# Presentation: 714145

## CRESTOR® (ZD4522, rosuvastatin calcium) TABLETSAstraZenecaNew Drug Application (21-366) 

**Endocrinologic & Metabolic Drugs **
**Advisory Committee Meeting**
**William Lubas M.D., Ph.D.**

**Center for Drug Evaluation and Research**** **

## Issues to be addressed by the Advisory Committee

**Safety**
**Dosing**

## Statin associated muscle toxicity

**CK elevations**
**Myopathy **
**(CK>10xULN & Muscle Symptoms)**
**Rhabdomyolysis **
**(Clinical Diagnosis)**

## Incidence of CK elevations and myopathy seen in phase II/III

**Data from Tables 10, 11 FDA briefing packet**a

**Baycol**

**Rosuva**

**All marketed STATINS****a**

- (mg)		CK>10xULN		MYOPATHY
- 					(all cases)
- 0.4		1.6%			1.0-1.6%
- 0.8		2.1%			0.9-1.0%
- Pbo		0%			0%
- 5		0.4%			0.2%
- 10		0.2%			0.1%
- 20		0.2%			0.1%
- 40		0.4%			0.2%
- 80		1.9%			1.0%
- 5-80		0.03-0.9%		0-0.5%

## % of patients with proteinuria ( ++) at any visit 

- Data from AV_LUBR, i.e. All controlled/Uncontrolled & RTLD Pools

- % of patients

- Simvastatin

- Pravastatin

- Atorvastatin

- Rosuvastatin

- Placebo

- Dietary Run In

- 80

- 40

- 20

- 40

- 20

- 80

- 40

- 20

- 10

- 80

- 40

- 20

- 10

- 5

- 356

- 517

- All Patients
- (n)

- 337

- 67

- 191

- 377

- 245

- 667

- 710

- 1258

- 3578

- 2801

- 5592

- 988

- 372

- 5811

## % of patients with  proteinuria ( ++) by rosuvastatin dose (any visit) subgrouped by Cr change from baseline

- Data from AV_LUBR, i.e. All controlled/Uncontrolled & RTLD Pools, OLE-Open label extension

## % of patients with combined proteinuria ( ++) & hematuria ( +) at any visit subgrouped by Cr change from baseline

- Data from AV_LUBR, i.e. All controlled/Uncontrolled & RTLD Pools, OLE-Open label extension

## Renal adverse events

**2 cases of acute renal failure of unclear etiology after 15-31 days on 80mg dose (Biopsy-ATN)**
**1 case of chronic tubulo-interstitial nephritis after 18 months on 80mg (Biopsy-chronic interstitial inflammatory process, Positive Rechallenge Test)**

## Unanswered renal questions

**Have these renal effects of rosuva been adequately characterized?**
**Is monitoring necessary? At higher doses? (e.g., Cr, Urinalysis)**
**What investigations are needed to better describe the “natural history” of this drug effect?**
**Is this a class effect of statins?  **

## Safety Summary

**The frequency of CK elevations & Myopathy at doses of 40mg or less is similar to other statins**
**The frequency of Cr increase of >30% seen with proteinuria (> ++) is higher in patients at doses of 80mg compared to lower doses**
**The OK cell experimental model does not fully explain the clinical renal effects (e.g., proteinuria, microscopic hematuria, and Cr elevation)**
**Serum rosuvastatin levels above levels normally seen with 40mg may be associated with renal and muscle-related adverse events**

## Issues to be addressed by the Advisory Committee

**Safety**
**Dosing**

## Mean LDL-C (mg/dL) in Type IIA/IIB dyslipidemia Trials 8 and 23 pooled / Week 6 LOCF/ ITT

- Dose	  0	1	2.5	5	10	20	40 (mg)
**BSL**	**194****	****191****	****190****	****191****	****190****	****191****	****185****	**** **
**Final****	****187****	****128****	****115****	****110****	****  95****	****  90****	****  70****	****  **
- %CH	  **-4****	**** -33****	**** -40****	**** -43****	**** -50****	**** -53****	**** -62****	****  **

## Recommended start doses

**Data was taken from current labels for IIA & IIB dyslipidemia not placebo subtracted**

**STATIN****	****	****Dose****	****	****LDL-C **
**	****	****	****	****	****Mean % Change**
- Fluvastatin		20-40mg	- 22% (20mg)
- 					- 25% (25mg)
- Lovastatin		20mg		- 27%
- Pravastatin		40mg 		- 34%
- Simvastatin		20-40mg	- 38% (20mg)
-         (40mg for high risk of CHF)	- 41% (40mg)			Atorvastatin		10 or 		- 39% (10mg)
- 			20mg 		- 43% (20mg)
-     (40mg for pts needing >45%)	- 50% (40mg)
- Rosuvastatin		10-20mg	- 50% (10mg)
- 					- 53% (20mg)

## Mean LDL-C change in statin therapy clinical events trials

**Primary prevention**

**• ****Secondary Prevention**
**	****4S****	****	****	****	****	****-35%**
**	****CARE****	****	****	****	****-32%**
**	****HPS****	****	****	****	****	****-29%**
**	****LIPID ****	****	****	****	****-25%**

**WOSCOPS**	**	****	****   -26%**
**AFCAPS/TexCAPS****	****   -25%**

**Rosuvastatin**  **5 mg****	****	****       -43%**

- Ballantyne, CM  Am J Cardiol 82, 3-12Q 1998
- Lancet 360, 7-2, 2002

## Dosing considerations

-                    	AUC         Cmax
-    Cyclosporin                	   7x            11x
-    Gemfibrozil 		     	   2x		    2x
- Japanese Ancestry             2x             2x
- Severe Renal Failure          3x             3x
-    (CrCL< 30ml/min)
- Severe Liver Failure           2-4x         4-16x
-      (Maddrey df >54)

## Plasma rosuvastatin concentrations by dose and in 6  patients with rhabdomyolysis or renal toxicity

## Dosing SummarySpecial Populations

**Limit maximal doses****  **
**cyclosporin ****	****	****5mg**
**gemfibrozil****	****	****10mg**
**severe RF****	****	****10mg **

## Dosing SummaryStart Dose

**Proposed start dose of 10mg for patients with hypercholesterolemia and mixed dyslipidemia                 ****(baseline LDL-C < 190mg/dL)**
**Should the 5mg dose be recommended as an alternate start dose?**** **