SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT

Zarontin 250 mg/ 5 ml Syrup

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml syrup contains: ethosuximide 250 mg.

Excipients with known effect:

Each 5 ml contains sucrose 3 g and glucose 4.6 mg.

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Syrup

A clear, slightly yellowish to slightly pinkish, dye-free, raspberry flavoured syrup.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Primarily useful in absence seizures. When generalised tonic clonic seizures (grand mal) and other forms of epilepsy co-exist with absence seizures, Zarontin may be administered in combination with other antiepileptic drugs.

4.2.    Posology and method of administration

For oral use.

Adults, the Elderly and Children over 6 Years:

Start with a small dose - 500 mg (2 x 5 ml) daily with increments of 250 mg every five to seven days until control is achieved with 1000 - 1500 mg daily. Occasionally 2000 mg in divided doses may be necessary.

Children aged 0-6 years:

Begin with a daily dose of 250 mg (5 ml) 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 mcg per ml, but the clinical response should be the criteria for the regulation of the dosage. The half-life of ethosuximide in the 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 trial data regarding the use of ethosuximide in the paediatric population are described in section 5.1

4.3. Contraindications

Hypersensitivity to succinimides, ethosuximide or any of the components of this medicine listed in section 6.1.

Zarontin Syrup contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.4. Special warnings and precautions for use

General

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs 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.

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.

Haemopoietic Effect

Blood dyscrasias including some with fatal outcome have been reported to be associated with the use of ethosuximide; therefore, periodic blood count determinations should be performed. Should symptoms and/or signs of infection (e.g. sore throat, fever) develop, blood count determinations should be performed at that point.

Hepatic/Renal Impairment

Zarontin 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, lupuslike 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

Information for Patients

Patients taking 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 (see Haemopoietic Effect above).

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase should not take this medicine.

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).

Fertility, pregnancy and lactation

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 in 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:

f 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

MedDRA System Organ Class	Frequency!	Undesirable Effects
Blood and lymphatic system disorders	Uncommon	Agranulocytosis*, Aplastic anaemia*, Eosinophilia*, Leukopenia*, Pancytopenia*, Bone marrow failure
	Not Known	Monocytosis, Leucocytosis,
Immune system disorders	Uncommon	Hypersensitivity*, DRESS Syndrome (Drug rash with eosinophilia and systemic symptoms)*
Metabolism and nutrition disorders	Common	Decreased appetite

Psychiatric disorders	Uncommon	Aggression*, Sleep terror*, Depression*, Suicidal ideation*, Psychotic disorder*, Sleep disorder*
	Not known	Euphoric mood, Libido increased
Nervous system disorders	Common	Headache, Ataxia, Dizziness, Somnolence
	Uncommon	Pychomotor hyperactivity*, Lethargy, Disturbance in attention*
	Not Known	Extrapyramidal side effects
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	Alopecia
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 site conditions	Uncommon	Fatigue, Irritability*
Investigations	Uncommon	Weight decreased

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 at www.mhra.gov.uk/yellowcard.

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.

5.1.    Pharmacodynamic properties

Pharmacotherapeutic group: Succinimide derivatives, ATC code: N03AD01 Ethosuximide is an anticonvulsant.

Ethosuximide suppresses the paroxysmal spike and wave pattern common to absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. Compared with other succinimide anticonvulsants, ethosuximide is more specific for pure absence seizures.

In a double-blind, randomized trial of 20 week 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).

5.2.    Pharmacokinetic properties

Ethosuximide is given by mouth. It is completely and rapidly absorbed from the gastrointestinal tract. Peak serum levels occur 1 to 7 hours after a single oral dose. Ethosuximide is not significantly bound to plasma proteins and therefore the drug is present in saliva and CSF in concentrations that approximate to that of the plasma.

Therapeutic concentrations are in the range of 40 to 100 micrograms/ml.

Ethosuximide is extensively metabolised to at least 3 plasma metabolites. Only between 12% and 20% of the drug is excreted unchanged in the urine. The elimination half life of ethosuximide is long, 40 to 60 hours in adults and 30 hours in children.

5.3 Preclinical safety data

The results of the preclinical tests do not add anything of further significance to the prescriber.

6.1.    List of excipients

Sodium citrate Sodium benzoate (E211)

Saccharin sodium

Sucrose

Glycerol

Raspberry flavour including glucose Citric acid monohydrate Purified water

6.2.    Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 25⁰C.

Nature and contents of container

Amber round bottle stoppered with aluminium screw cap equipped with expanded PE disk surfaced on each face with PE films or stoppered with high density polyethylene plastic cap equipped with polyethylene/aluminium/polyethylene terephtalate liner containing 200 ml.

6.6. Special precautions for disposal and other handling

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich Kent

CT13 9NJ United Kingdom

8.    MARKETING AUTHORISATION NUMBER

PL 00057/0545

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

1 March 2003

10 DATE OF REVISION OF THE TEXT

24/07/2014