Stiripentol

UK SPC (Diacomit 250 mg powder for oral suspension in sachet) section 4.2: 'The dose of stiripentol is calculated on a mg/kg body weight basis. The daily dosage may be administered in 2 or 3 divided doses... upwards dose escalation to reach the recommended dose of 50 mg/kg/day administered in conjunction with clobazam and valproate.' Escalation is gradual: 20 mg/kg/day for 1 week, then 30 mg/kg/day for 1 week; thereafter escalation is age dependent, and patients above 12 years old should receive an additional 5 mg/kg/day each week until the optimum dose is reached based on clinical judgment. Patients aged 18 years and over: long-term data confirm maintenance of effect and treatment should be continued for as long as efficacy is observed; the SPC states that 'adults may require a lower maximum dose compared to younger patients'. No numeric maximum daily dose is given in the UK SPC section 4.2; the US FDA label for DIACOMIT states a maximum recommended total dosage of 3,000 mg/day. Stiripentol should only be administered under the supervision of a paediatrician, paediatric neurologist or neurologist experienced in the diagnosis and management of epilepsy. Do not take with carbonated drinks, fruit juice, or food and drinks that contain caffeine or theophylline. Dose adjustment of co-administered antiepileptics: in the pivotal studies clobazam was given at 0.5 mg/kg/day, usually in two divided doses, and was reduced by 25% every week if there were clinical signs of adverse reactions or overdose (drowsiness, hypotonia, irritability in young children); co-administration produces approximately two- to three-fold increases in clobazam and five-fold increases in norclobazam plasma levels. No modification of the valproate dose is usually needed, but in the pivotal studies valproate was reduced by around 30% every week in the event of gastrointestinal adverse reactions such as loss of appetite or weight loss. Carbamazepine, phenytoin and phenobarbital should not be used in conjunction with stiripentol in the management of Dravet syndrome (section 4.4). Blood counts and liver function should be assessed before starting and, unless otherwise clinically indicated, checked every 6 months. The sachet formulation has a slightly higher Cmax than the capsules and the formulations are not bioequivalent — switch only under clinical supervision. The powder should be mixed in a glass of water and taken immediately after mixing. NOTE ON INTERACTIONS: the UK SPC section 4.5 was not captured in this bundle; the interaction entries below are taken from sections 4.2 and 4.4 — verify against section 4.5 of the UK SPC.

DRAFT — clinician to confirm against a children's formulary before use. UK SPC (Diacomit) section 4.2: the recommended dose of 50 mg/kg/day is given as adjunctive therapy in conjunction with clobazam and valproate, and is reached by gradual escalation — 20 mg/kg/day for 1 week, then 30 mg/kg/day for 1 week, then: children less than 6 years receive an additional 20 mg/kg/day in the third week, reaching 50 mg/kg/day in three weeks; children from 6 to less than 12 years receive an additional 10 mg/kg/day each week, reaching 50 mg/kg/day in four weeks; patients above 12 years receive an additional 5 mg/kg/day each week until the optimum dose is reached based on clinical judgment. The pivotal clinical evaluation was in children of 3 years of age and over with Dravet syndrome; use in children under 3 years must be an individual clinical decision taken after the diagnosis has been clinically confirmed, and data below 12 months of age are limited so use must be under close medical supervision. Section 4.4 recommends that children between 6 months and 3 years of age are carefully monitored while on stiripentol. The sachet formulation contains aspartame (a source of phenylalanine, harmful in phenylketonuria) and glucose, and no data are available to assess aspartame use in infants below 12 weeks of age. Given the frequency of gastrointestinal adverse reactions with stiripentol plus valproate, the growth rate of children on this combination should be carefully monitored.