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Inovelon, INN-Rufinamide

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Inovelon, INN-Rufinamide SCIENTIFIC DISCUSSION 1 Introduction The Lennox-Gastaut syndrome (LGS) is a rare and one of the most severe forms of childhood epilepsy syndrome. The syndrome usually affects children between the ages of 1 and 8 years (typically between 3 and 5 years), but occasionally has its onset in children who are more than 8 years old. LGS begins in childhood but continues to manifest into adulthood in a large number of patients and has a significant morbidity and mortality. The hallmarks of the disease include the following triad: The presence of multiple seizure types: the most characteristic are tonic-atonic seizures and atypical absences, but tonic-clonic, myoclonic, and partial seizures are also frequently present. Tonic-atonic seizures often provoke sudden falls (commonly called drop attacks) and result in injuries. The presence of generalized discharges with slow spike-and-wave complexes in the electroencephalogram (EEG). The presence of mental retardation or a learning disability. In general, this is represented by a static encephalopathy, although the mental status may worsen in the course of the disease due to multiple causes, such as very frequent occurrence of seizures, sometimes subclinical, frequent head trauma from the falls associated with seizures (drop attacks), and undesirable cognitive effects of the high doses of antiepileptic drugs (AEDs) used to treat this very refractory type of epilepsy. The aetiology of LGS remains unidentified in about half of the cases (cryptogenic LGS), whereas in others, the syndrome results from obvious brain injury (symptomatic LGS). The most common identifiable factor is a history of infantile spasms, occurring in up to one-third of the cases. Other causes include perinatal central nervous system trauma, meningitis and encephalitis, tumour, and severe head trauma. However, the electroclinical features are identical in cryptogenic and symptomatic LGS. LGS accounts for approximately 1% of all new cases of epilepsy, although it may account for as many as 10% of the cases of severe epilepsy. Within European populations, the prevalence of LGS is 0.9 per 10,000 population across all age groups, and 0.7, 1 and 2 per 10,000 population in age groups between 0 and 19 years (EMEA/COMP Summary Report on an application for Orphan Medicinal Product Designation, COMP/390/03, 2004). The long-term prognosis of LGS is frequently poor, with deteriorating mental function and persistently high rates of seizures. It is considered as an epileptic encephalopathy since epileptic phenomenon contributes to worsen the children condition. Seizure-free recovery is rare; fewer than 10% of patients became seizure-free in most reported series. Remission with preserved mentation occurs in very few patients; rather, IQ tends to deteriorate with age, and tonic seizures persist, but the slow spike-and- wave pattern does tend to resolve. Psychomotor delay and neuropsychiatric symptoms occur in 90% of LGS patients. Prolonged reaction time and information processing are the most impaired cognitive functions, which explains why these patients have a slow behaviour and are often rejected from school, even if intellectual capacity remains. Behavioural abnormalities occur in half the cases, including hyperactivity (most commonly), emotional instability, aggressiveness, destructive behaviour, autism, and antisocial personality. Such abnormalities and the arrest of educational progress are more prominent in older children and adolescents than in younger children. Chronic psychosis with episodes of acute exacerbation may also occur. The mortality rate is difficult to assess: about 3% in the series of Gastaut, with a mean follow-up of 8 years and 7 months, and 7% in that of Loubier with a mean follow-up of 9 years and 9 months. Current management of LGS is not satisfactory because the seizures associated with LGS are frequently unresponsive to standard anticonvulsants, in particular carbamazepine, phenytoin, and barbiturates. Valproate, often used as the drug of first choice, may help in controlling some seizure types, particularly atypical absence and myoclonic seizures. However, no controlled trials demonstrating its efficacy in LGS have been published. Benzodiazepines (clonazepam, clobazam, and 1/55 ©EMEA 2007 nitrazepam) are also frequently used as adjuvant intermittent treatment for LGS patients who have clusters of seizures. Nevertheless, no formal studies with these drugs have been reported. Newer AEDs, i.e., lamotrigine, felbamate and topiramate may be of benefit in patients with LGS. In one randomised clinical trial dedicated to LGS (adults and children mixed) for each of these compounds, the percentage change in tonic-atonic seizures or drop attacks with these AEDs has reportedly been about 25% greater than that seen with placebo A small number of patients became seizure free. In addition to their moderate efficacy, they are associated with potentially severe adverse reactions (aplasia and hepatitis with felbamate, skin rash with lamotrigine, cognitive disorders with topiramate). Typically, either a benzodiazepine or one of the newer AEDs (lamotrigine, topiramate or felbamate) is used as add-on treatment, generally with valproate. Treatment with benzodiazepines, however, has sometimes been reported to worsen LGS and even to induce status epilepticus. The treatment of patients with LGS often involves polytherapy due to the lack of full response to any single AED. Even when a drug is initially effective, this may not persist long term. Nonetheless, patients usually benefit only minor improvements in seizure frequency and severity, as treatment success is uncommon in this condition. Evaluation for a surgical approach (corpus callosotomy) is warranted in patients who are refractory to all these drug therapies. Surgery is purely palliative, however, and seldom produces total control of seizures. Non-drug treatments for LGS, including ketogenic diet, vagal nerve stimulation for intractable drop attacks are used occasionally. Rufinamide is a triazole derivative used as an antiepileptic drug (AED), structurally unrelated to currently marketed AEDs. The primary in vitro pharmacodynamic data indicate that interacts with the inactivated state of the sodium channel and slows conversion to the active state thereby reducing the frequency of sodium- dependent action potentials in rat neurons, an effect that could contribute to blocking the spread of seizure activity from an epileptogenic focus. Evidence from in vivo studies using animal seizure models showed that rufinamide is active in a broad range of animal models of epilepsy. No tolerance was observed in animals after repeated dosing. Ciba-Geigy in Europe initiated the earliest clinical studies with rufinamide in 1987. Novartis, (merging of Ciba-Geigy and Sandoz), continued the development until 2001. Eisai Company, Limited. acquired the worldwide development rights to rufinamide from Novartis on 6 February 2004 for the submitted indication and further development work since this date has been carried out by Eisai. Rufinamide was designated as Orphan in this indication by the Committee on Orphan Medicinal Products (COMP) (EMEA/OD/047/04) on 9th September 2004, adopted by the European Commission on 20th October 2004 (EU/3/04/240). It was designated as an Orphan on the basis that although satisfactory methods of treatment of LGS have been authorized in the Community, justifications have been provided to the COMP that rufinamide may be of significant benefit to those affected by the condition. No protocol assistance in this indication was requested by the applicant. 2 Quality aspects Introduction Inovelon is presented as film-coated tablets containing 100, 200 or 400 mg rufinamide. The tablets are pink, ‘ovaloid’ in shape, slightly convex, scored on both sides. Each strength is identified by an embossed marking “Є 261”, “Є 262” and “Є 263” only on one side of the tablet, for the 100, 200, and 400 mg strength, respectively. Inovelon tablets are packaged in push-through PA/AL/PVC blister pack, also referred to as Alu/Alu blister pack in pack sizes of 10, 30, 50, 60 100 film-coated tablets for all strengths, whereas for the 400 mg strength only, an additional pack size of 200 tablets also exists. 2/55 ©EMEA 2007 Active Substance Rufinamide, a triazole derivative, is the INN name of the active substance 1-(2, 6-difluoro-phenyl) methyl-1H-1, 2, 3-triazole-4-carboxamide. The molecular formula is C10H8F2N4O and the Relative Molecular Mass 238.2. It appears as a fine, white, odourless and slightly bitter, not hygroscopic powder of needle shaped crystals with aggregates. It is practically insoluble in water, slightly soluble in methanol and very slightly soluble in ethanol. Due to the needle shaped crystals, the drug substance has a low bulk density, poor flow properties and strong tendency to agglomerate. The partition coefficient, log Po/w is 0.65, and the melting range is between 233°C and 238°C. There are four known polymorphic forms, A, Α΄ , B and C; A being the thermodynamically stable form. • Manufacture The synthesis of the rufinamide drug substance is a 7-stage process. For an individual step, several batches may be combined for workup. If a batch of an intermediate or the drug substance fails to meet specifications, the material may be reworked according to the procedure described in the synthetic description, starting at an appropriate stage. The product is isolated and purified by several steps of re- crystallisation initially with 2-propanol and later with methanol. The manufacturing
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