GENERIC NAME ROSUVASTATIN / CRESTOR®

PROPRIETARY NAME CRESTOR® / ASTRAZENECA

Consider adding based upon its comparative cost to other statin products.

As an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson type IIa and IIb); as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV); and to reduce LDL-C, total-C, and ApoB in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Rosuvastatin is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is used for the treatment of hypercholesterolemia. HMG-CoA reductase is the rate-limiting enzyme in de novo cholesterol synthesis. HMG-CoA reductase inhibitors reduce the production of mevalonic acid from HMG-CoA, resulting in a reduction in hepatic cholesterol synthesis. This in turn results in a compensatory increase in the expression of high affinity low-density lipoprotein (LDL) receptors on hepatocyte membranes and stimulation of LDL catabolism. It is in this manner that rosuvastatin produces the lowering of plasma total and LDL cholesterol levels observed in patients with hypercholesterolemia. Reductions in the hepatic pool of cholesterol has also been associated with a decrease in the rate of production of very-low-density lipoprotein (VLDL) and/or LDL by the liver. The high potency of rosuvastatin relative to other statins probably relates to rosuvastatin's low lipophilicity and high hepatocyte selectivity due to its large polar side chain.

Several clinical trials have demonstrated the efficacy of rosuvastatin as an adjunct to diet for the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) and in the treatment of mixed dyslipidemia (Fredrickson Type IIa and IIb). In these studies rosuvastatin was shown to significantly reduce total-C, LDL-C, nonHDL-C, TG, and ApoB across the dose range and to increase HDL-C. In comparator trials, rosuvastatin has been shown to significantly reduce LDL-C levels compared to atorvastatin, pravastatin, and simvastatin. Clinical trials have also demonstrated the effectiveness of rosuvastatin in significantly reducing LDL-C levels in patients with homozygous familial hypercholesterolemia and in significantly reducing TG levels in patients with hypertriglyceridemia (Fredrickson Type IIb and IV). Outcome data (morbidity and mortality) are lacking.

Rosuvastatin is more effective than atorvastatin, simvastatin, and pravastatin across dose ranges for the reduction of LDL cholesterol in patients with hypercholesterolemia.

Rosuvastatin is effective in the treatment of hypertriglyceridemia.

• Hypersensitivity to any product component.
• Active liver disease or unexplained persistent elevations of serum transaminases.
• Pregnancy and lactation.

• HMG-CoA reductase inhibitors have been associated with biochemical abnormalities of liver function. It is recommended that liver function tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter.
• Use with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
• Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with rosuvastatin and other drugs in this class.
• Use with caution in patients with predisposing factors for myopathy, such as renal impairment, advanced age, and hypothyroidism. Discontinue therapy if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
• The risk of myopathy may be increased with concurrent use of other lipid-lowering therapies or cyclosporine. Combination therapy with rosuvastatin and gemfibrozil should generally be avoided.
• The risk of myopathy may be increased in circumstances which increase rosuvastatin drug levels.
• Therapy should be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

(Most common, 2-9%)

• Pharyngitis (9%)
• Headache (5.5%)
• Diarrhea (3.4%)
• Dyspepsia (3.4%)
• Nausea (3.4%)
• Myalgia (2.8%)
• Asthenia (2.7%)
• Back pain (2.6%)
• Flu syndrome (2.3%)
• UTI (2.3%)
• Rhinitis (2.2%)
• Sinusitis (2.0%)

• Cyclosporine
• Gemfibrozil
• Warfarin

*AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.

** Cost calculations are based on once daily administration.

Rosuvastatin is a selective HMG-CoA reductase inhibitor that has demonstrated efficacy as an adjunct to diet for the treatment of various lipid disorders including primary hypercholesterolemia, mixed dyslipidemia, and isolated hypertriglyceridemia. Studies have demonstrated that rosuvastatin provides superior LDL-C reduction compared to atorvastatin, pravastatin, and simvastatin, but comparative data regarding its effects on overall mortality and coronary events are not available. Rosuvastatin appears to exhibit a favorable pharmacodynamic and pharmacokinetic profile, which includes low lipophilicity, high hepatocyte selectivity, along with minimal metabolism and limited cytochrome P-450 interactions. However, until more data are available, cost will be an important consideration in the selection of statin therapy. The use of 80 mg was stopped due to rhabdomyolysis and renal impairment during trials. The myotoxic potential (myopathy) of rosuvastatin 10 mg to 40 mg is similar to other statins. Recommendations for liver function test monitoring are similar with most other statins. Due to concerns regarding renal toxicity (proteinuria), the manufacturer will conduct postmarketing surveillance to assess any link between rosuvastatin and kidney problems. Additional studies include an atherosclerosis regression trial, an intervascular ultrasound study, outcome studies, a study in patients with renal failure on dialysis, and a study in patients with elevated C-reactive protein.

1. Product Information: Crestor®, rosuvastatin. AstraZeneca Pharmaceuticals, Wilmington, DE (revised 08/2003) reviewed 09/2003.
2. McTaggart F, Buckett L, Davidson R et al: Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001; 87(suppl):28B-32B.
3. Istvan ES & Deisenhofer J: Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001; 292:1160-1164.
4. Buckett L, Ballard P, Davidson R et al: Selectivity of ZD4522 for inhibition of cholesterol synthesis in hepatic versus non-hepatic cells (abstract). Atherosclerosis 2000; 151:41.
5. Olsson AG: A new statin: a new standard. Clin Cardiol 2001; 24(Suppl 111):18-23.
6. Jones PH, Davidson MH, Stein EA et al: Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003; 92:152-160.
7. Davidson M, Ma P, Stein EA et al: Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol 2002;89:268-275.
8. Olsson AG, Southworth H, Wilpshaar JW: Long-term efficacy and safety of rosuvastatin: Results of a 52-week comparator-controlled trial versus atorvastatin (abstract). Eur Heart J 2001; 22(Suppl):253.
9. Brown WV, Zedler BK, Bays HE et al: Long-term efficacy and safety of rosuvastatin: Results of a 52-week comparator-controlled trial versus pravastatin and simvastatin (abstract). Eur Heart J 2001; 22(Suppl):270.
10. Stein E, Strutt KL, Miller E, Southworth H: ZD4522 is superior to atorvastatin in the treatment of patients with heterozygous familial hypercholesterolemia (abstract). J Am Coll Cardiol 2001; 37(Suppl):292A. Abstract 1261-176.
11. Hunninghake DB, Chitra RR, Simonson SG, Schneck DW: Rosuvastatin markedly improved the atherogenic lipid profile in hypertriglyceridemic patients (abstract). Eur Heart J 2001; 22(Suppl):270.
12. Shepherd J, Hunninghake DB, Barter P et al: Guidelines for lowering lipids to reduce coronary artery disease risk: A comparison of rosuvastatin with atorvastatin, pravastatin, and simvastatin for achieving lipid-lowering goals. Am J Cardiol 2003; 91(Suppl):11C-19C.
13. Brewer HB: Benefit-risk assessment of rosuvastatin 10 to 40 milligrams. Am J Cardiol 2003; 92(Suppl 2):23-29.
14. Anon: First GALAXY results build Crestor profile. SCRIP No. 2839, April 9, 2003, p.25. PJB Publications.
15. Anon: AstraZeneca Crestor Renal monitoring recommended by advisory cmte. The Pink Sheet July 14, 2003; 65(28).
16. McTaggart F, Buckett L, Davidson R et al: Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001; 87(Suppl):28B-32B.
17. Warwick MJ, Dane AL, Raza A et al: Single-and multiple-dose pharmacokinetics and safety of the new HMG-CoA reductase inhibitor ZD4522 (abstract). Atherosclerosis 2000; 151:39.
18. Product Information: Lipitor®, atorvastatin. Pfizer Inc., New York, NY, (PI revised 4/2002) reviewed 8/2002.
19. Product Information: Zocor®, simvastatin. Merck & Co., Inc., Whiteshouse Station, NJ, (PI revised 5/2002) reviewed 7/2002.

Published October 2003. Content based on medical literature and product information available at that time.