Summary of product characteristics
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
The medicinal product is used for the alternative treatment for Rolandic epilepsy w hen the treatment w ith other anti-epileptics has not produced the desired effect.
Note: The treatment w ith Sultiame should only be performed by neuropaediatricians w ith experience in the treatment of epilepsy. The efficacy and safety of Sultiame for the above therapeutic indication have not been verified in controlled studies. Before starting a treatment w ith Sultiame careful differential diagnosis is required to distinguish the particular case from other forms of epilepsy in childhood. Rolandic epilepsy has a high spontaneous remission rate and in most cases a good outcome and a good prognosis - even w ithout medication.
4.2 Posology and method of administration
Dosage The dose is determined and checked by the attending doctor on an individual basis. The daily maintenance dose is approx. 5 to 10 mg/kg body w eight. The treatment should be started at low initial doses and increased gradually to optimum amounts w ithin one w eek.
Due to the short half-life of Sultiame the daily dose should be divided into three single doses, if possible. Provided the daily dose is distributed evenly over the day, constant plasma levels can be reached after five or six days. Therapeutic plasma concentrations for Sultiame have not been determined yet.
Sw itching from another medicinal product or a combination treatment should be gradual.
A neuropaediatrician w ith experience in the treatment of epilepsy should decide about the duration and discontinuation of the treatment on an individual basis. If the treatment does not produce the desired clinical response, Sultiame should be stopped after approx. one or tw o months of treatment. Sultiame should not be stopped suddenly.
Route(s) and/or method of administration
4.3 Contraindications
- hypersensitivity to the active substance, other sulphonamides or to any of the excipients listed in section 6.1. - know n acute porphyria, - hyperthyroidism or arterial hypertension.
4.4 Special warnings and precautions for use
Sultiame should be used only w ith adequate monitoring in patients - w ith impaired renal function, - w ith a history of psychiatric disorders, - w ho are pregnant or breast-feeding (also see section 4.6).
Note: Patients or their parents should be instructed to consult the attending doctor immediately if fever, sore throat, allergic skin reactions w ith lymph node sw elling and/or flu-like symptoms occur during the treatment w ith Sultiame. Progressive thrombocytopenia or leucopenia accompanied by clinical symptoms such as fever or sore throat requires interruption of treatment. In cases of severe allergic reactions Sultiame must be discontinued immediately. Treatment should also be interrupted if a lasting increase in creatinine occurs. The blood count, liver enzymes and urine should be checked regularly.
Suicidal ideation and behaviour Suicidal thoughts and behaviour have been reported in patients treated w ith anti-epileptic medicinal products for various indications. A meta-analysis of randomised, placebo-controlled studies w ith anti-epileptics also show ed a slightly increased risk for suicidal thoughts and behaviour. The mechanism triggering this undesirable effect is unknow n, and the data available do not exclude a potentially increased risk w hen taking Sultiame.
Therefore, patients should be monitored for the emergence of suicidal thoughts and behaviour, and an appropriate treatment should be considered. Patients (and their caregivers) should be advised to seek medical help if symptoms of suicidal thoughts or behaviour occur.
Effect on laboratory tests Sultiame may interfere w ith the estimation of barbiturates in laboratory tests on blood.
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on Sultiame Primidone The concomitant use of Sultiame and primidone may increase the intensity of undesirable effects of Sultiame; in particular in children dizziness, unstable gait and drow siness may occur.
Carbamazepine There is evidence that Sultiame serum levels may decrease if carbamazepine is taken concomitantly.
Effects of Sultiame on other medicinal products Phenytoin The combination of Sultiame and phenytoin may increase the plasma level of phenytoin significantly. This combination requires especially strict monitoring and frequent controls of phenytoin plasma levels, in particular in the case of impaired renal function.
Lamotrigine In combination w ith lamotrigine, an elevation of lamotrigine levels in the blood has also been observed in individual cases. Therefore, lamotrigine levels should be checked more frequently at the beginning of such treatment.
Carbonic anhydrase inhibitors Concomitant use of Sultiame and other carbonic anhydrase inhibitors (e.g. topiramate, acetazolamide) may increase the risk of undesirable effects due to carbonic anhydrase inhibition (also see section 4.8.).
Alcohol Alcohol should not be consumed during the treatment w ith sultiame. As sulphonamides have an effect similar to that of disulfiram, Sultiame as a sulphonamide derivative can theoretically have a similar effect. These symptoms include a very unpleasant, although generally self- limiting systemic reaction caused by vasodilatation w ith pulsating headache, respiratory depression, nausea, vomiting, tachycardia, hypotension, amblyopia, confusion, shock reactions, arrhythmia, loss of consciousness and seizures. The degree and duration of these symptoms can vary to a great extent.
4.6 Fertility, pregnancy and lactation
Pregnancy There is no systematic data available from the use of sultiame in pregnant w omen. Studies in animals have show n reproductive toxicity (see section 5.3). Sultiame is not recommended during pregnancy.
Breast-feeding It is unknow n w hether sultiame is excreted in human milk. A risk to the suckling child cannot be excluded. Sultiame should not be used during breast-feeding.
Fertility There are no clinical data available on the effects of sultiame on human fertility. Studies in animals have not been performed (see section 5.3).
4.7 Effects on ability to drive and use machines
This medicinal product can change reactivity to an extent that patients are no longer able to participate safely in road traffic or operate machines, in particular at the beginning of treatment. This is even more so w hen drinking alcohol.
4.8 Undesirable effects
The follow ing frequency categories form the basis for classification of undesirable effects: Very common (≥ 1/10) Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1.000 to < 1/100) Not know n (frequency cannot be estimated from the available data):
Metabolism and nutrition disorders Common Loss of w eight, loss of appetite Psychiatric disorders Uncommon Hallucination, anxiety, lack of drive Not know n Behavioural anomaly such as aggressiveness, irritability, mood sw ings, deterioration in cognitive function Nervous system disorders Common Paraesthesia in the extremities and in the face (dose dependent), dizziness, headache Uncommon Myastenic phenomena, grand-mal state, increased seizure activity Not know n Polyneuritis, somnolence Eye disorders Common Double vision Cardiac disorders Common Stenocardia, tachycardia Respiratory, thoracic and mediastinal disorders Common Tachypnoea, hyperpnoea, dyspnoea, singultus Gastrointestinal disorders Very common Gastric disorder Hepatobiliary disorders Not know n Hepatotoxic reactions, elevated liver enzymes Skin and subcutaneous tissue disorders Not know n Stevens-Johnson syndrome, Lyell's syndrome Musculoskeletal and connective tissue disorders Uncommon Joint pain Renal and urinary disorders Not know n Acute renal failure
In one case, the administration of Sultiame led to progressive w eakness of limbs, hypersalivation, slurred speech, increasing drow siness up to coma. The symptoms abated w ithin a few hours of Sultiame being discontinued.
Sultiame is a carbonic anhydrase inhibitor. Therefore, the undesired effects of carbonic anhydrase inhibition such as renal stone formation, metabolic acidoses, haemodilution and changes in serum electrolyte values, cannot be excluded w hen taking Sultiame (also see section 4.5.)
Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allow s continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9 Overdose
Symptoms of intoxication Headache, dizziness, ataxia, clouding of consciousness, metabolic acidosis, crystals in urine. Sultiame has a low toxicity. Patients survived overdoses of 4 or 5 g Sultiame. In a single case, 20 g Sultiame taken by an adult w ith suicidal intent led to exitus letalis. In another case, full recovery (restitutio ad integrum) w as reached.
Treatment of intoxications There is no specific antidote. Treatment consists of usual measures (gastric lavage and activated charcoal) to reduce absorption and maintain vital functions. Acidosis can be treated by sodium bicarbonate infusion. Alkaline diuresis is recommended to prevent kidney damage and crystalluria.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-epileptics, other anti-epileptics ATC code: N03AX03
Sultiame is classified as a carbonic anhydrase inhibitor and displays an anticonvulsive effect in the electroconvulsion test (rats and mice) and the convulsion test w ith pentamethylene tetrazole (mice).
5.2 Pharmacokinetic properties
Pharmacokinetics of Sultiame has not been studied systematically in the various stages of childhood and adolescence.
Absorption After oral administration Sultiame is rapidly and completely absorbed, preferentially from the upper section of the small intestine. Maximum plasma concentrations are measured after 1-5 hours.
Distribution About 29% of the active substance is bound to plasma proteins.
Elimination 80-90% of the active substance is eliminated w ith the urine and 10-20% w ith faeces after biliary secretion. Within 24 hours, 32% of the administered dose is eliminated unchanged via the kidneys.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on repeated dose toxicity and genotoxicity. At high doses kidney damage w as observed due to crystallisation of the substance. Studies on the carcinogenic potential of sultiame have not been performed.
Sultiame has not been tested sufficiently for reproductive toxicity. A study of embryotoxicity in rats show ed embryotoxic effects at the low est dose studied (30 mg/kg/day). No studies on fertility disorders and impacts on the perinatal and postnatal development of progeny have been performed.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core Lactose monohydrate Maize starch Gelatine Silica, colloidal anhydrous Magnesium stearate (Ph. Eur.)
Film-coating Hypromellose Titanium dioxide (E171) Macrogol 4000 Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
OPA/AI/PVC//Al blisters.
Pack sizes
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
[to be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[to be completed nationally]
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
[to be completed nationally]
10. DATE OF REVISION OF THE TEXT
{MM.YYYY}