CRESTOR
(ZD4522, rosuvastatin calcium) TABLETS
FDA Advisory Committee Meeting Briefing Document NDA 21-366 for the use of CRESTOR
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
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:
- number of patients studied and duration of
trials
- 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.
|
Statin (approved dose range) |
Approved Start Doses |
Mean LDL-C Change* at Approved Start Dose |
Start Dose in Special Populations |
|
Pravastatin (10 to 80 mg) |
40 mg once daily |
-34% |
10 mg daily start dose recommended in patients with significant renal or hepatic impairment or concomitant use of immunosuppresives |
|
Simvastatin (5 to 80 mg) |
20 to 40 mg daily 40 mg recommended for those individuals at high risk of CHD |
-38% (20 mg) -41% (40 mg) |
5 mg in patients with concomitant use of cyclosporine or with severe renal insufficiency |
|
Atorvastatin (10-80 mg) |
10 or 20 mg daily 40 mg daily for patients requiring large (>45%) reductions in
LDL-C |
-39% (10 mg) -43% (20 mg) -50% (40 mg) |
none specified |
|
Rosuvastatin (5-40 mg) |
10 mg 20 mg for patients with severe hypercholesterolemia (LDL>190
mg/dL) |
-50% (10 mg) -53% (20 mg) |
5 mg for patients with concomitant use of cyclosporine |
*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.
|
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
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.
[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).
|
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 |
0 |
1 |
2.2 |
|||||
|
CK>10xULN |
|
|
|
|
0 |
0 |
0 |
0 |
0 |
0 |
|||||
|
aData were derived from
AV_LBUR.xpt submitted |
|||||||||||||||
In the All Controlled/Uncontrolled and RTLD Patient Pools, which contain many more patients exposed to rosuvastatin for longer periods of time, it is possible to get a better estimate of the true frequency of dose-related CK elevations (see Table 9). These data show that 80 mg of rosuvastatin has a high frequency of elevations (CK>10xULN=1.9%), between what was seen in clinical trials for cerivastatin doses of 0.4 mg (1.55%) and 0.8 mg (2.1%) and higher than seen for all other currently approved statins (see Table 10). This increased frequency at 80 mg is true even when you look at more severe cases of myopathy with multiple CK elevations, or CK elevations associated with transaminase elevations or myalgias (see Table 9). There is also a slight increase in CK elevations for 40 mg of rosuvastatin but it is not clear if this represents a clear signal of a substantial risk of myotoxicity. The frequency at 40 mg (CK>10xULN=0.4%) is not higher than seen in clinical trials submitted for initial approval of other currently approved statins (Table 10) or in published clinical trials (Table 11).
|
Table 9 CK ELEVATIONS IN PATIENTS TAKING ROSUVASTATIN IN THE ALL
CONTROLLED/UNCONTROLLED and RTLD POOLS a |
||||||||||||
|
|
5mg |
10mg b |
20mg |
40mg |
80mg |
|||||||
|
|
N (1317) |
% |
N (7727) |
% |
N (3883) |
% |
N (3700) |
% |
N (1574) |
% |
||
|
Single CK elevations
|
||||||||||||
|
CK >5xULN |
14 |
1.1 |
69 |
0.9 |
19 |
0.5 |
39 |
1.1 |
55 |
3.5 |
||
|
CK>10xULN |
5 |
0.4 |
17 |
0.2 |
7 |
0.2 |
15 |
0.4 |
30 |
1.9 |
||
|
Multiple
CK elevations |
||||||||||||
|
CK >5xULN |
3 |
0.2 |
11 |
0.1 |
3 |
0.08 |
7 |
0.2 |
21 |
1.3 |
||
|
CK>10xULN |
3 |
0.2 |
1 |
0.01 |
1 |
0.03 |
5 |
0.1 |
12 |
0.8 |
||
|
Single CK elevations associated
with Alt >3xULN c |
||||||||||||
|
CK >5xULN |
1 |
0.08 |
2 |
0.03 |
0 |
0 |
4 |
0.1 |
16 |
1.0 |
||
|
CK>10xULN |
1 |
0.08 |
2 |
0.03 |
0 |
0 |
4 |
0.1 |
12 |
0.8 |
||
|
Single CK Elevations associated
with clinical symptoms |
||||||||||||
|
Myopathy (All) |
3 |
0.2 |
9 |
0.1 |
4 |
0.1 |
6 |
0.2 |
16 |
1.0 |
||
|
Myopathy (Not related to exercise
or injury) |
0 |
0 |
1 |
0.01 |
1 |
0.03 |
1 |
0.03 |
11 |
0.7 |
||
|
Rhabdo or IV
hydrationd |
0 |
0 |
1 |
0.01 |
0 |
0 |
0 |
0 |
7 |
0.4 |
||
|
|
|
|
|
|
|
|
|
|
|
|
||
|
aData
were derived from AV_LBUR.xpt submitted b Includes data from a initial Med Watch report on a 75 y/o female in the GISSI-HF study diagnosed with rhabdomyolysis on 4/20/03 see appendix for full case report c ALT≥ 75U/L, d All
patients diagnosed with rhabdomyolysis received IV hydration, two other
patients who had peak CK’s of 34,548 and 16,280 U/L with increased plasma
myoglobulin were also hospitalized for IV hydration but did not get a formal
diagnosis of rhabdomyolysis. |
||||||||||||
|
Table 10 CK Elevations, Myopathy and
Rhabdomyolysis in Pre-Approval Clinical Trials |
|||||||
|
Statin |
Approval |
NDA Dose |
Pts N |
CK>10xULN % (N) |
Myopathy % (N) |
Drug Stopped % (N) |
Hospitalized IV Hydration % (N) |
|
Pravastatin 19-898 |
Oct. 1991 |
5-40 |
1,925 |
0.1% (2) |
0.1% (2) (1 clofibrate) |
0.2% (3) |
0 |
|
S-046 Se-000 4F |
Dec. 2001 (Phase IV) |
80 |
581 |
0.9% (5) |
0.4% (2) |
0.3% (2) |
0 |
|
Unapproved |
(Phase IV) |
160 |
604 |
0.3% (2) |
0 |
0.2% (1) |
0 |
|
Simvastatin 19-766 |
Dec. 1991 |
5-40 |
2,423 |
0.6% (13) |
0.04% (1) |
0.1% (2) |
0 |
|
S-026 |
July 1998 IIb, III |
80 |
669 |
0.7% (5) |
0.5% (5) (1 nefazodone + clarithromycin, 1 verapamil) |
0.7% (5) |
0 |
|
Merck press release |
GEM extended release form |
160 |
~400 |
~0.8% (3) |
~0.8% (3) |
|
~0.8% (3) |
|
Fluvastatin 20-261 |
Dec. 93 |
20-40 |
2,342 |
0.1% (3) |
|
0.1% (2) |
0 |
|
21-192 |
Nov. 1999 |
40 |
543 |
0.4% (2) |
|
|
0 |
|
21-192 |
Nov. 1999 |
80 XL |
912 |
0% |
|
|
0 |
|
Atorvastatin 20-702 |
Dec. 1996 |
10-40 |
1,965 |
0.4% (8) |
|
|
0 |
|
|
April 2000 |
80 |
346 |
0.9% (3) |
|
|
0 |
|
Protocol A2581042 |
Phase IV |
10-40 |
688 |
0.3% (2) |
0% |
0.1% (1) (20mg) |
0 |
|
|
“ |
80 |
231 |
0% |
|
|
0 |
|
Lovastatin 19-643 |
Aug. 1997 |
5-80 |
873 |
N/A |
N/A |
0 |
0 |
|
Cerivastatin |
June 1997 |
0.05-0.3 |
2,815 |
0% |
|
|
0 |
|
S-002 |
May 1999 |
0.4 |
448 |
0.2% (1) |
|
0.7% (3) |
0 |
|
S-008 |
July 2000 |
0.4 |
193 |
1.55%
(3) |
1.55% (3) (1 gemfibrozil) |
|
0* |
|
S-008 |
July 2000 |
0.8 |
770 |
2.1%
(16) |
1.0% (8) |
|
0* |
|
Rosuvastatin |
|
5 |
1,317 |
0.4% (5) |
0.2% (3) |
0.2% (2) |
0 |
|
|
|
10 |
7,728 |
0.2% (17) |
0.1% (9) |
0.04% (3) |
0.01% (1) |
|
|
|
20 |
3,883 |
0.2% (7) |
0.1% (4) |
0.08% (3) |
0 |
|
|
|
40 |
3,700 |
0.4% (15) |
0.2% (6) |
0.1% (4) |
0 |
|
|
|
80 |
1,574 |
1.9% (30) |
1.0% (16) |
0.8% (13) |
0.4% (7) |
|
*Possible cases of rhabdomyolysis may have been labeled as myopathy only. |
|||||||
|
Table 11 CK Elevations, Myopathy and
Rhabdomyolysis in Published Clinical Trials or Approved Label |
|||||||||
|
Statin |
Data Source |
NDA Dose |
Pts N |
CK >10xULN |
All
Myopathy |
Rhabdomyolysis |
|||
|
% |
N |
% |
N |
% |
N |
||||
|
Pravastatin |
Approved Label |
5-80 |
|
- |
- |
<0.1 |
- |
|
|
|
40 |
115 |
0 |
0 |
0 |
0 |
|
|
||
|
80 |
464 |
0.9 |
4 |
0 |
0 |
|
|
||
|
|
WOSCOPS NEJM 333, Nov.1995 |
Placebo |
3293 |
0.03 |
1 |
0 |
0 |
|
|
|
40 |
3302 |
0.09 |
3 |
0 |
0 |
|
|
||
|
Simvastatin |
Approved Label |
20 |
|
- |
- |
0.02 |
|
|
|
|
40 |
|
- |
- |
0.07 |
|
|
|
||
|
80 |
|
- |
- |
0.3 |
|
|
|
||
|
|
4S- Lancet 344, Nov. 1994 |
Placebo |
2,223 |
0.04 |
1 |
0 |
0 |
|
|
|
10-40 |
2,221 |
0.3 |
6 |
0 |
0 |
0.05 |
1 (20mg) |
||
|
J-LIT Japanese Pts Circ J 67, April 2003 |
5-10 |
51,321 |
0.01 |
6 |
0.01 |
4 (1 hosp) |
0 |
0 |
|
|
HPS (Lancet 360, July 2002) |
Placebo |
10,267 |
0.06 |
6 |
0.04 |
4 |
0.03 |
3 |
|
|
40 |
10,269 |
0.11 |
11 |
0.1 |
10 |
0.05 |
5 |
||
|
Fluvastatin |
Approved Label |
20-40 |
|
- |
- |
- |
- |
|
|
|
80XL |
|
- |
- |
- |
- |
|
|
||
|
|
American Journal of Cardiology 89, Jan 2002 |
Placebo |
2,323 |
0.2 |
5 |
- |
- |
|
|
|
20 |
2,590 |
0.2 |
4 |
- |
- |
|
|
||
|
40 |
4,369 |
0.3 |
13 |
- |
- |
|
|
||
|
80 XL |
1,724 |
0 |
0 |
- |
- |
|
|
||
|
Atorvastatin |
Approved Label |
10-40 |
|
- |
- |
- |
- |
|
|
|
80 |
|
- |
- |
- |
- |
|
|
||
|
Lovastatin |
Approved Label |
10 |
|
- |
- |
- |
- |
|
|
|
20-40 |
4,933 |
- |
- |
0.02 |
1 |
|
|
||
|
80 |
1,649 |
- |
- |
0.2 |
4 |
|
|
||
|
|
EXCEL study Arch Int Med 151, Jan. 1991 |
placebo |
1,663 |
0.4 |
7 |
0 |
0 |
|
|
|
20 |
1,642 |
0.2 |
3 |
0 |
0 |
|
|
||
|
40 |
3,291 |
0.2 |
6 |
0.03 |
1 |
|
|
||
|
80 |
1,649 |
0.5 |
8 |
0.2 |
4 |
|
|
||
|
AFCAPS/TexCAPS JAMA 279, May 1998 |
Placebo |
3,248 |
0.6 |
21 |
0 |
0 |
0.06 |
2 |
|
|
20 |
1,586 |
0.7 |
11 |
0 |
0 |
0.03 |
1( s/p cancer surgery) |
||
|
40 |
1,657 |
0.6 |
10 |
0 |
0 |
||||
|
Cerivastatin |
Last Approved Label |
0.2-0.8 |
|
- |
- |
0.4 |
- |
|
|
|
|
J Int Med Res 28, Mar 2000 |
placebo |
198 |
0 |
0 |
0 |
0 |
0 |
0 |
|
0.4mg |
194 |
1.0 |
2 |
1.0 |
2 (1 gem- fibrozil) |
0 |
0 |
||
|
0.8mg |
774 |
1.3 |
10 |
0.9 |
7 |
0 |
0 |
||
FREQUENCY of CK ELEVATIONS and MYOPATHY DOES NOT CORRELATE with CHANGE in LDL
It
has been reported in the literature that there is no clear association between
final LDL level or percent decrease in LDL and the risk of myopathy or
rhabdomyolysis (Berg et al. 1996). Similarly, data from trials with
atorvastatin (Bakker-Akema et al. 2000) showed that lowering LDL-cholesterol to
< 50 mg/dl did not alter the safety profile of that statin.
One possible explanation for these observations is that changes in LDL reflect drug activity at the level of the liver in contrast to myopathy and rhabdomyolysis which may be more likely to reflect serum drug levels and drug penetration into muscle.
Data from the clinical studies with rosuvastatin all
show that there is no correlation between the baseline LDL, the % decrease in
LDL, or final LDL value, and the development of myopathy at any of the doses of
rosuvastatin. Patients with LDL values above 100mg/dL, who had not yet met NCEP
goals, developed myopathy and rhabdomyolysis (see Table 12).
Yet out of 149 subjects identified in the
rosuvastatin All Controlled Pool who achieved LDL-cholesterol < 50mg/dl,
only one (0.7%) had increased CK (>1xULN) and two (1.3%) had myalgia. The
frequency of these events was less than observed in the total rosuvastatin
group. In addition nine patients in this All Controlled Pool achieved LDL-cholesterol
below 30 mg/dl and only two adverse events, both unlikely to be related to the
study drug i.e. pharyngitis and lacrimation disorder, were observed.
Table 12
Change In
LDL-Cholesterol associated with CK >10xULN and Myopathy in Patients on
Rosuvastatin in the All Controlled/Uncontrolled Pool
|
|||||
|
Dose (mg) |
Max CK (U/L) |
LDL (mg/dL) Baseline |
LDL (mg/dL) Treateda |
% decrease in LDL |
(*) Rhabdo/ IV
hydration (#) unknown
etiology (e) Exercise or
injury related |
|
5 |
3,954 |
165 |
114 |
-31 |
e |
|
|
3,492 |
204 |
139 |
-32 |
e |
|
|
2,496 |
183 |
106 |
-42 |
e |
|
|
|
|
|
|
|
|
10 |
21,632 |
N/A |
N/A |
N/A |
* |
|
|
5,810 |
165 |
112 |
-32 |
e |
|
|
2,730 |
171 |
69 |
-60 |
e |
|
|
1,888 |
117 |
66 |
-44 |
e |
|
|
1,626 |
195 |
119 |
-39 |
e |
|
|
1,490 |
167 |
71 |
-57 |
e |
|
|
1,490 |
187 |
118 |
-37 |
e |
|
|
1,421 |
159 |
82 |
-48 |
e |
|
|
1,312 |
135 |
91 |
-33 |
e |
|
|
|
|
|
|
|
|
20 |
7,580 |
185 |
101 |
-45 |
# |
|
|
4,550 |
202 |
94 |
-53 |
e |
|
|
1,266 |
174 |
77 |
-56 |
e |
|
|
1,211 |
177 |
92 |
-48 |
e |
|
|
|
|
|
|
|
|
40 |
15,858 |
178 |
63 |
-65 |
# |
|
|
8,470 |
251 |
148 |
-41 |
e |
|
|
3,636 |
194 |
80 |
-59 |
e |
|
|
2,577 |
179 |
66 |
-63 |
e |
|
|
1,836 |
179 |
83 |
-54 |
e |
|
|
1,518 |
200 |
88 |
-56 |
e |
|
|
|
|
|
|
|
|
80 |
34,548 |
221 |
75 |
-66 |
* |
|
|
>20,000 |
272 |
74 |
-73 |
* |
|
|
16,280 |
237 |
59 |
-75 |
* |
|
|
11,132 |
58 |
38 |
-34 |
* |
|
|
7,484 |
217 |
126 |
-42 |
* |
|
|
3,486 |
385 |
163 |
-58 |
* |
|
|
2,509 |
211 |
80 |
-62 |
* |
|
|
5,480 |
167 |
48 |
-71 |
# |
|
|
5,380 |
287 |
N/A |
N/A |
# |
|
|
2,154 |
105 |
N/A |
N/A |
# |
|
|
1,780 |
226 |
96 |
-58 |
# |
|
|
3,610 |
244 |
122 |
-50 |
e |
|
|
2,570 |
334 |
131 |
-61 |
e |
|
|
2,294 |
232 |
113 |
-51 |
e |
|
|
2,184 |
211 |
66 |
-69 |
e |
|
|
1,393 |
288 |
122 |
-58 |
e |
|
a
Data
taken from AV_LUBR |
|||||
MYOPATHY IN CLINICAL TRIALS with ROSUVASTATIN
The frequency of myopathy (CK>10xULN and muscle
symptoms) associated with the use of 80 mg rosuvastatin (i.e. 1.0%) was higher
than had been seen in the pre-approval clinical trials (Table 10) or in current
labels or published clinical trials for all marketed statins (Table 11) except
for 0.4 to 0.8 mg doses of cerivastatin. While most of the rosuvastatin cases
at 80 mg and all but one of the cases at doses of 5 to 40 mg were associated
with muscle injury or excessive exercise, this does not necessarily mean that
these episodes were not drug-related. By comparison there were no cases of
exercise-induced myopathy in any of the other statins in the All Controlled
Pool. Similarly, exercise is rarely a contributing factor in the few cases of
statin related myopathy reported in the literature.
RHABDOMYOLYSIS in CLINICAL TRIALS with ROSUVASTATIN
All 7 cases of rhabdomyolysis at the 80 mg dose
occurred during the open-label extension trials. The average length of time on
the current drug dose prior to the development of rhabdomyolysis was 282 days
(9.4 months) with a standard deviation of 212 days (7 months). The median was
246 days (8.2 months) with a range of 29 to 698 days. Most patients were
titrated up to the 80 mg dose so the total time on rosuvastatin at any dose was
even greater at 386 days (12.9 months). Clearly these patients were able to
tolerate the medication for a long time prior to the adverse event. Most
hospitalizations were preceded by a 3 to 28 day prodrome suggesting a viral
illness with subsequent dehydration as a possible precipitating event. Typical
symptoms included loss in appetite, fatigue, malaise, muscle soreness, muscle
weakness, nausea, vomiting, diarrhea and abdominal distension. This is in
contrast to rhabdomyolysis produced by other clearly myotoxic drugs reviewed by
this division that primarily produced muscle symptoms in healthy individuals
within two to four weeks after starting therapy. These medications still show
individual variability so that not all patients exposed develop myopathy by 4
weeks, but as the dose is increased and the length of exposure is increased a
higher percentage of patients developed rhabdomyolysis.
None of the patients who developed rhabdomyolysis on
rosuvastatin had CK elevations noted prior to the actual episode so periodic CK
monitoring is unlikely to be of benefit in identifying the patients at risk for
rhabdomyolysis.
The one case of rhabdomyolysis on the 10 mg dose
occurred in the double blind study GISSI-HF. This patient had been randomized
on
DEMOGRAPHIC
ANALYIS OF PATIENTS WITH CK ELEVATIONS
Available
patient characteristics were screened to see if any were associated with a
higher risk of developing CK elevations since such patient populations might
require different safety labeling. Data were analyzed to see if there was an
association with CK elevations and the patient’s age, sex, baseline
(creatinine, CK, or LDL-C) levels or past medical history of cardiovascular
heart disease, diabetes, or hypertension (see Table 13).
|
Table 13- Demographic Information on Patients with CK Elevations >10xULN a |
|||||||||
|
Dose |
Age (yrs, Mean±SD) |
Sex (male) |
Baseline (Mean ± SD) |
>30% inc in Cr |
CHD |
Htn |
DM |
||
|
LDL-C (mg/dL) |
CK (U/L) |
Cr (Umol/L) |
|||||||
|
Control (all randomized subjects) N=12,371 |
58 ± 12 |
53% |
190 ± 47 |
70 ± 71 |
97 ± 17 |
3.5% |
36% |
52% |
17% |
|
Control b (trials with rhabdo
patients i.e. 25, 30, 31 and 35) N=1,315 |
54 ± 14 |
57% |
237 ± 76 |
64 ± 46 |
99 ± 17 |
7% |
49% |
37% |
6% |
|
CK>10xULN (N=73) |
52 ± 15 |
77% |
206 ± 51 |
92 ± 57 |
107 ± 19 |
20.5% |
42% |
45% |
11% |
|
Rhabdomyolysis (N=7) |
67 ± 7 |
29% |
229 ± 97 |
66 ± 53 |
103 ± 15 |
86% |
86% |
71% |
14% |
|
a Data were taken from the
latest submission LV_LUBR submitted to the EDR on |
|||||||||
Patients, who developed rhabdomyolysis, were more
likely to be older women with cardiovascular heart disease and hypertension. It
is possible that these co-morbid conditions may impact on their baseline renal
function or alternatively this may reflect a potential interaction with cardiac
or antihypertensive medications and rosuvastatin.
Concomitant medications for the seven patients with
rhabdomyolysis at 80mg (COMMED.xpt files from the
In conclusion, there is a higher incidence of
myopathy (1.0%) and rhabdomyolysis (0.4%) observed in the clinical trials with
80 mg of rosuvastatin than reported in the original NDA or current labels for
any of the currently approved statins. Most cases of myopathy not associated
with exercise or physical injury, including seven out of the eight cases of
rhabdomyolysis, occurred at the 80 mg dose. The risk for 5 to 40 mg doses
appears to be comparable to rates observed in clinical trials for other
approved statins. However, drug interactions (e.g., cyclosporine or
gemfibrozil) and special populations (co-morbid medical conditions, renal
impairment) pose a special challenge to the safe use of this product in the general
population and will clearly need to be addressed in product labeling.
5.4 Renal-Related Adverse Events
SUMMARY- In contrast to currently approved statins, rosuvastatin was also associated with renal findings not previously reported with other statins. A small percentage of patients exposed primarily to the 80 mg dose of rosuvastatin had an increased frequency of persistent proteinuria and hematuria, which in some patients was also associated with an increase in serum creatinine. The sponsor argues that these findings are likely to be a previously unobserved class effect due to inhibition of HMG-CoA reductase in proximal tubular cells as demonstrated in Opossum kidney cells and are reversible following down titration to lower doses. However, the clinical data submitted by the sponsor do not show a similar degree of proteinuria with any of the other statins. In addition the animal model would not account for the hematuria, which was also seen in the clinical studies. It should be noted that hematuria in this database is based on urine dipstick findings, not on microscopic detection of RBCs in the urine. Finally there were two cases of renal failure and one case of renal insufficiency on rosuvastatin 80 mg associated with hematuria and proteinuria and not associated with rhabdomyolysis. Renal biopsies in two of these cases suggested tubular inflammation or necrosis. The sponsor argues that these cases are idiosyncratic.
PROTEINURIA IS SEEN in PATIENTS TAKING 40 and 80 mg DAILY DOSES of ROSUVASTATIN
In the All Controlled Pool it was observed that
there was an increase from baseline in the frequency of proteinuria in the
rosuvastatin group. The number of patients with all grades of proteinuria, from
trace to ++++, went from 20.5% at baseline to 29.5% at the end of the
controlled phase of the trials on rosuvastatin. This is in contrast to a
decrease from 21.0% to 17.3% for patients on total other statins and a decrease
of 27.6% to 23.3% for patients on placebo (see Table 56 ISS).
In response to these unexpected findings in the All Controlled Pool, the sponsor amended the protocols in the open label extension to add urinalysis testing and serum creatinine measurements for all subjects at follow-up visits. Data in Table 14 was separated by drug dose at the onset of proteinuria. These data show an increase of proteinuria at rosuvastatin 40 and 80 mg for patients with 1, 2 or 3 grade increases in proteinuria and an increase of 4 grades in proteinuria in patients on 80 mg of rosuvastatin as well.
|
Proteinuria from Open Label Extension Trials Submitted in PreApproval SUR |
||||||||||
|
Increase
from baseline |
Rosuvastatin Dose |
|||||||||
|
5
mg |
10
mg |
20
mg |
40 mg |
80 mg |
||||||
|
N=270 |
% |
N=577 |
% |
N=123 |
% |
N=155 |
% |
N=631 |
% |
|
|
≥1
grade |
34 |
12.6 |
56 |
9.7 |
17 |
13.8 |
39 |
25.2 |
201 |
31.9 |
|
≥2
grades |
12 |
4.4 |
12 |
2.1 |
7 |
5.7 |
17 |
11.0 |
106 |
16.8 |
|
≥3
grades |
0 |
0 |
2 |
0.3 |
1 |
0.8 |
3 |
1.9 |
34 |
5.4 |
|
≥4
grades |
0 |
0 |
1 |
0.2 |
0 |
0 |
0 |
0 |
5 |
0.8 |
|
Data from Table 14 PreApproval SUR |
||||||||||
The sponsor did
not perform 24 hour urine collections to quantify urine protein in these
patients. Instead the sponsor used (total urine protein-to-urine creatinine)
ratios from spot collections to estimate total urinary protein. 28.8% of the
subjects who had at least a two category shift in urine protein dipstick
measurements had a (total urine protein-to-creatinine) ratio of >0.5
representing a urine protein excretion > 3XULN according to the sponsor.
In an attempt to focus on patients likely to have
more significant levels of proteinuria, the
most current urinalysis data (i.e. AV_LBUR.xpt) were analyzed to look
for patients who had at least a (++) grade of proteinuria and an increase of at
least one grade above their baseline value. In addition, these data were
screened to identify patients with urine dipstick positive hematuria of ³ (+) grade that had an increase of at least
one grade above their baseline value. Data from patients using other statins or
from all patients in the dietary-run in period were used as controls.
These data showed an increase in dipstick-positive
proteinuria, hematuria and proteinuria associated with hematuria, at the
rosuvastatin 80 mg dose (see Table 15). There is a trend suggesting an
intermediate effect at 40 mg whereas the 20 mg and lower doses have rates that
are similar to the background seen with other statins.
|
Table 15 PROTEINURIA AND HEMATURIA in the ALL Controlled
and Uncontrolled and RTLD Pools a |
||||
|
Treatment (mg) |
Total patients |
Urine Dipstick Proteinuria ³ ++ |
Urine
Dipstick Hematuria ³ + |
Proteinuria
³ ++
& Hematuria ³ + |
|
|
N |
% |
% |
% |
|
Dietary
Run-In |
5,811 |
1 |
3 |
0.1 |
|
|
||||
|
Placebo |
372 |
3 |
5 |
0 |
|
|
||||
|
Pravastatin |
|
|
|
|
|
20 |
191 |
1 |
7 |
0.5 |
|
40 |
67 |
0 |
4 |
0 |
|
|
||||
|
Atorvastatin |
|
|
|
|
|
10 |
710 |
2 |
4 |
0.6 |
|
20 |
667 |
2 |
3 |
0.3 |
|
40 |
245 |
0.4 |
2 |
0.4 |
|
80 |
377 |
0.5 |
2 |
0 |
|
|
||||
|
Simvastatin |
|
|
|
|
|
20 |
517 |
4 |
5 |
0.6 |
|
40 |
356 |
2 |
5 |
0.8 |
|
80 |
337 |
0.6 |
8 |
0.3 |
|
|
||||
|
Rosuvastatin |
|
|
|
|
|
5 |
653 |
1 |
6 |
0 |
|
5
OLEb |
438 |
4 |
14 |
1.6 |
|
10 |
1,202 |
2 |
7 |
0.3 |
|
10
OLEb |
5,011 |
3 |
10 |
0.8 |
|
20 |
1,460 |
2 |
4 |
0.3 |
|
20
OLEb |
1,894 |
4 |
8 |
0.7 |
|
40c |
2,384 |
4 |
10 |
1.3 |
|
40
OLEb |
1,684 |
5 |
10 |
1.5 |
|
80 |
804 |
12 |
12 |
6.1 |
|
80
OLEb |
959 |
17 |
22 |
10.5 |
|
a This
data includes only patients with an increase of at least one protein category
above baseline. In the few cases where no baseline values were present it was
assumed the baseline value was no protein and no blood. Data
taken from AV_LBUR.xpt data file b Refers to samples
from the Open Label Extension c
There was one less patient with hematuria results i.e. N=2,383 |
||||
CHANGES IN SERUM CREATININE IN PATIENTS TAKING
ROSUVASTATIN
The sponsor’s analysis of serum creatinine levels in the
All Controlled and RTLD Pools (see Table 27 Sponsor’s briefing packet) showed a
slight decrease from baseline in mean creatinine levels of 1 to 4% for all
statins including rosuvastatin doses up to 40 mg. At the rosuvastatin 80 mg
dose there was a slight increase of 2.2% in the mean serum creatinine. The
significance of such a finding is hard to interpret since the standard
deviation about the mean of the baseline creatinine values range from 15 to
18%. Substantial changes in a small subgroup of patients could be easily missed
by such an analysis.
Out of
all the patients enrolled in these trials only 3% had an increase in serum
creatinine of > 30% above baseline
during the clinical trials (data from AV_LBUR.xpt).
However, in the subgroup of patients with dipstick-positive urine (≥++
protein and ≥+ blood), the percentage of patients with an increase of
serum creatinine of 30% over baseline was 14%, 16%, 24%, 33%, and 41% for 5 mg,
10 mg, 20 mg, 40 mg and 80 mg of rosuvastatin, respectively. A similar earlier analysis
by the sponsor also showed an increase in serum creatinine in patients with
combined hematuria and proteinuria (see appendix). These data suggest that some patients with
greater levels of proteinuria and hematuria may progress to clinically relevant
renal disease.
PERSISTENCE OF PROTEINURIA FROM THE CONTROLLED TRIALS
DURING THE OPEN LABEL EXTENSION
To get an estimate
for the persistence of the proteinuria identified during the controlled feeder
trials, the sponsor originally looked at a subgroup of 297 patients who
demonstrated an increase in urine protein in their last feeder trial visit.
These patients were screened to see how many had no change or a further
increase in their level of proteinuria at the last recorded visit of the open
label extension. Out of these patients
71.4% improved, 20.9% showed no change, and 7.7% showed worsening of
proteinuria on therapy with rosuvastatin. While the data for no change are
mixed across all doses, it is clear that patients on 80 mg are more likely to
have progressive proteinuria.
|
Table 16- Urine Protein Change in Patients with an
Increase in Urine Protein Noted
During the Feeder Trial |
||||||||||||
|
|
5 mg N=18 |
10 mg N=60 |
20 mg N=21 |
40 mg N=37 |
80 mg N=161 |
All doses N=297 |
||||||
|
|
N |
% |
N |
% |
N |
% |
N |
% |
N |
% |
N |
% |
|
No change in proteinuria |
5 |
28 |
12 |
20 |
1 |
5 |
3 |
8 |
41 |
25 |
62 |
20.9 |
|
Increase in proteinuria |
0 |
0 |
1 |
2 |
1 |
5 |
2 |
5 |
19 |
12 |
23 |
7.7 |
|
Data taken from Table
15 PreApproval SUR |
||||||||||||
The sponsor emphasized that
most patients (71.4%) with proteinuria improve on continued therapy (including
data from all doses). While the number of patients who progress on therapy may
be small, this may still be clinically significant if it can be associated with
increases in creatinine and renal insufficiency.
Following down titration of
the patients on rosuvastatin 80 mg to 40 mg the sponsor reports that the
frequency of patients with proteinuria ≥++ fell from 7.5% to 1.9% on the
first follow–up visit suggesting that proteinuria at 80 mg is reversible.
A prospective
analysis of the incidence of proteinuria would be more informative than the
down-titration of patients from rosuvastatin 80 to 40 mg. The sponsor attempted
such an analysis in Trial 99, which has yet to be completed. This was a 6-week,
open-label, randomized trial comparing rosuvastatin 40 mg to simvastatin 80 mg
in patients with type IIa and IIb hypercholesterolemia. Frequent monitoring of
proteinuria, hematuria, creatinine, and urinary protein excretion pattern was
incorporated into the trial. Preliminary results from the trial suggest, as
might have been predicted, that it will be more difficult to clarify the
frequency and duration of the proteinuria associated with rosuvastatin 40 mg
since it is much less frequent than seen with 80 mg. The frequency of
proteinuria (≥ ++) in this 6-week trial was much lower than was seen in
the larger ALL Controlled/Uncontrolled and RTLD Pools (Table 15), which
included data from the long-term extension trials. Consequently, data for the
occurrence of a lower degree of proteinuria
(≥ +) were also included for comparison. Clearly six weeks may be
insufficient time to detect enough cases of proteinuria, yet there is a
suggestion that rosuvastatin 40 mg is still more likely to cause proteinuria
than simvastatin 80 mg. It is not clear why there is such a high frequency of
dipstick positive (≥ +) hematuria in both the simvastatin and
rosuvastatin groups in this trial.
|
Table 17 Frequency of Proteinuria in Trial 99a |
|||||||
|
|
Patient (N) |
≥ + proteinuria |
≥ ++ proteinuria |
≥ + hematuria |
|||
|
|
|
N |
% |
N |
% |
N |
% |
|
Dietary Lead-In |
620 |
21 |
3.4 |
4 |
0.6 |
49 |
7.9 |
|
Simvastatin 80 mg |
315 |
6 |
1.9 |
2 |
0.6 |
27 |
8.6 |
|
Rosuvastatin 40 mg |
316 |
25 |
7.9 |
5 |
1.6 |
27 |
8.6 |
|
aData
derived from AV_LUBR.xpt dat file Because of the low
frequency of (++) proteinuria seen at 6 weeks in this trial the frequency of
(+) proteinuria was also calculated. |
|||||||
POSSIBLE RENAL TUBULAR DAMAGE ASSOCIATED WITH
ROSUVASTATIN
Analysis of the urine protein in patients taking
rosuvastatin revealed elevated levels of beta-2-microglobulin and
N-acetyl-beta-D-glucosaminidase suggesting a renal tubular etiology according
to the sponsor. Drug insolubility or crystallization in the renal tubules would
be an alternative hypothesis of a potential mechanism for renal tubular
damage.
KIDNEY FAILURE/ INSUFFICIENCY in PATIENTS on 80 MG of ROSUVASTATIN
Two cases of renal failure and
one case of renal insufficiency, all with unknown etiology were seen in the
open label extensions and ongoing trials in patients receiving 80 mg of
rosuvastatin. Narratives for these three patients will be presented below but
additional information from the latest MedWatch forms can be found in the
appendix.
A 46 year old female (0065/0044/0014) with normal baseline
lab values presented with nausea, anorexia, and fatigue and an abnormal
urinalysis [proteinuria (30mg/dL), hematuria (small), 15-20 RBC/hpf, 10-15
WBC/hpf, coarse granular and hyaline casts in the urine sediment] after 31
days on rosuvastatin. The urine culture grew mixed organisms. Her
creatinine went from 1.1 to 13.7 mg/dL.
CPK was normal at 41 U/L. A renal scan showed multiple cystic masses in
both kidneys. The drug was stopped. She responded to IV hydration and was
discharged from the hospital with a serum creatinine of 3.8 mg/dl. Azithromycin
and candesartan were possible contributing medications.
A 70 y/o female (0065/0026/0049) taking rosuvastatin 80
mg developed acute tubular necrosis on Day 15 of ongoing Trial 65. She
was also taking rofecoxib, valsartan and amlodipine at the time of the adverse
event. She presented with generalized body aches, right-sided abdominal pain
radiating to the right flank, nausea and vomiting.
A 69-y/o male (0034/0316/0025)
developed chronic
tubulo-interstitial nephritis with proteinuria, active urine sediment and a
rise in serum creatinine after he had been on 80 mg of rosuvastatin for 1
year and 6 months. He had a h/o hospitalization at 8 years of age for
inflammation of the kidneys, which resolved without known sequelae. (Probably,
“minimal change disease” and unrelated to the present episode). During the
6-week dietary lead-in he had one urine sample with no protein but active
sediment? (Not described), and one urine sample with 1+ protein and some
bacteria but no active sediment. He also had a normal baseline serum creatinine
1.1 mg/dl. At the one-year visit his creatinine was up to 1.6 mg/dl but a
urinalysis was not done. His urinalysis at the time of the renal biopsy was 1+
protein, 3+ blood and numerous granular casts with moderate numbers of renal
tubular cells. Daily protein excretion was 1.6 g/day, serum creatinine was
still 1.6 mg/dL. The biopsy showed moderate increase in fibrous tissue and
occasional inflammatory cells in the interstitium, suggestive of a chronic
process present for many months and resulting in gradual collagen deposition
within the interstitium rather than an acute process. Rosuvastatin was
officially stopped at 2 years (
These three cases of renal
insufficiency of unknown etiology are of concern because they present with a
clinical pattern, which is similar to the renal disease seen with rosuvastatin
in these clinical trials. There is mild proteinuria associated with hematuria
and the suggestion of tubular inflammation or necrosis. All cases occurred at
the 80 mg dose which was also associated with the greatest number of patients
with abnormal renal findings in these clinical trials. Proteinuria and hematuria
could be potentially managed with regular urinalysis screening. However, if
they are the signals for the potential progression to renal failure in a small
number of patients, this may represent an unacceptable risk since currently
approved statins do not have similar renal effects.
In conclusion, in addition to
the known association of statins with rhabdomyolysis and elevation in liver
transaminases, rosuvastatin appears to be associated with the development of
proteinuria with and without hematuria at higher doses.
The mechanism for proteinuria
is unknown although the sponsor postulates that protein uptake by renal tubular
cells is inhibited by the statin effect on HMG-CoA reductase activity in renal
proximal tubule cells. The finding of
increased beta-2-microglobulin and N-acetyl-beta-D-glucosaminidase may also
suggest renal tubular damage.
The incidence of proteinuria
is clearly higher in patients treated with rosuvastatin 80 mg. The frequency of proteinuria with and without
hematuria is lower in the 40 mg dose group but remains slightly higher than the
lower dose groups. It is not clear from
the current trials if the proteinuria is transient, waxes and wanes or is
likely to progress to renal failure in a small number of patients. Such
concerns may potentially be addressed in phase IV trials.
5.5 Correlation with Serious Adverse Events and Serum Rosuvastatin Levels
At the request of the agency, the sponsor
submitted the limited data they had for rosuvastatin serum levels in patients
with serious adverse events. Plasma concentrations for asymptomatic patients
receiving 20, 40 or 80 mg of rosuvastatin in clinical trials 8, 23, 33, and 35
are shown in Figure 1 below. These values are compared to nine plasma samples
obtained from six patients with serious adverse events involving muscle and or
renal toxicity. These data correspond to Figure 22 in the sponsor’s submission.
Figure 1 Steady State Plasma
Rosuvastatin Levels
Two of these patients had myopathy with peak CK values of 5,380 and 2,154, two patients had rhabdomyolysis with peak CK values of 16,280 and >20,000 and two patients had renal failure of unknown etiology with normal CK values.
There is no overlap in exposure among patients
receiving 20 mg and those showing evidence of toxicity. 5/273 patients (<2%)
at 40 mg and 33/272 (33%) at 80 mg had steady-state plasma concentrations above
50ng/ml, the lowest observed plasma concentration associated with toxicity in
these six patients. These data are derived from only a subset of patients
studied in the entire clinical development program. Furthermore, one cannot definitively conclude
from this analysis that a cut-off in drug level has been identified which will
divide patients into an “at-risk” and “no-risk” category as other predisposing
factors aside from drug levels may contribute to clinical toxicity. These data, however, support the
recommendation for dose limitation in special populations wherein drug exposure
would be increased secondary to drug-drug interactions, diminished metabolism,
or compromised clearance. While appropriate labeling restricting drug
doses in certain situations can attempt to address potential safety concerns,
labeling changes alone have not proven to be effective in changing prescriber
behavior.
6. APPENDIX
6.1 MedWatch Forms for Cases of Special Interest:
Appendix subsection 6.1 has
been removed from this document. See
cover page link entitled: Clinical Review Appendix subsection 6.1 MedWatch
Forms for Cases of Special Interest.