Eptaza

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EPTASE (EPTASE)

Composition:

Active substance: eslicarbazepine;

1 tablet contains 200 mg, 400 mg, or 800 mg of eslicarbazepine acetate;

Excipients: sodium croscarmellose, hypromellose, microcrystalline cellulose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties:

200 mg tablets: elongated, uncoated tablets, white or almost white, with embossing "EC 1" on one side and a functional score line on the other;

400 mg tablets: biconvex, round, uncoated tablets, white or almost white, with embossing "EC 2" on one side and flat on the other;

800 mg tablets: elongated, uncoated tablets, white or almost white, with embossing "EC 4" on one side and a functional score line on the other.

Pharmacotherapeutic group.

Antiepileptic agents, carboxamide derivatives. ATC code N03AF04.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

The exact mechanism of action of eslicarbazepine acetate is unknown. However, according to in vitro electrophysiological studies, eslicarbazepine acetate and its metabolites stabilize the inactivated state of voltage-gated sodium channels, preventing their activation, and thereby inhibit neuronal repetitive firing.

Pharmacodynamic Effects

Eslicarbazepine acetate and its active metabolites prevent the development of epileptic seizures in preclinical models, suggesting its anticonvulsant activity in humans. In humans, the pharmacological activity of eslicarbazepine acetate is primarily mediated by its active metabolite – eslicarbazepine.

Pharmacokinetics

Absorption

Eslicarbazepine acetate is extensively metabolized to eslicarbazepine. After oral administration, plasma concentrations of eslicarbazepine acetate are generally below the quantification limit. For eslicarbazepine, Cmax is reached within 2–3 hours after administration (tmax). The bioavailability of the drug can be considered high, as urinary recovery of metabolites accounts for more than 90% of the administered dose of eslicarbazepine acetate.

Distribution

Protein binding of eslicarbazepine to plasma proteins is relatively low (< 40%) and independent of its concentration. In vitro studies have shown that the presence of warfarin, diazepam, digoxin, phenytoin, or tolbutamide does not affect the degree of eslicarbazepine binding to plasma proteins. Conversely, eslicarbazepine has virtually no effect on the plasma protein binding of warfarin, diazepam, digoxin, phenytoin, or tolbutamide.

Metabolism

Eslicarbazepine acetate undergoes rapid and extensive first-pass metabolism in the liver to its main active metabolite – eslicarbazepine – via presystemic hydrolysis. Steady-state plasma concentrations of eslicarbazepine are achieved within 4–5 days of once-daily dosing, corresponding to an effective half-life of approximately 20–24 hours. In studies involving healthy volunteers and adult patients with epilepsy, the elimination half-life ranged from 10–20 hours and 13–20 hours, respectively. Minor metabolites detected in plasma include R-licarbazepine and oxcarbazepine, which are active, as well as glucuronide conjugates of eslicarbazepine acetate, eslicarbazepine, R-licarbazepine, and oxcarbazepine.

Eslicarbazepine acetate does not affect its own metabolism or clearance.

Eslicarbazepine is a weak inducer of the CYP3A4 isoenzyme and inhibits the CYP2C19 isoenzyme.

In studies with eslicarbazepine in fresh human hepatocytes, moderate induction of glucuronidation mediated by the UGT1A1 isoenzyme was observed.

Elimination

Metabolites of eslicarbazepine acetate are primarily eliminated from systemic circulation via renal excretion, both unchanged and as glucuronide conjugates. Overall, eslicarbazepine and its glucuronide account for more than 90% of total metabolites excreted in urine (approximately 2/3 unchanged and 1/3 as glucuronide).

Linearity / Non-linearity

Within the dose range of 400–1200 mg, eslicarbazepine acetate exhibits linear, dose-proportional pharmacokinetics in both healthy volunteers and patients with epilepsy.

Geriatric Patients (aged 65 years and older)

The pharmacokinetic profile of eslicarbazepine acetate is not altered in elderly patients with creatinine clearance greater than 60 ml/min.

Patients with Renal Impairment

Metabolites of eslicarbazepine acetate are primarily eliminated via the kidneys. In studies involving patients with mild to severe renal impairment, drug clearance was shown to depend on renal function. Dose adjustment is recommended for patients (adults and children aged 6 years and older) with creatinine clearance below 60 ml/min when treated with eslicarbazepine acetate.

Use of eslicarbazepine acetate is not recommended in children aged 2 to 6 years, as the intrinsic activity of elimination processes is still immature at this age.

Hemodialysis removes eslicarbazepine acetate metabolites from plasma.

Patients with Hepatic Impairment

The pharmacokinetics and metabolism of eslicarbazepine acetate were evaluated in healthy volunteers and patients with moderate hepatic impairment after multiple oral doses. Moderate hepatic impairment did not affect the pharmacokinetics of eslicarbazepine acetate. Dose adjustment is not required in patients with mild or moderate hepatic impairment.

Pharmacokinetics of eslicarbazepine have not been studied in patients with severe hepatic impairment.

Gender

Studies in patients and healthy volunteers have not revealed any gender-related differences in the pharmacokinetics of eslicarbazepine acetate.

Children

As in adults, eslicarbazepine acetate is extensively metabolized to eslicarbazepine. After oral administration, plasma concentrations of eslicarbazepine acetate are generally below the quantification limit. Cmax of eslicarbazepine is reached within 2–3 hours after administration (tmax). Body weight has been shown to influence volume of distribution and clearance. Additionally, age, independent of body weight, may play a role in the clearance of eslicarbazepine acetate, particularly in the youngest age group (2–6 years).

Children under 6 years of age

Population pharmacokinetics indicate that doses of 27.5 mg/kg/day and 40 mg/kg/day are required in the subgroup of children aged 2 to 6 years to achieve exposure equivalent to therapeutic doses of 20 and 30 mg/kg/day in children aged 6 years and older.

Children aged 6 years and older

Population pharmacokinetics indicate that exposure to eslicarbazepine observed at doses of 20 and 30 mg/kg/day in children aged 6 years and older is comparable to that observed in adults receiving 800 and 1200 mg of eslicarbazepine acetate once daily.

Clinical characteristics.

Indications.

Use the medicinal product for:

• monotherapy in partial seizure attacks, with or without secondary generalization, in adult patients with newly diagnosed epilepsy;
• adjunctive therapy in partial seizure attacks, with or without secondary generalization, in adult patients and children aged 6 years and older.

Contraindications.

Hypersensitivity to the active substance or to any derivative substance (e.g., carbamazepine, oxcarbazepine), as well as to any of the excipients.

Atrioventricular (AV) block of grade II or III.

Interaction with other medicinal products and other forms of interactions.

Interaction studies have been conducted only in adult patients.

Eslicarbazepine acetate is actively metabolized, forming eslicarbazepine, which is primarily eliminated via glucuronidation. In vitro, eslicarbazepine acetate exhibits properties of a weak inducer of the CYP3A4 isoenzyme and UDP-glucuronosyltransferase. In vivo, eslicarbazepine induces the metabolism of medicinal products that are predominantly metabolized by the CYP3A4 enzyme (e.g., simvastatin). Therefore, when co-administered with eslicarbazepine acetate, an increase in the dose of medicinal products metabolized by the CYP3A4 enzyme may be necessary. In vivo, eslicarbazepine may induce the metabolism of medicinal products primarily eliminated via conjugation by UDP-glucuronosyltransferase. It may take 2–3 weeks at the beginning or end of treatment with eslicarbazepine, or when changing the dose, to reach a new level of enzyme activity. This time delay should be taken into account when eslicarbazepine is administered immediately before or in combination with other medicinal products for which dose adjustment may be required during concomitant use with eslicarbazepine. Eslicarbazepine has inhibitory properties towards CYP2C19. Therefore, interactions may occur when high doses of eslicarbazepine acetate are taken concomitantly with medicinal products primarily metabolized by CYP2C19 (e.g., phenytoin).

Interactions with other antiepileptic medicinal products

Carbamazepine

In a study involving healthy volunteers, concomitant administration of 800 mg eslicarbazepine acetate once daily and 400 mg carbamazepine twice daily resulted in a 32% reduction in exposure of the active metabolite—eslicarbazepine, likely due to induction of glucuronidation. No changes in carbamazepine or its metabolite carbamazepine epoxide activity were observed. Depending on individual response, dose adjustment of eslicarbazepine acetate may be necessary when used concomitantly with carbamazepine. Studies in patients have shown that concomitant use with carbamazepine increases the risk of adverse reactions such as diplopia, coordination abnormalities, and dizziness. An increased risk of other specific adverse reactions due to concomitant use of carbamazepine and eslicarbazepine acetate cannot be ruled out.

Phenytoin

In a study involving healthy volunteers, concomitant administration of 1200 mg eslicarbazepine acetate once daily and phenytoin resulted in a 31–33% reduction in exposure of the active metabolite eslicarbazepine, likely due to induction of glucuronidation, as well as a mean increase of 31–35% in phenytoin exposure, likely due to inhibition of CYP2C19. Therefore, depending on individual response, dose adjustment may be necessary—increasing the dose of eslicarbazepine acetate and reducing the dose of phenytoin.

Lamotrigine

Glucuronidation is the main metabolic pathway for both eslicarbazepine and lamotrigine; therefore, interaction is expected. In a study involving healthy volunteers, concomitant administration of 1200 mg eslicarbazepine acetate once daily and lamotrigine was associated with a minor mean pharmacokinetic interaction (a 15% decrease in lamotrigine exposure) between eslicarbazepine acetate and lamotrigine, thus no dose adjustment is required. However, due to possible individual variability in the interaction between eslicarbazepine acetate and lamotrigine in some individuals, this effect may be clinically significant.

Topiramate

In a study involving healthy volunteers, concomitant administration of 1200 mg eslicarbazepine acetate once daily and topiramate did not lead to significant changes in eslicarbazepine activity, but decreased topiramate exposure by 18%, likely due to reduced bioavailability of topiramate. No dose adjustment is necessary.

Valproate and levetiracetam

Analysis of pharmacokinetic data obtained from a phase III study in adult patients with epilepsy showed that concomitant use with valproate and levetiracetam does not affect eslicarbazepine exposure; however, this information is not supported by standard drug interaction studies.

Oxcarbazepine

Concomitant use of eslicarbazepine acetate with oxcarbazepine is not recommended, as it may lead to excessive exposure to active metabolites.

Other medicinal products

Oral contraceptives

When eslicarbazepine acetate 1200 mg once daily was administered to women using combined oral contraceptives, a mean reduction in systemic exposure of levonorgestrel and ethinylestradiol by 37% and 42%, respectively, was observed, likely due to induction of CYP3A4. Therefore, women of reproductive age should use adequate contraception during treatment with eslicarbazepine and continue until the end of the current menstrual cycle after discontinuation of treatment.

Simvastatin

In a study involving healthy volunteers, concomitant administration of simvastatin with 800 mg eslicarbazepine acetate once daily resulted in a mean 50% reduction in systemic exposure to simvastatin, likely due to induction of CYP3A4. An increase in simvastatin dose may be necessary when co-administered with eslicarbazepine acetate.

Rosuvastatin

In a study involving healthy volunteers, concomitant administration of rosuvastatin with 1200 mg eslicarbazepine acetate once daily resulted in a mean 36–39% reduction in systemic exposure to rosuvastatin. The mechanism of this reduction is unknown but may be related either solely to effects on rosuvastatin transporter activity or also to induction of its metabolism. Since the relationship between exposure and drug efficacy is unclear, monitoring of treatment response (e.g., cholesterol levels) is recommended.

Warfarin

Concomitant administration of warfarin with 1200 mg eslicarbazepine acetate once daily resulted in a small (23%), but statistically significant, reduction in exposure to S-warfarin. No effect on the pharmacokinetics of R-warfarin or on coagulation was observed. However, due to possible individual variability in interaction, special attention to monitoring the international normalized ratio (INR) is required during the first weeks after initiation or discontinuation of concomitant treatment with warfarin and eslicarbazepine acetate.

Digoxin

In a study involving healthy volunteers, no effect of 1200 mg eslicarbazepine acetate once daily on digoxin pharmacokinetics was observed. This confirms that eslicarbazepine acetate does not affect P-glycoprotein transport.

Monoamine oxidase inhibitors (MAO inhibitors)

Due to the structural relationship of eslicarbazepine acetate with tricyclic antidepressants, interaction between eslicarbazepine acetate and MAO inhibitors is theoretically possible.

Special precautions for use.

Suicidal behavior

Suicidal thoughts and behavior have been reported in patients treated with antiepileptic drugs for various indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs also showed a slightly increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, but available data do not exclude an increased risk with eslicarbazepine acetate. Therefore, patients should be monitored for signs of suicidal thoughts and behavior; consideration should be given to appropriate treatment. Patients (and caregivers) should be advised to seek medical help if symptoms of suicidal thoughts or behavioral changes occur.

Disorders of the nervous system

Treatment with eslicarbazepine acetate may be associated with adverse reactions affecting the nervous system, such as dizziness and somnolence, which may increase the risk of accidental injury.

Other special precautions

If discontinuation of the medicinal product is required, it is recommended to gradually withdraw the drug to minimize the possibility of increased seizure frequency.

Skin reactions

During clinical trials in patients with epilepsy, rash occurred as an adverse reaction in 1.2% of the overall population treated with eslicarbazepine. Cases of urticaria and angioedema have been reported in patients taking eslicarbazepine. Angioedema due to hypersensitivity / anaphylactic reaction, involving swelling of the larynx, may be fatal. If signs or symptoms of hypersensitivity occur, eslicarbazepine acetate must be discontinued and alternative treatment initiated.

During post-marketing surveillance of eslicarbazepine acetate, life-threatening or severe skin adverse reactions, including Stevens–Johnson syndrome / toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS), some with fatal outcomes, have been reported. When prescribing the drug, patients should be informed about the signs and symptoms of skin reactions. If signs or symptoms suggestive of these reactions occur, eslicarbazepine must be discontinued immediately and alternative therapy considered (if needed). Patients who have experienced such reactions should never be re-exposed to eslicarbazepine.

Presence of the HLA-B*1502 allele in Han Chinese patients (originating from China, Thailand, and other Asian countries)

The HLA-B*1502 allele in Han Chinese patients (originating from China, Thailand) is strongly associated with the risk of developing severe skin reactions, known as Stevens–Johnson syndrome, during treatment with carbamazepine. The chemical structure of eslicarbazepine acetate is similar to that of carbamazepine; therefore, there is a risk of Stevens–Johnson syndrome in HLA-B*1502-positive patients during treatment with eslicarbazepine acetate. In Han Chinese populations from China and Thailand, HLA-B*1502 carriers constitute approximately 10%. Screening for this allele should be considered, if possible, in such individuals before initiating treatment with carbamazepine or structurally similar active substances. If the presence of the HLA-B*1502 allele is confirmed, the use of eslicarbazepine acetate should only be considered if the expected benefit outweighs the risks.

Due to the high prevalence of this allele in other Asian populations (e.g., over 15% in residents of the Philippines and Malaysia), genetic testing for HLA-B*1502 is recommended in individuals of ethnic groups at risk.

Presence of the HLA-A*3101 allele in patients of European descent and Japanese patients

Data indicate that the HLA-A*3101 allele is associated with an increased risk of skin reactions to carbamazepine, including Stevens–Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), or less severe acute generalized exanthematous pustulosis and maculopapular rash in patients of European descent and Japanese patients.

The frequency of the HLA-A*3101 allele varies significantly among different ethnic populations. The HLA-A*3101 allele is found in 2–5% of Europeans and approximately 10% of Japanese.

The presence of the HLA-A*3101 allele increases the risk of skin reactions (mostly less severe) during carbamazepine treatment from 5.0% in the general population to 26.0% among patients of European descent, whereas absence of this allele may reduce the risk from 5.0% to 3.8%.

There is insufficient information on the necessity of screening for HLA-A*3101 prior to initiating carbamazepine or chemically similar substances.

In cases where patients of European or Japanese descent are known to carry the HLA-A*3101 allele, the decision to use carbamazepine or chemically similar compounds should be made by the physician only if the benefit outweighs the risk.

Hypoponatremia

Hypoponatremia occurred as an adverse reaction in 1.5% of patients receiving the drug. In most cases, hypoponatremia is asymptomatic, but it may be associated with clinical symptoms such as increased seizure frequency, confusion, and impaired consciousness. The incidence of hypoponatremia increases with higher doses of eslicarbazepine acetate. Serum sodium levels should be monitored before and during treatment in patients with a history of renal disorders predisposing to hypoponatremia or in patients receiving concomitant medications that may cause hypoponatremia (e.g., diuretics, desmopressin). Additionally, serum sodium levels should be determined if clinical signs of hypoponatremia occur. Serum sodium levels should also be routinely assessed during regular laboratory monitoring. If clinically significant hypoponatremia develops, eslicarbazepine acetate should be discontinued.

PR interval prolongation

Prolongation of the PR interval was observed during clinical trials with eslicarbazepine acetate. Caution is required when administering the drug to patients with certain medical conditions (e.g., low thyroxine levels, cardiac conduction disorders) or those receiving concomitant medications that prolong the PR interval.

Patients with renal impairment

Caution is required when treating patients with impaired renal function, and the dose should be adjusted according to creatinine clearance. Administration of the drug is not recommended in patients with creatinine clearance (CrCl) < 30 mL/min due to insufficient data.

Patients with hepatic impairment

Due to limited clinical data in patients with mild or moderate hepatic impairment and lack of clinical and pharmacokinetic data in patients with severe hepatic impairment, eslicarbazepine acetate should be used with caution in patients with mild or moderate hepatic dysfunction. Because of the absence of clinical data, the use of the drug is not recommended in patients with severe hepatic impairment.

Use during pregnancy or breastfeeding.

Pregnancy

General risk associated with epilepsy and antiepileptic drugs

Children born to women with epilepsy have a two- to threefold higher incidence of congenital malformations compared to the 3% rate in the general population. The most commonly reported malformations include cleft lip, cardiovascular defects, and neural tube defects. The risk of congenital malformations is higher with combination antiepileptic therapy than with monotherapy. Therefore, monotherapy should be used whenever possible. Specialist advice is essential for women planning pregnancy and women of childbearing potential. The need for antiepileptic therapy should be reviewed when pregnancy is planned. Antiepileptic therapy should not be abruptly discontinued, as this may lead to increased seizure frequency, which could have serious consequences for both mother and child.

Women of childbearing potential / contraception

Women of childbearing potential should use effective contraceptive methods during treatment with eslicarbazepine acetate. Eslicarbazepine acetate may interact negatively with oral contraceptives. Therefore, other effective and safe contraceptive methods should be used during treatment and throughout the current menstrual cycle after discontinuation of treatment. Women of childbearing potential should be counseled regarding the use of alternative effective contraceptive methods. At least one effective method of contraception (e.g., intrauterine device) or two complementary forms of contraception, including a barrier method, should be used. Individual circumstances should be evaluated in each case, with patient involvement in the choice of contraceptive method.

Risk associated with eslicarbazepine acetate

There are no data on the use of eslicarbazepine acetate in pregnant women. Animal studies have shown toxic effects on reproductive function. The risk in humans is unknown (including major congenital malformations, nervous system disorders, and other reproductive toxic effects).

Eslicarbazepine acetate should not be used during pregnancy except when the potential benefit outweighs the risks after careful consideration of alternative treatment options.

If a woman taking eslicarbazepine acetate becomes pregnant or plans pregnancy, treatment with eslicarbazepine acetate should be carefully reviewed. The lowest effective dose should be used, and, if possible, monotherapy should be maintained during the first trimester of pregnancy. Patients should be informed about the increased risk of developmental defects and offered prenatal screening.

Monitoring and prevention

Antiepileptic drugs may cause folic acid deficiency, leading to fetal developmental abnormalities. Supplementation with folic acid is recommended before and during pregnancy. Since the effectiveness of folic acid supplementation is not fully proven, specialized prenatal diagnostics should be offered, even to women taking folic acid.

Newborns

Impaired hemostasis has been observed in newborns whose mothers took antiepileptic drugs. As a preventive measure, vitamin K1 should be administered to the mother in the last weeks of pregnancy and to the newborn.

Breastfeeding

It is unknown whether eslicarbazepine acetate passes into human breast milk. Animal studies have shown excretion of eslicarbazepine into breast milk. Because a risk to the infant cannot be excluded during treatment with eslicarbazepine acetate, breastfeeding should be discontinued.

Fertility

There are no data on the effect of eslicarbazepine acetate on human fertility. Animal studies have shown reduced fertility after treatment with eslicarbazepine acetate.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product has a minor or moderate influence on reaction speed when driving or operating machinery. Some patients may experience dizziness, somnolence, or visual disturbances, particularly at the beginning of treatment. Therefore, patients should not drive or operate machinery until they are certain they can perform such tasks safely.

Method of Administration and Dosage

Dosing Regimen

Adult Patients

Eslicarbazepine acetate can be used as monotherapy or added to current antiepileptic therapy. The recommended initial dose is 400 mg once daily. After 1–2 weeks, the dose may be increased to 800 mg once daily. Depending on individual response, the dose may be further increased up to 1200 mg once daily. For some patients receiving monotherapy, an effective dose may be 1600 mg once daily.

Special Patient Groups

Elderly Patients (aged 65 years and older)

Dose adjustment is not required in elderly patients provided renal function is not impaired. Due to limited data on the use of the 1600 mg dose during monotherapy in elderly patients, this dosage is not recommended for this patient group.

Patients with Renal Impairment

Caution is required when treating adult patients and children aged 6 years and older with renal impairment, and the dose should be adjusted according to creatinine clearance (CrCl) values:

• CrCl > 60 mL/min: no dose adjustment necessary;
• CrCl 30–60 mL/min: initial dose is 200 mg (or 5 mg/kg in children aged 6 years and older) once daily or 400 mg (or 10 mg/kg in children aged 6 years and older) every other day for 2 weeks, followed by 400 mg (or 10 mg/kg in children aged 6 years and older) once daily. However, the dose may be increased based on individual response;
• CrCl < 30 mL/min: use is not recommended in patients with severe renal impairment due to insufficient data.

Patients with Hepatic Impairment

No dose adjustment is necessary in patients with mild to moderate hepatic impairment.

The pharmacokinetics of eslicarbazepine have not been evaluated in patients with severe hepatic impairment; therefore, its use is not recommended in these patients.

Method of Administration

Oral use.

The medicinal product can be taken independently of food intake.

For patients unable to swallow the whole tablet, it may be crushed and mixed with water or soft food such as applesauce immediately before oral administration.

Switching to Another Pharmaceutical Form

Based on comparative bioavailability data between the tablet and suspension forms, patients may be switched from one pharmaceutical form to another.

Children

Children Aged 6 Years and Older

The recommended initial dose is 10 mg/kg/day once daily. The dose should be increased weekly or every other week by increments of 10 mg/kg/day up to a maximum of 30 mg/kg/day, depending on individual response. The maximum dose is 1200 mg once daily.

Children with Body Weight ≥ 60 kg

Children with a body weight of 60 kg or more should receive the same dose as adults.

The safety and efficacy of eslicarbazepine acetate in children under 6 years of age have not been established.

Overdose

Symptoms observed in eslicarbazepine acetate overdose are mainly related to central nervous system reactions (e.g., seizures of all types, epileptic status) and cardiac disorders (e.g., cardiac arrhythmia). There is no specific antidote. In case of overdose, appropriate symptomatic and supportive treatment is indicated. If necessary, metabolites of eslicarbazepine acetate are effectively removed by hemodialysis.

Adverse reactions

During clinical studies (adjunctive therapy and monotherapy), eslicarbazepine acetate was administered to 2,434 patients with partial-onset seizures (1,983 adult patients and 451 pediatric patients), and 51% of them experienced adverse reactions.

The adverse reactions were mostly mild or moderate in intensity and occurred primarily during the first weeks of treatment with eslicarbazepine acetate.

The identified risks are mainly dose-dependent adverse reactions associated with the drug's belonging to the carboxamide class. The most common adverse reactions in placebo-controlled adjunctive therapy studies in adult patients with epilepsy and in active-controlled monotherapy studies comparing eslicarbazepine acetate with controlled-release carbamazepine were dizziness, somnolence, headache, and nausea. The majority of adverse reactions were reported in < 3% of patients in any treatment group.

During post-marketing surveillance of eslicarbazepine acetate treatment, serious skin adverse reactions have been reported, including Stevens-Johnson syndrome/toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS).

List of adverse reactions

Table 1 lists the adverse reactions associated with eslicarbazepine acetate observed during clinical studies and post-marketing surveillance.

Classification of frequency of adverse events: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), frequency not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 1

Adverse reactions associated with eslicarbazepine observed during

clinical studies and post-marketing surveillance

System Organ Classes	Very common	Common	Uncommon	Frequency not known
Blood and lymphatic system disorders			Anaemia	Thrombocytopenia, leukopenia
Immune system disorders			Hypersensitivity
Endocrine disorders			Hypothyroidism
Metabolism and nutrition disorders		Hypokalaemia, decreased appetite	Electrolyte imbalance, dehydration, hypochloraemia	Syndrome resembling inappropriate ADH secretion with symptoms of lethargy, nausea, dizziness, low serum osmolality, vomiting, headache, confusion or other neurological signs and symptoms
Psychiatric disorders		Insomnia	Psychotic disorder, apathy, depression, nervousness, agitation, irritability, decreased attention/hyperkinetic disorders, psychosis, mood changes, tearfulness, psychomotor retardation, anxiety
Nervous system disorders	Dizziness, somnolence	Headache, attention disturbance, tremor, ataxia, loss of balance	Coordination disturbance, memory impairment, amnesia, hypersomnia, sedation, aphasia, dysaesthesia, dystonia, lethargy, parosmia, cerebellar syndrome, convulsion, peripheral neuropathy, nystagmus, speech disorder, dysarthria, burning sensation, paraesthesia, migraine
Eye disorders		Diplopia, blurred vision	Visual disturbance, oscillopsia, disturbance of binocular eye movement, eye hyperaemia
Ear and labyrinth disorders		Vertigo	Hypoacusis, tinnitus
Cardiac disorders			Palpitations, bradycardia
Vascular disorders			Hypertension (including hypertensive crisis), hypotension, orthostatic hypotension, flushing, peripheral coldness
Respiratory, thoracic and mediastinal disorders			Nosebleed, chest pain
Gastrointestinal disorders		Nausea, vomiting, diarrhoea	Constipation, dyspepsia, gastritis, abdominal pain, dry mouth, abdominal discomfort, bloating, gingivitis, melena, toothache	Pancreatitis
Hepatobiliary disorders			Liver function disorders
Skin and subcutaneous tissue disorders		Rash	Alopecia, dry skin, hyperhidrosis, erythema, skin inflammation, pruritus, dermatitis, allergic reaction	Toxic epidermal necrolysis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), angioedema, urticaria
Musculoskeletal and connective tissue disorders			Myalgia, bone metabolism disorders, muscle weakness, limb pain
Renal and urinary disorders			Urinary tract infections
General disorders and administration site conditions		Fatigue, gait disturbance, asthenia	Malaise, chills, peripheral oedema
Investigations		Weight increased	Blood pressure decreased, weight decreased, blood pressure increased, blood sodium decreased, blood chloride decreased, osteocalcin increased, haematocrit decreased, haemoglobin decreased, liver enzyme levels increased
Injury, poisoning and procedural complications			Drug toxicity, fall, thermal burn

Description of individual adverse reactions

Eye and nervous system disorders

During placebo-controlled studies, the following adverse reactions were observed when eslicarbazepine acetate was administered concomitantly with carbamazepine: diplopia (11.4% of patients receiving carbamazepine concomitantly vs. 2.4% of patients not receiving carbamazepine), coordination disorders (6.7% of patients receiving carbamazepine concomitantly vs. 2.7% of patients not receiving carbamazepine), and dizziness (30.0% of patients receiving carbamazepine concomitantly vs. 11.5% of patients not receiving carbamazepine).

PR interval

PR interval prolongation has been associated with eslicarbazepine use. This may lead to adverse reactions such as AV block, syncope, and bradycardia.

Adverse reactions related to carboxamide class

During placebo-controlled epilepsy studies with eslicarbazepine acetate, rare adverse reactions such as bone marrow depression, anaphylactic reaction, systemic lupus erythematosus, or severe arrhythmia were not observed. However, such reactions have been reported with oxcarbazepine. Therefore, these reactions cannot be excluded during treatment with eslicarbazepine acetate.

Long-term use in combination with structurally related antiepileptic drugs—carbamazepine and oxcarbazepine—has been associated with decreased bone mineral density, osteopenia, osteoporosis, and fractures. The mechanism by which these drugs affect bone metabolism is unknown.

Children

In placebo-controlled studies involving patients aged 2 to 18 years with partial seizure episodes (238 patients receiving eslicarbazepine acetate and 189 receiving placebo), 35.7% of patients receiving eslicarbazepine acetate and 19% of those receiving placebo experienced adverse reactions. The most common adverse reactions in the eslicarbazepine acetate group were diplopia (5.0%), somnolence (8.0%), and vomiting (4.6%).

The adverse reaction profile of eslicarbazepine acetate is generally similar across different age groups. In the age group 6 to 11 years, the most commonly observed adverse reactions occurring in more than two patients receiving eslicarbazepine acetate were diplopia (9.5%), somnolence (7.4%), dizziness (6.3%), seizures (6.3%), and nausea (3.2%). In the age group 12 to 18 years, the most common adverse reactions were somnolence (7.4%), vomiting (4.2%), diplopia (3.2%), and fatigue (3.2%). The safety of eslicarbazepine in children under 6 years of age has not been established.

The safety profile of eslicarbazepine acetate was generally similar in adults and children, except for agitation (common – 1.3%) and abdominal pain (common – 2.1%), which occurred more frequently in children than in adults. Dizziness, somnolence, vertigo, asthenia, gait disturbance, tremor, ataxia, balance disorder, blurred vision, diarrhea, and rash occurred less frequently in children than in adults. Hyponatremia occurred only in adults. Allergic dermatitis (rare – 0.8%) was observed only in children.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

30 tablets in a high-density polyethylene (HDPE) container with a child-resistant cap. One container in a cardboard box (for 200 mg and 400 mg strengths).

30 or 90 tablets in a high-density polyethylene (HDPE) container with a child-resistant cap. One container in a cardboard box (for 800 mg strength).

Prescription category.

Prescription only.

Manufacturer.

Dr. Reddy’s Laboratories Ltd.

Manufacturer’s address and site of operations.

Unit 1 SEZ, Plot Nos. 57-59, 60, 62 and 72, Sectors 9-14 and 17-20, Devunipalavalsa (V), Ranastalam (M), Srikakulam District, Andhra Pradesh, 532 409, India.

You can report adverse reactions or lack of efficacy during the use of this medicinal product at the following phone numbers (24/7):

+380 44 207 51 97 or +380 50 414 39 39; or via email: [email protected]