Topics. A. Simple partial seizures

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1 Management of Partial Epilepsy: Focus on Sodium Valproate Asia Pacific Epilepsy Meeting 8 Associate Professor Somsak Tiamkao Division of Neurology, Department of Medicine Srinagarind Epilepsy Research Group, Faculty of Medicine Khon Kaen University, Khon Kaen, THAILAND somtia@kku.ac.th Topics General consideration in partial epilepsy Clinical trial of monotherapy AEDs V. I. P.e study Objectives How to manage partial epilepsy Review clinical trials of monotherapy AEDs V. I. P. e study International Classification of Epileptic Seizures Partial seizures A. Simple partial seizures B. Complex partial seizures C. Partial seizures evolving to secondary generalized seizures International Classification of Epileptic Seizures Partial seizures A. Simple partial seizures. With motor signs. With somatosensory or specialsensory sensory symptoms. With autonomic symptoms or signs. With psychic symptoms ILAE 98 Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia. 98;:96. International Classification of Epileptic Seizures B. Complex partial seizures. Simple partial seizures at onset, followed by impairment of consciousness a. With simple partial features b. With automatisms. With impairment of consciousness at onset a. With impairment of consciousness only b. With automatismsilae 98 Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia. 98;:96.

2 International Classification of Epileptic Seizures Diagnosis partial epilepsy: easy or not C. Partial seizures evolving to secondary generalized seizures.. Simple partial seizures evolving to generalized seizures. Complex partial seizures evolving to generalized seizures. Simple partial seizures evolving to complex partial seizures evolving to generalized seizures ILAE 98 Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia. 98;:96. Diagnosis partial epilepsy: easy or not Home VDO by mobile phone Management of Epilepsy Goals of therapy Control seizures Minimize adverse events Improve quality of life Important considerations Comorbidities, Psychosocial needs Antiepileptic Drugs in the United States phenobarbital felbamate VALPROATE carbamazepine ethosuximide phenytoin topiramate tiagabine lamotrigine gabapentin pregabalin oxcarbazepine zonisamide levetiracetam. Dam M. In: Engel J Jr, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. Vol. Philadelphia, Pa: LippincottRaven; 997:5.. Boro A, Haut S. Epilepsy Behav. ;:SS.. Karceski S, et al. Epilepsy Behav. 5;7:SS6.. Schachter SC. Epilepsy Behav. ;:

3 Standard AEDs Phenobarbital Carbamazepine Sodium valproate New AEDs Topiramate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Felbamate Pregabalin Others TABLE : Variables that affect a specific AED s suitability for patients with newly diagnosed or untreated epilepsy AEDspecific variables Seizure or epilepsy syndrome specific efficacy/ effectiveness Dosedependent adverse effects Idiosyncratic reactions Chronic toxicities Teratogenicity Carcinogenicity Pharmacokinetics Interaction potential Formulations Patientspecific variables Genetic background Gender Age Comedications Comorbidities Insurance coverage Relative wealth Ability to swallow pills/tablets Nationspecific variables AED availability AED cost Journal of Neurology, Neurosurgery and Neuropsychiatry 985;8:69 A prospective study between carbamazepine,, phenytoin and sodium valproate as monotherapy in previously untreated and recently diagnosed patients with epilepsy N CALLAGHAN, RA KENNY, BO NEILL, M CROWLEY, T GOGGIN From the Department of Neurology and Neurology Research Laboratory, ry, Cork Regional Hospital, and Department of Statistics, University College, Cork, Eire SUMMARY One hundred and eighty one patients with previously untreated epilepsy were randomised to sodium valproate, phenytoin or carbamazepine as monotherapy and followed up for a median period which ranged from to months. All three drugs were highly effective in the control of generalised seizures but less effective for partial seizures. Excellent or good control was achieved with therapeutic levels of sodium valproate and carbamazepine,, but with subtherapeutic levels of phenytoin. Table : Overall response in patients with partial seizures with or without secondary generalised attacks Drug Carbamazepine Valproate Total Control Excellent N (PC 5 SP 7) (57.%) N (PC 5 SP 6) (.5%) N (PC 6 SP 6) (.%) N 5 (.%) PC = Partial Complex. SP = Simple Partial. Good N (PC SP ) (9.%) N (PC SP ) (8.7%) N 9 (PC 7 SP ) (.%) N 5 (.6%) Poor N 5 (PC SP ) (.8%) N 8 (PC 6 SP ) (5.8%) N 6 (PC SP ) (.%) N 9 (%) Vol. 7 No. THE NEW ENGLAND JOURNAL OF MEDICINE 99;7: A COMPARISON OF VALPROATE WITH CARBAMAZEPINE FOR THE TREATMEMT OF COMPLEX PARTIAL SEIZURES AND SECONDARILY GENERALIZED TONICCLONIC SEIZURES IN ADULTS Richard H. Mattson, M.D., Joyce A. Cramer, B.S., Joseph F. Collines, Sc.D., And the Department of Veterans Affairs Epilepsy Cooperative Study No. 6 Group Conclusion: VPA is as effective as carbamazepine for treatment of secondarily GTC Journal of Neurology, Neurosurgery and Neuropsychiatry 99;57:6887. A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy A Richens, D L W Davidson, N E F Cartlidge, D J Easter on behalf of the Adult EPITEG Collaborative Group

4 % Patients achieving remission Figure Remission analysis: percentage of patients free of seizures for months: patients with partial seizures with or without generalisation. Sodium valproate (n=7) Carbamazepine (n=7) Months on treatment Table Adverse events reported by four or more patients at any time during treatment Adverse event Fatigue Somnolence Nausea/vomiting/dyspepsia Weight increase Rash Headache Dizziness Tremor Amnesia Depression Pregnancy Alopecia Abnormal hepatic function Ataxia Appetite increase Aphasia Other events Total no adverse events Number of patients reporting adverse event Sodium valproate *p =.5; **p =. between treatments, Fisher s s exact test. Data from 7 patients on valproate (65 for at least three months) and 78 patients on carbamazepine (7 for at least three months) 5 ** Carbamazepine 7 5 8** * 6 6 Journal of Neurology, Neurosurgery and Neuropsychiatry 995;58:5 Figure Actuarial percentages of patients remaining seizure free in the four durg groups. Phenobarbitone,, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial % Patients 8 6 Carbamazepine Phenobarbitone Sodium valproate A J Heller, P Chesterman, R D C Elwes, P Crawford, D Chadwick, A L Johnson, E H Reynolds 6 8 Time (Weeks) % Patients Figure Actuarial percentages of patients achieving one year remission in the four drug groups. 6 8 Time (Weeks) Carbamazepine Phenobarbitone Sodium valproate PB PHT CBZ VPA 8% 78% 8 67% 6% 6 Patients, % Newly Diagnosed Epilepsy : Randomised Comparative Trial % 5% % % (N=) (N=5) (N=5) (N=9) yr remission yrs seizure free de Silva M et al. Lancet 7:79, 996

5 Results: efficacy Randomized comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine or sodium valproate for newly diagnosed childhood epilepsy Actuarial percentage seizure free by selected times from randomization Treatment Phenobabitone Carbamazepine Sodium Valproate randomised * Number of children With seizure recurrence 8* 7 9 Seizure free * 7 6 m. * 6 7 Actual % seizure free m. * 9 8 m. * 7 * 5 6 m. Total THE LANCET, vol 7, March 6, 997 *Number at risk small No significant different in efficacy between PHB, PHT, CBZ, VPA Fig. Patients remaining in the trial KaplanMeier curve. not discontinued prematurely trial duration () () Weeks between randomisation visit and last regularly visit Monotherapy Comparison Trial Physician selects best standard treatment (CBZ or VPA) for individual patient Patient assigned to CBZ or VPA branch Patient randomised to physician s s selected treatment or TPM ( or mg/day) % Patients Monotherapy Comparison Trial: Patients SeizureFree >6 6 Months* 8 6 9% Overall % % % TPM TPM CBZ VPA (N) () (99) (6) (78) 8 6 6% Children 59% 9% 5% TPM TPM CBZ VPA (8) (9) () (9) Privitera MD et al. Epilepsia (Suppl 7):9, *Last 6 months of study Privitera MD et al. Epilepsia (Suppl 7):9, Wheless JW et al. Neurology 56(Suppl ):A, 5

6 Discontinuations Due to Adverse Events *Treatment duration up to yrs Patients Discontinuing* Overall, % Children, % TPM 9% % TPM 8% 5% CBZ 6 5% % VPA 5 % % Privitera MD et al. Epilepsia (Suppl 7):9, Wheless JW et al. Neurology 56(Suppl ):A, Cognitive Complaints TPM (N=) CBZ 6 (N=6) VPA 5 (N=78) Somnolence 5 Memory difficulty Concentration/attention difficulty Psychomotor slowing Confusion Language problems 6 Cognitive problems Speech problems Privitera MD et al. Epilepsia (Suppl 7):9, Neurology 997;8:888 Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: A doublebind, concentrationresponse design clinical trial Comparison versus Sodium valproate, Outcome : Time to I month remission Partial onset seizures Study n/n Sodium Valproate n/n Peto Odds Ratio 95% CI Weight (%) Peto Odds Ratio 95% CI Craig I99 5/9 / [.8,.] A. Beydoun,MD; J.C. Sackellares, MD; V. Shu, PhD; and the Depakote Monotherapy for Partial Seizures Study Group de Silva I996 Heller I995 5/9 /8 /5 7/ [.5,.8].9 [.8,.8] Tumbull I985 5/ 8/...9 [.9, 7.58] Median reduction for secondarily GTC was 7% Efficacy of divalproex sodium as monotherapy for patient with partial epilepsy Subtotal (95% CI) [.68,.5] Favours valproate Favours phenytoin Cochrane Database of Systematic Reviews, Issue. Art. No.: CD769. Comparison Carbamazepine versus Sodium valproate, Outcome : Time to I month remission from seizures Partial epilepsy Study de Silva I996 n/n /5 Sodium Valproate n/n 5/9 Peto Odds Ratio 95% CI. Weight (%) 7. Peto Odds Ratio 95% CI.8 [.6,.96] Epilepsia (5):555, Blackwell Publishing Inc. International League Against Epilepsy Carbamazepine versus Valproate Monotherapy for Epilepsy: A Metaanalysis Heller I995 7/5 /..8.7 [.6,.6] Mattson I99 Richens I99 9/9 5/7 /7 58/ [.9,.95].6 [.,.95] Antohny G. Marson, Paula R. Williamson, Helen Clough, Jane L. Hutton, and David W. Chadwick, on behalf of the Epilepsy Monotherapy Trial Group Verity I995 Sobtotal (95% CI) 6/55 9/ [.7,.89].8 [.67,.] Department of Neurological Science, Faculty of Medicine, and Division of Statistics and Operational Research, University of Liverpool, Liverpool; and Department of Statistics, University of Warwick, England Carbamazepine better Valproate better Cochrane Database of Systematic Reviews, Issue. Art. No.: CD. 6

7 Partial onset seizures: Hazard Ratio.95 (.5.6) p=.95 Recommendations Regard the Initial Medication Choice With Maintenance Dosing for Epilepsy in Adults.6 (.5.78).78) p=.79. (.57.5) p=.5.87 (.6.9) p= (.65.) p=.89 AEDs as Monotherapy of Partial Seizures Phenobarbital AAN st NICE SIGN Typical Dose (mg)/day Cost/Unit, U.S.$.7 (97. mg) Cost/Mth U.S.$ (Day Supply) Carbamazepine st st st,.8 ( mg) 7. (.79.6) p=.986 st st. ( mg ) 8 Valproic acid st st st,.9 (5 mg ) Gabapentin st,.85 ( mg )..5 5 Valproate better carbamazepine better A Comparison of CPGs in the Initial Pharmacological Management of NewOnset Epilepsy in Adults. Nalin P. Journal of Managed Care Pharmacy 6;: Assessment of Cost effectiveness: Monotherapy for Newly Diagnosed Integrated economic analysis showed similar health benefits for various AEDs and that new AEDs were more expensive than older AEDs. Consequently, the older AEDs were more likely to be costeffective. Epilepsia 7(7):9, 6 Blackwell Publishing Inc. 6 International League Against Epilepsy Original Research ILAE Treatment Guidelines: Evidencebased Analysis of Antiepileptic Drug Efficacy and Effectiveness as Initial Monotherapy for Epileptic Seizures and Syndromes Tracy Glauser, Elinor BenMenachem Menachem, Blaise Bourgeois, Avital Cnaan,, David Chadwick, Carlos Guerreiro, Reetta Kalviainen,, Richard Mattson, Emilio Perucca, And Torbjorn Tomson TABLE : Summary of studies and level of evidence for each seizure e type and epilepsy syndrome TABLE : Adults with partialonset seizures: number of relevant studies categorized by class of study and AED involved Class I II IIIDB IIIOL Total CBZ 6 9 PT 6 VPA 8 LTG 5 PB 5 OXC TPM Seizure type or epilepsy syndrome Adults with partialonset seizures Children with partialonset seizures Elderly adults partialonset seizures Class I studies Class II studies Class III studies 7 Level of efficacy and effectiveness evidence (in alphabetic order) Level A: CBZ, PHT Level B: VPA Level C: GBP, LTG, OXC, PB, TPM, VGB Level A: OXC Level B: None Level C: CBZ, PB, PHT, TPM, VPA Level A: GBP, LTG Level B: None Level C: CBZ 7

8 OBJECTIVES THAILAND DEPAKINE CHRONO STUDY To assess the compliance and satisfaction consequences in epileptic patients switched from more than two times daily enteric R coated tablet of Depakine regimen to the same total daily dose of R Depakine Chrono given once or twice daily RESULT of SECONDARY OUTCOME 8% 76.% 65.% 6% % Frequency of Seizure P=. RESULTS of SECONDARY OUTCOME AED Therapy: seizures controlled 98.9% % 9.% p=. 5% % %.6%.%.5% None < seizure/month >= seizure/month Enteric Coated Depakine Chrono % 7.9%.% Fairly/very well controlled poorly controlled Enteric Coated Depakine Chrono Sig. Diff. in seizure frequency between Enteric Coated & Depakine Chrono, p<.5 Sig. Diff. in seizures control between Enteric Coated & Depakine Chrono, p<.5 A MULTINATIONAL, OBSERVATIONAL STUDY OF THE EFFECTIVENESS AND TOLERABILITY OF FIRSTLINE MONOTHERAPY WITH SODIUM VALPROATE IN FOCAL EPILEPSY 5():667, 8. 8

9 Study design V.I.P.e Valproate In Partial epilepsy V V V V Baseline 6 weeks months 6 months Study dates: Study period: 6 months (or months*) for each patient * Study period was chosen by participating countries 5():667, 8. Croatia Czech Republic India Korea Lebanon Malaysia Poland Portugal Romania Russia Slovenia South Africa Taïwan Thailand Morocco Tunisia Participating countries N=989 patients Study objective Observational, openlabel, multinational prospective study To assess the safety and efficacy of sustainedreleased valproate (Depakine Chrono ) used as first monotherapy in a cohort of patients newly or recently diagnosed with partial epilepsy To assess efficacy according to the type, aetiology and topographic localisation of partial seizures Inclusion criteria Adults and children over six years Male or female (in women of childbearing potential, the patients practicing efficient contraception) Patient newly or recently diagnosed with partial epilepsy with or without secondary generalized seizure and requiring a first antiepileptic treatment Patients able to complete the patient s diary seizure card and to follow the study procedures 5():667, 8. 5():667, 8. Inclusion criteria Patients requiring a first monotherapy treatment for partial epilepsy and who may benefit from the use of valproate Patients who reported at least partial seizures with or without secondary generalisation during the previous 6 months Patients or his / her legal representative (for children) signed the informed consent form after the nature of the study has been fully explained (if required by local regulations) Exclusion criteria according to the local SmPC Patients with: Acute or chronic hepatitis, personal or family history of hepatitis Hypersensitivity to valproate Hepatic porphyria History of non epileptic seizures Active CNS infection, demyelinating disease, any CNS disease deemed to be significantly progressive during the course of the study (low grade brain tumor can be included) History of drug or alcohol abuse Patients who: Are pregnant/ trying to become pregnant or who are lactating Have taken investigational drug within days prior to first visit 5():667, 8. 5():667, 8. 9

10 Evaluation criteria Primary efficacy endpoint remission rate: proportion of seizurefree patients at 6 months Safety spontaneous reporting of adverse events adverse events leading to drop out Evaluation criteria Secondary efficacy endpoints retention rate: proportion of patients who completed the 6month study Clinical Global Impression dose to reach maximal efficacy according to the age range efficacy according to type, aetiology, topographic localisation and age of the patient 5():667, 8. 5():667, 8. Patient flow diagram Patients included N=5 ITT population N=989 Untreated subjects: 6 Loss to followup: 75 Lack of efficacy: 6 Adverse events: Poor compliance: Patient characteristics Sex ratio (men/women/missing data) Mean age (years) Mean duration of epilepsy (months) 5.5% / 5.% /.%.5 +/ / 9.5 Other: Completed 6 months patient was not taken into account in the statistical analysis (no ICF) % of the patients were children 5 years N= 88 5():667, 8. 5():667, 8. Clinical patient characteristics Simple Partial (SP) Complex Partial (CP) Secondary Generalized TonicClonic (SGTC) SP + CP SP + SGTC CP + SGTC SP + CP + SGTC Not determined Idiopathic Symptomatic Cryptogenic Not Determined Missing data Temporal Extratemporal Temporal + extratemporal Not Determined Type of Seizure (n %) Aetiology (n %) Localisation (n %) 8 9,%,%,7% Missing data,% 5():667, ,5%,7% 6,5%,5%,%,% 7,%,% 9,7%,% 8,% 6,8%,%,7% Mean daily dose of sustainedrelease valproate Patients Seizure Type SP seizures CP seizures SGTC seizures SP + CP seizures SP + SGTC seizures CP + SGTC seizures SP + CP + SGTC seizures SP simple partial, CP complex partial, SGTC secondary generalised tonic clonic n Mean daily dose (mg/d) ():667, 8.

11 High rates of remission at six months by type of epileptic seizures High rates of remission at six months by aetiology of seizures Primary efficacy rate of remission by type of epileptic seizures Primary efficacy rate of remission by aetiology of seizures remission rate 9,% 8,% 7,% 6,% 5,% 8,%,% 7,5% 8,% 78,% 77,% 66,% 69,%,% 5,%,%,%,%,% SP CP SGTC SP + CP SP + CP + SP + CP + Not TOTAL n=8 n= n=57 n=8 SGTC SGTC SGTC determined n= n= n=9 remission rate 9,% 8,% 7,% 6,% 5,%,%,%,%,%,% 8,% 77,% 7,% 77,% 7,% Idiopathic Symptomatic Cryptogenic Not Detemined TOTAL n=68 n=78 n=8 n=95 5():667, 8. 5():667, 8. Seizure free rate improved over the 6month period remission rate % 9% 8% 7% 6% 5% % % % % % At months At months At 6 months 5 years old (n=79) > 5 years old (n=9) High retention rates and marked improvement in CGI scale SEIZURE OUTCOME Retention Rate (%) Neurological exam CLINICAL GLOBAL IMPRESSION Improvement Marked Unchanged or worsened Side effects None 5 years (N = 79) 9. [9. 9.9] 9.6% normal 66 (89.%) 9 (.%) 67 (9.6%) Age group > 5 years (N = 9) 88.7 [ ] 85.% normal 98 (8.9%) 7 (.6%) 98 (89.6%) Total (N = 989) 9. [ ] 87.5% normal 57 (85.%) 6 (.9%) 658 (9.%) 5():667, 8. 5():667, 8. Overall good safety profile All adverse events Leading to treatment discontinuation Severity Mild Moderate N of subjects with AEs 5 (.%) (.7%) 6 (6.8%) 7 (5.%) N of subjects with SAEs 5 (.8%) (.%) (<.%) 5 (.%) Conclusion Efficacy Overall high remission rates at six months 77% in patients with focal epilepsy Severe Individual AEs Weight gain 6 (.8%) 5 (.6%) 9 (.5%) High 9% treatment retention Alopecia Nausea Vomiting Tremor Somnolence (.%) (.%) (.%) (.%) (.6%) (<.%) Safety Overall good safety of the treatment Dizziness (.6%) Headache (.6%) AE adverse event, SAE serious adverse event (<.%) 5():667, 8. CGI Clinical Global Impression 5():667, 8.

12 SUSTAINED RELEASE SODIUM VALPROATE IS EFFECTIVE AND SHOWS OVERALL GOOD TOLERABILITY AS FIRSTLINE MONOTHERAPY IN FOCAL EPILEPSY Good Quality of Life 5():667, 8.