CRESTOR (ZD4522, rosuvastatin calcium) TABLETS

 

FDA Advisory Committee Meeting Briefing Document NDA 21-366 for the use of CRESTOR

 

June 11, 2003

 

Table of Contents

 

1.    EXECUTIVE SUMMARY............................................................................................ 3

1.1 Questions to the Committee......................................................................................................................... 5

2.    EFFICACY REVIEW.................................................................................................... 7

2.1 Introduction-.................................................................................................................................................. 7

2.2 Lowering LDL-Cholesterol In Patients with Familial and Nonfamilial Hypercholesterolemia (Fredrickson Type IIA And IIB)-......................................................................................................................... 7

2.3 Lowering LDL-Cholesterol Levels in Patients with Heterozygous Familial Hypercholesterolemia-.. 8

2.4 Lowering LDL-Cholesterol Levels in Patients with Homozygous Familial Hypercholesterolemia as an Adjunct to Other Treatment Modalities (e.g., LDL-Apheresis) or if Such Treatments Were Unavailable-.......................................................................................................................................................... 9

2.5 Lowering Triglycerides in Patients with Fredrickson Type IIB And IV Dyslipidemia as an Adjunct to Diet-...................................................................................................................................................................... 9

2. DOSING, REGIMEN AND ADMINISTRATION....................................................... 10

3. DRUG-DRUG INTERACTIONS................................................................................. 10

3.1 Cyclosporine................................................................................................................................................ 10

3.2 Gemfibrozil.................................................................................................................................................. 10

3.3 Cytochrome-p450 inhibitors...................................................................................................................... 10

4. SPECIAL POPULATIONS........................................................................................... 11

4.1 Renal Insufficiency..................................................................................................................................... 11

4.2 Liver Insufficiency...................................................................................................................................... 11

4.3 Japanese........................................................................................................................................................ 11

4.4 Special Populations Patient Exposure....................................................................................................... 11

5. SAFETY REVIEW......................................................................................................... 12

5.1 Description of Patient Exposure................................................................................................................ 12

5.2 Liver-Related Adverse Events.................................................................................................................... 14

5.3 Musculoskeletal-Related Adverse Events................................................................................................. 17

5.4 Renal-Related Adverse Events................................................................................................................... 28

5.5 Correlation with Serious Adverse Events and Serum Rosuvastatin Levels............................................ 35

6. APPENDIX..................................................................................................................... 36

6.1 MedWatch Forms for Cases of Special Interest:..................................................................................... 36

6.2 Proteinuria, Hematuria and Increase in Serum Creatinine by Rosuvastatin Dose................................. 37

6.3 References................................................................................................................................................... 38

 

1.    EXECUTIVE SUMMARY

 

Rosuvastatin is the newest member of the statin class of lipid-lowering compounds, which inhibit HMG-CoA reductase and reduce cholesterol synthesis. The safety and effectiveness of rosuvastatin was reviewed under NDA 21-366 submitted to the Agency on June 26, 2001.  In this original submission, rosuvastatin at daily doses of 1 to 80 mg effectively lowered total and LDL-C in patients with familial and nonfamilial hypercholesterolemia.  The mean percent change from baseline in LDL-C ranged from –33% (1 mg) to –65% (80 mg) in this patient population.  Rosuvastatin 80 mg provided an average 2 to 4% further reduction in LDL-C over the 40 mg dose; however, the range of efficacy overlapped markedly for these two doses.  Rosuvastatin therapy significantly lowered TGs in patients with severe hypertriglyceridemia (200 or 300 mg/dL £ TG £ 800 mg/dL); however, a dose-relationship was not evident across the entire dosage range studied.  Although rosuvastatin therapy increased HDL-C from baseline at all doses studied, the results were highly variable.  Increases in HDL-C were most notable in those patients with HDL-C < 34 mg/dL at entry.  Similarly, reductions in TGs were more pronounced in patients whose baseline TG levels exceeded 200 mg/dL.  

 

The sponsor had originally proposed to market rosuvastatin at doses ranging from 10 to 80 mg.  Review of the original application revealed safety concerns at the 80 mg dose that led to the conclusion that the risks of treatment at this dose outweighed the benefits associated with the modest incremental reduction in cholesterol.  These safety concerns consisted of cases of myopathy and rhabdomyolysis observed at the 80 mg dose.  In addition, proteinuria with and without hematuria and elevations in serum creatinine levels unrelated to myotoxicity were also documented at a greater frequency in the 80 mg dose group.  An approvable action was taken on this application because the benefit-to-risk ratio at doses below 40 mg could not be assessed as a result of inadequate patient exposure.  Clinical development of the 80 mg dose has since been discontinued and the sponsor has now resubmitted an application responding to the concerns raised by the Agency in its initial review of NDA 21-366. This resubmission includes an updated and expanded clinical development program with efficacy and safety data derived from approximately 12,500 patients to support the marketing of rosuvastatin 5 to 40 mg.  More patients were studied at the 20 and 40 mg doses, and patients previously treated with the 80 mg dose were back-titrated to 40 mg and analyzed separately.  

 

Data presented by the sponsor showed that the development of severe myopathy or rhabdomyolysis requiring hospitalization for IV hydration occurred only at the 80 mg dose. The incidences of CK elevations > 10xULN and myopathy in clinical trials of rosuvastatin 5 to 40 mg were between 0.2-0.4% and 0.1-0.2%, respectively, which are similar to rates seen with other currently approved statins. No cases of irreversible renal failure or death due to rhabdomyolysis were seen in these clinical trials.

 

While there have been rare case reports of proteinuria with other statins, this is not currently considered a class effect. Data from the clinical trials in this application show that patients receiving rosuvastatin had an increased rate of developing proteinuria with and without hematuria, and in a small percentage of these cases the findings were persistent and associated with an increase in serum creatinine. Proteinuria was most pronounced at the 80 mg dose and the rate decreased in patients back-titrated from 80 to 40 mg suggesting reversibility. The sponsor argues that isolated proteinuria is a class effect due to the inhibition of HMG-CoA reductase in proximal tubular cells as demonstrated in an Opossum kidney cell model. There were two cases of renal failure and one case of renal insufficiency in patients receiving rosuvastatin 80 mg associated with proteinuria and hematuria. Renal biopsies in two of these cases suggested tubular inflammation and necrosis. Clinical trials, to date, have not clarified the natural history of proteinuria and hematuria seen with rosuvastatin in clinical trials.

 

The risks of muscle and renal toxicity appear dose-related and are clearly evident at the 80 mg dose.  Nine plasma concentrations of rosuvastatin were obtained from 6 patients receiving rosuvastatin 80 mg who developed muscle and renal toxicity.  Rosuvastatin levels were > 50 ng/mL in all 9 samples.  Drug levels corresponding to therapy with 20, 40, and 80 mg doses were obtained in a subset of asymptomatic patients enrolled in 5 different clinical studies.   Drug levels across the 3 different doses in asymptomatic patients were compared to the drug levels in the patients experiencing muscle and renal toxicty.  No patients treated with rosuvastatin 20 mg daily had drug levels in the range observed with clinical toxicity.  Only a few patients treated with rosuvastatin 40 mg (2%) had drug levels within this range and a greater proportion of patients treated with 80 mg (33%) achieved drug levels > 50 ng/mL.  This analysis suggests a potential threshold in the drug level at which risks of muscle and renal toxicity are increased.  Treatment at the 20 mg and lower doses does not appear to raise drug levels into this ‘range of concern’.  However, clinical situations (e.g., drug-drug interactions, special populations) which may increase drug levels require careful consideration as patients in these settings may be exposed to drug levels beyond what is typical for the 20 and 40 mg doses.

 

This briefing packet reviews for the Advisory Committee the effect of rosuvastatin on several different lipid parameters in patients with Fredrickson Type IIa, IIb, IV dyslipidemia and in patients with homozygous familial hypercholesterolemia.  It reviews the updated safety database to determine if the risk of myotoxicity observed at the 80 mg dose is distinct from the lower doses and if the risk observed at the 5 to 40 mg doses is comparable to other marketed statins.  The findings of proteinuria, hematuria, and serum creatinine levels are also summarized.  Unresolved safety issues here include the clinical progression of these renal findings at doses below 80 mg and whether screening and monitoring tools need to be implemented with rosuvastatin therapy.

 

Finally, unresolved  issues exist around the proposed start dose.  Currently, rosuvastatin 10 mg is recommended in the general population with the 20 mg dose reserved for severe hypercholesterolemia (³ 190 mg/dL) and HoFH while the 5 mg dose is reserved for patients taking cyclosporine.  It is evident that the entire dose range, down to 1 mg, effectively lowers cholesterol and produces favorable changes on other lipid parameters.  Furthermore, the LDL-lowering effect of rosuvastatin exceeds that of all currently marketed statins on a mg-to-mg basis.  This and prior statin applications have focused on start doses that provide superior LDL-lowering to marketed products.  The review of this NDA raises the question of whether a range of start doses should be considered which allows prescribers to select a dose based on CHD risk factors present, baseline LDL-C levels, and degree of LDL-lowering needed. 

 

In reviewing this briefing packet the members of the Endocrinologic and Metabolic Drugs Advisory Committee are asked to consider the following questions:

 

1.1 Questions to the Committee

 

Efficacy

1.     Has the sponsor provided sufficient rationale for the addition of a new statin to the therapeutic armamentarium for the treatment of dyslipidemia to prevent or delay cardiovascular disease?

 

2.     Do the efficacy data support a dose-response sufficient to justify use of the 40 mg dose?

 

Safety

Myotoxicity

1.     Has the sponsor provided sufficient evidence that the myotoxic potential  per LDL-lowering efficacy of rosuvastatin is similar to that of currently marketed statins?

 

2.     Has the risk of muscle toxicity associated with rosuvastatin therapy been adequately evaluated in the clinical development program with respect to:

 

1. number of patients studied and duration of trials
2. special populations (e.g., elderly, drug-drug interactions, renal impairment, co-morbid medical conditions)

 

3.     The sponsor does not propose clinical use of doses above 40 mg. Is there sufficient information on the safety and tolerability of the proposed doses (particularly 40 mg daily) to support clinical use?

 

Renal Toxicity

1.     Has the sponsor adequately addressed the clinical safety finding of rosuvastatin-associated proteinuria?  Has the risk of renal functional impairment been adequately investigated?

 

2.     Is proteinuria a statin class effect?  Is the potential for rosuvastatin to induce proteinuria similar to that of other statins?  Is monitoring in clinical use recommended for this drug and possibly for all statins?

 

Dosing Recommendations

1.     Are the data adequate to support the 5, 10, or 20 mg doses as safe start doses?

 

2.     If yes, does the committee recommend a range of start doses (e.g., 5 to 20 mg) in which an individual may be initiated on therapy based on CHD risks, baseline LDL-C levels, and targeted goals OR should there be a fixed start dose of 10 mg recommended for the general population with 5 and 20 mg reserved for special circumstances, as proposed by the sponsor?

 

In answering this question please consider the following approved dosing recommendations for pravastatin, simvastatin, and atorvastatin in adults with hypercholesterolemia and mixed dyslipidemia and the expected mean LDL reductions observed with the specified dose.  The proposed dosing regimen for rosuvastatin is also included for reference.

 

     

*from most recently approved label for marketed statins or NDA database for rosuvastatin

 

 

 

 

 

 

 

 

2.    EFFICACY REVIEW

 

2.1 Introduction-

Rosuvastatin is the newest member of the statin class of lipid-lowering compounds, which inhibit HMG-CoA reductase and reduce cholesterol synthesis. The clinical program was designed to show that rosuvastatin is effective at:

-       lowering total and LDL-cholesterol in patients with familial and nonfamilial hypercholesterolemia (Fredrickson Type IIA and IIB)

-       lowering total and LDL-cholesterol levels in patients with heterozygous familial hypercholesterolemia

-       lowering total and LDL-cholesterol levels in patients with homozygous familial hypercholesterolemia as an adjunct to other treatment modalities (e.g., LDL-apheresis) or if such treatments were unavailable

-       lowering triglycerides in patients with Fredrickson Type IIB and IV dyslipidemia as an adjunct to diet

 

2.2 Lowering LDL-Cholesterol In Patients with Familial and Nonfamilial Hypercholesterolemia (Fredrickson Type IIA And IIB)-

Therapy with rosuvastatin 1 to 40 mg daily results in significant mean % reductions from baseline in total cholesterol and LDL-cholesterol, in subjects with Fredrickson type IIA and IIB dyslipidemia relative to placebo (see Table 1). The mean % changes from baseline in LDL-cholesterol ranged from -33% (1 mg) to -62% (40 mg). Most patients reached NCEP target LDL-cholesterol on 5 or 10 mg of rosuvastatin (67 and 81%, respectively). Increasing the daily dose to 20 or 40 mg resulted in only an additional 6 and 2%, respectively, of patients reaching NCEP goals. While increases in HDL-cholesterol and decreases in triglycerides, from baseline, were seen for daily doses of 1 to 40 mg, there was no dose-response relationship and the mean % changes were not statistically significant at all doses. However, patients with low HDL-cholesterol at trial entry, <34 mg/dl, had greater increases in HDL-cholesterol on 5 to 10 mg of rosuvastatin than patients with HDL ³ 35mg/dl (15.6% vs. 7.3%). Similarly, patients with Type IIB dyslipidemia (TG> 200mg/dl at baseline) had greater mean decreases from baseline in TG than patients with Type IIA (TG<200 mg/dl at baseline, -23.1% vs. -11.8%). An insufficient number of African Americans, Hispanics and Asians were included in these studies to independently confirm the effectiveness of rosuvastatin therapy in these subpopulations. The sponsor is currently studying these populations in ongoing trials.

 

Table 1 Rosuvastatin Dose Response vs. Placebo Mean % Change from Baseline to Week 6 Type IIA/IIB Dyslipidemia: Trials 8 and 23 Pooleda
Efficacy Endpoint	Placebo	Rosuvastatin Dose
		1.0 mg	2.5 mg	5 mg	10 mg	20 mg	40 mg	80 mg
	(N=31)	(N=14)	(N=15)	(N=18)	(N=17)	(N=17)	(N=34)	(N=31)
LDL-C
BL, mg/dL	194	191	190	191	190	191	185	188
Ls mean %	–3.8	–33.2***	–39.6***	–42.6***	–49.8***	–53.1***	–62.2***	–64.9***
change (SE)	(1.7)	(2.8)	(2.7)	(2.6)	(2.6)	(2.6)	(1.6)	(2.1)
TC
BL, mg/dL	271	267	265	268	267	268	261	263
Ls mean %	–2.5	–22.5***	–28.1***	–31.1***	–34.4***	–38.4***	–45.1***	–46.8***
change (SE)	(1.4)	(2.3)	(2.2)	(2.1)	(2.1)	(2.1)	(1.4)	(1.7)
HDL-C
BL, mg/dL	53	55	49	53	50	51	52	51
Ls mean %	3.2	9.4	8.8	13.7*	14.6*	8.2	10.1	14.1**
change (SE)	(2.1)	(3.5)	(3.3)	(3.2)	(3.2)	(3.2)	(2.0)	(2.6)
TG
BL, mg/dL	122	116	133	121	135	134	117	119
Ls mean %	–1.9	–17.0	–11.6	–34.2**	–8.9	–21.9	–27.4**	–24.6**
change (SE)	(4.8)	(7.8)	(7.6)	(7.2)	(7.2)	(7.2)	(4.5)	(5.8)
Table 5 ISE Data derived from tables on pages A63, A66, A69, A72, A84, A87, A101, A597 to A604 in Appendix A. a Main analysis of LOCF data from the ITT population. BL = baseline; N = All subjects in ITT population; SE = standard error. * p<0.05 versus placebo; ** p<0.01 versus placebo; *** p<0.001 versus placebo.

 

 

2.3 Lowering LDL-Cholesterol Levels in Patients with Heterozygous Familial Hypercholesterolemia-

Rosuvastatin therapy at daily doses of 20 to 80 mg effectively reduced total cholesterol and LDL-cholesterol in subjects with severe hypercholesterolemia (LDL-cholesterol > 220mg/dL, see Table 2).

Table 2 Patients with Heterozygous Familial Hypercholesterolemia Treated with Rosuvastatin (ITT population)
0 mg (0wks)	20mg    (6wks)		40mg    (12wks)		80mg    (18wks)
Baseline LDL (mean)	% LDL	LDL (mean)	% LDL	LDL (mean)	% LDL	LDL (mean)
292	-47%	154	-54%	135	-58%	123
Data derived from sponsor’s Table T10.1.1

 

 

The majority of the decrease in LDL-cholesterol was seen with 20 mg of rosuvastatin (wk 6). Titration from 20 mg to 40 mg provided an average 7% further reduction in LDL-cholesterol while titration from 40 mg to 80 mg produced an average 4% further reduction.

 

2.4 Lowering LDL-Cholesterol Levels in Patients with Homozygous Familial Hypercholesterolemia as an Adjunct to Other Treatment Modalities (e.g., LDL-Apheresis) or if Such Treatments Were Unavailable-

Therapy with rosuvastatin 20 mg significantly reduced total cholesterol and LDL-cholesterol in subjects with homozygous familial hypercholesterolemia (mean baseline LDL-cholesterol of 515 ± 115 mg/dl). There was little additional benefit for daily doses greater than 20 mg (see Table 3). The statistical review showed that approximately one-third of patients titrated to doses higher than 20 mg did achieve an additional 6% lowering in LDL-cholesterol, which corresponds to an additional decrease of about 30 mg/dl. It is unclear what clinical impact this small additional reduction will have in these patients whose mean LDL-cholesterol are still > 400 mg/dl.  Changes in HDL-cholesterol and triglycerides were variable.

 

Table 3 All Patients with Homozygous Familial Hypercholesterolemia Treated with Rosuvastatin (ITT population)
0 mg (0wks)	20mg    (6wks)		40mg    (12wks)		80mg    (18wks)
Baseline LDL (mean)	% LDL	LDL (mean)	% LDL	LDL (mean)	% LDL	LDL (mean)
515	-19%	416	-22%	409	-22%	403
Data derived from sponsor’s Table T10.2.1 to T10.1.1

 

 

2.5 Lowering Triglycerides in Patients with Fredrickson Type IIB And IV Dyslipidemia as an Adjunct to Diet-

Therapy at daily doses of 5 to 40 mg of rosuvastatin significantly reduced triglycerides in subjects with Fredrickson type IIB and IV dyslipidemia compared to placebo (see Table 4). The mean dose response curve was flat at doses above 10 mg.

 

Table 4	Analysis of Mean % Change from Baseline to Week 6 LOCF in total TG levels in study  4522IL/0035 a
	Placebo N=26	ZD4522 N=25	ZD4522 N=23	ZD4522 N=27	ZD4522 N=25	ZD4522 N=27
		5 mg	10 mg	20 mg	40 mg	80 mg
Baseline(mean, SD): mg/dl	511 (138)	462 (104)	447 (96)	446 (119)	471 (142)	448 (138)
Final (mean, SD):mg/dl	521 (222)	376 (140)	271 (65)	278 (114)	270 (81)	267 (96)
Ls mean of % change (SE)      median	2.9 (4.4) 0.8	–18.1 (4.5) –20.6	–37.0 (4.7) –36.5	–36.8 (4.3) –37.0	–40.0 (4.5) –43.1	–39.5 (4.3) –46.2
Difference (%) relative to placebo	NA	–21.0 (6.3)	–39.9 (6.4)	–39.6 (6.2)	–42.9 (6.3)	–42.4 (6.1)
95% CI of difference	NA	–33.4, –8.6	–52.5, –27.3	–51.8, –27.5	–55.3, –30.5	–54.5, –30.2
p-value of difference	NA	0.001	<0.001	<0.001	<0.001	<0.001
Table 16 study 4522IL/0035.  Data derived from Tables T10.1.1, T10.1.2, T10.3.1, and H1.1.1. a Main analysis of last observation carried forward from the intent-to-treat population. CI = Confidence interval; LOCF = last observation carried forward; ls mean = Least squares mean; NA = Not Aplicable; SD = Standard deviation; SE = Standard error.

 

 

2. DOSING, REGIMEN AND ADMINISTRATION

[Dosing1] 

Rosuvastatin was studied at single daily oral doses of 1, 2.5, 5, 10, 20, 40 and 80 mg. The sponsor proposes a starting dose of 10 mg daily with a dose range of 10 mg to 40 mg once daily for patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIA and IIB). The sponsor proposed the option of a daily start dose of 20 mg for patients with heterozygous or homozygous familial hypercholesterolemia, with severe hypercholesterolemia (LDL-cholesterol >190mg/dl).

 

 

3. DRUG-DRUG INTERACTIONS

[SpecPop2] 

3.1 Cyclosporine

Heart transplant patients treated with cyclosporine and receiving daily doses of 10 mg of rosuvastatin had a 10.6-fold increase in Cmax and a 6.8-fold increase in AUC (0-t) for rosuvastatin drug levels compared to values obtained in healthy subjects. The sponsor proposes limiting the dose of rosuvastatin to 5 mg in subjects receiving concomitant cyclosporine.

 

3.2 Gemfibrozil

Healthy subjects receiving 600 mg twice daily of gemfibrozil and a single dose of rosuvastatin 80 mg had a 2.2-fold increase in Cmax and a 1.9-fold increase in AUC (0-t) for rosuvastatin drug levels compared to placebo. The sponsor proposes limiting the daily dose of rosuvastatin to 10 mg in subjects receiving concomitant gemfibrozil.

 

3.3 Cytochrome-p450 inhibitors

In-vitro data suggest that rosuvastatin is not metabolized by CYP3A4 to a clinically significant extent. No clinically relevant changes in AUC (0-t) or Cmax for rosuvastatin were seen when it was administered with known CYP3A4 inhibitors such as itraconazole, ketoconazole and erythromycin.

 

No clinically relevant changes in AUC (0-t) or Cmax were seen for rosuvastatin when it was administered with the known CYP2C9 inhibitor fluconazole.

 

4. SPECIAL POPULATIONS

 

4.1 Renal Insufficiency

Subjects with severe renal impairment, (baseline CrCL < 30ml/min), had a 3.1-fold increase in Cmax and a 3.2 fold increase in AUC (0-24) for rosuvastatin compared to healthy subjects treated with 20 mg of rosuvastatin. The sponsor proposes limiting the daily dose of rosuvastatin to 10mg in subjects with severe renal impairment.

 

4.2 Liver Insufficiency

Two subjects with alcohol-induced cirrhosis of the liver described as severe by the Maddrey discriminant function  (df³54) had a 4 to 16-fold increase in Cmax and a 2 to 4-fold increase in AUC (0-24) for rosuvastatin compared to patients with normal hepatic function treated with 10 mg of rosuvastatin. The sponsor does not feel the need to cap the dose in patients with severe liver disease but instead proposes contraindicating the use of rosuvastatin in patients with active liver disease or unexplained persistent elevations of serum transaminases.

 

4.3 Japanese

After single or seven-day repeat oral dosing with 20 mg of rosuvastatin, Cmax was 1.9 to 2.3-fold higher and AUC (0-24) was 2.0 to 2.5-fold higher for rosuvastatin in healthy Japanese male volunteers compared to Caucasians. The sponsor has not proposed limiting the daily dose of rosuvastatin in patients of Asian ethnicity in the US. They currently have an application in Japan with a dose range of 10 to 20 mg with 5mg recommended for special treatment circumstances. The sponsor admits that at this time they do not know if the increased exposure in Japanese patients is related to genetic or environmental factors and whether these findings apply to other Asian populations or to patients with mixed genetic profiles.

 

4.4 Special Populations Patient Exposure

No specific safety concerns were identified in these special population trials with respect to rosuvastatin. However, since the number of subjects enrolled in these trials was low (Renal-impaired study N=26, Hepatically impaired study N=18, Japanese study N=18), and these PK studies lasted at most 2 weeks, the safety profile of rosuvastatin in these special populations can not be adequately assessed based on the results of these trials alone.

 

5. SAFETY REVIEW

            5.1 Description of Patient Exposure

 

The original application, including the pre-approval safety update submitted by the sponsor, included data from 3,900 patients exposed to daily doses of 5 to 80 mg of rosuvastatin. However, because of the force-titration design of many of the trials, exposures were greatest at 5, 10 and 80 mg with fewer than 200 patients exposed to 20 or 40 mg of rosuvastatin for greater than 24 weeks and fewer than 100 patients exposed to these doses for greater than 48 weeks. Because of muscle and renal safety issues associated with exposure to the 80 mg dose in these trials, (to be discussed in more detail later in this review) the 80 mg dose was not approved and the sponsor was asked to submit additional safety data on the 20 and 40 mg doses. Table 5 shows the cumulative exposure to all doses in the current clinical trial program, which now includes data on over 11,000 patients. Note that once the agency was aware of the potential toxicity of the 80 mg dose the sponsor was asked to withdraw all patients from the 80 mg dose and to follow them at lower doses as appropriate. Most of these patients were down-titrated to 40 mg and are included as a separate column in this table.

 

 

Table 5    Maximum continuous duration of treatment for each dose of rosuvastatin in the All Controlled / Uncontrolled and RTLD Pool
	Rosuvastatin dose a,b
Cumulative duration of treatment c	5 mg   N=1,324	10 mg   N=7,246	20 mg   N=3,391	40 mg   N=3,021	Originally on 80 mg then down titrated to 40 mg N=826	80 mg   N=1,580	Total rosuvastatin d,e N=11,210
³6 weeks	1235	6919	3032	2554	785	1419	10,658
³24 weeks	647	4,787	940	657	209	977	7,695
³48 weeks	541	2,631	285	195	0	898	4,786
³60 weeks	349	1,466	189	164	0	868	3,238
³96 weeks	274	831	89	73	0	639	2,260
Mean weeks of treatment	49	45	20	17	18	65	55
Subject years	1,248	6,199	1,296	959	282	1,952	11,725
RTLD= Real Time Lab Data Data derived from ISSU Table S2.8.3 and S2.8.4. from Table 24 Integrated Summary of Safety Update Jan. 31, 2003 a Subjects are counted in each dose group to which they are exposed; therefore, subjects may be counted in more than 1 treatment group.  For subjects with more than 1 exposure to a given rosuvastatin dose, only the longest duration of exposure to that dose is counted. b Subjects were down titrated from rosuvastatin 80 mg as a result of a protocol amendment for Studies 34, 65, and 81.  Not all subjects given rosuvastatin 40 mg were down-titrated from 80 mg; these subjects were either up-titrated to 40 mg from a lower start dose or were directly randomized to 40 mg. c If a subject received 40 mg prior to the protocol amendments for Studies 34, 65, and 81 and then were down-titrated from 80 mg to 40 mg after the protocol amendments were put into effect, the subject is counted in both the “not down-titrated to 40 mg” and “down-titrated to 40 mg” columns. d Maximum continuous exposure in the Total rosuvastatin column includes all rosuvastatin continuous exposure, regardless of titration of dose.  For this reason, counts of subjects in the individual duration categories cannot be added across doses to obtain the count in the Total rosuvastatin column. e The reason for the missing counts is that there were no return dates to calculate the treatment durations.  In most of these cases, the subjects were not only dispensed these doses for the first time, but also these doses were the last dispensed dose before the database lock for the subject. Note: Participation in Phase II/III controlled and uncontrolled clinical studies includes participation in any controlled clinical study and/or participation in an extension study.  Subjects received rosuvastatin either alone or with another lipid-lowering agent at any point during a feeder study and/or an extension study. ND  not determined

[Note3] 

ICH guidelines recommend that the total number of patients exposed to an investigational drug for long-term treatment of non-life-threatening conditions should be at least 1500, with 300 to 600 exposed at 6 months and at least 100 patients exposed at one year. The Division of Metabolic and Endocrine Drug Products has routinely required a minimum of 200 patients exposed for at least one year for the approval of medications intended for chronic use. While the sponsor has now roughly achieved these guidelines even at the highest to be marketed dose of 40 mg, the total patient-years of exposure at 40 mg is still about half (i.e. 959 pt-years) of what was seen with the 80 mg dose (i.e. 1,952 pt-years) where the main safety concerns were identified. The total patient exposure in clinical trials submitted for initial approval for rosuvastatin (N=11,210) is considerably greater than the 2,000-3,000 patients submitted for most of the currently approved statins (See Table 10).

 

The rest of this briefing packet will focus on three areas of potential concern, which were identified during the pre-approval safety review:

 

-       Liver-related adverse events

-       Musculoskeletal-related adverse events

-       Renal-related adverse events

 

5.2 Liver-Related Adverse Events

SUMMARY-As a group, statins have been associated with liver transaminase elevations and rarely hepatitis and liver failure. The data presented by the sponsor show a frequency of transaminase elevations similar to that seen in currently approved statins. No cases of irreversible liver disease or liver failure were seen in these clinical trials.

 

LIVER TRANSAMINASE ELEVATIONS -

Liver transaminase elevations have been widely used to screen statins for potential hepatotoxicity.  Since patients can have random isolated elevations which turn out to be nonspecific and unrelated to the study drug, sponsors typically present data for persistent elevations to try to identify patients who are more likely to have clinically significant elevations.

 

Total single elevations are also useful for analysis and comparison between control groups as long as it is taken into account that they may over represent the incidence of significant disease. Data for single elevations are typically obtained at scheduled study visits or if clinically warranted.  Pre-specified criteria for consecutive elevations in liver transaminases often include a time restriction between measurements (e.g., measurements must be made 4 to 10 days apart).  Consequently, the incidence of LFT abnormalities reported as consecutive transaminase elevations may miss clinically relevant cases if repeat tests occur beyond the arbitrary time frame defined by the protocol. When analyzing single elevations it is useful to compare the drug to active controls or placebo and by degree of enzyme elevation, such as >6xULN or >9xULN. Higher single elevations are more likely to represent relevant toxicity.

 

An analysis of single, and multiple ALT elevations was performed. Multiple elevations do not depend on the time of the measurement and therefore do not necessarily represent consecutive elevations as reported by the sponsor.

 

Table 6 ALT Elevations in the Rosuvastatin All Controlled/Uncontrolled and RTLD Pool
	5mg		10mg		20mg		40mg		80mg
Single elevations	N (1317)	%	N (7726)	%	N (3882)	%	N (3957)	%	N (1574)	%
>3xULN	14a	1.1	61a	0.8	26	0.7	44a	1.1	62a	3.9
>6xULN	0	0	9	0.1	2	0.05	4	0.1	15b	1.0
>9xULN	0	0	3	0.04	1	0.03	1	0.03	8b	0.5
Multiple elevations
>3xULN	5	0.4	9	0.1	4	0.1	15	0.4	22	1.4
>6xULN	0	0	3	0.04	0	0	1	0.03	6	0.4
>9xULN	0	0	0	0	0	0	1	0.03	4	0.3
aWhile rhabdomyolysis can also be associated with elevations in transaminases most of the mild elevations in Alt > 3xULN reported here were not associated with CK elevations > 10xULN. Only 19/207 pts with Alt > 3xULN also had CK elevations >10xULN. One on 5 mg, two on 10 mg, four on 40 mg and 12 on 80mg.
bAt the higher transaminase elevations 6/30 patients with ALT>6xULN and 2/13 with ALT >9xULN also had CK > 10xULN but all were at the 80 mg dose of rosuvastatin
Data were derived from AV_LUBR.xpt data file submitted 5/20/03, Where the lab ULN was not known from data in the Lab.xpt dataset submitted 6/26/01, it was assumed that 3xULN=75 which was true for most values in the dataset.

 

 

There is a clear increase in the incidence of single and multiple transaminase elevations >3xULN, > 6xULN and >9xULN only at the 80 mg dose of rosuvastatin. The frequency of elevations >3xULN at doses of 5 to 40 mg was in the range of 0.7 to 1.1% which is less than the frequency of transaminase elevations >3xULN reported in healthy patients in Phase 1 trials receiving placebo i.e. < 2% (Rosenzweig et al. 1999). Even though direct comparisons of data from independent trials are difficult because of different patient populations, study eligibility criteria and different lengths of drug exposure, these data suggest that the occurrence of transaminase elevations at the lower doses in these clinical trials may not be due to the study drug.

 

The frequency of single elevations >3xULN at 80 mg is increased (3.9%) in comparison to rates observed at the 40 mg and lower doses (0.7 to 1.1%). This might suggest the potential for a clinically significant signal. In comparison to other currently approved statins however, similar elevations in transaminases have also been seen at the highest approved doses and careful monitoring has shown statins to be relatively safe and rarely associated with cases of liver failure. The incidence of persistent elevations in transaminases, as it is currently reported in the labels of these drugs, is shown in the Table 7 below. These data are in the same range as the frequency of multiple elevations >3xULN reported above for 80 mg of rosuvastatin (1.4%).

 

 

 

Table 7 Dose Related Incidence of Persistent Transaminase Elevations in Statins in Clinical Trials
Statin	Placebo	10 mg	20 mg	40 mg	80 mg
Pravachol	0.3%			0.3%
Mevacor	0.1%		0.1%	0.9%	1.5%
Lipitor		0.2%	0.2%	0.6%	2.3%
Zocor				0.9%	2.1%
Lescol			0.2%	1.5%	2.7%
Data taken from currently approved labels or NDA19898/Se8-042.

 

Liver function monitoring appears to identify a small group of subjects with evidence of hepatotoxicity for which the study drug should be discontinued. Out of 45 different subjects with 2 or more consecutive elevations identified by the sponsor in the All Controlled/Uncontrolled and RTDL Pools (data obtained from Tables 37 and 38 in sponsor’s ISS  dated 1/31/03), at least 21 had the drug withdrawn, two had the dose lowered and four had the drug withheld temporarily. Hence about half of these patients were able to continue on treatment despite consecutive ALT elevations. For all subjects, for whom follow up data were available, transaminase levels improved. A small number of subjects (n=5) continued to have mild low grade elevations <3xULN when continued on the study drug.

 

There were two cases of jaundice for which relationship to rosuvastatin therapy could not be excluded. Both cases occurred on the 10 mg dose of rosuvastatin and resolved after the discontinuation of therapy (see appendix for MedWatch forms D3560L0001/0310/01237 and D3560L0001/2265/09060). No cases of liver failure or irreversible liver disease were observed in these trials. In these clinical trials liver function tests appear to adequately monitor for hepatotoxicity in patients on rosuvastatin.

 

In conclusion, statins have been associated with liver transaminases elevations but rarely hepatitis and liver failure. Rosuvastatin, like other statins, shows a dose-related increase in liver transaminases. The incidence of multiple transaminase elevations is similar at 80 mg of rosuvastatin to that seen at the highest approved doses of other statins. Liver function monitoring, as currently recommended for all members of the statin drug class, is also recommended for patients receiving treatment with rosuvastatin.

 

5.3 Musculoskeletal-Related Adverse Events 

SUMMARY- Myopathy and rare cases of rhabdomyolysis, which can lead to acute renal failure and death, have been reported post-marketing for all currently approved statins.  The data presented here show, for the first time, the development of severe myopathy and rhabdomyolysis in clinical trials submitted for the original approval of a new statin. This risk is clearly increased at the highest dose studied (80 mg), which has subsequently been discontinued from development.  While the risks of myopathy at lower doses appear comparable to other marketed statins, these risks may increase in special populations in which patients are exposed to higher levels of drug (drug-drug interactions, renal impairment, Japanese descent).

 

CK ELEVATIONS IN PATIENTS TAKING ROSUVASTATIN

Skeletal muscle damage results in the release of intracellular proteins into the bloodstream. One of these proteins, myoglobin, is normally filtered out of the body by the kidneys. Under conditions in which there is a large degree of skeletal muscle damage, excessive amounts of myoglobin can be released, overwhelming the kidney’s filtering capacity, occluding it and leading to renal failure and possibly death.  Adequate IV hydration during this time can maintain renal output and prevent the progression to renal failure.

 

Other intracellular muscle proteins have been commonly used as markers to estimate the extent of muscle damage. The best example of this is creatine phosphokinase (CK) which has isoenzymes also present in heart muscle and brain. Mild elevations of CK are common after vigorous exertion but typically do not lead to myopathy (CK>10xULN and muscle symptoms) or the more severe condition of rhabdomyolysis. Rhabdomyolysis is a clinical diagnosis, which unlike myopathy has been poorly defined. For example, in this current database there was one patient on 80 mg of rosuvastatin with muscle weakness, myalgia, back pain, CK=34,548 (288xULN), and a plasma myoglobin of 13,810ng/ml who developed acute renal failure and was diagnosed with “myoglobin associated renal failure due to toxicity of myoglobin on the renal tubules” but not “rhabdomyolysis”. Clearly this case was misclassified. While most reviewers would include CK elevations > 10,000 IU/L with muscle symptoms, there are reports of rhabdomyolysis with CK <10xULN (Omar et al. Annals of Pharm Sept. 2001) and not all patients have myalgia. Some patients can have nonspecific symptoms such as loss of appetite, fatigue, weakness, malaise, nausea, vomiting and abdominal distention. For the purpose of this review I will refer to cases of rhabdomyolysis (i.e. severe myopathy) as those patients with myopathy (CK>10xULN and muscle symptoms) who required hospitalization for IV hydration, with the reasoning that in such cases the level of muscle toxicity is so severe that it would likely have lead to renal failure if left untreated.

 

CK elevations have been commonly used to screen for potentially myotoxic drugs even though there is no clear indication that patients who develop transient unexplained CK elevations are more likely to progress to myopathy or rhabdomyolysis in the future. Therefore, while monitoring CK levels may not predict who is at risk of developing rhabdomyolysis, it is a useful marker to compare potentially myotoxic drugs. For example, the frequency of CK elevations for cerivastatin, which was eventually removed from the market because it was associated with a higher unexceptable risk of rhabdomyolysis, was higher in clinical trials than had been seen for other marketed statins (see Table 10).

 

In addition to CK, transaminases (AST > ALT) are also released from necrotic muscle cells and can be used to identify more severe cases of myopathy. Also, an increase in creatinine as a result of decreasing renal function associated with myopathy is likely to signal more severe muscle damage. While serum and urine myoglobin tests would be useful to diagnose rhabdomyolysis they are rarely done and can not be relied upon to make the diagnosis.

 

The clinical manifestations of myotoxicity are observed over a continuum. Most patients with normal baseline renal function and who are otherwise healthy can handle certain levels of myoglobinuria. These patients may experience only CK elevations without symptoms or myopathy without renal function deterioration.  Co-morbid medical conditions, dehydration, age, mental status, certain concomitant medications or genetic factors may play a role in making some patients more susceptible at certain times to potentially myotoxic drugs. Increased serum levels of myotoxic drugs have clearly been associated with an increased risk for developing rhabdomyolysis.  In addition, conditions which result in increased levels of these drugs, such as drug-drug interactions or renal dysfunction, may also increase the risk of developing rhabdomyolysis.

 

The data presented in Table 8 compare CK elevations seen in patients with rosuvastatin to placebo and other statins in the All Controlled Data Pool. There is clearly an increase in the frequency of CK elevations for all statins compared to placebo. The increase is greatest in patients taking the rosuvastatin 80 mg dose (CK>10xULN=0.9%). The frequency observed at 40 mg of rosuvastatin is similar to what was seen for 80 mg of simvastatin (CK>10xULN=0.4%). It is likely that the high frequency of 1.2% for 10 mg of simvastatin is an over estimation because of the small number of patients in this subgroup (N=163) especially since there is no clear dose response (0.1 and 0% for 20 and 40 mg simvastatin doses, respectively). It is also likely that no CK elevations >10xULN were seen for cerivastatin in these trials because of the low number of patients in these groups (N=45 to 64).

 

 

 

 

Table 8 CK ELEVATIONS IN THE ALL CONTROLLED POOLa
	5mg		10mg			20mg			40mg				80mg
Rosuvastatin	N=833	%	N=3193		%	N=2113		%	N=2804		%		N=988		%
CK >5xULN	7	0.8	8		0.3	7		0.3	28		1.0		11		1.1
CK>10xULN	3	0.4	4		0.1	3		0.1	11		0.4		9		0.9
	Placebo		10mg			20mg			40mg				80mg
Atorvastatin	N=381	%	N=1573		%	N=1772		%	N=522		%		N=555		%
CK >5xULN	0	0	8		0.5	7		0.4	3		0.6		2		0.4
CK>10xULN	0	0	1		0.1	2		0.1	0		0		0		0
			10mg			20mg			40mg				80mg
Simvastatin			N=163		%	N=1272	%		N=532		%		N=501		%
CK >5xULN			2		1.2	2	0.2		0		0		3		0.6
CK>10xULN			2		1.2	1	0.1		0		0		2		0.4
			10mg			20mg			40mg
Pravastatin			N=161		%	N=416	%		N=751	%
CK >5xULN			2		1.2	2	0.5		0	0
CK>10xULN			0		0	0	0		0	0
						0.3mg			0.4mg			0.8mg
Cerivastatin						N=64	%		N=54	%		N=45		%
CK >5xULN						0	0		0