1. Be free Epilim® takes care of epilepsy. Life takes care of itself. Bob Peter Okello PAN AFRICAN ASSOCIATION OF NEUROLOGICAL SCIENCE CONGRESS Aficana Hotel Kampala 7 th June, 2016

2. SANOFI AND NEUROLOGY Belief that Epilepsy is still a public health concern Epilepsy not well understood-stigma Treatment areas not well understood. Will not define epilepsy-share experiences with Epilim Epilim-Gaba-transaminase inhibitor Epilim satisfies most of the medical epilepsy treatment goals  Achieve Seizure free status  Monotherapy preferably  Tolerability of treatment of choice  Aspect of social and vocational rehabilitation

3. CONSTANT PROOF OF EFFICACY 1994 1985 1967 Carraz et al. First clinical trial to demonstrate VPA efficacy in seizures 1 Turnbull et. al. First large randomized study showing efficacy of VPA in generalized seizures 2 Richen et. al. Large randomized Study showing equal efficacy of VPA and CBZ, irrespective of seizure type 3 Ref: 1. Carraz G, Fau Chateau R et al. Ann Med Psychol.(Paris) 1964;122(Tome 2):557-584 2. Turnbull DM, Howel D, Rawlins MD et al. Br. Med J(Clin Res Ed.) 1985;290(6471)815-819 3.Richens A, Davidson DL, Cartridge NE et al. J Neurol. Neurosurg. Psychiatry. 1994;57(6): 682-687 4. De Silva M,MacArdle B, McGowan M, et al. Lancet: 1996; 347 (9003): 709-713 5. Marson AG, Al-Kharusi AM, Alwaidh M et al. Lancet. 2007 Mar 24; 369 (9566): 1016-1026 6. Jedrzejczak J, Kunikova, M Magureanu S. Eur J Neurol 2008, 15:66-72 1996 2007 De Silva et. al. Large long term RCT Comparing VPA,CBZ PHT&PB showed similar Efficacy lower withdrawal for VPA and CBZ 4 Marson AG et. al. SANAD study. E effectiveness of VPA, LTG or TPM for generalized seizures and unclassifiable epilepsy: Unblinded RCT 5 2008 Jedrzejczak J et. al. VIPE study: An observational study of first line VPA monotherapy in partial epilepsy 6 VPA: valporate CBZ: carbamazepine LTG: lamotrigine TPM: topiramate PHT: phenytoin PB: phenobarbital Regardless of seizure type or aetiology * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

4. Epilim®: effective in all types of seizures 5,7 * Monotherapy in children under 12 years is not recommended 9 Epilim® has a broad spectrum of activity across a wide range of seizure types and epilepsy syndromes 7 Atonic seizures Myoclonic seizures Abscence seizures Clonic seizures Tonic seizures Tonic-clonic seizures Partial seizures lamotrigine 9* ≥2yrs topiramate 10 >4yrs phenytoin 11 carbama- zepine 12 Monotherapy allowed only after previous treatment failure Spectrum of indications of anti-epileptic drugs * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

5. Percentage of seizure-free patients 100 90 80 70 60 50 40 30 20 10 0 N= 1192 adults 2 months 3 months 6 months Adapted from Jedrzejczak J, et al. 2008 % of seizure-free adult patients at 2, 3 and 6 months in the intent-to-treat population Epilim® effective first-line in partial seizures 6 Epilim® provides patients the reassurance of seizure freedom as early as 2 months 6

6. Epilim® effective first-line in partial seizures 6 Significant control of seizures 6 High retention rate at 6 months 6 Favourable tolerance profile 6 72.7% 88.7% 10.4% remission rate* at 6 months * proportion of seizure-free subjects during the last 3 months of the study; age group >15yrs retention rate** ** proportion of subjects remaining on treatment at 6 months of the study; age group >15yrs reported side-effects (drug related)

7. Epilim® first choice therapy for generalised and unclassified epilepsies 5 Epilim® is more effective than lamotrigine and topiramate in patients with generalised and unclassified epilepsy 5 % 12-month remission - per protocol population EPILIM® lamotrigine topiramate Percentage of 12-month remission 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 Time from randomisation (years) Adapted from Marson, et al. 2007 *The SANAD Study * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

8. Probability of remaining on drug EPILIM® lamotrigine topiramate 1.0 0.8 0.6 0.4 0.2 0 Time from randomisation 1 2 3 4 5 6 Adapted from Marson, et al. 2007 Epilim® first choice therapy for generalised and unclassified epilepsies 5 “Epilim® should remain the drug of first choice for many patients with generalised and unclassified epilepsies” 5 p= 0.006 Time to treatment failure for any reason *The SANAD Study 5 *Standard And Newer Antepileptic Drugs * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

9. Epilim® is effective & shows acceptable tolerability as first-line monotherapy in partial epilepsy 1st-line treatment Endorsed first-line monotherapy 14 For all seizure types and most epilepsy syndromes * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

10. Tiagabine Vigabatrin Carbamazepine Gabapentin Oxcarbazepine Tiagabine Vigabatrin Carbamazepine Gabapentin Oxcarbazepine Tiagabine Vigabatrin Carbamazepine Oxcarbazepine Carbamazepine Oxcarbazepine Phenytoin 1st-line Drugs to be avoided (may worsen seizures) Generalised Tonic-clonic Absence Myoclonic Tonic Atomic Focal with/without Secondary generalisation Seizure type Recommended for first-line treatment regardless of seizure type NICE Guidelines 2012 14 * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

11. Epilim® effective first-line for the treatment of partial epilepsy in children 6 Demonstrates significant efficacy 6 remission rate* at 6 months * proportion of seizure-free subjects during the last 3 months of the study; age group ≥ 15yrs High retention rate at 6 months 6 retention** rate ** proportion of subjects remaining on treatment at 6 months of the study ; age group ≥ 15yrs Epilim® is effective & shows acceptable tolerability as first-line monotherapy in partial epilepsy 6 92.0%83.7% * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

12. * A survey on paediatric epilepsy and seizures completed by 42 European physicians specialising in paediatric epilepsy Epilim® is the gold standard anti-epileptic drug for the treatment of children 7 Treatment selection for benign childhood epilepsy with centro-temporal spikes 13 Treatment selection for cryptogenic complex partial seizures 95% Confidence Intervals (correlated to the length of rectangles) Usually not appropriate Equivocal Usually appropriate N carbamazepine oxcarbazepine EPILIM® lamotrigine 1 2 3 4 5 6 7 8 9 Paediatric epilepsy survey rating evaluation scale 41 42 95% Confidence Intervals (correlated to the length of rectangles) Usually not appropriate Equivocal Usually appropriate N EPILIM® Carbamazepine oxcarbazepine 1 2 3 4 5 6 7 8 9 Paediatric epilepsy survey rating evaluation scale 42 41 *Opinion European 13Dec 2007 Expert * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

13. OpinionEuropean 13Dec 2007Expert A survey on paediatric epilepsy and seizures completed by 42 European physicians specialising in paediatric epilepsy Paediatric epilepsy survey rating evaluation scale 1 2 3 4 5 6 7 8 9 95% Confidence Intervals (correlated to the length of rectangles) Usually not appropriate Equivocal Usually appropriate N Childhood EPILIM® ethosuximide lamotrigine 42 Treatment selection for absence epilepsy 13 Paediatric epilepsy survey rating evaluation scale 1 2 3 4 5 6 7 8 9 95% Confidence Intervals (correlated to the length of rectangles) Usually not appropriate Equivocal Usually appropriate N EPILIM® Lamotrigine Levetiracetam Topiramate clobazam clonazepam 40 39 40 Treatment selection for myoclonic and generalised tonic-clonic Seizures 13 Epilim® is the gold standard anti-epileptic drug for the treatment of children7 * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

14. Epilim ® is recommended as first-line treatment of epilepsy syndromes 7 Epilepsy/syndrome Usual first-line drug Infantile spasms-west syndrome Severe myoclonic epilepsy of infancy - Dravet syndrome IGE with absences Epilepsy with CSWS Lennox-Gastut and related syndrome IGE with myoclonus with or without GTCS IGE with myoclonus with GTCS Focal epilepsy Undetermined epilepsy CSWS= Continous Spikes and Waves during Sleep; GTCS=Generalised Tonic-Clonic Seizures; IGE= Idiopathic Generalised Epilepsy Vigabatrin, corticosteroids Epilim ®, topiramate Epilim ®, ethosuximide Epilim ®, Epilim ® + lamotrigine Epilim ® Epilim ®, carbamazepine Epilim ® * except Status epilepticus * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

15. Indicated for all seizure types* Does not cause clinically significant cardiac or respiratory depression Does not cause irritation at site of injection Injectable in less than 5 minutes Generally linear pharmacokinetics, offering a more predictable stable profile Continuous infusion may be used, when repeated doses are needed * except Status epilepticus Epilim ® IV vs. phenytoin IV

16. Epilim® IV represents an effective alternative to phenytoin in all seizure emergency situations with no evidence of sedation, cardiorespiratory disturbances and hypotension 15 N = 102 patients; initial Epilim® IV bolus dose varied between 4-16 mg/kg, depending on the severity of the condition, with 74% of patients receiving 15-16 mg/kg, admin. 5-10 mins followed by a continuous infusion of 0.5-4.0 mg/kg/h maintenance dose within 2 hrs to 10 days Series of seizures Change of medication/IV switch 85.3% 96.0% Percentage of pts with termination of seizures 0 10 20 30 40 50 60 70 80 90 100 Epilim® IV is effective therapy in seizure Emergency situations 15

17.  Epilim® has over 45 years of clinical experience in millions of patients worldwide 1   Epilim® is distinguished by its broad spectrum of efficacy against seizures 7   Epilim® remains the mainstay for treatment of epilepsy in all age groups 7   Epilim® is the gold standard AED for the treatment of children 7   Epilim® has a low risk of causing paradoxical seizure aggravation 7 * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

18. Epilim® Adult Dosing Guidelines8 Epilim® should preferably be taken with or after food The tablets should be swallowed whole and not crushed or chewed, and not taken with aerated mineral water Epilim® Chrono is a controlled-release formulation and may be given once or twice daily *Increasing by 200 mg/day at 3 day intervals until control is achieved. Maximum dose is 2500mg /day 600 mg/day* Starting dose * Epilim® Adult Dosing Guidelines 8 * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

19. Initial dose: 400 mg/day, irrespective of body mass 20-30 mg/kg/day given in divided doses 20 mg/kg/day given in divided doses Epilim® Paediatric Dosing Guidelines 8 Weight (kg) Average Daily Dose In mg 400 to 600 mg 5 40 Children 20 kg and over Children under 20 kg Weight (kg ) Average Daily Dose In mg In ml 15 100 mg 2.5 ml 300 mg 7.5 ml 20 800 to 1200 mg 10 20 200 mg 5 m l 400 mg 10 m l

20. 1.Reconstitute with the solvent provided 2. Loading Dose: 400-800 mg IV over 3-5 minutes 3. Maintenance Dose: continuous or repeated infusion up to a maximum of 2 500 mg/day Epilim® IV Dosage Guidelines 8 * Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.

21. IMPORTANT  Children exposed in utero to valproate are at a high risk of serious developmental disorders (in up to 30-40% of cases) and/or congenital malformations (in approximately 10% of cases).  Valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.  Valproate treatment must be started and supervised by a doctor experienced in managing epilepsy or bipolar disorder.  Carefully balance the benets of valproate treatment against the risks when prescribing valproate for the rst time, at routine treatment reviews, when a female child reaches puberty and when a woman plans a pregnancy or becomes pregnant.  Prescriber must ensure that all female patients are informed of and understand: - risks associated with valproate during pregnancy; - need to use eective contraception; - need for regular review of treatment; - the need to rapidly consult if she is planning a pregnancy or becomes pregnant.

22. REFERENCES: Abbreviated Prescribing Information. Please read full package insert carefully before prescribing. Epilim® REGISTRATION NUMBERS: Epilim® Liquid Sugar-free: J/2.5/148; Epilim® CR 200: 27/2.5/0322; Epilim® CR 300: Y/2.5/286; Epilim® CR 500: 27/2.5/0323; Epilim® 100 Crushable: 27/2.5/0500. Epilim® Intravenous: Y/2.5/43;Water for Injection - Epilim®: Y/34/156. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION: sanofi-aventis south africa (pty) ltd., sanofi- aventis House, 2 Bond Street, Midrand, 1685. ZASE.VPA.13.10.02 1. Carraz G, Fau R, Chateau R, et al. Ann Med Psychol (Paris) 1964;122(Tome 2):577-584.2. Turnbull DM, Howel D, Rawlins MD, et al. Br Med J (Clin Res Ed) 1985; 290(6471): 815- 819. 3). Richens A, Davidson DL, Cartlidge NE, et al. J Neurol Neurosurg Psychiatry 1994; 57(6): 682-687. 4. De Silva M, MacArdle B, McGowan M, et al. Lancet 1996;347(9003):709-713. 5. Marson AG, et al. The SANAD Study of Effectiveness of Valproate, Lamotrigine, or Topiramate for Generalised & UnclassifiableEpilepsy: An Unblinded Randomised Controlled Trial. The Lancet 2007;369:1016-26. 6. Jedrzejczak J, et al. An Observational Study of First-line Valproate Monotherapy in Focal Epilepsy. Eur Jnl of Neurology 2008(15): 66-72. 7. Guerrini R, et al. Paediatric Drugs. 2006;8(2):113-129. 8. Epilim® Package Insert; sanofi-aventis south africa (Pty) Ltd. 9. Lamotrigine Package Insert; GlaxoSmithKline South Africa (Pty) Ltd. 10. Topiramate Package Insert; Janssen Pharmaceutica (Pty) Ltd. 11. Phenytoin Package Insert; Pfizer Laboratories (Pty) Ltd. 12. Carbamazepine Package Insert; Novartis South Africa (Pty) Ltd. 13. Wheless JW, et al. Treatment of Paediatric Epilepsy: European Expert Opinion 2007. Epileptic Disorders 2007;9:S1-S62. 14. National Institute for Clinical Excellence (NICE) Clinical Guideline 20. The Epilepsies: The Diagnosis and Management of Epilepsies in Adults and Children in Primary and Secondary care. October 2004. (www.nice.org.uk/CG020NICEguideline).www.nice.org.uk/CG020NICEguideline 15. Peters CNA, et al. IV Valproate as an Innovative Therapy in Seizure Emergency Situations Including Status Epilepticus Experience in 102 Adult Patients. Seizure 2005(1):164-169. 16. Morton LD, et al.Treatment Options for Acute Seizure Acre. CNS Drugs 1998;10(6)405-416.