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[e-drug] petition to ban rosuvastatin

E-DRUG: petition to ban rosuvastatin

March 4, 2004

Mark B. McClellan, M.D., Ph.D., Commissioner
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20854

Dear Commissioner McClellan:

Public Citizen, representing 160,000 consumers nationwide, hereby
petitions the U.S. Food and Drug Administration (FDA) pursuant to the
Federal Food, Drug and Cosmetic Act 21, U.S.C. Section 355(e)(3), and 21
C.F.R. 10.30, to immediately remove from the market  rosuvastatin
(Crestor-AstraZeneca) before additional cases of life-threatening
rhabdomyolysis and kidney failure/kidney damage occur.

We have obtained new information from the FDA and health agencies in
Canada and the U.K. concerning serious post-marketing adverse reactions
? including seven cases of life-threatening rhabdomyolysis (muscle
destruction) and nine cases of kidney failure or kidney damage ? in
patients mostly using lower doses of this recently-approved
cholesterol-lowering drug, rosuvastatin.  We have also become aware of
decisions by major U.S. health insurers and by the Swedish government
not to reimburse for the drug. This information re-emphasizes the basis
for which we strongly urged the FDA not to approve it last year and
subsequently advised people not to use the drug once it was approved.
The urgency of this petition is heightened by the fact that AstraZeneca
is currently launching a major direct-to-consumer advertising campaign
to promote the drug.

In opposing the drug?s approval at a July 9, 2003 FDA advisory
committee meeting, we pointed to two cases of kidney failure and one
case of kidney insufficiency in clinical trials prior to approval in
which patients had also experienced both protein and blood in the urine.
There were also a large number of patients who had blood and/or protein
in their urine but had not suffered from kidney failure. In addition to
this kidney toxicity, unique among all of the statin drugs, rosuvastatin
is the only one of these drugs in which any cases of the
life-threatening muscle destruction known as rhabdomyolysis was found to
occur prior to approval. Even cerivastatin (Baycol), which was
ultimately banned after at least 31 cases of fatal rhabdomyolysis, had
not caused a single case of this adverse reaction prior to approval. In
contrast, there were seven cases of rhabdomyolysis in patients receiving
rosuvastatin before its approval. Although all were receiving a dose (80
milligrams) that was not approved, a small patient getting even the 40
milligram dose might be receiving the same amount of drug per pound of
body weight and we were concerned that cases would occur at this 40
milligram dose or even lower doses. We stated that it was likely, if not
certain, that if it were approved, rosuvastatin would have to be banned
because of post-marketing cases of rhabdomyolysis and kidney failure
that would inevitably occur.

In the United States, where the drug has only been on the market for a
little more than 5 months, a 39-year-old woman, taking only 20
milligrams a day, died of rhabdomyolysis and renal insufficiency. In
addition, a 63-year-old man in the U.S. developed acute renal failure
using a dose of only 10 milligrams a day and another patient in the U.S.
developed renal insufficiency and renal tubular necrosis after using
rosuvastatin at a dose of 10 milligrams a day for only 2 weeks. The
total number of new cases of adverse reactions after approval in the
U.S., Canada and the U.K. combined include:

? 7 patients with rhabdomyolysis (patients using doses of 10, 20, 20,
20-40, 40, 40 and 80 milligrams per day)

? 4 patients with acute kidney failure (patients using 10, 10, 10 and
40 milligrams per day)

? 5 additional patients with kidney damage (patients using 10, 10, 10,
20 and 40 milligrams per day)

? 6 patients with bleeding or abnormal bleeding tests who were also
using blood-thinning drugs such as coumadin, known to have an abnormal
interaction with rosuvastatin (patients using  10, 10, 10, 10, 20 and
unknown milligrams per day)

Two major U.S. insurers, WellPoint/Blue Cross, with 15 million patients
insured, and Group Health Cooperative of Puget Sound (GHCPS) with more
than 500,000 members have refused to reimburse for Crestor. "We've
already been Baycolled," said Dr. Robert Seidman, chief pharmacy officer
for the Thousand Oaks, Calif.-based WellPoint. "There is a level of
nervousness, and we're being conservative and we're being cautious,"
Seidman also said.

Group Health Cooperative of Puget Sound (GHCPS) stated, in its decision
not to reimburse for the drug, that ?Rosuvastatin offers no advantage
over current formulary HMG-CoA reductase inhibitors [other statins] in
terms of efficacy, safety, and cost. The effect of rosuvastatin on
cardiovascular outcomes has not yet been studied and the safety of
rosuvastatin beyond the one-year duration of clinical trials is unknown.
Due to the recall of cerivastatin, a statin associated with several
cases of rhabdomyolysis, the committee recommends using caution before
prescribing statins with limited safety data.?  In addition, a
spokesperson from GHCPS expressed some concern about questions of safety
based on evidence from the clinical trials.

It is of particular interest that GHCPS has decided to reject from
their formulary rosuvastatin because in the past, they similarly
rejected other drugs that had come on the market with serious safety
questions such as the pain-killer Duract, the high blood pressure drug
Posicor, the diabetes drug Rezulin, and the weight reduction drug Redux,
all of which were eventually banned by the FDA.

In Sweden, regional governmental drug advisors recommended against the
use of the drug. The committees said in a statement that newer drugs
such as Crestor were not recommended because they did not meet the
criteria of documented safety and cost effectiveness. The decision was
unusual, because the representatives for Sweden's regional governments
were unanimous in their decision.

In an editorial in the October 25, 2003 issue of the British medical
journal, The Lancet, editor Dr. Richard Horton wrote:

?AstraZeneca's tactics in marketing its cholesterol-lowering drug,
rosuvastatin, raise disturbing questions about how drugs enter clinical
practice and what measures exist to protect patients from inadequately
investigated medicines.
?After a damaging delay over safety concerns, rosuvastatin finally won
US FDA approval in August and was launched last month, winning a 2%
market share after only three weeks. [AstraZeneca CEO] McKillop has
pledged to do whatever it takes to persuade doctors to prescribe
rosuvastatin, including launching an estimated $1 billion first-year
promotional campaign. "We've got to drive the momentum", he said at a
recent investors meeting. "You get one shot at launching a major new
product. This is our shot."

Why does the quality of debate about statins matter? First, because
safety cannot be assured. Bayer withdrew cerivastatin in August, 2001,
after the occurrence of unexpected cases of fatal rhabdomyolysis. The 80
mg dose of rosuvastatin was withdrawn by AstraZeneca because of safety
concerns. Some critics are even anxious about the 40 mg dose. The
finding of proteinuria [protein in the urine] and microscopic haematuria
[blood in the urine] associated with rosuvastatin use are additional
worries?.Since there are no reliable data about efficacy [that is,
actually decreasing heart attacks and strokes, not merely lowering
cholesterol levels] and safety--and AstraZeneca is facing unusually
acute commercial pressure to force rosuvastatin into the market--doctors
should pause before prescribing this drug. Physicians must tell their
patients the truth about rosuvastatin--that, compared with its
competitors, rosuvastatin has an inferior evidence base supporting its
safe use. AstraZeneca has pushed its marketing machine too hard and too
fast. It is time for McKillop to desist from this unprincipled

At the FDA advisory committee meeting on July 9, 2003 concerning  the
possible approval of rosuvastatin, I stated:

       ?In summary, we strongly oppose the approval of rosuvastatin
because of its unique renal toxicity. We are also seriously concerned
because of the seven cases of rhabdomyolysis that were common enough to
have shown up in clinical trials, unlike the pre-approval studies with
all previously approved statins, including cerivastatin. The fact that
so few patients on the 20 or 40 mg doses took the drug for a sufficient
period of time to have had a chance to develop rhabdomyolysis seems to
have imparted a false sense of security about the safety of these doses
concerning muscle toxicity?If this drug is approved, it is highly likely
it will have to be removed from the market after ?enough?  further
damage to patients occurs.?

 The new information from the U.K, Canadian and U.S. governments
documenting cases of rhabdomyolysis and kidney damage in people using
the using lower (10, 20 and 40 milligram) doses of rosuvastatin confirms
these concerns and emphasizes the need for banning this drug.


Sidney M.Wolfe M.D.
Director, Public Citizen's Health Research Group
1600 20th St. NW, Washington, DC. 20009
202 588-7735  fax 588-7796
e-mail swolfe@citizen.org
Web site: www.citizen.org/hrg

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