Exalieff

Exalief is an antiepileptic drug.

Indications Exalieff

It is indicated for the elimination of local epileptic seizures (with or without the secondary stage of generalization) in adults (as an adjuvant drug).

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 strips.

Pharmacodynamics

The exact mechanism of action of eslicarbazepine acetate is unknown, but in vitro electrophysiological tests have shown that the active component and its breakdown products stabilize inactivated voltage-gated sodium channels. This prevents their activation, allowing periodic neuronal excitability to be maintained.

Eslicarbazepine acetate with its active decay products prevents the occurrence of epileptic seizures in preclinical models, making it possible to predict the anticonvulsant effect on humans. At the same time, its pharmacological properties are manifested in humans mainly through the active decay product of this substance - eslicarbazepine.

Pharmacokinetics

The active ingredient is metabolized into eslicarbazepine. When taken orally, the plasma concentration of the active substance usually remains below the quantitative determination values. The peak concentration of eslicarbazepine is observed 2-3 hours after taking the tablet. The bioavailability of the drug is considered high, since the number of decay products observed in the urine is equal to more than 90% of the dose of the active ingredient taken.

Metabolite synthesis with plasma protein is quite low (<40%) and does not depend on the concentration of the substance. In vitro testing shows that the presence of diazepam with warfarin, phenytoin, and digoxin with tolbutamide has little effect on the synthesis of the substance with protein - the same is observed in the opposite direction.

The active component after the first liver passage is intensively and very quickly converted by hydrolysis into its main active decay product – eslicarbazepine.

It reaches its peak plasma concentration 2-3 hours after taking the drug, and steady-state concentration is observed after 4-5 days of taking tablets once a day. This corresponds to the effective half-life of approximately 20-24 hours. When tested on healthy volunteers and adults with epilepsy, the apparent half-life was 10-20 and 13-20 hours, respectively.

A small proportion of the following breakdown products are observed in the plasma: oxcarbazepine, as well as R-licarbazepine (have pharmacological properties), and in addition conjugates of the active substance with the breakdown product, as well as R-licarbazepine together with oxcarbazepine and glucuronic acid.

The active component of the tablets does not affect the body's own purification coefficient and metabolism.

Experimental testing on fresh human hepatocytes showed that eslicarbazepine is able to weakly induce the activity of UGT1A1 isoenism, which is involved in glucuronidation processes.

The excretion of the drug's breakdown products is carried out mainly through the kidneys (unchanged and in the form of conjugates together with glucuronic acid). At the same time, eslicarbazepine together with its glucuronide makes up more than 90% of the breakdown products excreted with urine (approximately 2/3 are excreted in the form of eslicarbazepine, and another 1/3 as glucuronide).

Dosing and administration

Oral administration, regardless of food intake. The drug is an auxiliary drug during the course of anticonvulsant treatment. The tablet may be divided into equal halves.

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

[ 2 ]

Use Exalieff during pregnancy

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

It is necessary to re-evaluate the appropriateness of using the drug if pregnancy is planned or has already occurred during the course of treatment. In this case, Exalief should be prescribed in the minimum effective dosages, and in addition, if possible, at least in the first trimester, monotherapy should be used.

Patients should be warned that the use of drugs increases the risk of congenital defects in the fetus, and in addition, they should be given the opportunity to carry out prenatal screening procedures.

Contraindications

Among the contraindications of the drug:

• intolerance to the active component of the drug, as well as other derivatives of carboxamide (such as carbamazepine or oxcarbazepine) or auxiliary elements;
• AV block (II or III degree);
• severe renal failure (there is insufficient information on the use of drugs in this group of patients);
• severe liver failure (the pharmacokinetics of the active component of Exalief have not been studied in this group of patients);
• children under 18 years of age (since there is no data on the effectiveness and safety of this drug in the above-mentioned group of patients).

Should be taken with caution:

• elderly patients (65+ years) (since there is insufficient information on the safety of drug use in this group);
• if there is a low level of thyroxine in the blood;
• in cardiac conduction disorders or in combination with drugs that prolong the PR interval;
• in case of moderate or mild renal failure (in such cases, the dosage is adjusted according to the creatinine clearance rate) or liver failure (in this case, caution should be exercised, since clinical data regarding this category of patients is limited);
• in case of hyponatremia.

Side effects Exalieff

Side effects were generally moderate to mild and occurred mainly in the early stages of treatment.

Side effects usually depend on the dosage of the drug and are related to the fact that it belongs to the carboxamide group. Most often, during studies of patients suffering from epilepsy, such manifestations as the development of nausea and severe headaches with dizziness, as well as a feeling of drowsiness were observed. In addition, the following symptoms were observed:

• lymphatic and hematopoietic systems: anemia rarely develops, even more rarely – thrombocytopenia or leukopenia;
• Immune system organs: signs of hypersensitivity have occasionally appeared;
• endocrine system organs: hypothyroidism occasionally develops;
• nutrition and metabolism: rarely, a decrease or, on the contrary, an increase in appetite develops, and in addition, obesity, electrolyte imbalance and hyponatremia. Dehydration or cachexia also rarely occurs;
• mental disorders: depression, apathy, nervousness, irritability, agitation are occasionally observed. Insomnia, confusion, tearfulness, unstable mood, development of ADHD are possible, as well as inhibition of psychomotor reactions, the appearance of psychotic disorders and the development of a stressful state;
• NS organs: most often there is a feeling of drowsiness or dizziness; headaches, tremor, attention disorders or motor coordination are also quite common. Less common are amnesia or memory impairment, balance disorder, severe drowsiness, dysesthesia, sedative effect or aphasia. Such manifestations as lethargy, dystonia, olfactory disorder, imbalance of the autonomic nervous system, cerebellar ataxia or cerebellar syndrome are possible. In addition, nystagmus, speech and sleep phase disorders, grand mal seizures, nerve neuropathy, burning sensation, dysarthria, ageustia and hypoesthesia may develop;
• visual organs: most often blurred vision or diplopia; rarely – oscillopsia, visual disturbance or associated movements of the eyeballs, redness of the eye mucosa, saccadic movements or pain in the eyes;
• organs of hearing together with labyrinthine disorders: most often vertigo appears; occasionally – hearing loss, noise or pain in the ears;
• cardiovascular system: bradycardia or its sinus form occasionally appears, and in addition, a feeling of heart rhythm. In addition, hypo- or hypertension occasionally develops, as well as orthostatic collapse;
• respiratory tract, sternum and mediastinum: occasionally, pain in the sternum, nosebleeds, and in addition, dysphonia develop;
• Gastrointestinal organs: most often vomiting with nausea and diarrhea; occasionally - gastritis, discomfort or pain in the abdomen, flatulence, dyspeptic symptoms, dry mouth, as well as discomfort 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 biliary tract: liver dysfunction is occasionally observed;
• subcutaneous tissues and skin: most often rashes occur; less often dry skin, alopecia, skin or nail damage, and also erythema or hyperhidrosis develop;
• connective and musculoskeletal tissues: pain in the neck or back, as well as muscles, occasionally appears;
• kidneys and urinary system: rarely - infectious process or nocturia;
• mammary glands together with the reproductive system: occasionally, menstrual cycle disorders develop;
• General reactions: most often – gait disturbances and a feeling of fatigue; rarely, malaise, peripheral edema, asthenia, cold extremities, a feeling of malaise and chills occur;
• Instrumental data and analyses: occasionally there is a decrease/increase in blood pressure, and also weight loss, a decrease in the diastolic or sapid blood pressure. It is also possible to decrease the sodium or hemoglobin concentration in the blood, decrease the hematocrit number, and also the concentration of T3 or T4. The activity of liver transaminases, the concentration of triglycerides and the heart rate may increase.

[ 1 ]

Overdose

Accidental overdose of the drug causes the following symptoms - hemiplegia, dizziness, and unsteady gait. Exalief has no specific antidote.

In such cases, supportive measures and elimination of symptoms of the disorder are assumed. If necessary, the decay products of the active substance of the drug are effectively eliminated by hemodialysis.

Interactions with other drugs

Eslicarbazepine acetate is actively converted into the substance eslicarbazepine, and it is excreted mainly through glucuronidation. In vitro studies show that eslicarbazepine acts as a weak inducer of the CYP3A4 isoenzyme, and also of UDP-GT. This allows us to conclude that eslicarbazepine is capable of inducing the metabolism of various drugs in vivo (metabolized mainly by the CYP3A4 isoenzyme or through conjugation via UDP-GT).

At the beginning of Exalief use, or during the period of drug withdrawal or change in its dosage, enzymes acquire new activity over the course of 2-3 weeks. This delay must be taken into account before and during the use of other drugs that require dosage adjustment when used in combination with Exalief.

Eslicarbazepine inhibits the activity of the isoenzyme CYP2C19, which may result in the possibility of dose-dependent interactions with drugs that are primarily metabolized by the above-mentioned isoenzyme.

When tested on healthy volunteers, the combination of the active component Exalief (800 mg once daily) and carbamazepine (400 mg twice daily) resulted in a decrease in the effectiveness of the active breakdown product, eslicarbazepine (by approximately 32%). This effect is most likely due to the induction of the glucuronidation process. It should be noted that the effect of carbamazepine together with its breakdown product, carbamazepine epoxide, was not enhanced. Therefore, given the individual response of each patient to therapy, in the case of combining the drug with carbamazepine, it is possible that the dosage of Exalief will need to be increased. Studies have shown that combined use with carbamazepine increases the risk of the following side effects in a patient: diplopia (in approximately 11.4% of all patients); motor coordination disorder (in approximately 6.7% of all patients); and dizziness (in approximately 30% of all patients). In addition, it is possible that other specific side effects may be enhanced, which may be caused by the combination of the above medicinal elements.

Tests involving healthy volunteers have shown that the combined use of the drug with phenytoin at a daily dose of 1200 mg (single dose) weakened the effectiveness of eslicarbazepine (by approximately 31-33%) - this effect probably develops due to the induction of glucuronidation processes. During this, an increase in the effect of phenytoin was also noted (average value - approximately 31-35%). This effect is assumed to be caused by the suppression of the isoenzyme CYP2C19. Therefore, given the individual patient's response to the therapy process, it may be necessary to increase the dosage of Exalief and simultaneously reduce the dosage of phenytoin.

Glucuronidation is the main route of metabolism of eslicarbazepine and lamotrigine. As a result, there is a possibility of interaction between these drugs. Tests involving healthy volunteers who were given eslicarbazepine acetate once in the amount of 1200 mg per day showed that their interaction is quite weak (there is a decrease in the effectiveness of lamotrigine by about 15%) - this allows avoiding dosage adjustments. However, due to the individual reaction of each organism, in some patients such interaction can cause drug-significant effects.

In the process of testing the interaction of topiramate and eslicarbazepine acetate taken simultaneously (in a single dose of 1200 mg) on healthy volunteers, no significant changes in the effect of the latter were observed, but the effectiveness of topiramate decreased by 18% (this is probably due to a decrease in the bioavailability of the substance). In such cases, no dosage adjustment is necessary.

An analysis of pharmacokinetic data obtained during phase 3 testing (in adult patients with epilepsy) showed that combination with levetiracetam or valproate does not affect the efficacy of eslicarbazepine, but this information is not supported by the results of interaction testing between these drugs.

Administration of Exalief (single daily dose of 1200 mg) to women using oral contraception results in a decrease in the systemic exposure to levonorgestrel and ethinyl estradiol (mean values, respectively: 37 and 42%). It is assumed that the effect is due to the induction of the CYP3A4 isoenzyme.

Women who retain their reproductive potential are advised to use proven methods of contraception during the period of taking the drug, as well as until the end of the current menstrual cycle - after its cancellation.

Studies in healthy volunteers of the combination of the drug (single daily dose of 800 mg) with simvastatin demonstrated a decrease in the systemic exposure of the latter by approximately 50%. This reaction is likely due to induction of the isoenzyme CYP3A4. Concomitant administration of these two drugs may require an increase in the dosage of simvastatin.

When testing a combination of Exalief (1200 mg dosage) with rosuvastatin in healthy volunteers, a decrease in the systemic effectiveness of the latter was observed (the average indicator was 36-39%). It was not possible to determine the cause of this interaction, but it is assumed that the cause is a violation of the activity of rosuvastatin transfer or a combination of this factor with the process of inducing the metabolism of this substance. Due to the fact that the relationship between the activity and the effect of drugs has not yet been identified, it is necessary to carefully monitor the patient's response to treatment (for example, monitor cholesterol levels).

When Exalief (1200 mg dosage) was combined with warfarin, a slight (23%) but statistically significant decrease in the effectiveness of the latter was observed. No effect of the drug on blood clotting or the pharmacokinetic properties of R-warfarin was detected. Since individual reactions to this drug combination in patients (at the initial stages of treatment or after completion of the course) may vary, it is necessary to carefully monitor the INR monitoring indicators.

During interaction testing in healthy volunteers between the drug (1200 mg dose) and digoxin, no effect of eslicarbazepine acetate on the pharmacokinetic parameters of the latter was observed. These data suggest that Exalief does not affect the substance P-glycoprotein.

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

[ 3 ]

Storage conditions

The medicine is stored in standard conditions for medicinal preparations, inaccessible to small children. The temperature cannot exceed 30°C.

Shelf life

Exalief is permitted to be used for 2 years from the date of release of the drug.