Update on Newer AEDs What is their role? Master Class Nov 2012 Young Epilepsy K.B. Das Learning objectives To understand the role of newer AEDs in managing epilepsy Discuss some newer drugs Assumptions Newer drugs are more efficacious They have novel modes of action Their side effects are less Drug interactions are less They are more cost effective Drug-resistant Epilepsy (ILAE 2010) ‘Failure of adequate trials of two tolerated, appropriate chosen and used AED schedules (where as monotherapy or in combination) to achieve seizure freedom’ Previously : intractable, refractory, difficult epilepsy Cumulative probability of being seizure-free by time from start of treatment and number of antiepileptic drug regimens Lucky 7 ! Brodie ,Neurology 2012 ,78:1548 Zonisamide 2005 Japan 1989, US 2000 Broad spectrum Indications Adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation in adult patients (>18 yrs) Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy Mechanism The mechanism of action of zonisamide is not fully elucidated It appears to act on voltage-sensitive sodium and calcium channels Zonisamide also has a modulatory effect on GABA-mediated neuronal inhibition Dosing 1-2 - 5-8 mg/kg/day ; build up 2 weekly Adults:100mg/day – 200 mg/day – 300- 500mg/day Can be given OD for focal sz Steady state 13 days Half life 105 hrs Zonegran Effectiveness Placebo Zonisamide Sz reduction 16% 51% Very common (>1 in 10) Side Effects Somnolence , dizziness ,loss of appetite Agitation, irritability, confusion, depression, ataxia,memory impairment, diplopia and decreased blood bicarbonate levels. Common (1/10 - 1/100) Weight decreased Ecchymosis ,Rash ,Hypersensitivity (including cases of Stevens-Johnson syndrome ) Abdominal pain Anxiety, Insomnia Psychotic disorder Nephrolithiasis Nausea, Constipation ,Diarrhoea ,Dyspepsia Pruritis ,Alopecia Fatigue Influenza-like illness Pyrexia Peripheral oedema Caution Unexplained Rash Serious rashes can occur including cases of Stevens- Johnson syndrome. Sulphonamide reactions Serious immune based adverse reactions include rash, allergic reaction and major haematological disturbances including aplastic anaemia, which very rarely can be fatal. Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and leucocytosis have been reported. Pancreatitis Rhabdomyolysis Heat stroke Kidney stones Renal stones have occurred in patients treated with zonisamide. It should be used with caution in patients who have risk factors for nephrolithiasis, including prior stone formation, a family history of nephrolithiasis and hypercalcuria. Metabolic acidosis Hyperchloraemic, non-anion gap, metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase. The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger patients. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing it as osteopenia may develop. Should be used with caution in patients being treated concomitantly with carbonic anhydrase inhibitors such as topiramate. Rufinamide 2007 (Orphan ) Used to treat patients aged 4 years or older who have Lennox-Gastaut syndrome Tablets (100 mg, 200 mg or 400 mg) Oral suspension (40 mg/ml) Adults with focal sz 20 % reduction ( in those not on Carbamazepine) Inovelon Mechanism Rufinamide modulates the activity of sodium channels, prolonging their inactive state Dosing Use in children four years of age or older and less than 30 kg Patients <30 kg not receiving valproate: Treatment should be initiated at a daily dose of 200 mg Increase by 200 mg/day increments, as frequently as every two days, up to a maximum recommended dose of 1000 mg/day Patients <30 kg also receiving valproate: As valproate significantly decreases clearance of rufinamide, a lower maximum dose of Rufinamide is recommended for patients <30 kg being co-administered valproate. Treatment should be initiated at a daily dose of 200 mgs The dose may be increased by 200 mg/day, to the maximum recommended dose of 600 mg/day. Use in adults, adolescents and children four years of age or older of 30 kg or over Treatment should be initiated at a daily dose of 400 mg The dose may be increased by 400 mg/day increments, as frequently as every two days, up to max 1-8-3.2gm/day. Side effects >1 in 10 patients somnolence headache vomiting dizziness nausea fatigue Caution Status epilepticus Status epilepticus cases have been observed during clinical development studies, under rufinamide whereas no such cases have been observed under placebo. These events led to rufinamide discontinuation in 20 % of the cases. Central Nervous System reactions Dizziness, somnolence, ataxia and gait disturbances can occur, which could increase the occurrence of accidental falls. Hypersensitivity reactions Fever and rash associated with other organ system involvement. Other associated manifestations included lymphadenopathy, liver function tests abnormalities, and haematuria. QT shortening Rufinamide produced a decrease in QTc interval proportional to concentration. Interactions No clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate No effect on OCP Stiripentol 2007 (Orphan) It is available as capsules and sachets (250 and 500 mg) Start 10mg/kg/day in 2-3 doses The normal dose is 50 mg per kg/day, divided into two or three doses Add on therapy for Dravet ( with Valproate + Clobazam) Also tried in drug resistant epilepsy Diacomit Stiripentol in SMEI Side effects Seen >1 in 10 patients: loss of appetite weight loss insomnia drowsiness hypotonia dystonia behaviour Monitor FBC,LFT/6 monthly, growth Need to monitor drug levels, adjust dose Pregablin The active substance, pregabalin, is a gamma- aminobutyric acid analogue ((S)-3- (aminomethyl)-5-methylhexanoic acid). Pregabalin binds to an auxiliary subunit (α2-δ protein) of voltage-gated calcium channels in the central nervous system Indications Is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation In the treatment of peripheral and central neuropathic pain in adults Generalised Anxiety Disorder in adults Dosing Pregabalin treatment can be started with a dose of 150 mg per day given as two or three divided doses. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after 1 week. The maximum dose of 600 mg per day may be achieved after an additional week. Lyrica Side effects Dizziness Somnolence Weight gain (Diabetic) Hypersensitivity Blurred vision Renal failure CCF Benefits No interactions with other drugs No interactions with OCP Lacosamide 2008 Adjunctive treatment of focal seizures >16yrs Selectively enhance slow inactivation of Na channels ( others act on fast inactivation) Start 50 mg /day , increase to 100 mg bd , max 200 mg bd IV formulation available Vimpat Indications It is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in adult and adolescent (16-18 years) patients with epilepsy. Solution for infusion: Is an alternative for patients when oral administration is temporarily not feasible. Dosing The recommended starting dose is 50 mg twice a day which should be increased to an initial therapeutic dose of 100 mg twice a day after one week. Depending on response and tolerability, the maintenance dose can be further increased by 50 mg twice a day every week, to a maximum recommended daily dose of 400 mg (200 mg twice a day) Efficacy Placebo Lacosamide Lacosamide Lacosamide 200mg 400mg 600mg 50% reduction 23% 34% 40% 40% + in the number of seizures Side effects Very common(1/10) :dizziness ,headache , diplopia, nausea Common(1/100): depression, conduction defects, CNS, GIT Not sedative Caution Dizziness Treatment with lacosamide has been associated with dizziness which could increase the occurrence of accidental injury or falls. Cardiac Rhythm and Conduction Prolongations in PR interval with lacosamide have been observed in clinical studies. Lacosamide should be used with caution in patients with known conduction problems or severe cardiac disease such as a history of myocardial infarction or heart failure. Second degree or higher AV block has been reported in post- marketing experience. In the placebo-controlled trials of lacosamide in epilepsy patients, atrial fibrillation or flutter were not reported; however both have been reported in open-label epilepsy trials and in post-marketing experience Interactions No interaction with CMZ, Valproate concentrations Enzyme inducers reduce Lacosamide levels No significant interaction with OCP Eslicarbazepine Acetate 2009 Eslicarbazepine acetate is a third generation of a family of antiepileptic drugs (AEDs), which includes carbamazepine (first generation) and oxcarbazepine (second generation) Eslicarbazepine is thought to work by blocking ‘voltage-gated sodium channels’ Less hyponatraemia (1%), rash(1.1%) and CNS side effects It is used to treat adults with partial-onset seizures with or without secondary generalisation (Children- trial on) Tab 200 mg, 400 mg, 600 mg and 800 mg Start at 400 mg once a day, before increasing it to 800 mg once