Class: HMG-CoA Reductase Inhibitors
- Statins
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, Ezallor

Medically reviewed by Drugs.com on Jul 26, 2021. Written by ASHP.

• Uses
• Dosage
• Cautions
• Interactions
• Pharmacokinetics
• Patient advice
• Preparations

Introduction

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

Uses for Rosuvastatin

Reduction in Risk of Cardiovascular Events

Adjunct to nondrug therapies (i.e., lifestyle modifications) in patients without clinical evidence of CHD who have multiple risk factors (e.g., age, smoking, hypertension, low HDL-cholesterol concentrations, family history of early CHD) to reduce the risk of MI, stroke, or angina and the risk of undergoing revascularization procedures.

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.

Also used for secondary prevention† in patients with established atherosclerotic cardiovascular disease (ASCVD), defined as acute coronary syndromes (ACS), history of MI, stable or unstable angina or coronary or other arterial revascularization, stroke, TIA, or peripheral artery disease.

Extensive evidence demonstrates that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD; may be used for secondary prevention or primary prevention in high-risk patients.

AHA/ACC cholesterol management guideline states that lifestyle modification is the foundation of ASCVD risk reduction. Patients with established ASCVD or high risk of ASCVD should also be treated with a statin.

Because relative ASCVD risk reduction is correlated with degree of LDL-cholesterol lowering, use maximum tolerated intensity of a statin to achieve greatest benefit. High-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by ≥50%) is recommended; if high-intensity statin therapy not possible (e.g., because of a contraindication or intolerable adverse effect), may consider moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30–49%). AHA/ACC considers rosuvastatin 20–40 mg daily to be a high-intensity statin and rosuvastatin 5–10 mg daily to be a moderate-intensity statin.

The addition of a nonstatin drug (e.g., ezetimibe, PCSK9 inhibitor) to statin therapy may be considered in certain high-risk patients who require further reduction in LDL-cholesterol concentrations, particularly if there is evidence from randomized controlled studies suggesting that the addition of the nonstatin drug further reduces ASCVD events.

When considering whether to initiate statin therapy for primary prevention, AHA/ACC recommends an individualized approach and shared decision making between patient and clinician. According to the guidelines, statin therapy may be considered in certain high-risk groups such as adults 20–75 years of age with LDL cholesterol ≥190 mg/dL, adults 40–75 years of age with diabetes mellitus, adults 40–75 years of age without diabetes mellitus but with LDL-cholesterol levels ≥70 mg/dL and an estimated 10-year ASCVD risk ≥7.5%, and adults 40–75 years of age with chronic kidney disease (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70–189 mg/dL who have a 10-year ASCVD risk ≥7.5%.

Dyslipidemias

Adjunct to nondrug therapies (e.g., dietary management) 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. May be used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are on optimal statin therapy; however, no incremental benefit on cardiovascular morbidity and mortality beyond that provided by statin monotherapy.

Adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the management of heterozygous familial hypercholesterolemia in children and adolescents 8–17 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.

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

Adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum LDL-cholesterol, total cholesterol, non-HDL-cholesterol, and apo B concentrations in children and adolescents 7–17 years of age with homozygous familial hypercholesterolemia; used alone or in conjunction with other lipid-lowering therapies (e.g., LDL apheresis).

Adjunct to nondrug therapies (e.g., dietary management) for the management of hypertriglyceridemia.

Adjunct to nondrug therapies (e.g., dietary management) for the management of primary dysbetalipoproteinemia (Fredrickson type III).

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

Rosuvastatin Dosage and Administration

General

Monitoring during Antilipemic Therapy

• Manufacturer recommends obtaining lipoprotein concentrations within 2–4 weeks following initiation and/or titration of rosuvastatin and adjusting dosage accordingly. AHA/ACC cholesterol management guideline recommends obtaining lipoprotein concentrations within 4–12 weeks following initiation of statin therapy and after dosage changes (to assess response and adherence); monitoring should continue every 3–12 months thereafter as clinically indicated.

• Periodically reinforce adherence to lifestyle modifications. Antilipemic therapy is an adjunct to, not a substitute for, lifestyle modification therapies that reduce the risk of ASCVD.

Administration

Oral Administration

Administer orally (as tablets or sprinkle capsules). The sprinkle capsule formulation is FDA-labeled for use in a narrower population of patients (adults with hypertriglyceridemia, primary dysbetalipoproteinemia, or homozygous familial hypercholesterolemia).

Both tablets and capsules may be administered at any time of day without regard to meals.

Do not take 2 doses within 12 hours of each other.

Tablets

Swallow whole.

Sprinkle Capsules

Swallow whole; do not crush or chew. For patients with difficulty swallowing, may open capsules and mix contents with a small amount (e.g., teaspoonful) of soft food (e.g., applesauce, pudding). Consume the drug/food mixture within 60 minutes and do not store for later use; discard any remaining portions.

May be administered through a nasogastric tube. Open sprinkle capsules, mix intact granules with water, and deliver into nasogastric tube according to manufacturer's instructions. Use mixture immediately and do not store for later use; discard any remaining portions.

Dosage

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

Select appropriate initial dosage, then carefully adjust dosage according to individual requirements and response.

Dosage modifications may be necessary when used concomitantly with certain drugs (see Specific Drugs under Interactions).

Pediatric Patients

Dyslipidemias

Heterozygous Familial Hypercholesterolemia

Oral

Children 8 to <10 years of age: Recommended dosage range is 5–10 mg once daily.

Children and adolescents 10–17 years of age: Recommended dosage range is 5–20 mg once daily.

Adjust dosage at intervals of ≥4 weeks.

Homozygous Familial Hypercholesterolemia

Oral

Children and adolescents 7–17 years of age: Recommended dosage is 20 mg once daily.

Adults

Reduction in Risk of Cardiovascular Events

Oral

Use maximally tolerated statin intensity to achieve optimal ASCVD risk reduction. High-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by ≥50%) is preferred; if high-intensity statin therapy not possible (e.g., because of a contraindication or intolerable adverse effect), may consider moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30–49%).

The AHA/ACC guideline panel considers rosuvastatin 20–40 mg daily to be a high-intensity statin and rosuvastatin 5–10 mg daily to be a moderate-intensity statin.

Dyslipidemias

General Dosage

Oral

Usual initial dosage is 10–20 mg once daily.

Dosage range is 5–40 mg once daily. Reserve maximum 40-mg daily dosage for patients who have not achieved adequate response with the 20-mg daily dosage.

Homozygous Familial Hypercholesterolemia

Oral

Usual initial dosage is 20 mg once daily.

Prescribing Limits

Pediatric Patients

Dyslipidemias

Oral

Maximum 20 mg once daily.

Adults

Reduction in Risk of Cardiovascular Events or Management of Dyslipidemias

Oral

Maximum 40 mg once daily.

Special Populations

Hepatic Impairment

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

Renal Impairment

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

Asian Patients

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

Consider increased systemic exposure when treating Asian patients not adequately controlled at dosages up to 20 mg daily.

Geriatric Patients

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

Cautions for Rosuvastatin

Contraindications

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

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

• Lactation.

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

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Suppression of cholesterol biosynthesis could cause fetal harm.

Increased risk of major congenital malformations or miscarriage not identified with rosuvastatin; however, congenital anomalies reported rarely with other statins. In animal studies, no adverse developmental effects, but decreased pup survival observed. (See Pregnancy under Cautions.)

Musculoskeletal Effects

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

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

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

AHA/ACC recommends measurement of CK levels in patients with severe statin-associated muscle symptoms; however, routine monitoring is not useful.

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

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). (See Advice to Patients.)

Immune-mediated Necrotizing Myopathy

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported rarely in patients receiving statins. Characterized by proximal muscle weakness and elevated CK concentrations that persist despite discontinuance of statin therapy, positive anti-HMG CoA reductase antibody, necrotizing myopathy without substantial inflammation, and improvement following therapy with immunosuppressive agents.

Additional neuromuscular and serologic testing may be necessary; treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiating therapy with another statin, and monitor for signs and symptoms.

Hepatic Effects

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

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

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

Perform liver function tests before initiation of therapy and as clinically indicated (e.g., presence of manifestations suggestive of liver damage). Serious statin-related liver injury is rare and unpredictable, and routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury. AHA/ACC cholesterol management guideline states that it is reasonable to obtain liver function tests in patients with symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of skin or sclera); however, routine monitoring not recommended.

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

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. (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. Clinical importance not known; however, consider reducing dosage in patients who have unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

Hyperglycemic Effects

Increases in HbA_1c and fasting serum glucose concentrations reported. Possible increased risk of developing diabetes. May need to monitor glucose concentrations following initiation of statin therapy.

AHA/ACC cholesterol management guideline states that in patients with increased risk of diabetes mellitus or new-onset diabetes mellitus, statin therapy and lifestyle modifications should be continued to reduce risk of ASCVD.

Endogenous Steroid Production

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

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

Hypersensitivity Reactions

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

Cognitive Impairment

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

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

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

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

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.

Specific Populations

Pregnancy

Safety in pregnant women not established; no known benefits with use during pregnancy. (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Discontinue immediately if pregnancy is known or suspected. Women of childbearing potential should use effective contraception during therapy. (See Advice to Patients.)

Lactation

Distributed into human milk; effects on breast-fed infants or milk production not known. Use is contraindicated in nursing women; women who require rosuvastatin therapy should not breast-feed their infants.

Pediatric Use

Safety and efficacy not established in children <8 years of age.

Safety and efficacy in pediatric patients 8–17 years of age with heterozygous familial hypercholesterolemia generally similar to those observed in the adult population. Pharmacokinetic studies indicated rosuvastatin exposure similar to or less than that observed in adults.

Safety profile in children and adolescents 7–15 years of age with homozygous familial hypercholesterolemia similar to that observed in adults.

No detectable adverse effects on growth, weight, body mass index (BMI), or sexual maturation in children and adolescents.

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

Geriatric Use

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

Use with caution, since age ≥65 is a predisposing risk factor for myopathy.

Patients >75 years of age may have a higher risk of adverse effects and lower adherence to therapy; consider expected benefits versus adverse effects before initiating statin therapy in this population.

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). (See Contraindications under Cautions.)

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

Renal Impairment

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

Common Adverse Effects

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

Interactions for Rosuvastatin

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

Drugs Affecting Transport Systems

Substrate for organic anion transport protein (OATP) 1B1 and breast cancer resistance protein (BCRP). Concomitant use with drugs that inhibit these transport proteins potentially may increase plasma concentrations of rosuvastatin and increase risk of myopathy. Consult relevant prescribing information of such drugs when considering concomitant use.

Specific Drugs

Rosuvastatin Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is approximately 20%.

Peak plasma concentrations attained within 3–5 hours.

AUC does not differ following evening or morning administration.

Onset

Maximal response occurs within 4 weeks.

Duration

Response maintained during continued therapy.

Food

Food does not affect AUC.

Special Populations

Pediatric patients: Exposure in children and adolescents (8–17 years of age) is similar to or less than that observed in adults.

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

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

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

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

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

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

Pharmacogenomic considerations: Genetic polymorphism of the OATP1B1 gene may affect rosuvastatin exposure. Higher plasma concentrations reported in a limited number of patients with 2 reduced-function variant OATP1B1 alleles. Frequency of this genotype is <5% in most populations; effect on efficacy and safety not established.

Distribution

Extent

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

Plasma Protein Binding

88% (mainly albumin).

Elimination

Metabolism

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

Metabolized by CYP2C9 to active metabolite.

Elimination Route

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

Half-life

Approximately 19 hours.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C). Protect from moisture.

Tablets

20–25°C. Protect from moisture.

Actions

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

• 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 advising patients to read the manufacturer's patient information.

• Importance of adhering to nondrug therapies and measures, including adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight.

• Importance of informing patients that 2 doses of rosuvastatin should not be taken within 12 hours of each other.

• Risk of myopathy and/or rhabdomyolysis; risk is increased with higher dosages (i.e., 40 mg daily) or when used concomitantly with certain drugs. Importance of promptly reporting any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, or if manifestations persist after discontinuance of therapy.

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

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

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

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

• Importance of avoiding breast-feeding during therapy.

• 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.

• 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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