Introduction
Rosuvastatin is a synthetic, competitive HMG-CoA reductase inhibitor belonging to the statin class of lipid-lowering agents. Marketed under the brand name Crestor®, it was approved by the FDA in 2003 and has become a cornerstone therapy for managing dyslipidemia and reducing cardiovascular risk. Rosuvastatin demonstrates potent LDL-cholesterol reduction and favorable effects on other lipid parameters.
Mechanism of Action
Rosuvastatin competitively inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis in the liver. This inhibition reduces hepatic cholesterol production, resulting in upregulation of hepatic LDL receptors and increased clearance of LDL-cholesterol from the bloodstream. Rosuvastatin also moderately increases HDL-cholesterol and reduces triglycerides through mechanisms involving reduced VLDL production.
Indications
- Primary hyperlipidemia and mixed dyslipidemia (Fredrickson type IIa and IIb)
- Hypertriglyceridemia (Fredrickson type IV)
- Primary dysbetalipoproteinemia (Fredrickson type III)
- Homozygous familial hypercholesterolemia
- Slowing the progression of atherosclerosis
- Primary prevention of cardiovascular disease in patients without clinical evidence of CAD but with increased risk factors
- Secondary prevention of cardiovascular events in patients with established cardiovascular disease
Dosage and Administration
Standard dosing: 5-40 mg orally once daily- Initial dose: 5-10 mg daily
- Dose adjustment: May be adjusted every 2-4 weeks based on lipid response
- Maximum dose: 40 mg daily (reserved for patients not achieving LDL-C goals with 20 mg)
- Renal impairment: CrCl <30 mL/min: Initial dose 5 mg, not to exceed 10 mg daily
- Asian patients: Consider initial dose of 5 mg due to increased drug exposure
- Elderly: No dose adjustment necessary unless renal impairment present
- Cytochrome P450 2C9 poor metabolizers: Consider reduced starting dose
Pharmacokinetics
- Absorption: Peak plasma concentrations reached in 3-5 hours; absolute bioavailability approximately 20%
- Distribution: Volume of distribution approximately 134 L; 88% protein-bound primarily to albumin
- Metabolism: Minimal hepatic metabolism (approximately 10%) primarily via CYP2C9; minor metabolism via CYP2C19
- Elimination: Elimination half-life approximately 19 hours; primarily excreted unchanged in feces (90%) with minor renal excretion (10%)
- Special considerations: Not significantly metabolized by CYP3A4 pathway
Contraindications
- Active liver disease or unexplained persistent elevations of serum transaminases
- Pregnancy and breastfeeding
- Hypersensitivity to rosuvastatin or any product components
- Concomitant use with cyclosporine
Warnings and Precautions
Hepatotoxicity: Monitor liver enzymes before initiation and periodically thereafter. Discontinue if persistent elevations >3× ULN occur. Myopathy/Rhabdomyolysis: Risk increases with higher doses, advanced age, renal impairment, hypothyroidism, and concomitant use with certain medications. Monitor for muscle pain, tenderness, or weakness. Renal effects: Proteinuria may occur, particularly at higher doses; monitor urinalysis periodically. Diabetes: May increase HbA1c and fasting serum glucose levels. Asian patients: Increased systemic exposure observed; consider lower starting doses.Drug Interactions
Major interactions:- Cyclosporine: Contraindicated (increases rosuvastatin exposure >7-fold)
- Gemfibrozil: Avoid combination (increases rosuvastatin exposure 2-fold and myopathy risk)
- Antacids: Separate administration by at least 2 hours (reduces rosuvastatin absorption)
- Warfarin: Monitor INR closely (may enhance anticoagulant effect)
- Other fibrates: Use with caution (increased myopathy risk)
- Niacin: Monitor for myopathy
- Protease inhibitors: Use with caution
Adverse Effects
Common (≥2%):- Headache (3.5%)
- Myalgia (3.1%)
- Constipation (2.3%)
- Nausea (2.2%)
- Abdominal pain (2.1%)
- Asthenia (2.0%)
- Rhabdomyolysis with renal failure
- Hepatotoxicity
- Immune-mediated necrotizing myopathy
- Memory loss/confusion
- Hemorrhagic stroke (in certain populations)
Monitoring Parameters
- Baseline: Lipid profile, LFTs, CK, renal function, HbA1c
- During therapy: Lipid profile at 4-12 weeks after initiation or dose change, then every 3-12 months
- Periodic: LFTs at 12 weeks, then semiannually or if symptoms develop
- CK: If muscle symptoms occur
- Renal function: Periodically, especially in elderly or those with risk factors
- Urinalysis: For proteinuria, particularly with 40 mg dose
Patient Education
- Take once daily with or without food; evening administration may provide slightly better LDL reduction
- Report unexplained muscle pain, tenderness, weakness, or brown urine immediately
- Avoid excessive alcohol consumption
- Inform all healthcare providers about rosuvastatin use, especially before new medications
- Maintain cholesterol-lowering diet and exercise regimen
- Notify physician if planning pregnancy or becoming pregnant
- Be aware of potential cognitive side effects (memory loss, confusion)
- Regular follow-up and laboratory monitoring are essential
References
1. FDA Prescribing Information: Crestor (rosuvastatin calcium) tablets. 2021. 2. Cholesterol Treatment Trialists' Collaboration. Lancet 2010;376:1670-1681. 3. Grundy SM, et al. J Am Coll Cardiol 2019;73:3168-3209. 4. Jones PH, et al. Am J Cardiol 2003;92:152-160. 5. Shepherd J, et al. N Engl J Med 2008;359:2195-2207. 6. Sirtori CR. Pharmacol Res 2014;88:3-11. 7. McKenney JM, et al. Am J Cardiol 2006;97:223-229. 8. ACC/AHA Guideline on the Management of Blood Cholesterol. Circulation 2019;139:e1082-e1143.