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FDA Safety Labeling Changes: Crestor, Diamox Sequels, Femring
Yael Waknine;
June 8, 2005 — The U.S. Food and Drug Administration (FDA) approved in March revisions to safety labeling to advise that use of rosuvastatin calcium tablets is associated with an increased risk of myopathy and rhabdomyolysis; use of acetazolamide extended-release capsules has been associated rarely with serious and fatal adverse reactions; and use of an estradiol acetate vaginal ring is associated with increased risks of coronary heart disease, stroke, and venous thromboembolism.
Rosuvastatin (Crestor) Linked to Risk of Myopathy, Rhabdomyolysis
On March 2, the FDA approved revisions to the safety labeling for rosuvastatin calcium (Crestor tablets, made by AstraZeneca Pharmaceuticals, LP) to warn of the increased risk of serious muscle toxicity (myopathy/rhabdomyolysis) associated with its use, especially at the highest approved dose of 40 mg.
In clinical trials, rosuvastatin has been associated with an increased incidence of myopathy and rhabdomyolysis when administered at doses exceeding 40 mg. Adverse effects on skeletal muscle (uncomplicated myalgia, myopathy, and rhabdomyolysis) also have been reported during marketed use of rosuvastatin and other 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins").
As with other drugs in this class, rhabdomyolysis with acute renal failure secondary to myoglobinuria has been reported rarely, but with the highest incidence at the highest approved dose.
Because the risk of muscle toxicity increases with drug levels, the 40-mg dose of rosuvastatin should be reserved for use only in patients not achieving adequate low-density lipoprotein cholesterol–lowering response with the 20-mg dose. An initial dose of 5 mg is recommended in patients with predisposing factors for myopathy such as advanced age (65 years or older), inadequately treated hypothyroidism, and renal insufficiency.
Concurrent administration of other lipid-lowering therapies or cyclosporine may also increase the risk of myopathy. The FDA advises that the benefit of further alterations in lipid levels be carefully weighed against potential risks when considering combination therapy with fibrates or niacin. Combination therapy with rosuvastatin and gemfibrozil generally should be avoided.
The risk of myopathy associated with rosuvastatin therapy also may be increased in patients of Asian descent. Results of a phase 4 pharmacokinetic study have shown rosuvastatin levels in Asian Americans to be approximately twofold that of whites who received the same dose.
All patients should be informed of these potential risks and advised to promptly report signs and symptoms of muscle pain and weakness, malaise, fever, dark urine, nausea, and vomiting.
Rosuvastatin therapy should be temporarily interrupted in any patient with an acute, serious condition that is suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis, such as sepsis, hypotension, dehydration, major surgery, trauma, uncontrolled seizures, or severe metabolic, endocrine, and electrolyte disorders.
Rosuvastatin is indicated for use as an adjunct to diet in the treatment of various lipid disorders including primary hypercholesterolemia, mixed dyslipidemia, and isolated hypertriglyceridemia.
Extended-Release Acetazolamide (Diamox Sequels) Linked Rarely to Fatalities
On March 15, the FDA approved revisions to the safety labeling for acetazolamide extended-release capsules (Diamox Sequels, made by Duramed Pharmaceuticals, Inc.) to warn of the potential for serious adverse reactions associated with their use.
The FDA has received rare reports of fatalities due to severe reactions to sulfonamides, including Stevens-Johnson syndrome, anaphylaxis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitizations may recur with reexposure to the drug, irrespective of the route of administration.
Acetazolamide therapy should be discontinued in patients who experience signs of hypersensitivity or other serious adverse reactions.
Acetazolamide extended-release capsules are indicated for the adjunctive treatment of chronic simple glaucoma and secondary glaucoma, preoperatively in acute angle-closure glaucoma where delay of surgery is desired to lower intraocular pressure, and for the prevention or amelioration of symptoms associated with acute mountain sickness despite gradual ascent.
Estradiol Acetate Vaginal Ring (Femring) Associated With Increased Cardiovascular Risks
On March 11, the FDA approved revisions to the safety labeling for an estradiol acetate vaginal ring (Femring, made by Galen Chemicals Inc.) to warn of the increased risks of coronary heart disease, stroke, and venous thromboembolism (VTE) associated with its use.
In the Women's Health Initiative study, administration of conjugated estrogens was associated with an increase in the number of strokes and an increased risk of deep vein thrombosis.
The FDA recommends appropriate management of risk factors for arterial vascular disease (hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or VTE (personal or family history of VTE, obesity, systemic lupus erythematosus) in patients receiving estrogen therapy.
The estradiol acetate vaginal ring is indicated for the treatment of moderate to severe symptoms (vasomotor, vulvar, and vaginal atrophy) associated with menopause.
Reviewed by Gary D. Vogin, MD
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