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.

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.

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

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.

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.

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. Ethosuximide interacts with other anticonvulsants such as phenytoin and valproic acid. It is recommended that serum concentrations of the individual substances be regularly determined.

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.

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

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 in human milk in such quantities that subtherapeutic concentrations may occur in the infant. Adverse reactions may occur in the infant, such as irritability, poor sucking reflex and drowsiness. Breast-feeding should be discontinued during treatment with ethosuximide.

Fertility

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

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.

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 µ g/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.

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.

Pharmacotherapeutic group: anticonvulsants, ATC code: N03AD01

Mechanism of action

Ethosuximide is a succinimide derivative. 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.

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.

Pharmacodynamic effects

In a double-blind randomized 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 prespecified and post hoc analyses, ethosuximide resulted in fewer attentional effects as compared with valproic acid (at week 16 and week 20, the percentage of 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).

Absorption

Ethosuximide is readily absorbed from the gastro-intestinal tract and extensively metabolized in the liver.

Distribution

It is widely distributed throughout the body but is not significantly bound to plasma proteins so saliva concentrations may be useful for monitoring. Peak serum levels occur 1 to 7 hours after single oral dose. Therapeutic levels are between 40 and 100 mcg/ml. It has a long elimination half-life: adults 40 - 60 hours; children 30 hours.

Elimination

It is excreted in the urine mainly in the form of its metabolites.

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 carcinogenic potential in animals have not been performed.

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

Capsule contents

Macrogol

Capsule shells

Gelatin

Glycerol (E 422)

Liquid sorbitol (E420) (Non-crystallising)

Erythrosine (E 127)

Purified water

Macrogol

Medium chain triglyceride

Lecithin

Not applicable.

Unopened: 24 months.

After first opening: 60 Days

Store below 25° C.

A bottle pack consisting of a high-density polyethylene container with outer white opaque polypropylene child resistant closure.

Pack sizes: 28, 56, 100, 112 capsules Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.