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FDA Public Health Advisory
on Crestor (rosuvastatin)
Astra-Zeneca Pharmaceuticals today released a
revised package insert for Crestor (rosuvastatin) (link to FDA
approved labeling). The changes to the label include results from a
Phase 4 pharmacokinetic study in Asian-Americans and highlight
important information on the safe use of Crestor to reduce the risk
for serious muscle toxicity (myopathy/rhabdomyolysis), especially at
the highest approved dose of 40 mg. At this time, the FDA is also
making statements about the muscle and kidney safety of Crestor
based on extensive review of available information.
Background
Crestor, a member of a class of cholesterol-lowering drugs commonly
referred to as “statins”, was approved in the U.S. in August 2003,
based on review of an extensive clinical database involving
approximately 12,000 patients. These data supported the safety and
efficacy of Crestor for use in lowering serum cholesterol, but also
showed that Crestor, like all statins, rarely could cause serious
muscle damage (myopathy and rhabdomyolysis). In the approved
labeling, the FDA identified in the WARNINGS section of the product
label those patients in whom more careful monitoring was warranted
when prescribed Crestor. In a section titled: “Myopathy/Rhabdomyolysis”,
the label states that patients who are of advanced age (> 65 years),
have hypothyroidism, and/or renal insufficiency should be considered
to have a greater risk for developing myopathy while receiving a
statin. Physicians are warned to prescribe Crestor with caution in
these patients, particularly at higher doses, as the risk of
myopathy increases with higher drug levels.
Based on these concerns, from the time of original approval, the FDA
required Astra-Zeneca to make available in the U.S. a 5-mg dose that
could be used in patients requiring less aggressive
cholesterol-lowering or who were taking concurrent cyclosporine. The
maximum recommended dose in the FDA-approved label is limited to 10
mg daily in patients with severe renal impairment or who are also
taking gemfibrozil.
Description of current changes to the Crestor label
In a pharmacokinetic study involving a diverse population of Asians
residing in the United States, rosuvastatin drug levels were found
to be elevated approximately 2-fold compared with a Caucasian
control group. As a result of these findings, the “Dosage and
Administration” section of the label now states that the 5 mg dose
of Crestor should be considered as the start dose for Asian patients
and any increase in dose should take into consideration the
increased drug exposure in this patient population. Results of this
pharmacokinetic study are further discussed under the “Clinical
Pharmacology” and “Precautions” section of labeling.
The “Warnings” and “Dosage and Administration” sections of the label
have been revised to more strongly emphasize the risks of myopathy,
particularly at the highest approved dose of 40 mg. In order to
minimize risks of myopathy and rhabdomyolysis (the most severe form
of statin muscle injury), the revised label now explicitly states
that the 5 mg dose is available as a start dose for those
individuals who do not require aggressive cholesterol reductions or
who have predisposing factors for myopathy. This includes patients
taking cyclosporine, Asian patients, and patients with severe renal
insufficiency. It also emphasizes that the 40 mg dose is not an
appropriate start dose and should be reserved only for those
patients who have not achieved their cholesterol goals with the 20
mg dose. This information is included in a bolded paragraph under
the “Dosage and Administration” section that also reminds
prescribers who switch patients from other statins to initiate
therapy only with approved doses of Crestor and titrate according to
the patient's individualized goal of therapy.
Healthcare professionals are reminded of the
following key safety messages from the Crestor label:
-
Start doses and maintenance doses of drug should be
based on individual cholesterol goals and apparent risks for
side-effects
-
All patients should be informed that statins can
cause muscle injury, which in rare, severe cases, can cause kidney
damage and organ failure that are potentially life-threatening
-
Patients should be told to promptly report to their
healthcare provider signs or symptoms of muscle pain and weakness,
malaise, fever, dark urine, nausea or vomiting
Review of Crestor muscle and kidney safety
Concerns have been raised about the possible increased muscle
toxicity of Crestor compared to other statins on the market and
about possible adverse effects on the kidney. The FDA has conducted
an extensive review of Crestor data from pre-marketing and
post-marketing clinical trials as well as adverse event reports
submitted to the agency.
Muscle
Crestor, like all statins, has been associated with a low incidence
of rhabdomyolysis (severe muscle damage). Data available to date
from controlled trials, as well as post-marketing safety
information, indicate that the risk of serious muscle damage is
similar with Crestor compared to other marketed statins. As with all
statins, some individuals taking Crestor will experience muscle side
effects, most commonly mild aches and very rarely severe muscle
damage. Like all drugs in this class, risks of muscle injury can be
minimized by adhering to labeled warnings and precautions, carefully
following dosing instructions, and instructing patients to be aware
of and to report possible side effects to the physician. Finally,
like all statins, Crestor should be prescribed at the lowest dose
that achieves the goals of therapy (e.g., target LDL-C level).
Kidney
Various forms of kidney failure have been reported in patients
taking Crestor, as well as with other statins. Renal failure due to
other factors is known to occur at a higher rate in patients who are
candidates for statin therapy (e.g., patients with diabetes,
hypertension, atherosclerosis, heart failure). No consistent pattern
of clinical presentation or of renal injury (i.e., pathology) is
evident among the cases of renal failure reported to date that
clearly indicate causation by Crestor or other statins.
Mild, transient proteinuria (or protein in the urine, usually from
the tubules), with and without microscopic hematuria (minute amounts
of blood in the urine), occurred with Crestor, as it has with other
statins, in Crestor’s pre-approval trials. The frequency of
occurrence of proteinuria appeared dose-related. In clinical trials
with doses from 5 to 40 mg daily, this effect was not associated
with renal impairment or renal failure (i.e., damage to the
kidneys). It is recommended, nevertheless, that a dose reduction and
an investigation into other potential causes be considered if a
patient on Crestor develops unexplained, persistent proteinuria.
Ongoing controlled clinical trials of Crestor and other statins,
epidemiologic studies of the safety and side effects of Crestor, and
ongoing pharmacovigilance by FDA will continue to provide
information on the balance of risks and benefits of Crestor and
other members of this important class of drugs. This information
will be made available and, as appropriate, applied to drug labeling
in a timely fashion.
The current FDA-approved label can be obtained at:
http://www.fda.gov/cder/foi/label/2005/21366slr005lbl.pdf
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Date created: March 2, 2005 |
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