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Rosuvastatin Calcium

Pronunciation

Pronunciation: roe-SOO-va-STAT-in KAL-see-um
Class: HMG-CoA reductase inhibitor

Trade Names

Crestor
- Tablets 5 mg
- Tablets 10 mg
- Tablets 20 mg
- Tablets 40 mg

Pharmacology

Inhibits HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

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Pharmacokinetics

Absorption

Absolute bioavailability is about 20%. C max is reached in 3 to 5 h. Administration with food did not affect the AUC.

Distribution

The mean steady-state Vd is about 134 L. Rosuvastatin is 88% protein bound, mainly to albumin.

Metabolism

Rosuvastatin's major metabolite is formed by CYP2C9.

Not extensively metabolized; approximately 10% is recovered as metabolite.

Elimination

Primarily excreted in the feces (90%). The elimination half-life is approximately 19 h.

Special Populations

Renal Function Impairment

Plasma concentrations increase about 3-fold in patients with severe renal impairment (CrCl less than 30 mL/min). Mild to moderate renal impairment did not affect plasma levels.

Hepatic Function Impairment

C max and AUC are increased.

Elderly

No differences in plasma concentrations between patients 65 yr of age and older compared with younger patients.

Gender

No differences in plasma concentrations between men and women.

Race

An approximate 2-fold increase in median exposure has been demonstrated in Asian subjects. No clinically important differences in pharmacokinetics have been found among Afro-Caribbean, black, white, or Hispanic patients.

Asian patients

Median exposure in Asian subjects was approximately 2-fold more compared with a white control group.

Hemodialysis

Steady-state plasma concentrations in patients on chronic hemodialysis are approximately 50% higher compared with subjects with healthy renal function.

Indications and Usage

As an adjunct to diet to reduce elevated total cholesterol (TC), LDL-C, non–HDL-C, apolipoprotein B (Apo B), and triglyceride (TG) levels, and to increase HDL-C in patients with primary hyperlipidemia or mixed dyslipidemia; as an adjunct to diet for the treatment of patients with hypertriglyceridemia; as an adjunct to other lipid-lowering treatments, or alone if such treatments are not available; to reduce LDL-C, TC, and Apo B in patients with homozygous familial hypercholesterolemia; as an adjunct to diet to slow the progression of atherosclerosis in adults as part of a treatment strategy to lower TC and LDL-C to target levels; as an adjunct to diet for the treatment of patients with primary dysbetalipoproteinemia (type III hyperlipoproteinemia); as an adjunct to diet to reduce TC, LDL-C, and Apo-B in children 10 to 17 yr of age (girls must be at least 1 yr postmenarche) with heterozygous familial hypercholesterolemia; to reduce the risk of stroke, MI, and arterial revascularization procedures in individuals without clinically evident coronary heart disease, but with an increased risk of CV disease based on age and other risk factors.

Contraindications

Breast-feeding; active liver disease or unexplained, persistent elevations of serum transaminases; hypersensitivity to any component of the product; women who are or may become pregnant.

Dosage and Administration

Heterozygous Familial Hypercholesterolemia
Children 10 to 17 yr of age

PO Usual dosage is 5 to 20 mg once daily (max, 20 mg/day). Individualize dosage according to the recommended goal of therapy; adjustments should be made at intervals of 4 wk or more.

Homozygous Familial Hypercholesterolemia
Adults

PO Start with 20 mg once daily (range, 5 to 40 mg/day). Estimate response to therapy from preapheresis LDL-C levels.

Hyperlipidemia, Hypertriglyceridemia, Mixed Dyslipidemia, Primary Dysbetalipoproteinemia, and Slowing of the Progression of Atherosclerosis
Adults

PO Start with 10 to 20 mg once daily. After initiation or upon titration, analyze lipid levels within 2 to 4 wk and adjust dosage accordingly (range, 5 to 40 mg once daily).

Primary Prevention of CV Disease
Adults

PO Start with 10 to 20 mg once daily (range, 5 to 40 mg once daily).

Asian Patients
Adults

PO Start with 5 mg once daily.

Concurrent Cyclosporine Therapy
Adults

PO Limit dosage of rosuvastatin to 5 mg/day.

Concurrent Lipid-Lowering Therapy
Adults

PO Avoid concurrent therapy with gemfibrozil; however, if used in combination with gemfibrozil, the dosage of rosuvastatin should be limited to 10 mg once daily. The risk of skeletal muscle effects may be enhanced when rosuvastatin is used in combination with fenofibrate or niacin; therefore, consider a reduction in rosuvastatin.

Concurrent Lopinavir/Ritonavir or Atazanavir/Ritonavir
Adults

PO Limit rosuvastatin dosage to 10 mg once daily.

Renal Function Impairment
Adults

PO In patients with severe renal impairment (CrCl less than 30 mL/min per 1.73 m 2 ) not on hemodialysis, start with 5 mg once daily (max, 10 mg once daily).

General Advice

  • Administer as a single dose at any time of day, with or without food.
  • Should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and nonpharmacologic interventions alone has been inadequate.
  • The 40 mg dose should be reserved for adult patients that do not achieve their LDL-C goal with the 20 mg dose.

Storage/Stability

Store tablets at 68° to 77°F. Protect from moisture.

Drug Interactions

Antacids (aluminum and magnesium combination)

Rosuvastatin plasma concentrations may be decreased. Administer antacid 2 h after rosuvastatin.

Baicalin

Baicalin, a flavone glucuronide from the plant Radix Scutellariae , may reduce rosuvastatin plasma concentrations by increasing hepatic uptake of rosuvastatin. Avoid baicalin in patients taking rosuvastatin.

Bile acid sequestrants (eg, cholestyramine)

Rosuvastatin may adsorb to the bile acid sequestrant, reducing the GI absorption of rosuvastatin. Separate the administration times of rosuvastatin and the bile acid sequestrant by as much as possible (at least 4 hr before rosuvastatin).

Colchicine

The risk of myopathy and rhabdomyolysis may be increased. If coadministration cannot be avoided, use with caution and closely monitor creatinine kinase during concurrent use of these agents and after dose increases. Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, especially if accompanied by fever or malaise.

Contraceptives, hormonal

Ethinyl estradiol and norgestrel plasma concentrations may be elevated. Observe the patient for adverse effects related to hormonal contraceptive therapy.

Cyclosporine, protease inhibitors (eg, atazanavir/ritonavir, lopinavir/ritonavir)

Rosuvastatin concentrations may be elevated, increasing adverse reactions (eg, rhabdomyolysis). Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, especially if accompanied by fever or malaise.

Daptomycin

The risk of rhabdomyolysis may be increased. Consider temporarily withholding rosuvastatin therapy. If rosuvastatin and daptomycin are coadministered, close clinical and laboratory monitoring are indicated. Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, especially if accompanied by fever or malaise.

Eltrombopag

Plasma concentrations and pharmacologic effects of rosuvastatin may be increased by eltrombopag. Close clinical and laboratory monitoring for signs of excessive rosuvastatin exposure is indicated. Consider a reduction of rosuvastatin dosage during coadministration of eltrombopag.

Fenofibrate

Both fenofibrate and rosuvastatin concentrations may be increased. Severe myopathy or rhabdomyolysis may occur. Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, especially if accompanied by fever or malaise.

Gemfibrozil, niacin

The risk of adverse reactions (eg, rhabdomyolysis) may be increased. Severe myopathy or rhabdomyolysis may occur. Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, especially if accompanied by fever or malaise.

Warfarin

Anticoagulant effect of warfarin may be enhanced, increasing the risk of bleeding. Monitor anticoagulant parameters when starting, stopping, or changing the rosuvastatin dose. Adjust the warfarin dose as needed.

Adverse Reactions

CNS

Headache (9%); asthenia (5%); dizziness (4%); memory loss (postmarketing).

GI

Nausea (6%); constipation (5%); abdominal pain (2%); pancreatitis.

Hepatic

Hepatic failure, hepatitis, jaundice (postmarketing).

Hypersensitivity

Hypersensitivity including rash, pruritus, urticaria, and angioedema.

Lab Tests

Elevated CPK (3%); elevated ALT (2%); dipstick-positive proteinuria and microscopic hematuria; elevated alkaline phosphatase, bilirubin, glucose, glutamyl transpeptidase, and transaminases; thyroid function abnormalities.

Metabolic

Diabetes mellitus (3%).

Musculoskeletal

Myalgia (13%); arthralgia (10%).

Precautions

Monitor

It is recommended that LFTs be performed before and at 12 wk following both the initiation of therapy and any elevation in dose, and periodically (eg, semiannually) thereafter.


Pregnancy

Category X .

Lactation

Contraindicated in breast-feeding women.

Children

Safety and efficacy not established in children younger than 10 yr of age or for indications other than heterozygous familial hypercholesterolemia.

Elderly

At higher risk for myopathy; use with caution.

Renal Function

Adjust the dose in patients with severe renal impairment (CrCl less than 30 mL/min) not requiring hemodialysis.

Hepatic Function

Contraindicated in patients with active liver disease, which may include patients with unexplained, persistent elevations in transaminase levels.

Endocrine effects

Use caution when administering with drugs that affect steroid levels or activity (eg, ketoconazole, spironolactone). Increases in HbA 1c and fasting serum glucose levels have been reported.

Liver enzyme abnormalities

Increases in transaminases have been reported. Use with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease.

Proteinuria and hematuria

Consider a dose reduction in patients with unexplained, persistent proteinuria and/or hematuria during routine urinalysis.

Skeletal muscle effects

Myopathy and rhabdomyolysis with renal dysfunction secondary to myoglobinuria have been reported with rosuvastatin. Temporarily withhold therapy in any patient experiencing an acute or serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (eg, dehydration, hypotension, sepsis). The risk of myopathy with other drugs in this class is increased if cyclosporine, gemfibrozil, lopinavir/ritonavir, or niacin is coadministered. Consider myopathy in any patient with diffuse myalgia, muscle tenderness or weakness, or marked elevation of CPK.

Overdosage

Symptoms

The symptoms of overdose are unknown.

Patient Information

  • Advise patient to take once daily as prescribed, without regard to meals, but to take with food if stomach upset occurs.
  • Advise patient to try to take each dose at about the same time each day.
  • Inform patient that drug helps control, but does not cure, elevated cholesterol, and to continue taking drug as prescribed if cholesterol levels are lowered.
  • Advise patient that if a dose is missed, to take it as soon as remembered, but to never take more than 1 dose of rosuvastatin daily.
  • Instruct patient to continue taking other cholesterol-lowering medications as prescribed by health care provider.
  • Emphasize to patient importance of the following other modalities of cholesterol control: dietary changes (reduce saturated fat intake, increase soluble fiber intake), weight control, regular exercise, and smoking cessation.
  • Advise women of childbearing potential to use effective contraception during treatment with rosuvastatin.
  • Advise patient who is also using an aluminum and magnesium hydroxide combination antacid to take the antacid at least 2 h after taking rosuvastatin.
  • Instruct patient to notify health care provider if experiencing any unexplained muscle pain, tenderness, and/or weakness, or any other unusual feelings.

Copyright © 2009 Wolters Kluwer Health.

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