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Rosuvastatin Calcium

Pronunciation

Class: HMG-CoA Reductase Inhibitors
VA Class: CV350
Chemical Name: 7 - [4 - (4 - fluorophenyl) - 6 - (1 - methylethyl) - 2 - [methylsulfonyl)amino] - 5 - pyrimi - dinyl] - 3,5 - dihydroxy - 6 - heptenoic acid calcium
Molecular Formula: 2C22H27FN3O6S • Ca
CAS Number: 147098-20-2
Brands: Crestor

Introduction

Antilipemic agent; hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin).1

Uses for Rosuvastatin Calcium

Prevention of Cardiovascular Events

To reduce the risk of stroke or MI and the risk of undergoing arterial revascularization procedures in patients without clinical evidence of CHD who have an increased risk of cardiovascular disease based on age (men ≥50 years of age, women ≥60 years of age), high-sensitivity C-reactive protein (hsCRP) concentrations ≥2 mg/L, and ≥1 additional cardiovascular disease risk factor (e.g., hypertension, low HDL-cholesterol concentrations, smoking, family history of premature CHD).1

Adjunct to dietary therapy to slow the progression of atherosclerosis as part of a treatment strategy to lower total and LDL-cholesterol concentrations to target levels.1

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Dyslipidemias

Adjunct to dietary therapy in adults to decrease elevated serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), non-HDL-cholesterol, and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the management of primary hyperlipidemia or mixed dyslipidemia.1

Adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the management of heterozygous familial hypercholesterolemia in boys and girls (≥1 year postmenarchal) 10–17 years of age who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration >190 mg/dL or a serum LDL-cholesterol concentration >160 mg/dL and either a family history of premature cardiovascular disease or ≥2 other cardiovascular risk factors.1

Reduction of elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or when such therapies are not available.1

Adjunct to dietary therapy in the management of hypertriglyceridemia.1

Adjunct to dietary therapy in the management of primary dysbetalipoproteinemia (Fredrickson type III).1 14

Produces greater reductions in LDL-cholesterol concentrations than atorvastatin, pravastatin, or simvastatin on a mg-for-mg basis.1

Rosuvastatin Calcium Dosage and Administration

General

  • Patients should be placed on a standard lipid-lowering diet before initiation of rosuvastatin therapy and should remain on this diet during treatment with the drug.1 7

Monitoring during Antilipemic Therapy

  • Monitor lipoprotein concentrations periodically to ensure that target LDL-cholesterol goals are achieved and maintained at <100 mg/dL (optional goal: <70 mg/dL) for patients with CHD or CHD risk equivalents; <130 mg/dL (optional goal: <100 mg/dL) for patients with ≥2 risk factors and 10-year risk of 10–20%; <130 mg/dL for patients with ≥2 risk factors and 10-year risk <10%; or <160 mg/dL for patients with 0–1 risk factor.

Administration

Oral Administration

Administer orally at any time of day without regard to meals.1

Dosage

Available as rosuvastatin calcium; dosage expressed in terms of rosuvastatin.1

When initiating statin therapy or switching from another statin, select appropriate initial dosage, then carefully adjust dosage according to individual requirements and response.1

Pediatric Patients

Dyslipidemias
Heterozygous Familial Hypercholesterolemia
Oral

Children 10–17 years of age: Usual dosage range is 5–20 mg once daily.1

Adjust dosage at intervals of ≥4 weeks.1

Adults

Prevention of Cardiovascular Events or Management of Dyslipidemias
General Dosage
Oral

Usual initial dosage is 10–20 mg once daily.1

Determine serum lipoprotein concentrations within 2–4 weeks after initiating and/or titrating therapy and adjust dosage accordingly.1

Usual dosage range is 5–40 mg once daily.1 Reserve 40-mg daily dosage for patients who have not achieved their LDL-cholesterol goal with the 20-mg daily dosage.1

Homozygous Familial Hypercholesterolemia
Oral

Initially, 20 mg once daily.1 Determine response to rosuvastatin based on pre-apheresis LDL-cholesterol concentrations.1

Prescribing Limits

Pediatric Patients

Dyslipidemias
Oral

Children 10–17 years of age: Maximum 20 mg daily.1 Safety and efficacy of dosages >20 mg daily not evaluated in controlled trials in this patient population.1

Adults

Prevention of Cardiovascular Events or Management of Dyslipidemias
Oral

Maximum 40 mg once daily.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Patients with severe renal impairment (Clcr <30 mL/minute) not undergoing hemodialysis: Initially, 5 mg once daily; do not exceed 10 mg once daily.1

Asian Patients

Consider initiating therapy at 5 mg once daily.1 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

No specific dosage recommendations at this time; however, use with caution.1 (See Geriatric Use under Cautions.)

Cautions for Rosuvastatin Calcium

Contraindications

  • Active liver disease, including unexplained, persistent elevations of hepatic aminotransferases.1

  • Pregnancy or lactation.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Known hypersensitivity to rosuvastatin or any ingredient in the formulation.1

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Suppression of cholesterol biosynthesis could cause fetal harm.1 Congenital anomalies following intrauterine exposure to statins reported rarely.1

Administer to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards.1 (See Advice to Patients.) If the patient becomes pregnant while taking the drug, discontinue therapy and apprise patient of the potential fetal hazard and the lack of known clinical benefit with continued use during pregnancy.1

Musculoskeletal Effects

Myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria reported.1 Can occur at any dosage, but risk is increased with highest dosage (40 mg daily).1

Certain drug interactions also may increase risk of myopathy and/or rhabdomyolysis.1 (See Interactions.)

Use with caution in patients with predisposing factors for myopathy (e.g., age ≥65 years, renal impairment, inadequately treated hypothyroidism).1 11

Discontinue therapy if serum CK concentrations increase markedly or if myopathy is diagnosed or suspected.1

Temporarily withhold or discontinue therapy in any patient experiencing an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures).1 (See Advice to Patients.)

Hepatic Effects

Increases in serum aminotransferase (AST, ALT) concentrations reported.1 Usually transient and resolve or improve with continued therapy or after temporary interruption of therapy.1

Jaundice reported in ≥2 patients in clinical studies but resolved following discontinuance of therapy; causal relationship to rosuvastatin not established.1

Liver failure or irreversible liver disease not reported in clinical studies; however, fatal and nonfatal hepatic failure reported rarely.1

Perform liver function tests before initiation of therapy and as clinically indicated (e.g., presence of manifestations suggestive of liver damage201 ).1 Although manufacturer previously recommended more frequent monitoring,13 FDA concluded that serious statin-related liver injury is rare and unpredictable, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.200

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, promptly interrupt rosuvastatin therapy.1 If an alternate etiology is not found, do not restart rosuvastatin.1

Also see Hepatic Impairment under Cautions.

Interactions with Coumarin-derivative Anticoagulants

Because of possible potentiation of anticoagulant effects, caution when used concomitantly with coumarin-derivative anticoagulants.1 (See Specific Drugs under Interactions.)

Proteinuria and Hematuria

Transient dipstick-positive proteinuria and microscopic hematuria (not associated with worsening renal function) reported; occurred more frequently with rosuvastatin 40 mg compared with lower doses of rosuvastatin or comparator statins.1 Clinical importance not known; however, consider reducing dosage in patients who have unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.1

Hyperglycemic Effects

Increases in HbA1c and fasting serum glucose concentrations reported.1 200 Possible increased risk of developing diabetes.200 May need to monitor glucose concentrations following initiation of statin therapy.201

FDA states that cardiovascular benefits of statins outweigh these small increased risks.200

Endogenous Steroid Production

No effects on basal plasma cortisol concentration or adrenal reserve observed with rosuvastatin.1

Caution advised if used concomitantly with drugs that may decrease concentrations or activity of endogenous steroid hormones (e.g. ketoconazole, spironolactone, cimetidine).1

Hypersensitivity Reactions

Hypersensitivity reactions, including rash, pruritus, urticaria, and angioedema, reported.1

Cognitive Impairment

Cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) reported rarely.1

Generally nonserious and reversible, with variable times to symptom onset (1 day to years) and resolution (median of 3 weeks following discontinuance of therapy).1 200 Not associated with fixed or progressive dementia (e.g., Alzheimer’s disease) or clinically important cognitive decline.200 Not associated with any specific statin, patient's age, statin dosage, or concomitant drug therapy.200

FDA states that cardiovascular benefits of statins outweigh the small increased risk of cognitive impairment.200

If manifestations consistent with cognitive impairment occur, National Lipid Association (NLA) statin safety assessment task force recommends evaluating and managing patients appropriately.202

Role as Adjunct Therapy

Prior to institution of antilipemic therapy, vigorously attempt to control serum cholesterol by appropriate dietary regimens, weight reduction, exercise, and treatment of any underlying disorder that might be the cause of lipid abnormality.1

Specific Populations

Pregnancy

Category X.1 (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use is contraindicated in nursing women; women who require rosuvastatin therapy should not breast-feed their infants.1

Pediatric Use

Safety and efficacy not established in prepubertal children or in children <10 years of age with heterozygous familial hypercholesterolemia.1 Experience in children and adolescents ≥8 years of age or older with homozygous familial hypercholesterolemia is limited.1

Advise adolescent girls to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults; however, increased sensitivity cannot be ruled out.1

Use with caution, since geriatric patients (≥65 years of age) are at increased risk of myopathy.1

Hepatic Impairment

Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease (e.g., chronic alcoholic liver disease).1 (See Contraindications under Cautions.)

Contraindicated in patients with active liver disease, including unexplained, persistent elevations in hepatic aminotransferase concentrations.1

Renal Impairment

Dosage adjustments necessary in patients with severe renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Headache, nausea, myalgia, asthenia, constipation, abdominal pain.1

Interactions for Rosuvastatin Calcium

Minimally (approximately 10%) metabolized by CYP2C9.1 Clearance not dependent on metabolism by CYP3A4 to a clinically important extent.1

Specific Drugs

Drug

Interaction

Comments

Antacids (aluminum hydroxide- and magnesium hydroxide-containing)

Substantially decreased rosuvastatin peak plasma concentration and AUC following simultaneous administration; less substantial decreases when antacid administered 2 hours after rosuvastatin1

Administer antacid ≥2 hours after rosuvastatin1

Antifungals, azoles

Fluconazole or itraconazole: Increased rosuvastatin concentrations1

Ketoconazole: Decreased rosuvastatin peak plasma concentration and increased rosuvastatin AUC1

Cyclosporine

Increased rosuvastatin peak plasma concentration and AUC1

Increased risk of myopathy1

If used concomitantly, do not exceed rosuvastatin dosage of 5 mg daily1

Digoxin

Slight increases in digoxin peak plasma concentration and AUC1

Erythromycin

Decreased rosuvastatin concentrations1

Fibric acid derivatives (fenofibrate, gemfibrozil)

Increased risk of myopathy and/or rhabdomyolysis1

Fenofibrate: Modest increase in rosuvastatin concentrations; not considered clinically important1

Gemfibrozil: Increased rosuvastatin peak plasma concentration and AUC1

Fenofibrate: Use concomitantly with caution1

Gemfibrozil: Avoid concomitant use; if used concomitantly, do not exceed rosuvastatin dosage of 10 mg daily1

HIV protease inhibitors

Increased risk of myopathy1

Ritonavir-boosted atazanavir or lopinavir/ritonavir: Increased rosuvastatin peak plasma concentration and AUC1

Ritonavir-boosted fosamprenavir or ritonavir-boosted tipranavir: Minimal to no change in exposure to rosuvastatin1

Ritonavir-boosted atazanavir or lopinavir/ritonavir: Use concomitantly with caution; limit rosuvastatin dosage to 10 mg once daily1

Ritonavir-boosted fosamprenavir or ritonavir-boosted tipranavir: Use concomitantly with caution1

Niacin (antilipemic dosages [≥1 g daily])

Increased risk of myopathy1

Use concomitantly with caution1

Oral contraceptives

Increased concentrations of ethinyl estradiol and norgestrel1

Warfarin

Potentiation of anticoagulant effects (e.g., increased INR)1

Use concomitantly with caution; ensure INR is stable before initiating rosuvastatin; monitor INR frequently enough during early therapy (or following rosuvastatin dosage adjustment) to ensure that no substantial alteration in INR occurs1

Rosuvastatin Calcium Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is approximately 20%.1

Peak plasma concentrations attained within 3–5 hours.1

AUC does not differ following evening or morning administration.1

Onset

Maximal response occurs within 4 weeks.13

Duration

Response maintained during continued therapy.1

Food

Food does not affect AUC.1

Special Populations

Pediatric patients: Peak plasma concentrations and AUC are similar in pediatric patients (10–17 years of age) and adults.1

Geriatric patients: Plasma concentrations are similar between geriatric (≥65 years of age) and younger patients.1

Race: Clinically important differences in pharmacokinetics among white, Hispanic, African American, or Afro-Caribbean groups not demonstrated.1 Compared with Caucasian patients residing in the US, median rosuvastatin exposure (peak plasma concentration and AUC) is approximately twofold higher in Asian patients.1 (See Asian Patients under Dosage and Administration.)

Mild to moderate renal impairment (Clcr ≥30 mL/minute): Plasma concentrations not altered.1

Severe renal impairment (Clcr <30 mL/minute not requiring hemodialysis): Plasma concentrations increased about threefold.1

Chronic hemodialysis: Steady-state plasma concentrations approximately 50% higher than in healthy individuals with normal renal function.1

Hepatic impairment (Child-Pugh class A or B or chronic alcoholic liver disease): Increased plasma concentrations.1

Distribution

Extent

Crosses the placenta.1 Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

88% (mainly albumin).1

Elimination

Metabolism

Not extensively metabolized; only 10% of dose is recovered as metabolite.1

Metabolized by CYP2C9 to active metabolite.1

Elimination Route

Excreted principally in feces (90%) as unchanged drug and metabolites.1

Half-life

Approximately 19 hours.1

Stability

Storage

Oral

Tablets

20–25°C.1 Protect from moisture.1

Actions

  • Selectively and competitively inhibits HMG-CoA reductase, causing subsequent reduction in hepatic cholesterol synthesis.1 2 Reduces serum concentrations of total cholesterol, LDL-cholesterol, VLDL-cholesterol, non-HDL-cholesterol, apo B, and triglycerides; increases HDL-cholesterol concentrations.1

  • Statins may slow progression of and/or induce regression of atherosclerosis in coronary and/or carotid arteries, modulate BP in hypercholesterolemic patients with hypertension, and possess anti-inflammatory activity.

Advice to Patients

  • Importance of adhering to nondrug therapies and measures, including dietary management, weight control, physical activity, and management of potentially contributory disease (e.g., diabetes mellitus).

  • Risk of myopathy and/or rhabdomyolysis.1 Importance of promptly reporting any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever,1 brown urine, and flu-like symptoms.9 10

  • Risk of adverse hepatic effects.1 Importance of promptly reporting any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).1

  • Risk of nonserious, reversible cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion).1 200

  • Risk of increased glucose concentrations and development of type 2 diabetes;1 200 may need to monitor glucose concentrations following initiation of statin therapy.201

  • Importance of advising women and adolescent girls to avoid pregnancy (i.e., using appropriate contraceptive methods) during therapy; if the patient becomes pregnant, importance of discontinuing rosuvastatin and contacting a clinician.1

  • Importance of avoiding breast-feeding during therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Rosuvastatin Calcium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

5 mg (of rosuvastatin)

Crestor

AstraZeneca

10 mg (of rosuvastatin)

Crestor

AstraZeneca

20 mg (of rosuvastatin)

Crestor

AstraZeneca

40 mg (of rosuvastatin)

Crestor

AstraZeneca

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Crestor 10MG Tablets (ASTRAZENECA): 30/$154.99 or 90/$426.96

Crestor 20MG Tablets (ASTRAZENECA): 30/$155.98 or 90/$435.99

Crestor 40MG Tablets (ASTRAZENECA): 30/$155.99 or 90/$435.95

Crestor 5MG Tablets (ASTRAZENECA): 30/$154.99 or 90/$426.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. AstraZeneca Pharmaceuticals. Crestor (rosuvastatin calcium) tablets prescribing information. Wilmington, DE. 2012 Feb.

2. Davidson M, Ma P, Stein EA. 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. 2003; 89:268-75.

3. 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; 92:152-60. [IDIS 502119] [PubMed 12860216]

4. Schneck DW, Knopp RH, Ballantyne CM. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Am J Cardiol. 2003; 91:33-41. [IDIS 491642] [PubMed 12505568]

5. Capuzzi DM, Morgan JM, Weiss RJ. Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with combined hyperlipidemia and low high-density lipoprotein cholesterol levels. Am J Cardiol. 2003; 91:1304-10. [IDIS 500482] [PubMed 12767421]

6. Carswell CI, Plosker GL, Jarvis B. Rosuvastatin. Drugs. 2002; 62:2075-85.

7. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Adult Treatment Panel III Report. From AHA web site.

8. Pasternak RC, Smith SC Jr, Bairey-Merz CN et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. American College of Cardiology/American Heart Association/National Heart, Lung and Blood Institute. Circulation. 2002;106:1024-8.

9. Anon. Bayer voluntarily withdraws Baycol. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2001 Aug 8.

10. Pasternak RC, Smith SC Jr, Bairey-Merz CN et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. American College of Cardiology/American Heart Association/National Heart, Lung and Blood Institute. Circulation. 2002;106:1024-8.

11. AstraZeneca, Wilmington, DE: Personal communication.

12. Anon. Rosuvastatin (marketed as Crestor). FDA Alert for Healthcare Professionals. Rockville, MD. From FDA website; accessed 2005 Mar 2.

13. AstraZeneca. Crestor (rosuvastatin calcium) tablets prescribing information. Wilmington, DE; 2005 Mar.

14. Blom DJ, Marais AD, Retterstøl K et al. Rosuvastatin reduces non-high-density lipoprotein cholesterol and lipoprotein remnants in patients with dysbetalipoproteinemia (Fredrickson type III hyperlipoproteinemia). J Clin Lipidol. 2008; 2:418-25. [PubMed 21291775]

15. Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359:2195-207. [PubMed 18997196]

16. Crouse JR, Raichlen JS, Riley WA et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA. 2007; 297:1344-53. [PubMed 17384434]

17. Martin Pd, Schneck DW, Dane AL. The effect of a combination antacid preparation containing aluminum hydroxide and magnesium hydroxide on rosuvastatin pharmacokinetics. Curr Med Res Opin. 2008; 24:1231-5. [PubMed 18355422]

200. Food and Drug Administration. FDA drug safety communication: Important safety label changes to cholesterol-lowering statin drugs. Rockville, MD; 2012 Feb 28. From FDA website.

201. Food and Drug Administration. FDA expands advice on statin risks. Rockville, MD; 2012 Feb 27. From FDA website.

202. McKenney JM, Davidson MH, Jacobson TA et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006; 97(suppl):89-94C.

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