# Presentation: 690124

## Certican (everolimus) tabletsProphylaxis of  Rejection in Heart TransplantationNew Drug Application 21-628 Cardiovascular and Renal Drugs Advisory Committee November 16, 2005Clinical Safety ReviewArturo Hernandez, M.D. Marc Cavaille-Coll, M.D., Ph.D.Division of Special Pathogen and Transplant ProductsCenter for Drug Evaluation and ResearchFood and Drug Administration 

## 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)**

## Targeted and Achieved Trough Cyclosporine Concentrations in Study B253

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

|  | RAD 1.5  
(n=209) | RAD 3
(n=211) | AZA
(n=214) |
| --- | --- | --- | --- |
| Methylprednisolone
      Total | 160 (76.5%) | 142 
(67%) | 170 (79%) |
| Antibody Therapy
     Total | 86
(41%) | 83 
(39%) | 95 
(44%) |

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

|  |  | RAD 1.5
(n=209) | RAD 3
(n=211) | AZA
(n=214) |
| --- | --- | --- | --- | --- |
| 12 month visit 
Time window: 312 - 415 days

Adverse events |  | 62
 (29.7%)
33
(53.2%) | 84 
(39.8%)
46
(54.8%) | 61 
(28.5%)
28
(45.9%)
 |
| 24 month visit
Time window: up to 810 days |  | 82
 (39.2%) | 104
 (49.3%) | 83 
(38.8%) |
|   | Adverse events | 43
 (52.4%) | 58 
(55.8%) | 40 
(48.2%) |

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

| Reason for Discontinuation from Study Medication | RAD 1.5 mg 
(n=209) | RAD 3 mg
(n=211) | AZA
(n=214) |
| --- | --- | --- | --- |
| Adverse events | 43 (52%) | 58 (56%) | 40 (48%) |
| Abnormal laboratory value(s) | 9 (11%) | 18 (17%) | 10 (12%) |
| Unsatisfactory therapeutic effect | 15 (18%) | 3 (3%) | 18 (22%) |
| Withdrawn consent | 6 (7%) | 11 (11%) | 3 (4%) |
| Death | 7 (5%) | 9 (9%) | 7 (8%) |
| Total Discontinuation 
from Study Medication | 82 (39%) | 104 (49%) | 83 (39%) |

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

|  |  | RAD 1.5 mg 
(n= 209) | RAD 3 mg 
(n=211) | AZA
(n=214) |
| --- | --- | --- | --- | --- |
| Any Dose Reduction Total  |  | 121
(58%) | 134
(64%) | 112
(52%) |
|   | Adverse Event | 56
(26.8%) | 68
(32.2%) | 20
(9.3%) |
|   | WBC Abnormality  | 51
(24.4%) | 58
(27.5%) | 71
(33.2%) |
|   | Platelet Abnormality | 22
(10.5%) | 25
(11.8%) | 3
(1.4%) |

## 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.**

## Infections: Safety Population - 24 Month Analysis

| Type of Organism or preferred term |  | RAD 1.5 
(n=209) | RAD 3
(n=211) | AZA
(n=214) |
| --- | --- | --- | --- | --- |
| Any Infection |  | 160
 (77%) | 169
 (80%) | 154
 (72%) |
| Bacterial |  | 78 (37%) | 85 (40%) | 55 (26%) |
| Fungal |  | 18 (9%) | 27 (13%) | 19 (9%) |
| Viral |  | 34 (16 %) | 39 (19%) | 69 (32%) |
|  | CMV  infection | 15 (7%) | 15 (7%) | 45 (21%) |
|  | Herpes simplex | 17 (8%) | 12 (6%) | 23 (11%) |

##  Pneumonias (Safety Population - 24 Month Analysis)

| Preferred Term | RAD 1.5 mg
 (n=209) | RAD 3 mg
(n=211) | AZA
(n=214) |
| --- | --- | --- | --- |
| Pneumonia  NOS (AE) | 29 (14%) | 20 (10%) | 6 (3%) |
| Bacterial pneumonia (AE) | 12(6%) | 9 (4%) | 3 (1%) |
| All types of pneumonia (AE) | 47 (23%) | 38 (18%) | 11 (5%) |
| Pneumonia (Severe ) | 13 (6%) | 21 (10%) | 4 (2%) |
| Pneumonia  (DAE*) | 1 (0.5%) | 6(3%) | 2 (1%) |
| Pneumonia  (NSAE**) | 33 (16%) | 36 (17%) | 11(5%) |

***DAE=discontinued due to AE (adverse event)**
****NSAE=non-fatal SAE (serious adverse event)**

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

| Preferred Term | RAD 1.5 
(n= 209) | RAD 3
(n=211) | AZA
(n=214) |
| --- | --- | --- | --- |
| Wound infection
	(AE) | 
15 (7%) | 
11 (5%) | 
6 (3%) |
| 	(NSAE) | 9 (4%) | 7 (3%) | 5 (2%) |
| Wound dehiscence / wound complication NOS (NSAE) | 4 (2%) | 5 (2%) | 1(0.5%) |
| Incisional hernia nos (AE) | 9 (4%) | 8 (4%) | 3 (1%) |
| Lymphocele 
	(AE) | 
10 (5%) | 
9 (4%) | 
2 (1%) |
| 	(NSAE) | 2 ( 1.0%) | 3 (1.4%) | 0 |
| Pleural Effusion (NSAE) | 4 ( 2%) | 9 (4%) | 2 ( 1%) |

## Pericardial Complications(Safety Population - 24 Month Analysis)

| System Organ Classification or Preferred Term | RAD 1.5 
(n= 209) | RAD 3
(n=211) | AZA
(n=214) |
| --- | --- | --- | --- |
| Pericardial effusion
     (AE) | 
48 (23%) | 
49 (23%) | 
36 (17%) |
|      (NSAE) | 22 (11%) | 16 (8%) | 6 (3%) |
| Cardiac tamponade 
     (AE) | 
6 (3%) | 
10 (5%) | 
3 (1%) |
|      (NSAE) | 4 (2%) | 9 (4%) | 3 (1%) |
| Pericarditis* (NSAE) | 2 (1%) | 5 (2%) | 2 (1%) |
| Mediastinitis (NSAE) | 5 (2%) | 6 ( 3%) | 3 (1%) |

## Gastrointestinal Hemorrhage (Safety Population - 24 Month Analysis)

| Preferred Term | RAD 1.5 
(n=209) | RAD 3
(n=211) | AZA
(n=214) |
| --- | --- | --- | --- |
| GI  HEMORRHAGE  TOTAL (AE) | 7 (3%) | 16 (8%) | 4 (2%) |
| Gastrointestinal hemorrhage NOS
    (AE) | 
2 (1 %) | 
9 (4%) | 
3 (1%) |
|     (NSAE) | 2 (1.0%) | 5 (2.4%) | 1 (0.5%) |
|     (DAE) | 0 | 3 (1%)* | 0 |
| Gastric ulcer hemorrhage and Hemorrhagic Gastritis 
     (AE) | 

3 (1%) | 

4 (2%) | 

0 |
|      (NSAE) | 2 | 1 | 0 |

- * One  patient died from this cause

## Hematological Toxicities(Safety Population - 24 Month Analysis)

| Preferred Term | RAD 1.5 
(n=209) | RAD 3
(n=211) | AZA
(n=214) |
| --- | --- | --- | --- |
| Anemia NOS 
           AE  | 
70 (34%) | 
93 (44%) | 
58 (27%) |
|            DAE | 0 | 5 (2%) | 1 (0.5%) |
|            NSAE | 6 (2.9%) | 17 (8%) | 8 (4%) |
| Leukopenia NOS 
            AE  | 
43 (21%) | 
44 (21%) | 
63 (29%) |
|             DAE | 4 (2%) | 5 (2%) | 7 (3%) |
|             NSAE | 1 (0.5%) | 4 (2%) | 5 (2%) |
| Thrombocytopenia 
           AE  | 
21 (10%) | 
37 (18%) | 
16(8%) |
|            DAE  | 1 (0.5%) | 4 (2%) | 1 (0.5%) |
|            NSAE  | 1 (0.5%) | 1 (0.5%) | 0 |

## Mean Hemoglobin [g/dL] and Mean Leukocyte count [10^9 /L] by Visit (Safety Population - 24 Month Analysis) 

## Lipid AbnormalitiesMean Triglycerides and Cholesterol [mmol/L] by Visit (Safety Population - 24 Month Analysis)

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

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

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

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

## 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.**

## 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.**

## 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.**

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