Zee
THE LANCET • Vol 363 • June 26, 2004 •
www.thelancet.com 2189
CORRESPONDENCE CORRESPONDENCE COMMENTARY
Dangers of rosuvastatin identified before and after
FDA approval
Sir—The lipid-lowering drug rosuvastatin is currently in the
midst of the most heavily financed launch of a prescription
drug ever. Here I present premarketing and postmarketing
evidence of the dangers of the drug, and call for its
removal from the market.
Detailed briefing documents including unpublished reviews of
safety and efficacy data from clinical trials are now made
public on the internet before all Food and Drug
Administration (FDA) advisory committee meetings discussing
the approval of a new drug.
Documents for the July 9, 2003, meeting on rosuvastatin,1
and the transcript of that meeting,2 were the source of the
preapproval data I present. FDA adverse event reporting
system (AERS) reports up to April 13, 2004, obtained through
the Federal Freedom of Information Act were the source of
postmarketing data.
The preapproval documents state that "The data. . . 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
(drugdrug interactions, renal impairment, Japanese
descent)."
There were eight cases of rhabdomyolysis, seven at 80 mg and
one at 10 mg, in clinical trials.1 The preapproval documents
also state that "80 mg of rosuvastatin has a high frequency
of [creatine kinase] elevations (CK>10_ULN=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" and that "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."1
The FDA stated at the meeting that "since safe and effective
statins with a low risk for the development of
rhabdomyolysis are already currently available, any future
statins which would be approved need to have a comparable or
lower risk for this adverse event".2 However, rosuvastatin
was approved under the belief that doses lower than 80 mg
would be much safer.
". . . 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
figure, based on the documents,1 shows a dose related
increase in haematuria and proteinuria, beginning with 1•3%
of patients at 40 mg. None of the other statins showed any
dose-related increase. "Out of all the patients enrolled in
these trials only 3% had an increase in serum creatinine of
>30% above baseline. . . 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. . . These data suggest that some patients with
greater levels of proteinuria and hematuria may progress to
clinically relevant renal disease".1
Three cases of renal insufficiency or renal failure during
the trials in people using 80 mg were "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. . .
However, if they [proteinuria and hematuria] 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".1
A statistical review of the efficacy of rosuvastatin
compared with higher doses of another statin found that
there was no significant difference in the percentage LDL
change from baseline between 5, 10, or 20 mg of rosuvastatin
and four times as much atorvastatin (20, 40, or 80 mg,
respectively).3
Since marketing began, there have been 18 additional cases
of rhabdomyolysis, including 11 in the USA, even though the
drug had only been on the market in that country for 7
months as of the April 13 date of the AERS data from the
FDA. All of the latest ten US cases had been reported in the
6 weeks before April 13. Two of the 18 patients were using
40 mg, five were using 20 mg, and 11 were using 10 mg. An
FDA review of reports of rhabdomyolysis in other currently
marketed statins found that the rate of reports per million
US prescriptions ranged from none for fluvastatin to 1•2 per
million for lovastatin, the next highest being 0•8 for
simvastatin, then •3 for atorvastatin.4
If the majority of the 11 US postmarketing reports of
rhabdomyolysis meet the case definition used in the FDA
paper4 (ie, creatine phosphokinase concentration _10 000
IU/L), as did 62% of the eight premarketing cases, and using
the FDA estimate of one million prescriptions for
rosuvastatin in the USA,5 the rate of rhabdomyolysis reports
for rosuvastatin is probably higher than the highest of any
other currently marketed statin, predictable from
preapproval trial data. Only cerivastatin, now banned, was
higher at 18•1 per million. There have been eight reported
cases of acute renal failure and four of renal insufficiency
in patients using rosuvastatin since marketing began. Of
these 12 cases, the dose was known in
11: nine were using the 10 mg dose, the other two 40 and 80
mg. By now, the number of reported cases of
rhabdomyolysis and renal insufficiency or renal
failure—20 of which have occurred in people using 10
mg—is certain to have increased substantially from the
number filed by April 13, 2004. The renal toxicity, high
rate of cases of rhabdomyolysis compared with other
statins, and lack of unique benefit are compelling
reasons to remove rosuvastatin from the market before
additional patients are injured or killed. To allow
AstraZeneca to continue desperately seeking a piece of
the estimated $20 billion a year statin market hardly
justifies governments allowing this ultimately doomed
drug to stay on the market.
Sidney M Wolfe Public Citizen's Health Research Group, 1600
20th Street Northwest, Washington, DC 20009, USA (e-mail:
swolfe@citizen.org)
1 Food and Drug Administration Center for Drug Evaluation
and Research (CDER). Endocrinologic and Metabolic Drugs
Advisory Committee Meeting, July 9, 2003.
Briefing information: Crestor: indicated for the treatment
of hypercholesterolemia and mixed dyslipidemia.
http://www.fda.gov/ohrms/dockets /ac/03/briefing/3968b1.htm
(accessed June 1, 2004).
2 Department of Health and Human Services, Food and Drug
Administration Center for Drug Evaluation and Research
Endocrinologic and Metabolic Drugs Advisory Committee. July
9, 2003, Bethesda, MD, USA. http:// (http:///)
www.fda.gov/ohrms/dockets/ac/03/ transcripts/3968T1.htm
(accessed June 1, 2004).
3 Mele J. Crestor (ZD4522, rosuvastatin calcium) tablets:
comments on efficacy.
http://www.fda.gov/ohrms/dockets/ac/03/ slides/3968S1_02_FDA-
Mele.ppt#8 (accessed June 10, 2004).
4 Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with
HMG-CoA reductase inhibitors and gemfibrozil combination
therapy. Pharmacoepidemiol Drug Safety 2004; 13: 417–26.
http:// (http:///) interscience.wiley.com DOI:
12.1002/pds.977
5 Gardner A. Group seeks ban on cholesterol drug.
http://www (http://www/). medicinenet.com/script/main/
art.asp?articlekey=32678 (accessed June 1, 2004).
www.thelancet.com 2189
CORRESPONDENCE CORRESPONDENCE COMMENTARY
Dangers of rosuvastatin identified before and after
FDA approval
Sir—The lipid-lowering drug rosuvastatin is currently in the
midst of the most heavily financed launch of a prescription
drug ever. Here I present premarketing and postmarketing
evidence of the dangers of the drug, and call for its
removal from the market.
Detailed briefing documents including unpublished reviews of
safety and efficacy data from clinical trials are now made
public on the internet before all Food and Drug
Administration (FDA) advisory committee meetings discussing
the approval of a new drug.
Documents for the July 9, 2003, meeting on rosuvastatin,1
and the transcript of that meeting,2 were the source of the
preapproval data I present. FDA adverse event reporting
system (AERS) reports up to April 13, 2004, obtained through
the Federal Freedom of Information Act were the source of
postmarketing data.
The preapproval documents state that "The data. . . 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
(drugdrug interactions, renal impairment, Japanese
descent)."
There were eight cases of rhabdomyolysis, seven at 80 mg and
one at 10 mg, in clinical trials.1 The preapproval documents
also state that "80 mg of rosuvastatin has a high frequency
of [creatine kinase] elevations (CK>10_ULN=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" and that "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."1
The FDA stated at the meeting that "since safe and effective
statins with a low risk for the development of
rhabdomyolysis are already currently available, any future
statins which would be approved need to have a comparable or
lower risk for this adverse event".2 However, rosuvastatin
was approved under the belief that doses lower than 80 mg
would be much safer.
". . . 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
figure, based on the documents,1 shows a dose related
increase in haematuria and proteinuria, beginning with 1•3%
of patients at 40 mg. None of the other statins showed any
dose-related increase. "Out of all the patients enrolled in
these trials only 3% had an increase in serum creatinine of
>30% above baseline. . . 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. . . These data suggest that some patients with
greater levels of proteinuria and hematuria may progress to
clinically relevant renal disease".1
Three cases of renal insufficiency or renal failure during
the trials in people using 80 mg were "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. . .
However, if they [proteinuria and hematuria] 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".1
A statistical review of the efficacy of rosuvastatin
compared with higher doses of another statin found that
there was no significant difference in the percentage LDL
change from baseline between 5, 10, or 20 mg of rosuvastatin
and four times as much atorvastatin (20, 40, or 80 mg,
respectively).3
Since marketing began, there have been 18 additional cases
of rhabdomyolysis, including 11 in the USA, even though the
drug had only been on the market in that country for 7
months as of the April 13 date of the AERS data from the
FDA. All of the latest ten US cases had been reported in the
6 weeks before April 13. Two of the 18 patients were using
40 mg, five were using 20 mg, and 11 were using 10 mg. An
FDA review of reports of rhabdomyolysis in other currently
marketed statins found that the rate of reports per million
US prescriptions ranged from none for fluvastatin to 1•2 per
million for lovastatin, the next highest being 0•8 for
simvastatin, then •3 for atorvastatin.4
If the majority of the 11 US postmarketing reports of
rhabdomyolysis meet the case definition used in the FDA
paper4 (ie, creatine phosphokinase concentration _10 000
IU/L), as did 62% of the eight premarketing cases, and using
the FDA estimate of one million prescriptions for
rosuvastatin in the USA,5 the rate of rhabdomyolysis reports
for rosuvastatin is probably higher than the highest of any
other currently marketed statin, predictable from
preapproval trial data. Only cerivastatin, now banned, was
higher at 18•1 per million. There have been eight reported
cases of acute renal failure and four of renal insufficiency
in patients using rosuvastatin since marketing began. Of
these 12 cases, the dose was known in
11: nine were using the 10 mg dose, the other two 40 and 80
mg. By now, the number of reported cases of
rhabdomyolysis and renal insufficiency or renal
failure—20 of which have occurred in people using 10
mg—is certain to have increased substantially from the
number filed by April 13, 2004. The renal toxicity, high
rate of cases of rhabdomyolysis compared with other
statins, and lack of unique benefit are compelling
reasons to remove rosuvastatin from the market before
additional patients are injured or killed. To allow
AstraZeneca to continue desperately seeking a piece of
the estimated $20 billion a year statin market hardly
justifies governments allowing this ultimately doomed
drug to stay on the market.
Sidney M Wolfe Public Citizen's Health Research Group, 1600
20th Street Northwest, Washington, DC 20009, USA (e-mail:
swolfe@citizen.org)
1 Food and Drug Administration Center for Drug Evaluation
and Research (CDER). Endocrinologic and Metabolic Drugs
Advisory Committee Meeting, July 9, 2003.
Briefing information: Crestor: indicated for the treatment
of hypercholesterolemia and mixed dyslipidemia.
http://www.fda.gov/ohrms/dockets /ac/03/briefing/3968b1.htm
(accessed June 1, 2004).
2 Department of Health and Human Services, Food and Drug
Administration Center for Drug Evaluation and Research
Endocrinologic and Metabolic Drugs Advisory Committee. July
9, 2003, Bethesda, MD, USA. http:// (http:///)
www.fda.gov/ohrms/dockets/ac/03/ transcripts/3968T1.htm
(accessed June 1, 2004).
3 Mele J. Crestor (ZD4522, rosuvastatin calcium) tablets:
comments on efficacy.
http://www.fda.gov/ohrms/dockets/ac/03/ slides/3968S1_02_FDA-
Mele.ppt#8 (accessed June 10, 2004).
4 Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with
HMG-CoA reductase inhibitors and gemfibrozil combination
therapy. Pharmacoepidemiol Drug Safety 2004; 13: 417–26.
http:// (http:///) interscience.wiley.com DOI:
12.1002/pds.977
5 Gardner A. Group seeks ban on cholesterol drug.
http://www (http://www/). medicinenet.com/script/main/
art.asp?articlekey=32678 (accessed June 1, 2004).
