Newer antiepileptic drugs

antiepileptic drugs

1. Newer Antiepileptics : When And How To Use Dr. Nishtha jain Senior resident Department of Neurology GMC, Kota.

2. Introduction Prevalence Resistant to drug treatment in 1/3 patients Newer AEDs 2.2/1000

3. Antiepileptic Drugs Conventional New

4. Eslicarbazepine : ESL MOA Stabilizes the inactive state of voltage-gated sodium channels preventing their return to the activated state For partial onset seizures FDA Approval 2013 Aptiom

5. Dose initiated with 400 mg every other day for 2 weeks, followed by 400 mg daily. Start with 400mg OD, increase dose by 400mg, maintenance dose of 800-1600mg OD Renal dose adjustment required : the doses be reduced to 50% if CrCl < 50ml/min

6. Vigabatrin MOA Irreversible inhibitor of GABA transaminase Infantile spasms Add-on therapy for refractory partial epilepsy in adults FDA Approval 2010 Sabril

7. 2005 2017 Vigabatrin shows better results in patients of TSC and hormonal treatment is better in cryptogenic seizures.

8. Advantages Disadvantages 74% spasm cessation in cases of infantile spasms in TSC cases. Good oral bioavailablity Drug interactions are minimal Permanent, bilateral concentric visual field constriction in 30% or more of patients Somnolence and fatigue, Edema , weight gain Peripheral neuropathy, Myoclonic seizures and abscence seizures New basal ganglia, thalamic, brainstem, and dentate nucleus DWI or T2 hyperintense lesions

9. Pediatric dose Adult dose -50 mg/kg/day to 150 mg/ kg/day. -increased by 30-40 mg/ kg/day every 4-5 days -Response time- 2 weeks - Stop after two weeks Good response stop after 6 months -500mg BD starting dose -Increase by 500mg/wk -Max. dose 1.5 g BD

10. 70% is excreted in the urine Mild renal impairment Decrease by 25% Moderate renal impairment Decrease by 50% Severe renal impairment Decrease by 75%

11. Rufinamide MOA Prolongation of inactive state of sodium channels Atonic seizures in LGS FDA Approval 2008 Banzel

12. Pediatric dose Adult dose - - - 200-400 mg/day -Increase by 400-800 mg EOD -Max. dose 3200mg/day 10 mg/kg/day -Increase by 10mg/kg EOD -Max. dose 45mg/kg/day Caution- avoid in patients with familial short QT syndrome or in combination with other drugs that shorten QT interval .

13. Drug interactions Increase the serum concentration of phenytoin by up to 21% Valproate administration increase the serum level of RUF by up to 70% Diminish the efficacy and serum levels of oral contraceptives

14. Lacosamide MOA Enhance slow inactivation of sodium channels Adjunctive therapy for partial seizures in adults FDA Approval 2009 Vimpat

15. Lancet neurol 2017 The proportion of patients predicted to be seizure-free at 6 months was 90% taking lacosamide and 91% taking carbamazepine -CR.

16. Advantages Disadvantages -both an oral and intravenous formulation -no dose adjustment in mild to moderate renal impairment. -no drug interactions -Not been studied specifically in children younger than 16 years of age. -dizziness (25%) and ataxia (6%). -dose-dependent PR-interval prolongation Dose- 50mg BD, increase by 50mg BD weekly to max. dose of 150-200mg BD

17. Perampanel MOA Reduces the ability of glutamate to activate AMPA receptors via a non-competitive mechanism Partial onset and generalised seizures Approved by FDA in 2012

18. Dose Start with 2mg HS Increase weekly by 2mg Max.dose 12mg/day Not established in < 12 yrs of age Dose modification needed in hepatic impairment Increase starting dose to 4mg if patient on enzyme inducers

19. Clobazam MOA Enhancement of GABAergic neurotransmission FDA approval 2011 for adjunctive treatment of LGS in patients 2 years or older

20. Advantages Disadvantages - low tendency to produce sedation -lower incidence of loss of therapeutic effect over time lethargy , somnolence, ataxia , aggression , fatigue, and insomnia Caution : Avoid other depressant drugs or alcohol and abrupt discontinuation of use.

21. Adult dose Pediatric dose - - - Starting dose: 5mg/day Dose escalation weekly Max. dose 20 mg/day(<30kg) 40 mg/day(>30Kg) Starting dose: 5mg BD Dose escalation weekly Max. dose- 40mg/day Dose adjustment needed in hepatic impairment

22. Ezogabine MOA Enhancement of potassium currents to reduce brain excitability Adjunctive treatment of partial epilepsy FDA Approval 2011 Potiga

23. ADR Drug Interactions - Urinary retention -neuropsychiatric symptoms -dizziness and somnolence -QT-interval lengthening. -Potential for abuse and dependence Carbamazepine and phenytoin decrease ezogabine serum concentrations by 31% to 34% -inhibit renal clearance of digoxin, leading to increased serum digoxin levels. -Ethanol use can increase serum ezogabine levels

24. Dose Starting dose: 100mg TDS Increase at weekly intervals Max. dose 400mg TDS Dose adjustment in renal impairment: Start with 50mg TDS Increase weekly by 50mgTDS Max. dose- 200mg TDS

25. Leviteracetam MOA inhibits high-voltage-activated calcium channels and also binds SV2A which is involved in the control of vesicle fusion and exocytosis Approved for treatment of partial epilepsy, primary generalised tonic clonic seizures, JME and status epilepticus Keppra 1999

26. Advantages Disadvantages - No dose adjustments needed -Minimum Drug interactions -aggression, -emotional lability, -oppositional behavior , and -psychosis . Dose: Adults : 500mg BD, max. dose 3000mg/day Children : 10 mg/kg/day (divided twice daily) to be hiked by 10-20 mg/kg every two weeks to a maximum dose of 40-60 mg/kg/day. .

27. Brivaracetam FDA Approval -2016 Partial onset seizures in adults analogue of levetiracetam no clinical trials in children younger than 16 years of age

28. Dose Start from 50mg BD Max. dose 100mg BD No adjustment in renal impairment Hepatic Impairment: start with 25mg BD Max. dose 75 mg BD

29. Clinical efficacy and safety of the newer antiepileptic drugs as adjunctive treatment in adults with refractory partial-onset epilepsy: A meta-analysis of randomized placebo-controlled trials

30. Topiramate MOA Act on voltage dependent sodium channels, enhancement of GABA, decrease in glutamate and inhibition of carbonic anhydrase. Adjunct in refractory partial or generalized epilepsy Topamax 1996

31. ADR Dose - Anorexia and mild weight loss -metabolic acidosis, -nephrolithiasis, -decreased sweating and resultant hyperthermia Children: 1-3 mg/kg/day (divided twice daily) hiked bi-weekly to 3-8 mg/kg/day. Adults : 25mg BD, increased weekly by 25mg BD to max. Dose of 200mg BD Caution : Individuals on combination of topiramate and valproate should be monitored for signs of encephalopathy resulting from hyperammonemia

32. Lamotrigine MOA block the voltage dependent sodium channels adjunct to refractory partial and generalized epilepsy. -absence seizure in Lennox Gastaut syndrome -myoclonic-astatic epilepsy. Lamictal 1994

33. Greater overall effectiveness for focal seizures of lamotrigine compared with carbamazepine , oxcarbazepine , and gabapentin Epilepsia , 56(3):460–472, 2015 carbamazepine versus lamotrigine , gabapentin , oxcarbazepine and topiramate , and valproate versus lamotrigine and topiramate

34. ADR Drug Interactions - Steven Johnson syndrome and toxic epidermal necrolysis. -exacerbate myoclonic seizures in patients with Dravet syndrome Phenytoin carbamazepine and estrogen may shorten the half life of Lamotrigine. -Valproate prolongs the half life of lamotrigine

35. Pediatric dose Adult dose - - - Starting dose: 25mg/day -Increase by 50mg/ week -Maintenance dose: 200-400mg/day Started at 1-2 mg/kg followed by slow hiking biweekly to 3-8 mg/kg/day

36. Oxcarbazipine MOA Blocks high frequency voltage dependent repetitive firing of sodium channels evidence-based effective initial monotherapy for children with partial-onset seizures and focal epilepsy Trileptal 2000

37. ADR Drug Interactions Hyponatremia, headache, dizziness, ataxia induce the breakdown of the oestrogenic component of oral contraception Advantage over carbamazepine- do not cause hepatic induction nor auto induction Dose : initial dose of 5 to 8 mg/kg/day in 2 divided doses increasing by 5 to 8 mg/kg after 5 to 7 days up to a maximum of 30 mg/kg.

38. Zonisamide MOA facilitation of dopaminergic and serotoninergic neurotransmission through the blockade of T-type calcium channels. -prolongation of sodium channel inactivation. -as a weak inhibitor of carbonic anhydrase. progressive myoclonic epilepsy syndromes -second-line agent for infantile spasms, Lennox- Gastaut syndrome, and juvenile myoclonic epilepsy. Zonegran 2000

39. ADR Dose Somnolence , poor appetite, weight loss, headache, pruritus, skin rash kidney stones, oligohydrosis hyperthermia problems of language development Pediatric dose: starting dose is 2–4 mg/kg/day, and the maintenance dose is 4–8 mg/kg/day; divided once or twice daily Adult dose : starting dose 100mg/day, increase by 100mg/week Maintenance dose: 400mg/day Max. dose: 600 mg/day

40. Felbamate MOA blocking of voltage gated sodium channels, NMDA and non NMDA glutamate receptors, voltage gated calcium receptors and GABA. USE Lennox– Gastaut patients over age 4 unresponsive to primary antiepileptic drugs. Intractable partial seizures in patients over 18 y of age 1993

41. Dose Pediatric dose: initial dosing of 15 mg/kg/day to be titrated up by 15 mg/kg upto 45 mg/kg/d over a period of three weeks Adult dose: 1200mg/day Max. dose: 3600mg/day Increase by 1200mg/week Side effects: Aplastic anemia Acute liver failure

42. Pregabalin MOA Reduces the synaptic release of several neurotransmitters increases neuronal GABA levels Treatment of partial onset seizures in adults Lyrica 2004

43. Dose 300-600mg/day in two divided doses Dose adjustment needed in renal impairment Creatinine clearance Dose (Max) > 60 ml/min 600 mg/D 30 – 60 ml/min 300 mg/ D 15 – 30 ml/min 150 mg/D < 15 ml/min 75 mg/D

44. Stiripentol MOA Enhances the inhibitory action of the neurotransmitter GABA by multiple mechanisms Severe Myoclonic Epilepsy of Infancy DIACOMIT

45. Dose Adverse effects -supplied in 250 mg capsules and sachets -target dose of 50 mg/kg in 2–3 divided doses to be reached over 3 d titration anorexia, weight loss, insomnia, drowsiness, ataxia, hypotonia Dystonia Transient aplastic anemia and leukopenia

46. Ganaxolone MOA potentiates the action of GABA at its receptors and directly activates the receptor at two distinct sites USE Partial onset epilepsy in adults Infantile spasms in children

47. Formulated in capsule, IV and suspension forms Dose used in trials- 1500mg/day

48. Status epilepticus Despite increase in the prescription of newer AEDs for SE, findings do not support an improved prognosis following their prescription, if considered as a group. Newer AEDs were independently related to a reduced likelihood of return to baseline(p<0.001). Older versus newer AEDs ( levetiracetam , pregabalin , topiramate , lacosamide )

49. Pregnancy In AED monotherapy (1,111 pregnancies), use of levetiracetam in pregnancies was associated with levels of seizure control similar to those that applied for the major older AEDs carbamazepine and valproate , but with levels of seizure control superior to those associated with use of lamotrigine and topiramate .

50. Teratogenecity

51. Newer Anticonvulsants: Lamotrigine , Topiramate and Gabapentin . Holmes et al. Birth Defects Research (Part A) 00:000000 (2012 )

52. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes

53. Drug Market name Price Eslicarbezipine Eslizen Rs. 15- 400mg tab Rs. 18- 600 mg tab Vigabatrin Sabril Rs. 36-500mg tab Lacosamide Lacosam Rs. 10-100mg tab Clobazam Aedon Rs. 3-50mg tab Rs. 6-10mg tab Leviteracetam Levera Rs. 10-500mg tab Lamotrigine Lametec Rs. 5- 50 mg tab. Topiramate Topaz Rs. 10-100 mg tab Zonisamide Zonisep Rs. 10- 100mg tab oxcarbezipine oxetol Rs. 11- 450 mg tab

54. Least drug- drug interactions Less side effects Useful in targeting the childhood epilepsy syndromes. Mostly used as adjunctive therapy. Lack of superiorty trials in comparison with conventional AEDs.

55. Referrences Newer Antiepileptic Drugs: Evidence Based Use. Passi G. Indian J Pediatr (October 2014) 81(10):1042–1051. Antiepileptic Drugs 2012: Recent Advances and Trends. Joseph I. Sirven et al. Mayo Clin Proc . 2012;87(9):879-889. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Tracy Glauser et al. Epilepsia:1–13, 2013. Newly emerging therapies for neonatal seizures. M pressler et al. Seminars in Fetal & Neonatal Medicine 18 (2013) 216-223 .