4.1. Therapeutic indications

Ethosuximide 250 mg Capsules, soft 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

The dosage should be determined individually based on the serum level.

Adults, Elderly and Children over 6 Years

Start with 250 mg twice per day.

The daily dose may be increased by 125 mg every 7 days in the outpatient setting and every 4 days in the clinical setting until the optimum dose has been reached. This will usually not exceed an amount of 1500-2000 mg per day (1000 mg for patients aged under six years).

Paediatric population

Children aged under 3 years

Initially 10 mg/kg body weight per day in 1-2 doses. Maintenance dosage: 20‑40 mg/kg body weight per day in 1‑2 doses.

Children aged between 3 and 6 years

Start with 125 mg twice per day.

In cases in which the dosage regimen is not feasible given the strength of the capsules and the weight of the child, use of the syrup is recommended.

Method of administration

Ethosuximide 250 mg capsules, soft is for oral use.

The capsules can be taken during or after meals with some liquid.

4.3. Contraindications

Hypersensitivity to the active substance ethosuximide or, other succinimides and lecithin (soya lecithin) or to any of the excipients listed in section 6.1.

Porphyrias.

4.4. Special warnings and precautions for use

Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported to occur in patients treated with anticonvulsants in various indications. A meta-analysis of randomised placebo- controlled studies with anticonvulsants also reveals a slight increase in the risk of suicidal ideation and behaviour. The mechanism behind this risk is not known and the available data do not exclude the possibility of an increased risk for ethosuximide.

Patients must therefore be closely monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and their caregivers) must be advised that, if signs of suicidal ideation or behaviour occur, medical advice must be sought.

In patients with combined forms of epilepsy, ethosuximide can induce generalised seizures. When switching from existing medication to ethosuximide or when discontinuing ethosuximide, this should be done gradually.

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

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.

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 there placement made gradually with overlap of the preparations otherwise petit mal may break through.

Ethosuximide should always be withdrawn slowly.

Severe skin reactions

Serious dermatologic reactions, including Stevens-Johnson Syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported duringethosuximide treatment. SJS and DRESS can be fatal. Patients appear to be at highest risk of these reactions at the start of the treatment, with the start of the reaction occurring in the majority of cases within the first month of treatment. Ethosuximide should be discontinued at the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.

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.

Excipients with known effects:

The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

If ethosuximide is administered in combination with other anticonvulsants, the dosage of ethosuximide and/or other anticonvulsants should be adjusted, depending on the patient's response.

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.

Concomitant use of ethosuximide and alcohol or substances with sedative properties should be avoided in order to prevent CNS depression.

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.

There are insufficient data on the use of ethosuximide in human pregnancy to assess the potential harm. Congenital abnormalities are known to occur more frequently in newborn infants of mothers using anticonvulsant agents than in other infants. The likelihood of harmful effects occurring in the unborn foetus appears to be greater in combination with other anticonvulsant agents. Ethosuximide has been shown to be harmful in animal trials.

In general, it is not desirable to discontinue anticonvulsant therapy during pregnancy. Where possible, preference should be given to monotherapy during pregnancy. The lowest, yet still effective, ethosuximide doses must be given and plasma concentrations must be monitored.

Some anticonvulsant agents may cause folic acid deficiency. Moreover, folic acid supplementation - at doses customary for all pregnant women - is strongly recommended. To avoid bleeding complications in the newborn infant due to possible vitamin K deficiency, which has been reported after maternal use of some anticonvulsant agents, consideration can be given to administering vitamin K to the mother in the last weeks of pregnancy. For the newborn infant, parenteral administration of vitamin K is advised immediately postpartum.

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..

Fertility

There are no data on the effects of Ethosuximide 250 mg capsules, soft on male or female fertility.

4.7. Effects on ability to drive and use machines

The possibility of a reduced ability to react should be taken into account when driving and using dangerous machinery.

Ethosuximide can impair a patient's reactivity and ability to react speedily and may cause side effects such as drowsiness or dizziness.

Therefore, during any adjustment phase, including higher doses or in combination with other medicinal products affecting the central nervous system, the ability to drive or operate machines safely may be affected. This may even be the case when ethosuximide is taken as prescribed, and especially in connection with alcohol.

Therefore, patients should not drive, operate machines or perform any other potentially hazardous activities, at least not during the adjustment phase of the treatment. The decision will be taken in each case by the attending doctor considering the patient's individual response and the respective dose.

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 (cannot be estimated from the available data)

* AE frequency estimated from post-marketing safety database

MedDRA

System Organ Class

Frequency†

Undesirable Effects

Blood and lymphatic system disorders

Uncommon

Agranulocytosis*, Aplastic anaemia*, Eosinophilia*,Leukopenia*, Pancytopenia*, Bone marrow failure

Not Known

Thrombocytopenia

Immune system disorders

Uncommon

Hypersensitivity*,

Metabolism and nutrition disorders

Common

Decreased appetite

Psychiatric disorders

Uncommon

Aggression*, Sleep terror*, Depression*, Suicidal ideation*, Psychotic disorder*, Sleep disorder*

Not known

Euphoric mood, Apathy, Libido increased

Nervous system disorders

Common

Headache, Ataxia, Dizziness, Somnolence

Uncommon

Psychomotor hyperactivity*, Lethargy, Disturbance in attention*

Not Known

Extrapyramidal side effects,Increased frequency of grand mal convulsions

Eye disorders

Uncommon

Myopia*

Respiratory, thoracic and mediastinal disorders

Uncommon

Hiccups

Gastrointestinal disorders

Common

Abdominal pain, Abdominal pain upper, Gastrointestinal disorder, Nausea, Abdominal discomfort, Vomiting

Uncommon

Diarrhoea, Gingival hypertrophy*, Swollen tongue*

Skin and subcutaneous tissue disorders

Common

Rash erythematous, Urticaria

Uncommon

Stevens-Johnson syndrome*

Not Known

Drug reaction with eosinophilia and systemicsymptoms (DRESS)

Musculoskeletal and connective tissue disorders

Uncommon

Systemic lupus erythematous*

Renal and urinary disorders

Uncommon

Haematuria*

Reproductive system and breast disorders

Uncommon

Vaginal haemorrhage*

General disorders and administration siteconditions

Uncommon

Fatigue, Irritability*

Investigations

Uncommon

Weight decreased

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).

Gastrointestinal problems, headache, dizziness, drowsiness, behavioural disorders, psychological changes (and even psychoses). In rare cases, abnormalities of the peripheral blood count (mild transient albuminuria, slight drop in the leukocyte count).

In combined forms of epilepsy and also in combination with other anti-epileptic agents, 20-30% of patients experienced nausea, vomiting, headache and dizziness and in a small number of cases states of excitement and episodic psychoses. In general these side effects disappear when the dosage is reduced and do not usually recur on subsequently increasing the dosage.

Aplastic anaemia, agranulocytosis, pancytopenia, eosinophilia and leukocytopenia have been reported rarely. Systemic lupus erythematosus (SLE) and Stevens-Johnson syndrome have been reported with ethosuximide. Undesirable effects necessitating a dose reduction occur at concentrations above 160 µg/mL.

Undesirable effects of unknown frequency: drug reaction with eosinophilia and systemic symptoms (DRESS) and thrombocytopenia.

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

Symptoms

Ethosuximide may cause nausea, vomiting, headache, dizziness, anorexia, ataxia, tremor, (motor) restlessness, choreiform movements, CNS depression (leading to coma), hypotension and respiratory depression. Due to the long half-life, effects can persist for a long time. Hepatic and renal damage may also occur. Idiosyncratic reactions may consist of skin rash, erythema, blood dyscrasias, allergic reactions, systemic lupus erythematosus, behavioural changes and psychoses.

Management

Absorption may be prevented by inducing emesis or gastric lavage, followed by administration of activated charcoal (adsorbent) and sodium sulphate (laxative). Intensive care admission is indicated. Haemodialysis may be used if necessary. Further treatment should be supportive and symptomatic.