Ethosuximide Aristo 250 mg/5 ml oral solution – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Ethosuximide Aristo 250 mg/5 ml oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml oral solution contains 50 mg ethosuximide.

Excipients with known effect:

1 ml oral solution contains 0.6 mg Methyl-4-hydroxybenzoate (E 218).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral solution

Clear, colourless to slightly yellow solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Ethosuximide gives selective control of absence seizures (petit mal) even when complicated by grand mal.

It is also indicated for myoclonic seizures

4.2 Posology and method of administration

Posology

Adults, elderly patients and children over 6 years of age:

Treatment is started at a low daily dose of 500 mg (2x 5ml) with increments of 250 mg every five to seven days until the seizures are controlled with 1000-1500 mg daily. Occasionally, 2000 mg in divided doses may be required.

Paediatric population aged 0-6 years

Begin with a daily dose of 250 mg (5ml) and increase the dose gradually by small increments every few days until control is achieved. The optimal dose in most children is 20 mg/kg/day. The maximum dose should be 1000 mg.

Effective plasma levels of ethosuximide normally lie between 40 and 100 µg/ml but the clinical response should be the criteria for the regulation of the dosage. The half-life of ethosuximide in plasma is more than 24 hours but the daily dose, if large, is more comfortably divided between morning and evening.

Older children and adults will normally take ethosuximide in capsule form. Currently available clinical data regarding the use of ethosuximide in the paediatric population are described in section 5.1.

Method of administration

Ethosuximide Aristo is for oral use.

The solution can be taken during or after meals.

The pack contains a 10 ml graduated oral syringe (0.5 ml steps) and an adapter for the oral syringe. A single dose of the oral solution is drawn into the oral syringe up to the required level and transferred into a glass of water or mixed with milk pudding. Alternatively, the oral solution can directly be applicated into the mouth. Afterwards, the patient should drink half a glass of water.

4.3 Contraindications

Hypersensitivity to the active substance, other succinimides or to any of the excipients listed in section 6.1.

Porphyrias.

4.4 Special warnings and precautions for use

General

Ethosuximide, when used alone in mixed types of epilepsy, may increase the frequency of generalised tonic clonic (grand mal) seizures in some patients.

As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt withdrawal of anticonvulsant medication may precipitate absence (petit mal) seizures.

Psychiatric symptoms

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of antiepileptic drugs (AEDs) has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for ethosuximide. Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

All patients treated with AEDs should be routinely evaluated for depression and anxiety.

In particular in patients with a history of psychiatric disorders psychic undesirable effects (see section 4.8, paranoid and hallucinatory symptoms, anxiety, agitation) may occur, therefore special caution is required when treating this group of patients with ethosuximide.

Haemopoietic Effect

Special attention should be given to clinical symptoms of bone marrow damage (fever, angina, haemorrhage) (see section 4.8). It is recommended to check the blood count regularly (initially monthly, after one year every six months) to identify potential bone marrow damage. At a leucocyte count of less than 3500/mm³ or a granulocyte ratio of less than 25%, the dose should be reduced or the therapy discontinued. The liver enzymes should also be checked regularly.

Hepatic/Renal Impairment

Ethosuximide should be used with extreme caution in patients with impaired hepatic or renal function.

Periodic urinalysis and liver function studies are advised for all patients receiving the drug.

Ethosuximide is capable of producing morphological and functional changes in the animal liver. In humans, abnormal liver and renal function studies have been reported.

Autoimmune Disorders

Cases of systemic lupus erythematosus have been reported with the use of ethosuximide. The physician should be alert to this possibility. Additionally, lupus-like reactions have been reported in children given ethosuximide. They vary in severity from systemic immunological disorders, which include the nephrotic syndrome, to the asymptomatic presence of antinuclear antibodies. The nephrotic syndrome is rare and a complete recovery has usually been reported on drug withdrawal.

Severe Cutaneous Adverse Reactions (SCARs)

Hypersensitivity Syndrome (HSS) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Hypersensitivity Syndrome (HSS) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking anticonvulsant drugs, including ethosuximide. Some of these events have been fatal or life threatening.

HSS/DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, haematological abnormalities, myocarditis, myositis or pneumonitis. Initial symptoms may resemble an acute viral infection. Other common manifestations include arthralgias, jaundice, hepatomegaly, leucocytosis, and eosinophilia. The interval between the first drug exposure and symptoms is usually 2 to 4 weeks but has been reported in individuals receiving anticonvulsants for 3 or more months. If such signs and symptoms occur, the patient should be evaluated immediately.

Ethosuximide should be discontinued if an alternative aetiology for the signs and symptoms cannot be established.

Patients at higher risk for developing HSS/DRESS include black patients, patients who have experienced this syndrome in the past (with ethosuximide or other anticonvulsant drugs), patients who have a family history of this syndrome and immuno-suppressed patients. The syndrome is more severe in previously sensitized individuals.

Stevens-Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN) Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN) have been reported with the use of ethosuximide. Although serious skin reactions may occur without warning, patients should be advised of the signs and symptoms of HSS/DRESS (see section 4.4), occurrence of rash and should be monitored closely for skin reactions. Patients should seek medical advice from their physician immediately when observing any indicative signs or symptoms. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, ethosuximide treatment should be discontinued. The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis. If the patient has developed SJS or TEN with the use of ethosuximide, ethosuximide must not be re-started in this patient at any time.

If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further ethosuximide medication is contraindicated. The risk of serious skin reactions and other hypersensitivity reactions to ethosuximide may be higher in black patients.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of human leukocyte antigen HLA-B*1502, an inherited allelic variant of the HLA-B gene, in patients using carbamazepine. HLA-B*1502 may be associated with increased risk of developing SJS/TEN in patients of Thai and Han Chinese ancestry taking drugs associated with SJS/TEN, including ethosuximide. If these patients are known to be positive for HLA-B*1502, the use of ethosuximide should only be considered if the benefits are thought to exceed the risks.

In the Caucasian and Japanese population, the frequency of HLA-B*1502 allele is extremely low, and thus it is not possible at present to conclude on risk association. Adequate information about risk association in other ethnicities is currently not available.

Information for Patients

Patients taking ethosuximide should be advised of the importance of adhering strictly to the prescribed dosage regimen.

Patients should be instructed to promptly contact their physician if they develop signs and/or symptoms (e.g. sore throat, fever) suggesting an infection.

Withdrawal

If ethosuximide is being substituted for another anti-epileptic drug the latter must not be withdrawn abruptly but the replacement made gradually with overlap of the preparations otherwise petit mal may break through.

Ethosuximide should always be withdrawn slowly.

Excipients

Ethosuximide Aristo contains Methyl-4-hydroxybenzoate (E 218), which may cause allergic reactions (possibly delayed).

4.5 Interaction with other medicinal products and other forms of interaction

Since ethosuximide may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (e.g. ethosuximide may elevate phenytoin serum levels and valproic acid has been reported to both increase and decrease ethosuximide levels).

The plasma concentrations of ethosuximide may be reduced by carbamazepine, primidone, phenobarbitone and lamotrigine and increased by isoniazid.

The simultaneous use of medicinal products affecting the central nervous system, alcohol or convulsion-inducing substances should be avoided.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should be advised by their doctor of the necessity of planning and monitoring a pregnancy before starting the treatment with ethosuximide. Patients should be advised to tell their doctor immediately if they have become pregnant during the treatment.

Pregnancy

Ethosuximide crosses the placenta. Reports suggest an association between the use of other anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to those women. Cases of birth defects have been reported with ethosuximide. The prescribing physician should weigh the benefit versus risk of ethosuximide in treating or counselling epileptic women of childbearing potential.

Breast-feeding

Ethosuximide is excreted into breast milk. Because the effects of ethosuximide on the nursing infant are unknown, caution should be exercised when ethosuximide is administered to a nursing mother. Ethosuximide should be used in nursing mothers only if the benefits clearly outweigh the risks. Breast feeding is best avoided.

4.7 Effects on ability to drive and use machines

Ethosuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving or other such activities requiring alertness. Therefore, the patient should be cautioned accordingly.

4.8 Undesirable effects

Frequencies reported are as follows:

Common (≥ 1/100 to < 1/10); Uncommon (> 1/1,000 to < 1/100); Rare (> 1/10,000 to < 1/1,000); Not known (frequency cannot be estimated from the available data)

* AE frequency estimated from post-marketing safety database.

Summary of safety profile

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with ethosuximide treatment (see section 4.4).

Psychiatric or psychological aberrations associated with ethosuximide administration may be noted particularly in patients who have previously exhibited psychological abnormalities.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Acute overdoses may produce nausea, vomiting and CNS depression including coma with respiratory depression. A relationship between ethosuximide toxicity and its plasma levels has not been established.

If less than 2 g have been taken, fluids should be given by mouth. If a larger dose has been taken the stomach should be emptied, respiration maintained, and any other symptoms treated accordingly. Activated charcoal and purgatives are known to be used in the treatment of overdosage. Haemodialysis may be useful. Forced diuresis and exchange transfusions are ineffective.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-epileptics, succinimide derivatives ATC code: N03AD01

Pharmacodynamic effects

Ethosuximide gives selective control of absence seizures (petit mal) even when complicated by grand mal. It is also indicated for myoclonic seizures. Compared to other anti-convulsants, ethosuximide is more specific for pure petit mal.

Mechanism of action

The reduction of seizure frequency is thought to be achieved by depression of the motor cortex and elevation of the threshold to convulsive stimuli as seen by the suppression of the characteristic spike and wave EEG pattern.

Paediatric population

In a double-blind, randomised trial of 20 weeks duration in 453 children aged 2.5 to 13 years old with newly diagnosed childhood absence epilepsy, the efficacy, tolerability and neuropsychological effects of ethosuximide, valproic acid and lamotrigine as monotherapy in childhood absence epilepsy were investigated. Those treated with either ethosuximide or valproic acid had higher freedom-from-failure rates (53% and 58%, respectively) than those given lamotrigine (29%, odds ratio with ethosuximide vs. lamotrigine, 2.66; 95% confidence interval [CI], 1.65 to 4.28; odds ratio with valproic acid vs. lamotrigine, 3.34; 95% CI, 2.06 to 5.42; P<0.001 for both comparisons). In both pre-specified and post-hoc analyses, ethosuximide resulted in fewer attentional effects as compared with valproic acid.

(at weeks 16 and 20, the percentage of test subjects with a confidence index score of 0.60 or higher in the Conners’ Continuous Performance Test was greater in the valproic acid group than in the ethosuximide group [49% vs. 33%; odds ratio, 1.95; 95% CI, 1.12 to 3.41; P=0.03] and the lamotrigine group [49% vs. 24%; odds ratio, 3.04; 95% CI, 1.69 to 5.49; P<0.001]).

5.2 Pharmacokinetic properties

Absorption

Ethosuximide is practically completely absorbed after oral administration. C_max values of 18-24 μg/ml were measured after the intake of 1 g ethosuximide in three test persons after 1-4 hours.

In adults under long-term treatment at a dose of ca. 15 mg/kg body weight a plasma concentration of about 50 μg/ml was measured. At an oral dose of 1 mg/kg per day a plasma concentration of 2-3 μg/ml is to be expected.

Steady state is expected to occur 8-10 days after start of treatment. Despite significant interindividual variation of plasma concentrations at the same oral dose, dose-linear dependence of plasma concentration was established.

The therapeutic plasma concentration of ethosuximide is 40-100 μg/ml. Plasma concentrations of more than 150 μg/ml may have toxic effects.

Distribution

Ethosuximide is not bound to plasma proteins.

Ethosuximide is present in liquor and saliva in the same concentration as in plasma. The apparent volume of distribution is specified to be approximately 0.7 l/kg body weight.

Biotransformation

Ethosuximide is extensivly metabolised in the liver by oxidation. Several metabolites are produced, in particular the two diastereomeres of 2-(1-hydroxyethyl)-2-methyl succinimide and of 2-ethyl-2-methyl-3-hydroxysuccinimide. The metabolites are probably inactive.

Elimination

Between 10% and 20% of ethosuximide only is excreted unchanged in the urine. The main metabolites of ethosuximide, the two diastereomeres of 2-(1-hydroxyethyl)-2-methyl succinimide and of 2-ethyl-2-methyl-3-hydroxysuccinimide are to some extent conjugated and excreted renally as glucuronide.

After a single oral dose of 13.1-18.0 mg ethosuximide/kg body weight given to 12 male test persons (20-23 years, 57.2-114.8 kg body weight) plasma half-lives of 38.3-66.6 hours were measured.

After a single dose of 500 mg ethosuximide (capsules) given to 5 children, plasma half-lives of

25.7-35.9 hours were measured, with oral solution the plasma half-lives were 24.8-41.7 hours.

Passage into breast milk

Ethosuximide passes into breast milk; the ratio of the ethosuximide concentration of breast milk vs. plasma is specified to be 0.94±0.06.

Paediatric population

In a study in children (7-8.5 years, 12.9-24.4 kg body weight) C_max values of 28.0-50.9 µg/ml were measured 3-7 hours after the children had taken a single dose of 500 mg ethosuximide.

Long-term treatment of children at 20 mg/kg body weight produces a plasma concentration of approximately 50 µg/ml. In children an oral daily dose of 1 mg/kg produces a plasma concentration of 1-2 µg/ml. Therefore, younger children require a slightly higher dose than older children.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of acute and repeated dose toxicity

Ethosuximide did not reveal a potential for mutagenicity or chromosome aberrations when studied in vitro.

Long-term studies of the carcinogenetic potential in animals have not been performed.

Embryotoxicity studies in rats and mice revealed a higher incidence rate of malformation and changes in behaviour.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Methyl-4-hydroxybenzoate (E 218)

Hypromellose

Macrogol 300

Sodium citrate dihydrate

Citric acid monohydrate

Saccharin sodium

Cream caramel flavour (contains propylene glycol and vanillin)

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months.

After first opening: 3 months.

6.4 Special precautions for storage

This medical product does not require any special storage conditions.

6.5 Nature and contents of container

Brown glass bottle (glass type III) with screw cap (polypropylene/polyethylene).

Packs of 125 ml, 200 ml or 250 ml (2 x 125 ml) oral solution in a carton containing also a 10 ml graduated oral syringe, graduated in 0.5 ml steps and an adapter for the oral syringe.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Aristo Pharma GmbH

Wallenroder Straße 8-10

13435 Berlin

Germany

8 MARKETING AUTHORISATION NUMBER(S)

PL 40546/0023

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

17/02/2025

10 DATE OF REVISION OF THE TEXT

24/03/2026