Diacomit (Stiripentol)

Diacomit (Stiripentol) belongs to a group of medicines called antiepileptics. Diacomit (Stiripentol) is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy (SMEI, Dravet’s syndrome) whose seizures are not adequately controlled with clobazam and valproate. Diacomit (Stiripentol) should always be taken in combination with other prescribed antiepileptic medicines. Diacomit (Stiripentol) should only be administered under the supervision of a paediatrician / paediatric neurologist experienced in the diagnosis and management of epilepsy in infants and children. The dose of Diacomit (Stiripentol) is calculated on a mg/kg body weight basis. The daily dosage of Diacomit (Stiripentol) may be administered in 2 or 3 divided doses. The initiation of adjunctive therapy with Diacomit (Stiripentol) should be undertaken over 3 days using upwards dose escalation to reach the recommended dose of 50 mg/kg/day administered in conjunction with clobazam and valproate. This recommended dose is based on the available clinical study findings and was the only dose of Diacomit (Stiripentol) evaluated in the pivotal studies. There are no clinical study data to support the clinical safety of Diacomit (Stiripentol) administered at daily doses greater than 50 mg/kg/day. There are no clinical study data to support the use of Diacomit (Stiripentol) as monotherapy in Dravet’s syndrome. Children aged less than 3 years The pivotal clinical evaluation of Diacomit (Stiripentol) was in children of 3 years of age and over with SMEI. The clinical decision for use of Diacomit (Stiripentol) in children with SMEI less than 3 years of age needs to be made on an individual patient basis taking into consideration the potential clinical benefits and risks. In this younger group of patients, adjunctive therapy with Diacomit (Stiripentol) should only be started when the diagnosis of SMEI has been clinically confirmed. Data are limited about the use of Diacomit (Stiripentol) under 12 months of age. For these children the use of Diacomit (stiripentol) will be done under the close supervision of the doctor. Contraindications Hypersensitivity to the active substance or to any of the excipients. A past history of psychoses in the form of episodes of delirium. Special warnings and precautions for use - Carbamazepine, phenytoin and phenobarbita these substances should not be used in conjunction with Diacomit (stiripentol) in the management of Dravet’s syndrome. The daily dosage of clobazam and/or valproate should be reduced according to the onset of side effects whilst on Diacomit (stiripentol) therapy. - Growth rate of children Given the frequency of gastrointestinal adverse reactions to treatment with Diacomit (stiripentol) and valproate (anorexia, loss of appetite, nausea, vomiting), the growth rate of children under this combination of treatment should be carefully monitored. - Blood count Neutropenia may be associated with the administration of Diacomit (stiripentol), clobazam and valproate. Blood counts should be assessed prior to starting treatment with Diacomit (stiripentol). Unless otherwise clinically indicated, blood counts should be checked every 6 months. - Liver function It should be assessed prior to starting treatment with Diacomit (stiripentol). Unless otherwise clinically indicated, liver function should be checked every 6 months. Hepatic or renal function In the absence of specific clinical data in patients with impaired hepatic or renal function, Diacomit (stiripentol) is not recommended for use in patients with impaired hepatic and/or renal function - Substances interfering with CYP enzymes Stiripentol is an inhibitor of the enzymes CYP2C19, CYP3A4 and CYP2D6 and may markedly increase the plasma concentrations of substances metabolised by these enzymes and increase the risk of adverse reactions. In vitro studies suggested that Diacomit (stiripentol) phase 1 metabolism is catalyzed by CYP1A2, CYP2C19 and CYP3A4 and possibly other enzymes. Caution is advised when combining Diacomit (stiripentol) with other substances that inhibit or induce one or more of these enzymes. The pivotal clinical studies did not include children below 3 years old. As a consequence, it is recommended that children between 6 months and 3 years of age are carefully monitored whilst on Diacomit (stiripentol) therapy Pharmacokinetic properties The following pharmacokinetic properties of Diacomit (stiripentol) have been reported from studies in adult healthy volunteers and adult patients. Absorption / Bioavailability Diacomit (Stiripentol) is quickly absorbed, with a time to peak plasma concentration of about 1.5 hours. The absolute bioavailability of Diacomit (stiripentol) is not known since an intravenous formulation is not available for testing. It is well absorbed by the oral route since the majority of an oral dose is excreted in urine. Distribution Diacomit (Stiripentol ) binds extensively to circulating plasma proteins (about 99%). Elimination Systemic exposure to Diacomit (stiripentol) increases markedly compared to dose proportionality. Plasma clearance decreases markedly at high doses; it falls from approximately 40 l/kg/day at the dose of 600 mg/day to about 8 l/kg/day at the dose of 2,400 mg. Clearance is decreased after repeated administration of stiripentol, probably due to inhibition of the cytochrome P450 isoenzymes responsible for its metabolism. The half-life of elimination was in the range of 4.5 hours to 13 hours, increasing with dose. Biotransformation Diacomit (Stiripentol) is extensively metabolized, 13 different metabolites having been found in urine. The main metabolic processes are demethylenation and glucuronidation, although precise identification of the enzymes involved has not yet been achieved. On the basis of in vitro studies, the principal liver cytochrome P450 isoenzymes involved in phase 1 metabolism are considered to be CYP1A2, CYP2C19 and CYP3A4. Excretion: Most Diacomit (stiripentol) is excreted via the kidney. Urinary metabolites of Diacomit (stiripentol) accounted collectively for the majority (73%) of an oral acute dose whereas a further 13-24% was recovered in faeces as unchanged substance. Bioavailability / Bioequivalence: Relative bioavailabilty between the capsules and powder for oral suspension in sachet formulations has been studied in healthy male volunteers after a 1,000 mg single oral administration. The two formulations were bioequivalent in terms of AUC but not in terms of Cmax. Cmax of the sachet was slightly higher (23%) compared with the capsule and did not meet the criteria for bioequivalence. Tmax was similar with both formulations. Clinical supervision is recommended if switching between the Diacomit (stiripentol) capsule and powder for oral suspension in sachet formulations. Paediatric Population Pharmacokinetic Study A population pharmacokinetic study was conducted in 35 children with Dravet Syndrome treated with Diacomit (stiripentol) and two substances not known to affect stiripentol pharmacokinetics, valproate and clobazam. The median age was 7.3 years (range: 1 to 17.6 years) and the median daily dose of Diacomit (stiripentol) was 45.4 mg/kg/day (range: 27.1 to 89.3 mg/kg/day) received in two or three divided doses. Diacomit is available in the following presentations:- Diacomit (Stiripentol) 250 mg powder for oral suspension in sachets. Each pack contains 60 sachets. Diacomit (Stiripentol) 500 mg powder for oral suspension in sachets. Each pack contains 60 sachets. Diacomit (Stiripentol) 250 mg. Each pack contains 60 capsules Diacomit (Stiripentol) 500 mg. Each pack contains 60 capsules

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