CENTER FOR DRUG EVALUATION
AND RESEARCH (CDER)
Endocrinologic and Metabolic Drugs Advisory Committee Meeting
1. Has the sponsor provided
sufficient evidence to support the efficacy of Crestor in the proposed target
populations?
2. Do the efficacy data support
a dose-response with respect to LDL-C lowering sufficient to justify use of the
40 mg dose?
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, among others:
a. number of patients studied
and duration of treatment over the
proposed dosage range
b. special populations (e.g.,
elderly, renal impairment, co-morbid medical conditions)
c. drug-drug interactions
1. Clinical laboratory
monitoring in the Crestor development program exposed a heretofore unknown
effect of a statin to cause mild proteinuria, sometimes associated with microscopic hematuria and mild renal impairment (increased
creatinine). This effect appears dose
related in frequency (and perhaps severity), and reversible on discontinuation
of therapy or on lowering the dose of drug.
a. Has the risk of adverse
renal effects of rosuvastatin been adequately evaluated over the proposed
dosage range?
b. What further investigations
are needed, if any, of this novel drug effect?
c. Comment on the data
presented suggesting this may be a statin class effect.
d. Is monitoring of renal
function recommended for this drug or potentially for all statins?
1. Are the data adequate to
support the 5, 10, or 20 mg doses as safe start doses?
2. Are the safety data adequate
to support a maximum dose of 40 mg daily?
3. 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 target
LDL-C?
4. Alternatively, 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?
1. Do you recommend that
Crestor 5-40 mg be approved by FDA as an adjunct to diet for the treatment of
patients with primary hypercholesterolemia and mixed dyslipidemia and isolated hypertriglyceridemia and for the treatment of patients with
homozygous familial hypercholesterolemia as an adjunct to LDL apheresis or if
apheresis is not available?