Rosuvastatin

HMG-CoA reductase inhibitor (statin), Antihyperlipidemic agent

Competitively inhibits HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. This inhibition: • Decreases hepatic cholesterol synthesis • Upregulates LDL receptors on hepatocytes • Enhances clearance of LDL and LDL precursors from circulation • Reduces VLDL synthesis and secretion

Absorption: Oral bioavailability ~20%, peak plasma concentration in 3-5 hours. Food decreases absorption rate but not extent. Distribution: Volume of distribution ~134L, 88% plasma protein bound. Selective uptake by hepatocytes via OATP1B1 transporters. Metabolism: Minimally metabolized (~10%) primarily via CYP2C9 to N-desmethyl metabolite (50% activity of parent). Non-CYP pathways involve lactonization. Excretion: Primarily fecal (90%) as unchanged drug, renal excretion accounts for ~10%. Half-life: ~19 hours (prolonged in hepatic impairment)

Dose-dependent reduction in LDL cholesterol (45-63% at 5-40mg doses). Additional effects include: • 8-14% increase in HDL cholesterol • 10-35% reduction in triglycerides • Reduced CRP levels (anti-inflammatory effect) • Stabilization of atherosclerotic plaques

• Primary hyperlipidemia and mixed dyslipidemia: As adjunct to diet to reduce elevated total-C, LDL-C, ApoB, non-HDL-C, and triglycerides • Hypertriglyceridemia: Management of adult patients with triglyceride levels >500 mg/dL • Primary prevention of cardiovascular disease: Reduction of risk in patients without clinically evident CAD but with increased risk factors • Slowing atherosclerosis progression: As part of comprehensive intervention in patients with established CAD • Pediatric heterozygous familial hypercholesterolemia: Treatment in children ≥8 years old (after failure of dietary management)

Absolute: • Active liver disease or unexplained persistent elevations in serum transaminases • Pregnancy and lactation • Hypersensitivity to rosuvastatin Relative: • Concurrent use with cyclosporine • Severe renal impairment (CrCl <30 mL/min) • Asian ancestry (consider lower starting dose) • History of statin-induced myopathy

Primary Hyperlipidemia: Initial dose: 10-20 mg once daily; may increase to 40 mg after 4 weeks if needed Heterozygous Familial Hypercholesterolemia: Initial: 20 mg daily; maximum 40 mg daily (reserved for severe cases) Pediatric Patients (≥8 years): 5-20 mg daily based on LDL goals and tolerability Dosing Adjustment: • Renal impairment (CrCl <30 mL/min): Start at 5 mg, do not exceed 10 mg • Asian patients: Consider starting dose of 5 mg • Cyclosporine coadministration: Limit to 5 mg daily

Pediatric: Safety established for ≥8 years with heterozygous FH. Monitor growth and development. Geriatric: No dose adjustment needed unless renal impairment present. Increased myopathy risk in >65 years. Renal impairment: Reduce dose in severe impairment (CrCl <30 mL/min). Contraindicated in dialysis patients. Hepatic impairment: Contraindicated in active liver disease. Use caution in chronic alcohol users. Avoid in Child-Pugh B/C cirrhosis.

Common (>10%): • Myalgia (mild muscle pain without CK elevation) • Headache • Constipation or diarrhea Serious (<1%): • Rhabdomyolysis with acute renal failure (CK >10x ULN) • Clinically significant liver injury (transaminases >3x ULN) • New-onset diabetes mellitus (HbA1c increase 0.3-0.5%) • Immune-mediated necrotizing myopathy • Cognitive impairment (memory loss, confusion)

• Cyclosporine: Increases rosuvastatin AUC by 7-fold - limit dose to 5 mg • Gemfibrozil: Increases rosuvastatin exposure by 90% - avoid combination • Warfarin: May enhance anticoagulant effect - monitor INR closely • Antacids (aluminum/magnesium hydroxide): Reduce absorption - separate administration by 2 hours • Oral contraceptives: Increases ethinyl estradiol and norgestrel levels by 26-34%

• Risk of myopathy/rhabdomyolysis - higher with 40mg dose, elderly, renal impairment, and interacting drugs • Hepatotoxicity - monitor LFTs before treatment and as clinically indicated • Increased HbA1c and fasting glucose - monitor diabetes parameters • Proteinuria - generally transient and tubular in origin, monitor renal function • CNS effects - reports of memory loss, confusion, and depression

Pregnancy: Category X. Contraindicated due to interference with cholesterol biosynthesis essential for fetal development. Discontinue immediately if pregnancy occurs. Lactation: Contraindicated. Rosuvastatin excreted in milk with potential for serious adverse reactions in infants.

• Lipid panel at baseline, 4 weeks after initiation/dose change, then every 3-6 months • Liver enzymes (ALT/AST) before starting, at 12 weeks, then annually • CK levels if muscle symptoms develop • Renal function tests (particularly with high-dose therapy) • HbA1c in patients with diabetes risk factors • Signs of myopathy (muscle pain, weakness, dark urine)

• Take once daily with or without food, preferably at same time each day • Report unexplained muscle pain/tenderness/weakness immediately • Avoid excessive alcohol consumption • Maintain cholesterol-lowering diet during treatment • Do not take antacids within 2 hours of rosuvastatin • Inform all healthcare providers about rosuvastatin use before any new medications • Use effective contraception during treatment

Store at 20-25°C (68-77°F). Protect from moisture. Keep bottle tightly closed. Discard unused tablets 30 days after opening bottle.

• Most potent statin for LDL reduction per mg dose (40mg achieves ~63% reduction) • Preferred statin for patients with renal impairment (non-renally cleared) • Consider 5mg starting dose in Asian patients due to increased exposure • Better tolerated in statin-intolerant patients compared to other statins • Demonstrates plaque regression in coronary arteries at high doses • Limited CYP450 metabolism reduces drug interaction potential compared to other statins

• Rosuvastatin (Crestor) Prescribing Information, AstraZeneca Pharmaceuticals LP • Cholesterol Treatment Trialists' Collaboration. Lancet 2010;376(9753):1670-81 • Stone NJ, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol. Circulation 2014;129(25 Suppl 2):S1-45 • Nissen SE, et al. Effect of Intensive Compared With Moderate Lipid-Lowering Therapy on Progression of Coronary Atherosclerosis. JAMA 2004;291(9):1071-80 • FDA Drug Safety Communication: New Restrictions, Contraindications, and Dose Limitations for Zocor (Simvastatin) to Reduce the Risk of Muscle Injury (2011)