Rosuvastatin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Sprinkle, Oral:

Ezallor Sprinkle: 5 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Ezallor Sprinkle: 10 mg, 20 mg [contains brilliant blue fcf (fd&c blue #1)]

Ezallor Sprinkle: 40 mg

Tablet, Oral:

Crestor: 5 mg, 10 mg, 20 mg, 40 mg

Generic: 5 mg, 10 mg, 20 mg, 40 mg

Pharmacology

Mechanism of Action

Inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis (reduces the production of mevalonic acid from HMG-CoA); this then results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and a stimulation of LDL catabolism. In addition to the ability of HMG-CoA reductase inhibitors to decrease levels of high-sensitivity C-reactive protein (hsCRP), they also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects (de Denus 2002; Ray 2005).

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 134 L

Metabolism

Hepatic (10%), via CYP2C9 (1 active metabolite identified: N-desmethyl rosuvastatin, one-sixth to one-half the HMG-CoA reductase activity of the parent compound)

Excretion

Feces (90%), primarily as unchanged drug

Onset of Action

Within 1 week; maximal at 4 weeks

Time to Peak

Plasma: 3 to 5 hours

Half-Life Elimination

19 hours

Protein Binding

88%

Use in Specific Populations

Special Populations: Renal Function Impairment

Plasma concentrations increase about 3-fold in patients with severe renal impairment (CrCl <30 mL/minute/1.73 m²) not requiring hemodialysis. Steady-state plasma concentrations in patients on chronic hemodialysis are ~50% higher compared with patients with normal renal function.

Special Populations: Hepatic Function Impairment

C_max and AUC are increased in patients with Child-Pugh class A or Child-Pugh class B hepatic impairment.

Special Populations: Race

Asian patients have ~2-fold elevation in exposure (AUC and C_max).

Use: Labeled Indications

Familial hypercholesterolemia:

Pediatric (excluding Ezallor): Adjunct to diet to reduce total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B) levels in children and adolescents 8 to 17 years of age with heterozygous familial hypercholesteremia (HeFH) if after an adequate trial of diet therapy the following findings are present: LDL-C more than 190 mg/dL or more than 160 mg/dL and there is a positive family history of premature cardiovascular (CV) disease or 2 or more other CV disease risk factors; to reduce LDL-C, total-C, nonhigh-density lipoprotein cholesterol (non-HDL-C) and apo B in children and adolescents 7 to 17 years of age with homozygous familial hypercholesterolemia (HoFH), either alone or with other lipid-lowering treatments (eg, LDL apheresis).

Adult: To reduce LDL-C, total cholesterol, and apo B in adults with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or alone if such treatments are unavailable.

Hyperlipidemia and mixed dyslipidemia (Crestor only): Adjunctive therapy to diet to reduce elevated total cholesterol, LDL-C, apo B, non-HDL-C, and triglyceride levels, and to increase HDL-C in adults with primary hyperlipidemia or mixed dyslipidemia.

Hypertriglyceridemia: Adjunct to diet for the treatment of adults with hypertriglyceridemia.

Primary dysbetalipoproteinemia (type III hyperlipoproteinemia): Adjunct to diet for the treatment of adults with primary dysbetalipoproteinemia (type III hyperlipoproteinemia).

Prevention of cardiovascular disease (Crestor only):

Primary prevention: To reduce the risk of stroke, myocardial infarction, or arterial revascularization procedures in patients without clinically evident coronary heart disease but with all of the following: 1) an increased risk of cardiovascular disease based on age ≥50 years old in men and ≥60 years old in women, 2) hsCRP ≥2 mg/L, and 3) the presence of at least one additional cardiovascular disease risk factor such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease.

Secondary prevention: Adjunctive therapy to diet to slow the progression of atherosclerosis in adults as part of a treatment strategy to lower total cholesterol and LDL-C to target levels.

Use: Off Label

Cardiac risk reduction for noncardiac surgery (perioperative therapy)yes

Based on the 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery, perioperative initiation of statins is reasonable for patients undergoing vascular surgery and may be considered in patients with clinical indications according to guideline-directed medical therapy who are undergoing elevated risk procedures. In patients undergoing non-cardiac surgery who are currently receiving a statin, the statin should be continued.

Noncardioembolic stroke/Transient ischemic attack (secondary prevention)yes

Based on the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the prevention of stroke in patients with stroke and transient ischemic attack (TIA), statin therapy with intensive lipid-lowering effects is recommended to reduce the risk of recurrent stroke and future cardiovascular events in patients with ischemic stroke or TIA presumed to be of atherosclerotic origin who have an LDL-C concentration ≥100 mg/dL (with or without evidence for other clinical atherosclerotic cardiovascular disease [ASCVD]) or who have an LDL-C concentration <100 mg/dL (without evidence for other clinical ASCVD).

Contraindications

Hypersensitivity to rosuvastatin or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; pregnancy; breastfeeding.

Canadian labeling: Additional contraindications (not in US labeling): Concomitant administration of cyclosporine; use of 40 mg dose in Asian patients, patients with predisposing risk factors for myopathy/rhabdomyolysis (eg, hereditary muscle disorders, history of myotoxicity with other HMG-CoA reductase inhibitors, concomitant use with fibrates or niacin, severe hepatic impairment, severe renal impairment [CrCl <30 mL/minute/1.73 m²], hypothyroidism, alcohol abuse, situations where an increase in rosuvastatin plasma levels may occur)

Dosage and Administration

Dosing: Adult

Note: Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and patient response; adjustments should be made at intervals of 4 weeks or more.

Hyperlipidemia, mixed dyslipidemia, hypertriglyceridemia, primary dysbetalipoproteinemia: Oral:

Initial dose:

General dosing: 10 to 20 mg once daily; 20 mg once daily may be used in patients with severe hyperlipidemia (LDL >190 mg/dL) and aggressive lipid targets (McKenney 2009)

Conservative dosing: Patients requiring less aggressive treatment or predisposed to myopathy (including patients of Asian descent): 5 mg once daily

Titration: After initiation or upon titration, analyze lipid levels within 2 to 4 weeks (peak, steady-state lowering effects usually seen between 4 to 6 weeks [McKenney 2009]) and adjust dose accordingly; usual dosage range: 5 to 40 mg once daily (maximum dose: 40 mg/day)

Note: The 40 mg dose should be reserved for patients who have not achieved goal cholesterol levels on a dose of 20 mg daily, including patients switched from another HMG-CoA reductase inhibitor.

Homozygous familial hypercholesterolemia (HoFH): Oral: Initial: 20 mg once daily; after initiation or upon titration, analyze lipid levels within 2 to 4 weeks (peak, steady-state lowering effects usually seen between 4 to 6 weeks [McKenney 2009]) and adjust dose accordingly; usual dosage range: 5 to 40 mg once daily (maximum dose: 40 mg/day)

Prevention of cardiovascular disease/reduce the risk of atherosclerotic cardiovascular disease: Oral:

ACC/AHA Blood Cholesterol Guideline recommendations (ACC/AHA [Grundy 2018]; ACC/AHA [Stone 2013]):

Note: When choosing to initiate therapy and selecting dose-intensity, consider atherosclerotic cardiovascular disease (ASCVD) risk, risk enhancing factors, possibility for side effects, and drug interactions.

Primary prevention:

LDL-C ≥190 mg/dL and age 20 to 75 years: High-intensity therapy: 20 to 40 mg once daily

Diabetes, age 40 to 75 years and an estimated 10-year ASCVD risk <7.5%: Moderate-intensity therapy: 5 to 10 mg once daily

Diabetes, age 40 to 75 years and an estimated 10-year ASCVD risk ≥7.5%: High-intensity therapy: 20 to 40 mg once daily

LDL-C 70 to 189 mg/dL, age 40 to 75 years and an estimated 10-year ASCVD risk ≥7.5%: Moderate- to high-intensity therapy: 5 to 40 mg once daily

Secondary prevention:

Patient has clinical ASCVD (eg, coronary heart disease, stroke/TIA, or peripheral arterial disease presumed to be of atherosclerotic origin) or is post-CABG (AHA [Kulik 2015]) and:

Age ≤75 years: High-intensity therapy: 20 to 40 mg once daily

Age >75 years: Moderate- to high-intensity therapy: 5 to 40 mg once daily (ACC/AHA [Grundy 2018]); if a moderate-intensity dose (5 to 10 mg once daily) is started and tolerated, increase to a high-intensity dose (20 to 40 mg once daily) within 3 months (Rosenson 2019).

Not a candidate for high-intensity therapy: Moderate-intensity therapy: 5 to 10 mg once daily

US Preventive Services Task Force recommendations (USPSTF 2016): Age 40 to 75 years, no history of CVD, with ≥1 CVD risk factor (dyslipidemia, diabetes, hypertension, or smoking), and calculated 10-year CVD event risk of ≥10%:

Primary prevention: Moderate-intensity therapy: 5 to 10 mg once daily

Note: These recommendations do not pertain to patients with very high cholesterol levels (eg, LDL >190 mg/dL, familial hypercholesterolemia; were excluded from primary prevention trials); use clinical judgment in the treatment of these patients. In patients with a calculated 10-year CVD event risk of 7.5% to 10%, statin use may be considered based on patient characteristics.

Dosage adjustment for rosuvastatin with concomitant medications: Oral:

Cyclosporine: Rosuvastatin dose should not exceed 5 mg once daily

Gemfibrozil: Avoid concurrent use; if unable to avoid concurrent use, initiate rosuvastatin at 5 mg once daily (maximum: 10 mg/day)

Atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir: Initiate rosuvastatin at 5 mg once daily (maximum: 10 mg/day).

Dosage adjustment for hematuria and/or persistent, unexplained proteinuria while on 40 mg daily: Reduce dose and evaluate causes.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and patient response; adjustments should be made at intervals of 4 weeks or more. A lower, conservative dosing regimen may be necessary in patient populations predisposed to myopathy, including patients of Asian descent or concurrently receiving other lipid-lowering agents (eg, gemfibrozil, niacin, fibric acid derivatives), amiodarone, atazanavir/ritonavir, cyclosporine, lopinavir/ritonavir, or indinavir (see conservative, maximum adult doses below).

Heterozygous familial hypercholesterolemia:

Children 8 to <10 years (females >1 year postmenarche): Oral: 5 to 10 mg once daily; maximum daily dose: 10 mg/day

Children ≥10 years and Adolescents (females >1 year postmenarche): Oral: 5 to 20 mg once daily; maximum daily dose: 20 mg/day

Homozygous familial hypercholesterolemia: Children ≥7 years and Adolescents: Oral: Initial dose: 20 mg once daily. Maximum daily dose in adults is 40 mg/day. Although higher doses have been used (ie, 80 mg/day), additional benefit has not been reported (Marais 2008). Note: Patients on a 40 mg daily dose who develop hematuria and/or persistent, unexplained proteinuria should have a dose reduction and diagnostic work-up for causes.

Dosing adjustment with concomitant medications: Children ≥7 years and Adolescents:

Atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir: Initiate rosuvastatin at 5 mg once daily; maximum daily dose: 10 mg/day

Cyclosporine: Do not exceed rosuvastatin maximum daily dose: 5 mg/day

Gemfibrozil: Avoid concurrent use; if unable to avoid concurrent use, initiate rosuvastatin at 5 mg once daily; maximum daily dose: 10 mg/day

Dosing adjustment for toxicity: Muscle symptoms (potential myopathy): Children ≥7 years and Adolescents: Discontinue use until symptoms can be evaluated; check creatine phosphokinase (CPK) level; based on experience in adult patients, also evaluate patient for conditions that may increase the risk for muscle symptoms (eg, hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases). Upon resolution (symptoms and any associated CPK abnormalities), resume the original or consider a lower dose of rosuvastatin and retitrate. If muscle symptoms recur, discontinue rosuvastatin use. After muscle symptom resolution, may then reinitiate a different statin at an initial low dose; gradually increase if tolerated. Based on experience in adult patients, if muscle symptoms or elevated CPK persists for 2 months in the absence of continued statin use, consider other causes of muscle symptoms. If determined to be due to another condition aside from statin use, may resume statin therapy at the original dose (NHLBI 2011; Stone 2013).

Dosing: Adjustment for Toxicity

Severe muscle symptoms or fatigue: Promptly discontinue use; evaluate CPK, creatinine, and urinalysis for myoglobinuria (ACC/AHA [Stone 2013]).

Mild to moderate muscle symptoms: Discontinue use until symptoms can be evaluated; evaluate patient for conditions that may increase the risk for muscle symptoms (eg, hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases). Upon resolution, resume the original or lower dose of rosuvastatin. If muscle symptoms recur, discontinue rosuvastatin use. After muscle symptom resolution, may then use a low dose of a different statin; gradually increase if tolerated. In the absence of continued statin use, if muscle symptoms or elevated CPK continues after 2 months, consider other causes of muscle symptoms. If determined to be due to another condition aside from statin use, may resume statin therapy at the original dose (ACC/AHA [Stone 2013]).

Administration

Capsule:

Oral: Administer with or without food. May be taken at any time of the day. Swallow capsule whole; do not crush or chew. Capsule may be opened and contents emptied onto 1 teaspoonful of applesauce; swallow immediately without chewing.

Nasogastric tube: Capsule may be opened and contents emptied into a 60 mL catheter tipped syringe. Add 40 mL of water, then replace plunger and shake syringe vigorously for 15 seconds. Attach syringe to a ≥16-French NG tube and administer contents; flush NG tube with additional 20 mL of water. Mixture must be used immediately after preparation.

Tablet: Administer with or without food. May be taken at any time of the day; swallow tablet whole.

Dietary Considerations

Red yeast rice contains variable amounts of several compounds that are structurally similar to HMG-CoA reductase inhibitors, primarily monacolin K (or mevinolin) which is structurally identical to lovastatin; concurrent use of red yeast rice with HMG-CoA reductase inhibitors may increase the incidence of adverse and toxic effects (Lapi 2008; Smith 2003).

Storage

Capsule: Store between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Protect from moisture.

Tablet: Store between 20°C and 25°C (68°F to 77°F). Protect from moisture.

Drug Interactions

Acipimox: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Antacids: May decrease the serum concentration of Rosuvastatin. Monitor therapy

Apalutamide: May decrease the serum concentration of Rosuvastatin. Monitor therapy

Asunaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Bezafibrate: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Bezafibrate may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). More specifically, bezafibrate may increase the serum concentration of fluvastatin Management: Monitor patients closely for myopathy with concomitant use of bezafibrate and HMG-CoA reductase inhibitors. Concomitant use is contraindicated in patients predisposed to myopathy and alternative therapy should be considered. Consider therapy modification

CarBAMazepine: May decrease the serum concentration of Rosuvastatin. Monitor therapy

Ciprofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Management: Avoid the use of HMG-CoA reductase inhibitors and ciprofibrate if possible. If concomitant therapy is considered, benefits should be carefully weighed against the risks, and patients should be monitored closely for signs/symptoms of muscle toxicity. Consider therapy modification

Clopidogrel: May increase the serum concentration of Rosuvastatin. Monitor therapy

Cobicistat: May increase the serum concentration of Rosuvastatin. Management: Rosuvastatin dose should not exceed 10 mg/day with concurrent use of atazanavir and cobicistat or 20 mg/day with concurrent use of darunavir and cobicistat. Consider therapy modification

Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Consider therapy modification

CycloSPORINE (Systemic): May increase the serum concentration of Rosuvastatin. Management: Limit rosuvastatin to 5 mg/day in patients who are also receiving cyclosporine. Canadian labeling contraindicates concomitant use of rosuvastatin with cyclosporine. Consider therapy modification

Daclatasvir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

DAPTOmycin: HMG-CoA Reductase Inhibitors (Statins) may enhance the adverse/toxic effect of DAPTOmycin. Specifically, the risk of skeletal muscle toxicity may be increased. Management: Consider temporarily stopping HMG-CoA reductase inhibitor therapy prior to daptomycin. If used together, regular (i.e., at least weekly) monitoring of CPK concentrations is recommended. Consider therapy modification

Darolutamide: May increase the serum concentration of Rosuvastatin. Management: Avoid coadministration of darolutamide and rosuvastatin if possible. If combined, monitor for increased rosuvastatin effects/toxicities and consider a rosuvastatin dose reduction. Consider therapy modification

Dasabuvir: May increase the serum concentration of Rosuvastatin. Management: Limit the rosuvastatin dose to a maximum of 10 mg per day when used with the ombitasvir/paritaprevir/ritonavir/dasabuvir combination product. Labeling outside of the US recommends limiting the rosuvastatin dose to 5 mg per day. Consider therapy modification

Dronedarone: May increase the serum concentration of Rosuvastatin. Monitor therapy

Elagolix: May decrease the serum concentration of Rosuvastatin. Monitor therapy

Elbasvir: May increase the serum concentration of Rosuvastatin. Management: Limit the dose of rosuvastatin to a maximum of 10 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

Eltrombopag: May increase the serum concentration of Rosuvastatin. Management: Consideration a preventive 50% reduction in rosuvastatin adult dose when starting this combination; Canadian labeling recommends limiting rosuvastatin to a maximum of 20 mg/day. Consider therapy modification

Eluxadoline: May increase the serum concentration of Rosuvastatin. Management: Use the lowest effective dose of rosuvastatin if combined with eluxadoline. Consider therapy modification

Eslicarbazepine: May decrease the serum concentration of Rosuvastatin. Monitor therapy

Fenofibrate and Derivatives: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Fostamatinib: May increase the serum concentration of Rosuvastatin. Monitor therapy

Fusidic Acid (Systemic): May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for muscle toxicities, including rhabdomyolysis may be significantly increased. Management: Avoid concurrent use whenever possible. Use is listed as contraindicated in product characteristic summaries in several countries, although UK labeling suggests that use could be considered under exceptional circumstances and with close supervision. Avoid combination

Gemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of Rosuvastatin. Gemfibrozil may increase the serum concentration of Rosuvastatin. Management: If possible, avoid concomitant use of rosuvastatin with gemfibrozil. If concomitant can not be avoided, limit rosuvastatin to 10 mg/day (US recommendation) or 20 mg/day (Canadian recommendation). Monitor for signs/symptoms of rhabdomyolysis. Avoid combination

Glecaprevir and Pibrentasvir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Use the lowest statin dose possible if combined with glecaprevir/pibrentasvir and monitor for increased statin effects/toxicities. Avoid concomitant use with atorva-, simva-, or lovastatin. Limit rosuvastatin to 10 mg daily and reduce pravastatin dose 50% Consider therapy modification

Grazoprevir: May increase the serum concentration of Rosuvastatin. Management: Limit the dose of rosuvastatin to a maximum of 10 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

Itraconazole: May increase the serum concentration of Rosuvastatin. Monitor therapy

Lanthanum: HMG-CoA Reductase Inhibitors (Statins) may decrease the serum concentration of Lanthanum. Management: Administer HMG-CoA reductase inhibitors at least two hours before or after lanthanum. Consider therapy modification

Lasmiditan: May increase the serum concentration of BCRP/ABCG2 Substrates. Avoid combination

Ledipasvir: May increase the serum concentration of Rosuvastatin. Avoid combination

Letermovir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Niacin: May enhance the myopathic (rhabdomyolysis) effect of Rosuvastatin. Monitor therapy

Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of Rosuvastatin. Management: Limit the rosuvastatin dose to a maximum of 10 mg per day when used with the ombitasvir/paritaprevir/ritonavir/dasabuvir combination product. Canadian labeling recommends limiting the rosuvastatin dose to 5 mg per day. Consider therapy modification

Osimertinib: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Protease Inhibitors: May increase the serum concentration of Rosuvastatin. Management: Start at the lowest rosuvastatin dose and monitor for toxicity. See full drug interaction monograph for details. Consider therapy modification

Raltegravir: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Red Yeast Rice: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Avoid combination

Regorafenib: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Repaglinide: HMG-CoA Reductase Inhibitors (Statins) may increase the serum concentration of Repaglinide. Monitor therapy

RifAMPin: May decrease the serum concentration of Rosuvastatin. Monitor therapy

Rolapitant: May increase the serum concentration of BCRP/ABCG2 Substrates. Management: Monitor patients receiving rolapitant for increased exposure to and/or effects of BCRP/ABCG2 substrates. Use the lowest effective rosuvastatin dose when used in combination with rolapitant. Monitor therapy

Rupatadine: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for increased CPK and/or other muscle toxicities may be increased. Monitor therapy

Simeprevir: May increase the serum concentration of Rosuvastatin. Management: Limit initial rosuvastatin dose to 5 mg/day when being started in a patient who is also being treated with simeprevir. The maximum rosuvastatin dose should not exceed 10 mg/day with concurrent use of simeprevir. Consider therapy modification

Tafamidis: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Tedizolid: May increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Teriflunomide: May increase the serum concentration of Rosuvastatin. Management: Limit the maximum adult rosuvastatin dose to 10 mg/day in patients receiving teriflunomide, and monitor for evidence of rosuvastatin toxicity (eg, muscle toxicity, elevated transaminase concentrations). Consider therapy modification

Tolvaptan: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Consider therapy modification

Tolvaptan: May increase the serum concentration of BCRP/ABCG2 Substrates. Consider therapy modification

Trabectedin: HMG-CoA Reductase Inhibitors (Statins) may enhance the myopathic (rhabdomyolysis) effect of Trabectedin. Monitor therapy

Velpatasvir: May increase the serum concentration of Rosuvastatin. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): HMG-CoA Reductase Inhibitors (Statins) may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Voxilaprevir: May increase the serum concentration of Rosuvastatin. Avoid combination

Adverse Reactions

>10%: Neuromuscular & skeletal: Myalgia (2% to 13%)

1% to 10%:

Central nervous system: Headache (6% to 9%), dizziness (4%)

Endocrine & metabolic: Diabetes mellitus (new onset: 3%)

Gastrointestinal: Nausea (4% to 6%), constipation (3% to 5%)

Genitourinary: Cystitis (interstitial; Huang 2015)

Hepatic: Increased serum ALT (2%; >3 times ULN)

Neuromuscular & skeletal: Arthralgia (4% to 10%), increased creatine phosphokinase (3%; >10 x ULN: Children 3%), weakness (5%)

<1%, postmarketing, and/or case reports: Abnormal thyroid function test, cognitive dysfunction (reversible; includes amnesia, confusion, memory impairment), depression, elevated glycosylated hemoglobin (HbA_1c), gynecomastia, hematuria (microscopic), hepatic failure, hepatitis, hypersensitivity reaction (including angioedema, pruritus, skin rash, urticaria), immune-mediated necrotizing myopathy, increased gamma-glutamyl transferase, increased serum alkaline phosphatase, increased serum bilirubin, increased serum glucose, increased serum transaminases, interstitial pulmonary disease, jaundice, myoglobinuria, myopathy, myositis, pancreatitis, peripheral neuropathy, proteinuria (dose related), renal failure, rhabdomyolysis, sleep disorder (including insomnia and nightmares), thrombocytopenia

Warnings/Precautions

Concerns related to adverse effects:

• Diabetes mellitus: Small increases in HbA_1c (mean: ~0.1%) and fasting blood glucose have been reported with rosuvastatin; however, the benefits of statin therapy far outweigh the risk of dysglycemia.
• Hematuria/proteinuria: Hematuria (microscopic) and proteinuria have been observed; more commonly reported in adults receiving rosuvastatin 40 mg daily. Typically, transient and not associated with a decrease in renal function. Consider dosage reduction if unexplained hematuria and proteinuria persists.
• Hepatotoxicity: Postmarketing reports of fatal and nonfatal hepatic failure are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy. If an alternate etiology is not identified, do not restart rosuvastatin. Liver enzyme tests should be obtained at baseline and as clinically indicated; routine periodic monitoring of liver enzymes is not necessary.
• Hypersensitivity: Hypersensitivity reactions, including rash, pruritus, urticaria, and angioedema, have been reported.
• Myopathy/rhabdomyolysis: Rhabdomyolysis with acute renal failure secondary to myoglobinuria and/or myopathy have been reported; patients should be monitored closely. This risk is dose-related and is increased with concurrent use of strong CYP3A4 inhibitors (eg, clarithromycin, itraconazole, protease inhibitors), cyclosporine, fibric acid derivatives (eg, gemfibrozil), or niacin (doses ≥1 g/day); if concurrent use is warranted, consider lower starting and maintenance doses of rosuvastatin. Use caution in patients with inadequately treated hypothyroidism, patients taking other drugs associated with myopathy (eg, colchicine), ≥65 years of age, and women; these patients are predisposed to myopathy. Immune-mediated necrotizing myopathy (IMNM) associated with HMG-CoA reductase inhibitors use has also been reported. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine, particularly if accompanied by malaise or fever. Discontinue therapy if markedly elevated CPK levels occur or myopathy is diagnosed/suspected.

Disease-related concerns:

• Hepatic impairment and/or ethanol use: Use with caution in patients who consume large amounts of ethanol or have a history of liver disease. Use is contraindicated with active liver disease or unexplained transaminase elevations.
• Renal impairment: Dosage adjustment required in patients with a CrCl <30 mL/minute/1.73 m² and not receiving hemodialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Asian population: Increased risk of rosuvastatin-associated myopathy in certain subgroups; dosage adjustment should be considered for patients of Asian descent.
• Elderly: Use with caution in patients with advanced age; these patients are more predisposed to myopathy.
• Surgical patients: The manufacturer recommends temporary discontinuation for elective major surgery, acute medical or surgical conditions, or in any patient experiencing an acute or serious condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled seizures). Based on current research and clinical guidelines, HMG-CoA reductase inhibitors should be continued in the perioperative period for noncardiac and cardiac surgery (ACC/AHA [Fleisher 2014]; ACC/AHA [Hillis 2011]). Perioperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality.

Other warnings/precautions:

• Appropriate use: Secondary causes of hyperlipidemia should be ruled out prior to therapy. Rosuvastatin has not been studied when the primary lipid abnormality is chylomicron elevation (Fredrickson types I and V).

Monitoring Parameters

ACC/AHA Blood Cholesterol Guideline recommendations (ACC/AHA [Grundy 2018]; ACC/AHA [Stone 2013]):

Lipid panel (total cholesterol, HDL, LDL, triglycerides): Lipid profile (fasting or nonfasting) before initiating treatment. Fasting lipid profile should be rechecked 4 to 12 weeks after starting therapy and every 3 to 12 months thereafter. If 2 consecutive LDL levels are <40 mg/dL, consider decreasing the dose.

Hepatic transaminase levels: Baseline measurement of hepatic transaminase levels (ie, AST and ALT); measure AST, ALT, total bilirubin, and alkaline phosphatase if symptoms suggest hepatotoxicity (eg, unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of skin or sclera) during therapy.

CPK: CPK should not be routinely measured. Baseline CPK measurement is reasonable for some individuals (eg, family history of statin intolerance or muscle disease, clinical presentation, concomitant drug therapy that may increase risk of myopathy). May measure CPK in any patient with symptoms suggestive of myopathy (pain, tenderness, stiffness, cramping, weakness, or generalized fatigue).

Evaluate for new-onset diabetes mellitus during therapy; if diabetes develops, continue statin therapy and encourage adherence to a heart-healthy diet, physical activity, a healthy body weight, and tobacco cessation.

If patient develops a confusional state or memory impairment, may evaluate patient for nonstatin causes (eg, exposure to other drugs), systemic and neuropsychiatric causes, and the possibility of adverse effects associated with statin therapy.

Pregnancy

Pregnancy Considerations

Rosuvastatin is contraindicated in pregnant females or those who may become pregnant.

Adverse events have been observed in some animal reproduction studies. There are reports of congenital anomalies following maternal use of HMG-CoA reductase inhibitors in pregnancy; however, maternal disease, differences in specific agents used, and the low rates of exposure limit the interpretation of the available data (Godfrey 2012; Lecarpentier 2012). Cholesterol biosynthesis may be important in fetal development; serum cholesterol and triglycerides increase normally during pregnancy. The discontinuation of lipid lowering medications temporarily during pregnancy is not expected to have significant impact on the long term outcomes of primary hypercholesterolemia treatment.

Rosuvastatin should be discontinued immediately if an unplanned pregnancy occurs during treatment.

Adequate contraception is recommended if an HMG-CoA reductase inhibitor is required in females of reproductive potential. Females planning a pregnancy should discontinue the HMG-CoA reductase inhibitor 1 to 2 months prior to attempting to conceive (AHA/ACC [Grundy 2018]).

Patient Education

What is this drug used for?

• It is used to lower bad cholesterol and raise good cholesterol (HDL).
• It is used to lower triglycerides.
• It is used to slow the progress of heart disease.
• It is used in some people to lower the chance of heart attack, stroke, and certain heart procedures.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Headache
• Abdominal pain
• Nausea
• Joint pain
• Weakness

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Liver problems like dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes.
• Blood in the urine
• Unable to pass urine
• Change in amount of urine passed
• Muscle pain
• Muscle tenderness
• Muscle weakness
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.