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Safety Population

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Safety Population

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  1. Certican (everolimus) tabletsProphylaxis of Rejection in Heart TransplantationNew Drug Application 21-628Cardiovascular and Renal Drugs Advisory Committee November 16, 2005Clinical Safety ReviewArturo Hernandez, M.D. Marc Cavaille-Coll, M.D., Ph.D.Division of Special Pathogen and Transplant ProductsCenter for Drug Evaluation and ResearchFood and Drug Administration

  2. Safety Population • All subjects who received at least one dose of study medication: RAD* 1.5 mg, n=209; RAD 3 mg, n=211; AZA, n=214. • Adverse events were reported while subjects were still on study medication, serious adverse events while subjects were still on study medication and up to 30 days after discontinuation. *RAD = Certican (everolimus)

  3. Targeted and Achieved Trough Cyclosporine Concentrations in Study B253

  4. Concomitant Administration of Immunosuppressive Agents Other than Randomized Study Medication and Neoral by WHO Preferred Drug Name(ITT Population - 24 Month Analysis)

  5. Premature Discontinuation from Study Medication (Safety population - 12 and 24 Month Visits)

  6. Patients Who Discontinue Study Medication(24 Months, Safety Population)Study B253

  7. Dose Reductions from Study Medication (Safety Population - 24 months analysis)

  8. Post Heart Transplant Morbidity in the Safety Population • Morbidity associated with immunosuppression: infections, pneumonia • Morbidity potentially associated with antiproliferative effect of mTOR inhibition: wound site complications, gastrointestinal hemorrhage, bone marrow effects, lymphocele, pericardial and pleural complications. • Morbidity potentially associated with the concurrent use of mTOR inhibitors and cyclosporine: lipid abnormalities, HUS, renal function impairment.

  9. Infections: Safety Population - 24 Month Analysis

  10. Pneumonias (Safety Population - 24 Month Analysis) *DAE=discontinued due to AE (adverse event) **NSAE=non-fatal SAE (serious adverse event)

  11. Wound Site Related Complications (Safety Population - 24 Month Analysis)

  12. Pericardial Complications(Safety Population - 24 Month Analysis)

  13. Gastrointestinal Hemorrhage (Safety Population - 24 Month Analysis) * One patient died from this cause

  14. Hematological Toxicities(Safety Population - 24 Month Analysis)

  15. 13 12.5 12 Hemoglobin g/dL 11.5 11 10.5 10 9.5 0 3 6 9 12 15 18 21 24 Months Post-transplantation Mean Hemoglobin [g/dL] and Mean Leukocyte count [10^9 /L] by Visit (Safety Population - 24 Month Analysis)

  16. Lipid AbnormalitiesMean Triglycerides and Cholesterol [mmol/L] by Visit (Safety Population - 24 Month Analysis)

  17. Mean Cockcroft-Gault Calculated Creatinine Clearance Study B253 (Safety Population - 24-Month Analysis)

  18. Mean Cockcroft-Gault calculated Creatinine Clearance Study B253 (Safety Population - 24-Month Analysis)

  19. Estimated Mean Creatinine Clearance (mL/min) Change from Baseline (Safety Population - 24 Month Analysis)

  20. Study B253 and ISHLT Registry Data Percentage of Patients with Creatinine  2.5 mg/dL

  21. Summary / Conclusions • The impact of full dose cyclosporine plus everolimus on renal function impairment was early and persistent, and may not be reversible if renal toxicity is sustained for a period of time sufficient to allow irreversible changes to take place. • Complications potentially related to antiproliferative effects of everolimus such as wound healing problems, pericardial complications and gastrointestinal bleeding were also more common in the everolimus arms.

  22. Summary / Conclusions • Pneumonias were more frequently observed in the everolimus arms. • Dyslipidemias occurred early or worsen after drug exposure and persisted despite the use of statins and attempts to optimize lipid lowering therapy.

  23. Summary / Conclusions • Overall, the potential risks associated with the use of the everolimus-cyclosporine combinations studied in B-253 were felt to outweigh the potential benefits. • There is a need to develop regimens that could minimize these toxicities while providing adequate protection against allograft rejection.

  24. Lipid AbnormalitiesMean Low Density Lipoprotein [mmol/L] by Visit(B-253 Safety Population - 24 Month Analysis)

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