Exalieff - instructions for use, analogs, reviews and release forms (tablets 800 mg) drugs for the treatment of partial seizures in epilepsy in adults, children and pregnancy. Composition

In this article, you can read the instructions for using the drug Exalieff. Presented are reviews of visitors to the site - consumers of this medication, as well as opinions of physicians specialists on the use of Exalife in their practice. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Analogues of Exalieuf in the presence of existing structural analogs. Use to treat partial seizures in epilepsy in adults, children, as well as during pregnancy and breast-feeding. Composition of the preparation.

 

Exalieff - antiepileptic drug (PEP). The exact mechanisms of action of eslikarbazepine acetate (active ingredient of the drug Exalieff) are unknown. However, according to the results of electrophysiological studies in vitro, eslikarbazepine acetate and its metabolites stabilize the inactivated state of the potential-dependent sodium channels, preventing their activation and, thus, supporting the periodic excitation of neurons. Eslikarbazepine acetate and its active metabolites prevent the development of epileptic seizures in pre-clinical models, which allows predicting its anticonvulsant effect in humans. In humans, the pharmacological activity of eslikarbazepine acetate is mainly due to its active metabolite, eslikarbazepine.

 

Composition

 

Eslikarbazepine acetate + excipients.

 

Pharmacokinetics

 

Eslikarbazepine acetate is largely metabolized in eslikarbazepine. After oral administration, the concentration of eslikarbazepine acetate in blood plasma, as a rule, remains below the level of quantitative determination.Bioavailability of the drug can be considered high, since the amount of metabolites found in the urine is more than 90% of the dose of eslikarbazepine acetate. The binding of eslikarbazepine to plasma proteins is relatively low (less than 40%), and does not depend on its concentration. Exalieff is rapidly and intensively metabolized into its main active metabolite, eslikarbazepine, by hydrolysis when it first passes through the liver. A small number of the following metabolites are found in the plasma: R-lycarbazepine and oxcarbazepine, which have pharmacological activity, as well as conjugates of eslikarbazepine acetate, eslikarbazepine, R-lycarbazepine and oxcarbazepine with glucuronic acid. Metabolites of Escalieff are excreted from the systemic blood stream, mainly by the kidneys, in unchanged form and in the form of conjugates with glucuronic acid.

 

Indications

• epilepsy;
• monotherapy of partial epileptic seizures with or without secondary generalization in newly diagnosed epilepsy in adults;
• additional therapy of partial epileptic seizures with secondary generalization or without it in adults.

 

Forms of release

 

Tablets 800 mg.

 

Instructions for use and dosing regimen

 

Excalife is taken orally regardless of food intake. The tablet can be divided into two equal parts.

 

Exalief is prescribed in monotherapy, or in addition to ongoing anticonvulsant therapy. The recommended initial dose is 400 mg once a day, after 1-2 weeks the dose is increased to 800 mg once a day. Taking into account the individual response to treatment, the dose can be increased to 1200 mg once a day. Some patients who take the drug Exalifef in monotherapy, can respond to a dose of 1600 mg 1 time per day.

 

Care should be taken when treating patients with renal insufficiency and dose adjustment, depending on the amount of creatinine clearance (CC). With QC greater than 60 ml per minute, dose adjustment is not required. If KK 30-60 ml per minute: the initial dose of 400 mg every other day for 2 weeks, then 400 mg once a day. However, taking into account the individual response, the dose can be increased. Use in patients with severe renal failure (CK less than 30 ml per minute) is not recommended because of insufficient data.

 

In patients with mild and moderate hepatic insufficiency, dose adjustment is not required.The pharmacokinetics of Exaliefa in patients with severe hepatic insufficiency have not been studied, and therefore its use in this category of patients is not recommended.

 

Side effect

• anemia, thrombocytopenia, leukopenia;
• hypersensitivity;
• hypothyroidism (decreased thyroid function and insufficient production of hormones);
• hyponatremia;
• decreased appetite;
• dehydration;
• hypochloremia (decrease in the level of chlorine in the blood);
• insomnia;
• psychotic disorders (apathy, depression, nervousness, agitation, irritability, attention deficit disorder, hyperactivity, confusion, lability of mood, tearfulness, slowing down of the speed of psychomotor reactions);
• dizziness, headache;
• violation of attention;
• tremor (rapid, rhythmic movements of limbs or trunk), ataxia (partial or complete loss of coordination of voluntary muscle movements);
• imbalance, impaired coordination of movements (cerebellar syndrome);
• memory loss, amnesia (pathological loss of memories of current or past life circumstances);
• sedative effect;
• aphasia (local absence or disruption of an already formed speech);
• dysesthesia (sensitivity disorder), paresthesia (spontaneous burning sensation, tingling, crawling);
• drowsiness, lethargy;
• parosmia (change of smell);
• convulsions;
• peripheral neuropathy;
• nystagmus (involuntary vibrational movements of the eyes of high frequency);
• speech disorder, dysarthria;
• migraine;
• Diplopia (double vision), defocused vision, oscilloscopy (illusion of rotation of the surrounding environment);
• violation of friendly movements of eyeballs;
• hyperemia (redness) of the conjunctiva;
• hearing loss, tinnitus;
• a feeling of palpitation, a bradycardia;
• arterial hypertension (including hypertensive crisis), arterial hypotension, orthostatic hypotension;
• tides, a feeling of coldness in the hands and feet;
• nose bleed;
• chest pain;
• nausea, vomiting;
• diarrhea, constipation;
• gastritis;
• abdominal pain;
• dry mouth;
• discomfort in the abdomen, bloating;
• gingivitis;
• melena (black semi-liquid stool with a characteristic unpleasant odor, formed from blood under the influence of the contents of the stomach and intestines);
• toothache;
• pancreatitis;
• abnormal liver function;
• rash on the skin;
• alopecia (baldness);
• dry skin, increased sweating;
• erythema (redness of the skin);
• itching;
• Myalgia (pain in the muscles);
• muscle weakness;
• pain in the limbs;
• urinary tract infections;
• violation of gait;
• asthenia, malaise;
• chills;
• peripheral edema;
• decrease in body weight.

 

Contraindications

• hypersensitivity to eslikarbazepine acetate, other carboxamide derivatives (eg, carbamazepine, oxcarbazepine) or to any of the excipients of the drug;
• atrioventricular block 2 or 3 degrees;
• patients with severe renal failure (QC less than 30 ml per minute), as the data on the use of the drug in this category of patients is not enough;
• patients with severe hepatic insufficiency (pharmacokinetics of Exaliefa in this category of patients has not been studied);
• children's age till 18 years.

 

Application in pregnancy and lactation

 

General risks associated with epilepsy and PEP

 

There is evidence that the prevalence of developmental malformations in children born to women with epilepsy is 2-3 times higher than the 3% in the general population. Most often, the following defects are detected: cleavage of the upper lip, anomalies in the development of the cardiovascular system, and neural tube defects.Combination therapy with anticonvulsant drugs is accompanied by an increased risk of developing congenital malformations in comparison with monotherapy, in connection with which, it is necessary, if possible, to prescribe monotherapy. Women with preserved reproductive potential, especially planning pregnancy, should be observed by a specialist. The need for antiepileptic therapy is evaluated in women planning a pregnancy. It is unacceptable to abruptly cancel anticonvulsant therapy because of the risk of developing an epileptic attack, which can lead to serious consequences for both the mother and the fetus.

 

Women with preserved childbearing potential and contraception

 

Undesirable interaction of Exalieff with oral contraceptives was noted. During treatment and until the end of the current menstrual cycle after its completion, it is necessary to use an alternative, effective and safe method of contraception.

 

Pregnancy

 

There are no data on the use of Exalife in pregnant women. In the course of animal studies, the drug showed reproductive toxicity.The expediency of prescribing the drug Exalief should be assessed repeatedly, if pregnancy occurs or is planned during its administration. It is recommended to prescribe minimum effective doses of the drug and, if possible, give preference to monotherapy at least in the first trimester of pregnancy. Patients should be warned about the increased risk of congenital malformations in the fetus and provide an opportunity for prenatal screening.

 

Antiepileptic drugs may contribute to the development of a deficiency of folic acid, which is an additional cause of anomalies in the fetus. When planning pregnancy and after its onset, it is recommended to take folic acid supplements in addition. Specific prenatal diagnosis of congenital malformations should be offered even to those women who take folic acid.

 

Newborns

 

In newborns, whose mothers received anticonvulsant therapy, there were cases of bleeding. As a preventive measure, women in the last weeks of pregnancy and newborns should be prescribed vitamin K1.

 

Breast-feeding

 

There is no data on the penetration of eslikarbazepine acetate into human breast milk. In the course of the studies, the penetration of Exalief into the breast milk of animals was revealed. Breastfeeding should be abolished for the duration of prescribing of eslikarbazepine acetate, as the risk to the child can not be ruled out.

 

Fertility

 

There is no evidence of the effects of Exalief on human fertility. Studies in animals have revealed a violation of fertility after the treatment of eslikarbazepine acetate.

 

Use in children

 

Contraindicated in the use of the drug Eksalef in childhood to 18 years.

 

Application in elderly patients

 

Correction of the dose of the drug is not required, provided that the kidney function is not impaired. Due to the limited data, it is not recommended to take a single daily dose of 1600 mg in the monotherapy regimen in elderly patients.

 

special instructions

 

Suicidal behavior

 

In the appointment of anticonvulsant drugs for several indications, there have been cases of suicidal behavior. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a slight increase in the risk of developing suicidal behavior.The mechanism of this phenomenon is unknown, the available data do not exclude the possibility of developing an analogous reaction against the background of the use of Exalief. Thus, patients should be monitored for signs of suicidal behavior, and options for appropriate treatment should be considered. If there are any signs of suicidal behavior, patients and caregivers should consult a doctor.

 

Disturbances from the nervous system

 

The use of Escalieff may be accompanied by unwanted reactions from the central nervous system, such as dizziness and drowsiness, which increases the risk of accidental injury.

 

Other Precautions

 

If it is necessary to discontinue the drug, Exalief should be administered gradually to minimize the risk of an increased incidence of epileptic seizures.

 

Skin Reactions

 

In clinical trials involving patients with epilepsy, an undesirable skin-rash response was noted in 1.2% of the entire population of patients receiving Exalief. When there are symptoms of hypersensitivity to the drug, Exalief should be canceled.

 

The presence of the allele HLA-B 1502 (Chinese Han people, natives of Thailand and other Asian countries)

 

There is evidence that the HLA-B 1502 allele, which is present in Han Chinese, natives of Thailand and other Asian countries, is associated with the risk of Stevens-Johnson syndrome in the treatment with carbamazepine. The chemical structure of eslikarbazepine acetate is similar to that of Carbamazepine and there is a possibility of an increased risk of Stevens-Johnson syndrome in patients with the presence of the HLA-B 1502 allele in the treatment with Exalief. The prevalence of the HLA-B 1502 allele among Chinese Han people and natives of Thailand is about 10%. Before prescribing carbamazepine or chemically related compounds, if possible, patients should be screened for this allele. The use of Exalieff in patients with a proven presence of the HLA-B 1502 allele may be justified if the benefit of the application exceeds the risk.

 

Because of the prevalence of this allele among natives of other Asian countries (about 15% among the inhabitants of the Philippines and Malaysia), screening for the presence of the HLA-B 1502 allele may also be appropriate.

 

The presence of the HLA-A 3101 allele (representatives of the European and Japanese populations)

 

There is evidence to suggest that the allele HLA-A 3101, present the representatives of the European and Japanese population, the treatment with carbamazepine increased the risk of allergic skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, or in less severe form, acute generalized exstematous pustulosis and maculopapular rash. Prevalence allele HLA-A 3101 varies widely and ethnic populations ranges from 2 to 5% in Europe and about 10% - in the Japanese population. The presence of the allele HLA-A 3101 may increase the risk of carbamazepine-induced cutaneous reactions (in most cases, less severe) from 5% in the general population to 26% of the representatives of the European population, while the lack of it, in turn, may reduce the risk of 5 up to 3.8%.

 

Data for recommending screening patients for the presence of the HLA-A 3101 allele prior to the appointment of Exalief is not enough.

 

Use of carbamazepine or chemically related compounds in patients with proven by the presence of allele HLA-A 3101 may be justified if the benefits of using outweigh the risks.

 

Hyponatremia

 

Hyponatremia was noted as an undesirable reaction to the use of the drug Exalieff in 1.5% of patients. In most cases, hyponatremia is asymptomatic, but it can be accompanied by clinical manifestations such as increased epileptic seizures, confusion, or impaired consciousness. The incidence of hyponatremia increases with an increase in the dose of Exalieph. In case of hyponatremia due to renal insufficiency in the history or as a result of simultaneous administration of drugs that can lead to hyponatremia (eg, diuretics, desmopressin, carbamazepine), before and during treatment with Exalief, as well as in the development of clinical symptoms of hyponatremia, it is necessary to control the concentration of sodium in serum blood. When developing clinically significant hyponatremia of eslikarbazepine acetate should be discarded.

 

PR interval

 

During clinical studies of eslikarbazepine acetate, the PR interval was prolonged on the electrocardiogram. Care must be taken in certain conditions (for example, with a low concentration of thyroxine,cardiac conduction abnormalities) or simultaneous administration of medications, which, according to available data, are accompanied by an extension of the PR interval.

 

Renal insufficiency

 

Care of patients with renal insufficiency should be carried out and dose adjustment should be carried out in accordance with the creatinine clearance.

 

Liver failure

 

In view of the limited number of clinical data for patients with mild and moderate hepatic impairment, Exalief is used with caution in this category of patients. Due to the lack of clinical data, it is not recommended to prescribe Eksalef to patients with severe hepatic insufficiency.

 

Impact on the ability to drive vehicles and manage mechanisms

 

Exalief has a low or moderate impact on the ability to drive vehicles and work with machinery. In some patients, dizziness, drowsiness, or visual impairment may occur (especially at the beginning of the treatment). Patients should be warned that physical and / or mental disability can be caused to drive a vehicle or mechanisms and recommend refrainingfrom such activities to the establishment of the effect on it of taking the drug.

 

Drug Interactions

 

Studies of drug interaction were conducted only in adults.

 

Excalife is actively metabolized in eslikarbazepine, which is excreted mainly by glucuronation. In vitro, eslikarbazepine is a weak inducer of the isoenzyme CYP3A4 and uridine-5-diphosphate glucuronyl transferases (UDF-HT). In vivo, it enhances the metabolism of drugs that are oxidized predominantly by the CYP3A4 isoenzyme (eg, simvastatin), which may require an increase in the dose of such drugs when combined with Exalief. Eslikarbazepine in vivo can enhance the metabolism of drugs that enter into a conjugation reaction involving UDF-HT. When the drug is prescribed or withdrawn, as well as when the dosage regimen is changed, the activity of the enzymes stabilizes within 2-3 weeks, which should be taken into account when it is necessary to correct the doses of drugs taken together with the drug Exalief. Eslikarbazepine inhibits the isoenzyme CYP2C19, which causes the potential for dose-dependent interactions with drugs that are metabolized mainly with the participation of the CYP2C19 isoenzyme (eg, phenytoin).

 

Interaction with other PEPs

 

Carbamazepine

 

In a study involving healthy volunteers simultaneous application Eksaliefa 800 mg 1 time per day and Carbamazepine 400 mg 2 times a day resulted in a reduction of the active metabolite - eslikarbazepina (average 32%), which most likely caused by induced glucuronation. At the same time, no increase in the action of carbamazepine or its metabolite, carbamazepine epoxide, was observed. Thus, taking into account the individual response to treatment, when combined with a prescription with carbamazepine, an increase in the dose of eslikarbazepine acetate may be required. Studies involving patients have shown that with the simultaneous administration of carbamazepine, the risk of the following undesirable reactions increases: diplopia, movement coordination disorders and dizziness. The risk of intensifying other specific undesirable reactions caused by simultaneous administration of carbamazepine and Exalieph can not be ruled out.

 

Phenytoin

 

In a study involving healthy volunteers, the simultaneous use of Exalieff 1200 mg once a day and phenytoin led to a decrease in the activity of the active metabolite, eslikarbazepine (an average of 31-33%), which is most likely caused by the induction of glucuronation.At the same time, the effect of phenytoin was increased (on average by 31-35%), which, presumably, was caused by inhibition of the isoenzyme CYP2C19. Thus, taking into account the individual response to treatment for a combined appointment, an increase in the dose of eslikarbazepine acetate and a decrease in the dose of phenytoin may be required.

 

Lamotrigine

 

Glucuronation is the main pathway of metabolism of eslikarbazepine and lamotrigine, so their interaction is possible. In a study involving healthy volunteers taking eslikarbazepine acetate at a dose of 1,200 mg once a day, there was a slight pharmacokinetic interaction with lamotrigine (15% decrease in the effect of the latter), and therefore, correction of their dosing regimen is usually not required. However, due to the possible individual variability, the interaction of Exalieff and lamotrigine may be clinically significant in some patients.

 

Topiramate

 

In a study involving healthy volunteers with simultaneous use of eslikarbazepine acetate at a dose of 1200 mg 1 time per day and topiramate, no significant changes in the effect of eslikarbazepine were noted, but the effect of topiramate decreased by 18%, which, most likely,is caused by a decrease in its bioavailability. Correction of the dose in this case is not required.

 

Valproate and levetiracetam

 

An analysis of the pharmacokinetic data obtained in Phase 3 trials with the participation of adult patients with epilepsy revealed that simultaneous administration of valproate or levetiracetam does not affect the effects of Exalief, but this information is not supported by the results of traditional drug interaction studies.

 

Oxcarbazepine

 

It is not recommended to prescribe eslikarbazepine acetate simultaneously with oxcarbazepine, since excessive exposure to active metabolites is possible.

 

Interaction with other drugs

 

Oral contraceptives

 

With the use of Exalieff 1200 mg once daily for women using oral contraceptives, the systemic effects of levonorgestrel and ethinyl estradiol were reduced by an average of 37% and 42%, respectively, which is most likely due to the induction of the CYP3A4 isoenzyme. Women with preserved reproductive potential should use adequate contraceptive methods during treatment with Exalief and before the end of the current menstrual cycle after the withdrawal of this drug.

 

Simvastatin

 

In a study involving healthy volunteers with simultaneous application of 800 mg once with eslcarbazepine acetate, the systemic effect of Simvastatin was reduced by an average of 50%, which is most likely due to the induction of the CYP3A4 isoenzyme. When combined with an appointment with Exalief, an increase in the dose of simvastatin may be required.

 

Rosuvastatin

 

In a study involving healthy volunteers with concomitant use with eslikarbazepine acetate at a dose of 1200 mg once daily, weakened the systemic effect of Rosuvastatin by an average of 36-39%. The mechanism of this interaction is unknown, but perhaps it is caused by a violation of the transport activity of rosuvastatin or a combination of this factor with the induction of its metabolism. Since the relationship between the action and activity of the drug is not clear, it is recommended to monitor the response to therapy (eg, control of cholesterol level).

 

Warfarin

 

With simultaneous use of Exalieff 1200 mg once a day and warfarin, a small (23%) but statistically significant weakening of S-warfarin is observed.Effects of eslacarbazepine acetate on the pharmacokinetics of R-warfarin or on blood coagulability have not been observed. Due to the possibility of individual variability in the interaction of drugs in the first weeks after the onset or end of the combined use of Warfarin and eslikarbazepine acetate, special attention should be paid to the monitoring of the International Normalized Ratio (INR).

 

Digoxin

 

In the course of the study with the participation of healthy volunteers, there was no effect of Exalieff in a dose of 1200 mg once a day on the pharmacokinetics of digoxin. This suggests that eslikarbazepine acetate has no effect on transport P-glycoprotein.

 

Inhibitors of monoamine oxidase (MAO)

 

Given the structural similarity of eslikarbazepine acetate and tricyclic antidepressants, the interaction between Exalief and MAO inhibitors is theoretically possible.

 

Analogues of the drug Exalief

 

Exalieff does not have a structural analogue for the active substance.

 

Analogues for the pharmacological group (antiepileptic drugs):

• Actinerval;
• Algerian;
• Acetazolamide;
• Benzobarbital;
• Benzon;
• Briviak;
• Valopixime;
• Valparin;
• Valproic acid;
• Wimpat;
• Gabagamma;
• Gabapentin;
• Habitryl;
• Halodiff;
• Gapentec;
• Hexamidine;
• Depakin;
• Depamid;
• Diazepam;
• Dipromal;
• Diphenine;
• Zagreton;
• Zenicetam;
• Zeptol;
• Zonegran;
• Inovevelon;
• Carbamazepine;
• Carbapine;
• Caten;
• Keppra;
• Clonazepam;
• Clonotril;
• Convilept;
• Convulex;
• Convulsant;
• Convulsofin;
• Lameptil;
• Lamyctal;
• Lamotrigine;
• Levetiracetam;
• Lethiram;
• Mazepine;
• Maxitope;
• Maliazine;
• Mysolin;
• Neuronthin;
• Pregabalin;
• Primidone;
• Relium;
• Rivotril;
• Ropimat;
• Sabril;
• Seizar;
• Stasepine;
• Suxilep;
• Tebantin;
• Tegretol;
• Topalepsin;
• Topiramate;
• Topiromax;
• Thoreal;
• Trileptal;
• Phenobarbital;
• Finlepsin;
• Chloracon;
• Eltator;
• Enkorat;
• Epimax;
• Epitera;
• Epitope;
• Epitropil.

 

Review of the neurologist's doctor

 

I prescribe the drug Exalief for patients with epilepsy before the age of 60 years. But only a few remain on constant therapy with this medication, since very often adverse reactions to it develop. Especially often it is migraine-like, sometimes unbearable, headaches. Many patients complain of lethargy and drowsiness, which interfere with work.In one patient, against the background of treatment with Exalief, there was a decrease in hearing and speech impairment. Because of these undesirable reactions, worsening the quality of life of patients, the drug has to be canceled and another treatment is selected.

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