Statins

[Guest guest]

FDA Public Health Advisory

on the Statin Drug Crestor

(rosuvastatin)

The following information was published by the U.S. Food and Drug

Administration, (FDA) on March 2, 2005

Astra-Zeneca Pharmaceuticals today released a revised package insert for

Crestor (rosuvastatin). 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. (This ends

the information from the FDA.)

[Guest guest]

statins are thought to interfere with complex 1 of the mitochondrial

electron transfer chain--and because statins deplete the body of

coenzyme q 10, could potentially interfere with all 5 complexes

within the mitochondrial transfer chain--definitely not a good thing

for someone with mitochondrial issues already--have you considered

niacin? as well as fish oil capsules you mentioned?