1. 1 Post Marketing Plan Earl Sands, M.D. Vice President and Chief Medical Officer US Research and Development Solvay Pharmaceuticals Earl Sands, M.D. Vice President and Chief Medical Officer US Research and Development Solvay Pharmaceuticals

2. 2 Post Marketing Plan Agenda RiskMAP PULZIUM ® Observational Study – “POST”

3. 3 RiskMAP Development Inclusion of multiple stakeholders in US and EU –Physicians, nurses and pharmacists Pretesting via user panels in US and EU –Iterative process; revisions made based on feedback Objective: to provide the optimal benefit/risk balance for tedisamil by ensuring product use consistent with prescribing information –Minimizing risks –Preserving benefits

4. 4 RiskMAP Objectives Align usage with the label Appropriate clinical setting (ECG monitoring and staff training) Appropriate patient selection Correct dose and administration Monitoring for a minimum of 2 hrs from the start of infusion and until QTc becomes normal

5. 5 Risks to be Minimized As with all antiarrhythmic drugs, tedisamil use has risks –Torsade de Pointes –Bradycardia –Hypotension These risks can be minimized by addressing the potential contributory factors/causes: –Miscalculation/misadministration of dose

6. 6 RiskMAP Tools Labeling –Comprehensive, first line of risk communication –Gender-specific, detailed height and weight-based dosing chart Targeted education and outreach –A number of tools will be used in educating physicians and HCPs, which also have a reminder function and are therefore listed in the section below –HCP website Reminder systems – Physician checklist – Infusion bag stickers – Arrhythmia diagnostic guide – QTc guide – Dose guide and calculator – Administration and monitoring guide

7. 7 Selected RiskMAP Tools

8. 8 Gender-specific Dosing Charts Separate charts for males and females, which provide dose volume based on weight and height Height Weight Height Weight

9. 9 Outline of the Two-Bag Regimen Pump 3-way-cock Infusion: Step1: Infuse Bag 1 at 10 ml / min over 10 min Step 2: Infuse Bag 1 at 5 ml / min over 20 min Bag 2 100 ml 20 min Bag 1 100 ml 10 min

10. 10 Multiplicity of RiskMAP Tools Risk Minimizing Tool Risk Physicia n checklist Infusio n bag sticker Arrhythmi a diagnostic guide Dose guide QTc guide HCP admin & monitoring guide HCP websit e Torsade de Pointes Ventricular tachycardia and bradycardia Miscalculation of dose by weight, height or gender Impaired electrolyte conditions, e.g. diarrhea Drug-drug interactions and CYP2D6 inhibition Use in severely renally-impaired patients Hypertension and hypotension

11. 11 Post Marketing Plan Earl Sands, M.D. Vice President and Chief Medical Officer US Research and Development Solvay Pharmaceuticals Earl Sands, M.D. Vice President and Chief Medical Officer US Research and Development Solvay Pharmaceuticals

12. 12 Post Marketing Plan Agenda RiskMAP PULZIUM ® Observational Study – “POST”

13. 13 RiskMAP Development Inclusion of multiple stakeholders in US and EU –Physicians, nurses and pharmacists Pretesting via user panels in US and EU –Iterative process; revisions made based on feedback Objective: to provide the optimal benefit/risk balance for tedisamil by ensuring product use consistent with prescribing information –Minimizing risks –Preserving benefits

14. 14 RiskMAP Objectives Align usage with the label Appropriate clinical setting (ECG monitoring and staff training) Appropriate patient selection Correct dose and administration Monitoring for a minimum of 2 hrs from the start of infusion and until QTc becomes normal

15. 15 Risks to be Minimized As with all antiarrhythmic drugs, tedisamil use has risks –Torsade de Pointes –Bradycardia –Hypotension These risks can be minimized by addressing the potential contributory factors/causes: –Miscalculation/misadministration of dose

16. 16 RiskMAP Tools Labeling –Comprehensive, first line of risk communication –Gender-specific, detailed height and weight-based dosing chart Targeted education and outreach –A number of tools will be used in educating physicians and HCPs, which also have a reminder function and are therefore listed in the section below –HCP website Reminder systems – Physician checklist – Infusion bag stickers – Arrhythmia diagnostic guide – QTc guide – Dose guide and calculator – Administration and monitoring guide

17. 17 Selected RiskMAP Tools

18. 18 Gender-specific Dosing Charts Separate charts for males and females, which provide dose volume based on weight and height Height Weight Height Weight

19. 19 Outline of the Two-Bag Regimen Pump 3-way-cock Infusion: Step1: Infuse Bag 1 at 10 ml / min over 10 min Step 2: Infuse Bag 1 at 5 ml / min over 20 min Bag 2 100 ml 20 min Bag 1 100 ml 10 min

20. 20 Multiplicity of RiskMAP Tools Risk Minimizing Tool Risk Physicia n checklist Infusio n bag sticker Arrhythmi a diagnostic guide Dose guide QTc guide HCP admin & monitoring guide HCP websit e Torsade de Pointes Ventricular tachycardia and bradycardia Miscalculation of dose by weight, height or gender Impaired electrolyte conditions, e.g. diarrhea Drug-drug interactions and CYP2D6 inhibition Use in severely renally-impaired patients Hypertension and hypotension

21. 21 PULZIUM ® Observational Study – “POST” A prospective observational study –1200 - 2000 patients –demographic, prescribing and adverse event data –120 geographically diverse sites The aim of the study would be to generate real-world benefit/risk data on tedisamil –detailed, real-time safety data –evaluating safety and efficacy in ethnic minorities, i.e. African-Americans, Hispanics, etc. –evaluating the success of the RiskMAP as a whole

22. 22 PULZIUM ® Observational Study The study would be under the auspices of an independent DSMB Data evaluated quarterly and every 300 treated patients Periodic and real-time updates to FDA as necessary to meet the new REMS criteria* *Source: Title II FDA Revitalization Act. Subtitle A – Risk Evaluation and Mitigation Strategy (from http://help.senate.gov/minpress/2007_04_18 accessed on 9-12-07http://help.senate.gov/minpress/2007_04_18

23. 23 Post Marketing Plan Conclusions Targeted interventions to address known risks Key objective – aligning usage with label Proactive, comprehensive program –Built-in redundancy to improve effectiveness Consistent with existing clinical practice Sponsor is committed to evaluation and program revision, as needed Robust observational study to reinforce a positive benefit/risk profile