Suxilep^® (Capsules) Instructions for Use

ATC Code

N03AD01 (Ethosuximide)

Active Substance

Ethosuximide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Antiepileptic agent

Pharmacological Action

Ethosuximide is an anticonvulsant drug belonging to the succinimides. The mechanism of action has not been definitively established; among other properties, an inhibitory effect on GABA degradation has been detected.

Pharmacokinetics

Absorption

After a single 1 g dose of ethosuximide, C_max in plasma was reached in 2-4 hours and was 18-24 µg/ml.

In children aged 7 to 8.5 years with a body weight of 12.8-24.4 kg, after a single 500 mg dose of ethosuximide, C_max in plasma was reached in 3-7 hours and was 28-50.9 µg/ml.

There is a linear relationship between the dose and the increase in plasma concentration; an increase in the oral dose by 1 mg/kg/day is expected to increase the plasma concentration by 2-3 µg/ml, and in children by 1-2 µg/ml. Therefore, younger children require slightly higher doses than older children.

The therapeutic plasma concentrations of ethosuximide range from 40 to 100 µg/ml. Toxic effects may develop at plasma concentrations above 150 µg/ml.

Distribution

In children with long-term use of the drug at a dose of 20 mg/kg, the plasma concentration increased to almost 50 µg/kg. In adults, this concentration was achieved with a dose of 15 mg/kg.

Steady state is expected to be reached 8-10 days after the start of therapy. There are significant interindividual differences in plasma concentrations when using the same doses in oral dosage forms.

Ethosuximide is slightly bound to plasma proteins.

Ethosuximide is found in cerebrospinal fluid and saliva at concentrations similar to those in plasma. The apparent V_d is 0.7 L/kg.

It crosses the blood-brain barrier and is excreted in breast milk (the ratio of ethosuximide concentration in plasma to breast milk is 0.94±0.06).

Metabolism and Excretion

In adults after a single oral dose of 13.1-18 mg/kg ethosuximide, the plasma T_1/2 was 38.3-66.6 hours. In children after a single oral dose of 500 mg ethosuximide, the plasma T_1/2 was 25.7-35.9 hours.

Ethosuximide undergoes significant oxidative metabolism in the liver. Several, apparently pharmacologically inactive, metabolites are formed, which are excreted by the kidneys, partly as conjugates with glucuronic acid. The main metabolites formed are 2 diastereomers: 2-(1-hydroxyethyl)-2-methyl-succinimide and 2-ethyl-2-methyl-3-hydroxysuccinimide.

10-20% is excreted unchanged by the kidneys.

Indications

• Pyknoleptic absence seizures, as well as complex and atypical convulsive seizures;

Note. To avoid the development of generalized tonic-clonic seizures, which often worsen the course of complex and atypical convulsive seizures, a combination of ethosuximide with other anticonvulsants (e.g., primidone, phenobarbital) can be used. Additional prophylaxis of generalized tonic-clonic seizures can be performed without exception in cases of pyknoleptic absence seizures in school-age children.

• Myoclonic-astatic petit mal seizures;
• Juvenile myoclonic seizures (impulsive petit mal).

ICD codes

Dosage Regimen

Capsules

The dose of Suxilep^® depends on the clinical picture of the disease, the individual patient response to treatment, and tolerance. Treatment is started with small doses. Doses are gradually increased.

In both children and adults, treatment is started with a total daily dose of ethosuximide in the range of 5 to 10 mg/kg body weight.

The total daily dose of ethosuximide can be increased by 5 mg/kg at intervals of 4 to 7 days (or, depending on achieving steady state: 8-10 days).

For maintenance therapy, a daily dose of ethosuximide of 20 mg/kg in children and 15 mg/kg in adults is usually sufficient.

The maximum daily dose of ethosuximide should not exceed 40 mg/kg body weight in children and 30 mg/kg in adults.

The daily dose is taken in 2-3 divided doses. Due to the long T_1/2 of ethosuximide, if it is well tolerated, the entire daily dose can be taken at once.

The therapeutic plasma concentration of ethosuximide is 40-100 µg/ml.

Examples of calculating the daily dose for adults and children over 12 years at a maintenance dose of 15 mg/kg.

Examples of calculating the daily dose for children under 12 years of age at a maintenance dose of ethosuximide of 20 mg/kg

Note: Ethosuximide is dialyzable. Therefore, patients on hemodialysis require an additional dose or a change in the dosing regimen. 39-52% of the administered dose is removed during a 4-hour hemodialysis session.

Method of Administration

Capsules should be swallowed whole with a sufficient amount of liquid (e.g., a glass of water) during or after meals.

Antiepileptic therapy is generally long-term. The decision on adjustment, duration, and discontinuation of Suxilep^® therapy should be made by a specialist experienced in the treatment of epilepsy.

Usually, dose reduction, possibly followed by drug withdrawal, should not be undertaken until the seizure-free period has lasted 2 or 3 years. Dose reduction for the purpose of drug withdrawal should be carried out in several stages over a period of 1 to 2 years. For children, “growing out” of their dose is allowed (the dose remains constant while body weight increases). However, there should be no deterioration in electroencephalogram parameters.

Adverse Reactions

Dose-dependent adverse effects

Nausea, vomiting, hiccups, and abdominal pain are frequently observed. Lethargy, withdrawal syndrome, severe headache, dizziness, anxiety, depression, sleep disturbances, decreased ability to concentrate, unusual fatigue, loss of appetite, weight loss, diarrhea or constipation, as well as ataxia sometimes occur. In rare cases, hallucinatory-paranoid ideas may develop over several days and weeks. In isolated cases, dyskinesias have been observed during the first 12 hours of treatment. They disappear after discontinuation of ethosuximide or are controlled by diphenhydramine.

Dose-independent adverse effects

Allergic skin reactions such as exanthema may occur; Stevens-Johnson syndrome may develop. Systemic lupus erythematosus of varying intensity, leukopenia, eosinophilia, thrombocytopenia, or agranulocytosis are rarely observed. In isolated cases, aplastic anemia and pancytopenia may develop.

Contraindications

• Hypersensitivity to the components of the drug.

Not recommended for use in children under 6 years of age due to the impossibility of precise dosing with this dosage form.

With caution

In patients with a history of mental illness (risk of developing corresponding side effects – anxiety states, hallucinatory symptoms); increased risk of myelotoxicity.

Hepatic and/or renal insufficiency.

Use in Pregnancy and Lactation

Pregnancy

Specific embryopathy in children whose mothers received Ethosuximide as monotherapy has not been identified.

The risk of malformations is increased with the use of antiepileptic drugs. This risk is higher with combination therapy, so monotherapy is recommended during pregnancy.

The minimum effective dose that controls seizures should be prescribed, especially between days 20 and 40 of pregnancy. The concentration of ethosuximide in the mother’s serum should be regularly determined.

In the last trimester of pregnancy, the woman should take vitamin K₁. This prevents the development of vitamin K deficiency in the newborn, which can lead to bleeding.

The patient should be warned of the need to immediately consult a doctor if pregnancy occurs during therapy.

Lactation

Breastfeeding should be discontinued during treatment with Suxilep^®, as the concentration in breast milk can reach up to 94% of the concentration in the mother’s plasma.

It is not recommended to take Suxilep^® during pregnancy. If pregnancy occurs, the attending physician should be informed.

Ethosuximide is excreted in breast milk, so if it is necessary to prescribe Suxilep^® during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Use with caution in patients with hepatic insufficiency.

Use in Renal Impairment

Use with caution in patients with renal insufficiency.

Pediatric Use

Not recommended for use in children under 6 years of age due to the impossibility of precise dosing with this dosage form.

Special Precautions

Special attention should be paid to any manifestations of myelotoxicity (e.g., fever, tonsillitis, adenoiditis, as well as a tendency to bleed); in such cases, the patient may need to consult a doctor. To determine possible myelotoxic effects, periodic blood cell count analysis should be performed (initially monthly, and after 12 months – at 6-month intervals). If the leukocyte count is less than 3500/µl or the granulocyte count is less than 25%, a reduction in the dose of Suxilep^® or its discontinuation is indicated. Liver and kidney function should also be regularly monitored.

The risk of dose-dependent adverse effects can be reduced if therapy is started slowly, the dose is increased gradually, and patients take Ethosuximide during or after meals.

If dose-dependent reversible side effects develop, Suxilep^® should be discontinued; if treatment with the drug is resumed, the possibility of their recurrence should be considered.

If dyskinesias develop, Ethosuximide should be discontinued. In addition, an intravenous injection of diphenhydramine may be required. Predominantly in patients with a history of mental illness, corresponding psychiatric side effects (anxiety states, hallucinatory symptoms) may develop. In this category of patients, Suxilep^® should be used with particular caution.

With prolonged therapy, a decrease in the patient’s physical activity and interest in the environment may occur (e.g., in children and adolescents, a deterioration in learning ability at school may be observed).

Effect on ability to drive and operate machinery

Even if Suxilep^® is used in accordance with the instructions, reactivity may be altered to such an extent that the ability to drive and operate machinery is impaired. This is more pronounced with simultaneous alcohol intake. Therefore, patients receiving Ethosuximide should refrain from driving vehicles, operating machinery, and other hazardous activities, at least during the stabilization phase. In each case, the decision is made by the attending physician, taking into account the individual reaction and the corresponding dose.

Overdose

Whenever an overdose is diagnosed, the possibility of multiple intoxication as a result of taking several drugs (e.g., in a suicide attempt) should be considered.

Symptoms of overdose are significantly enhanced under the influence of alcohol and other CNS depressants.

Symptoms of intoxication

Fatigue, lethargy, depressive states and states of agitation, sometimes irritability, as well as other dose-dependent adverse effects are most pronounced after an overdose.

Existing symptoms can be considered an overdose if the plasma concentration of ethosuximide is more than 150 µg/ml.

Treatment of intoxication

In case of severe overdose, gastric lavage and administration of activated charcoal are indicated initially. Resuscitation measures are necessary to maintain the functions of the cardiovascular and respiratory systems.

Drug Interactions

Ethosuximide usually does not cause changes in the plasma concentrations of other antiepileptic drugs (e.g., primidone, phenobarbital, phenytoin), as it is not an enzyme inducer. However, in some cases, an increase in the plasma concentration of phenytoin is possible.

Carbamazepine intake leads to an increase in the plasma clearance of ethosuximide. During therapy with valproic acid, a change in the serum concentration of ethosuximide is possible.

It cannot be excluded that when drugs that have a depressant effect on the CNS are used concomitantly with Suxilep^®, their sedative effects are enhanced.

Alcohol consumption should be avoided.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.