertension develops, as well as orthostatic collapse;
• organs of the respiratory tract, sternum and mediastinum: occasionally, pain develops in the sternum, bleeding from the nose, and in addition to this dysphonia;
• Gastrointestinal organs: most often vomiting along with nausea and diarrhea; Occasionally - gastritis, discomfort or abdominal pain, flatulence, dyspepsia, dryness in the oral cavity, as well as discomfort sensations in the epigastric region. In addition, duodenitis, simple gingivitis or its hypertrophic form, IBS, tarry stool, toothache and stomatitis, as well as dysphagia and pancreatitis;
• liver and ZHVP: occasionally there are disorders in the liver;
• subcutaneous tissue and skin: most often there are rashes; less often dry skin, alopecia, skin or nail damage, and in addition erythema or hyperhidrosis;
• connective and musculoskeletal tissues: occasionally there are pain in the neck or back, as well as muscles;
• kidney and urinary system: occasionally - infectious process or nocturia;
• mammary glands together with the reproductive system: occasionally develops a disorder of the cycle of menstruation;
• general reactions: most often - gait disorders and a feeling of fatigue; seldom have malaises, peripheral puffiness, asthenia, coldness in the limbs, a feeling of malaise and chills;
• instrumental information and analyzes: occasionally there is a decrease / increase in blood pressure, and in addition, weight loss, a decrease in DAD or SAD. It is also possible to reduce the sodium or hemoglobin concentration in the blood, lower the hematocrit number, and in addition to this, the concentration of T3 or T4. The activity of liver transaminases, the concentration of triacylglycerides and the increase in heart rate may increase.

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Overdose

Accidental overdose of the drug causes the following symptoms - hemiplegia, dizziness, as well as a shaky gait. Exalieff does not have a specific antidote.

In such cases, supportive measures and elimination of symptoms of the violation are anticipated. If necessary, the products of disintegration of the active substance of the drug are effectively eliminated by hemodialysis.

Interactions with other drugs

Acetate eslikarbazepine is actively converted to the substance of eslikarbazepine, and it is excreted, mainly in the process of glucuronation. In in vitro studies, eslikarbazepine appears as a non-strong inducer of isoenzyme CYP3A4, and in addition UDF-HT. This suggests that eslikarbazepine is able to induce the in vivo metabolism of various drugs (metabolized mainly by isoenzyme CYP3A4 or during conjugation via UDP-HT).

At the beginning of the use of Exalife, either during the period of drug cancellation or change in dosage, the enzymes acquire new activity within 2-3 weeks. This delay should be taken into account before and during the application of other drugs that require dosage adjustment when combined with Exalife.

Eslikarbazepine slows the activity of isoenzyme CYP2C19, resulting in the possibility of the appearance of a dose-dependent interaction with drugs, the metabolic processes of which occur mainly with the aforementioned isoenzyme.

When tested on healthy volunteers, a decrease in the efficacy of the active decay product, eslikarbazepine (approximately 32%), was observed as a result of the combination of the active ingredient of Exalife (800 mg once daily) and carbamazepine (400 mg twice daily). This effect is most likely caused by the induction of the glucuronation process. It should be noted that the effect of carbamazepine along with its carbamazepine degradation product with epoxide was not enhanced at the same time. Therefore, taking into account the individual reaction of each patient to therapy, in case of combination of the drug with carbamazepine, it is possible to increase the dosage of Exaliefa. Studies have shown that concomitant use with carbamazepine increases the risk of the appearance of such side effects in the patient: diplopia (about 11.4% of all patients); impairment of motor coordination (approximately in 6.7% of all patients); and dizziness (in about 30% of all patients). In addition, it is possible to increase other specific side effects, which can be triggered by a combination of the above-mentioned medicinal elements.

The tests, in which healthy volunteers participated, showed that the combined administration of the drug with phenytoin at a daily dosage of 1200 mg (single dose) weakened the effectiveness of the action of eslikarbazepine (by approximately 31-33%) - this effect is probably due to the induction of glucuronation processes. During this, the effect of phenytoin was also increased (the average figure was about 31-35%). This effect is supposed to be caused by the suppression of isoenzyme CYP2C19. Therefore, taking into account the individual reaction of the patient to the therapy process, there may be a need for an increase in the dosage of Escalieff and a simultaneous decrease in the dosage of phenytoin.

Glucuronation is the main way of metabolism of substances of eslikarbazepine, as well as lamotrigine. As a consequence, there is the possibility of interaction of these drugs. Testing with participation of healthy volunteers who received eslikarbazepine acetate once in the amount of 1200 mg per day showed that their interaction is rather weak (a decrease in the efficiency of lamotrigine by about 15% is observed) - this avoids the correction of dosage. But, because of the individual reaction of each organism, in some patients such interaction can cause drug-significant effects.

In the process of testing on healthy volunteers the interaction of the topiramate with eslikarbazepine acetate taken simultaneously (in a single dosage of 1200 mg) of topiramate with eslikarbazepine acetate showed no significant changes in the effect of the latter, but the efficacy of topiramate decreased by 18% (this is probably due to a decrease in the bioavailability of the substance). In such cases, dosage adjustment is not necessary.

When analyzing the pharmacokinetic information that was obtained during the Phase 3 testing (with the participation of adult patients with epilepsy), it was found that the combination with levetiracetam or valproate does not affect the performance of eslikarbazepine, but this information is not supported by the results of testing the interaction between these drugs.

The intake of Exalife (a single daily dosage of 1200 mg) by women using oral contationception causes a decrease in systemic exposure to levonorgestrel and ethinylestradiol (average values of 37 and 42%, respectively). It is suggested that the effect is caused by the induction of isoenzyme CYP3A4.

Women who preserve childbearing potential are advised to use proven contraceptive methods during the period of drug administration, and before the completion of the current cycle of menstruation - after its abolition.

Studies using a healthy volunteer combination of medication (a single daily dose of 800 mg) with simvastatin showed a decrease in the systemic effect of the latter by approximately 50%. A similar reaction is probably caused by the induction of isoenzyme CYP3A4. Simultaneous administration of these two drugs may require an increase in the dosage of simvastatin.

When tested on healthy volunteers, the combination of Exaliefa (dosage of 1200 mg) with rosuvastatin showed a decrease in the systemic efficacy of the latter (the average score was 36-39%). The cause of this interaction was not identified, but it is assumed that the cause is a disruption in the activity of rosuvastatin migration, or a combination of this factor with the process of inducing the metabolism of this substance. Due to the fact that the relationship between activity and exposure to drugs has not yet been identified, it is necessary to carefully monitor the patient's response to treatment (for example, to monitor cholesterol levels).

With the combination of Exalieff (dosage of 1200 mg) with warfarin, a slight (23%) was noted, but a significant reduction in the efficacy of the latter for statistical observations. The effect of the drug on blood coagulability or the pharmacokinetic properties of R-warfarin has not been revealed. Since the individual response to this drug combination in patients (at the initial stages of treatment or at the end of the course) may vary, careful monitoring of INR monitoring parameters is required.

During testing on healthy volunteers, the interaction between the drug (dosage of 1200 mg) and digoxin did not show the effect of eslacarbazepine acetate on the pharmacokinetic parameters of the latter. These data suggest that Exalieff does not affect substance P-glycoprotein.

Since the active ingredient of Exaliefa is similar in structure to tricyclics, there is a theoretical possibility of its interaction with MAO inhibitors.

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Storage conditions

The drug is stored in standard for drug preparations conditions that are inaccessible to small children. The temperature can not exceed 30 ° C.

Shelf life

Exalief is allowed to be used for 2 years from the date of release of the medicine.