Rosuvastatin (Crestor) is a lipid lowering drug used in the treatment of dyslipidemia and in the prevention of cardiovascular diseases as an adjunct to diet and exercise.

Rosuvastatin (Crestor) Uses:

• 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:
  • an increased risk of cardiovascular disease based on age ≥50 years old in men and ≥60 years old in women.
  • hsCRP ≥2 mg/L
  • the presence of at least one additional cardiovascular disease risk factors 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.

• Off Label Use of Rosuvastatin in Adults:

  • Cardiac risk reduction for noncardiac surgery (perioperative therapy);
  • Non-cardioembolic stroke/Transient ischemic attack (secondary prevention

Rosuvastatin (Crestor) dose in Adults

Note:

• Doses should be customised 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.

Rosuvastatin (Crestor) dose in 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.
  • 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, review lipid levels within 2 to 4 weeks (peak, steady-state lowering effects usually seen between 4 to 6 weeks and adjust dose accordingly;
    • The usual dosage range: 5 to 40 mg once daily (maximum dose: 40 mg/day)

Note:

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

Rosuvastatin (Crestor) Homozygous familial hypercholesterolemia (HoFH):

• Oral: Initial: 20 mg once daily;
• after initiation or upon titration, review lipid levels within 2 to 4 weeks (peak, steady-state lowering effects usually seen between 4 to 6 weeks and adjust dose accordingly;
• The usual dosage range: 5 to 40 mg once daily (maximum dose: 40 mg/day)

Rosuvastatin (Crestor) dose for the prevention of cardiovascular disease (to 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, possible 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:

  • The patient has clinical ASCVD (eg, coronary heart disease, stroke/TIA, or peripheral arterial disease assumably of atherosclerotic origin) or is post-CABG 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.
  • 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.

• Rosuvastatin (Crestor) Dosage adjustment for rosuvastatin with concomitant medications: Oral:

  • Cyclosporine:
    • Rosuvastatin dose should not exceed 5 mg once daily
  • Gemfibrozil:
    • Avoid concurrent use; if unavoidable, start rosuvastatin at 5 mg once daily (maximum: 10 mg/day)
  • Atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir:
    • start rosuvastatin at 5 mg once daily (maximum: 10 mg/day).

• Rosuvastatin (Crestor) Dosage adjustment for hematuria and/or persistent, unexplained proteinuria while on 40 mg daily:

  • Reduce dose and evaluate causes.

Rosuvastatin (Crestor) dose in Childrens

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).

Rosuvastatin (Crestor) dose in patients with Heterozygous familial hypercholesterolemia:

• Children 8 to <10 years (females >1 year postmenarche):

  • Oral: 5 to 10 mg once daily;
  • Do not exceed: 10 mg/day

• Children ≥10 years and Adolescents (females > 1-year post menarche):

  • Oral: 5 to 20 mg once daily;
  • Do not exceed: 20 mg/day

Rosuvastatin (Crestor) dose in patients with Homozygous familial hypercholesterolemia:

• Children ≥7 years and Adolescents:

  • Oral: Initial dose: 20 mg once daily.
  • The 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.
  • Note: Patients on a 40 mg daily dose who develop hematuria and/or persistent, unexplained proteinuria should have a dose reduction and diagnostic workup 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 the 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), restart the original, or consider a reduced dose of rosuvastatin and re-titrate.
    • If muscle symptoms recur, discontinue rosuvastatin use.
    • After muscle symptom resolution, may then start with 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.

Rosuvastatin (Crestor) Pregnancy Risk Category: X

• Rosuvastatin contraindicated for pregnant women or those at risk of becoming pregnant
• In some studies on animal reproduction, adverse events were observed.
• Congenital anomalies have been reported in cases of maternal HMG-CoA reductase inhibitions during pregnancy.
• However, the limited data available are difficult to interpret due to maternal disease, differences between agents and low exposure rates.
• The role of cholesterol biosynthesis in fetal development may be significant; serum cholesterol and total triglycerides rise normally during pregnancy.
• It is unlikely that the temporary discontinuation of lipid-lowering medication during pregnancy will have an impact on long-term outcomes of primary hypercholesterolemia treatment.
• If Rosuvastatin is used to treat unplanned pregnancies, it should be stopped immediately
• If an HMG-CoA reductase inhibitor for females with reproductive potential is needed, it is important to use appropriate contraception
• The HMG-CoA reductase inhibitor should be stopped by pregnant women at least 1 to 2 months prior to trying to conceive.

Rosuvastatin use during breastfeeding:

• Breast milk contains Rosuvastatin (limited data).
• Manufacturers have advised against breastfeeding because of the risk of serious adverse effects.

Rosuvastatin (Crestor) Dose in Kidney Disease:

• CrCl ≥30 mL/minute/1.73 m2:
  • No dosage adjustment necessary.
• CrCl <30 mL/minute/1.73 m2:
  • Initial: 5 mg once daily (maximum: 10 mg/day).

Rosuvastatin (Crestor) Dose in Liver disease:

There are no specific dosage adjustments provided in the manufacturer's labeling; however, systemic exposure may be increased in patients with liver disease (increased AUC and Cmax); Use is contraindicated in active liver disease or unexplained transaminase elevations.

• Chronic liver disease:
  • Some experts suggest initiating at a low dose (eg, 5 mg once daily) and adjusting gradually based on monitoring of aminotransferase levels.

Common Side Effects of Rosuvastatin (Crestor):

• Neuromuscular & skeletal:

  • Myalgia

Less Common Side Effects of Rosuvastatin (Crestor):

• Central Nervous System:

  • Headache
  • Dizziness

• Endocrine & Metabolic:

  • Diabetes Mellitus

• Gastrointestinal:

  • Nausea
  • Constipation

• Genitourinary:

  • Cystitis

• Hepatic:

  • Increased Serum ALT

• Neuromuscular & Skeletal:

  • Arthralgia
  • Increased Creatine Phosphokinase
  • Weakness

Contraindications to Rosuvastatin (Crestor):

• Hypersensitivity to rosuvastatin and any component of the formulation
• Active liver disease
• Unexplained persistent increases in serum transaminases
• pregnancy.
• Breastfeeding

Canadian labeling: Additional contraindications not in US labeling

• Simultaneous administrations of cyclosporine
• Use of 40 mg dose in Asian patients, patients with predisposing risk factors for myopathy/rhabdomyolysis such as
  • Hereditary muscle disorders, history with myotoxicity with HMG-CoA reductase inhibiters
  • Concomitant use of fibrates or Niacin
  • Grave hepatic impairment
  • severe renal impairment [CrCl >30 mL/minute/1.73m2],
  • hypothyroidism,
  • alcohol abuse,
  • There may be situations in which rosuvastatin plasma levels are increased

Warnings and precautions

• Diabetes mellitus:

  • Rosuvastatin has been shown to cause small increases in HbA (mean: 0.1%) and fasting glucose.
  • However, statin therapy offers many benefits that far outweigh the risks of diabetes.

• Hematuria/proteinuria:

  • Microscopic hematuria and proteinuria have been described. This is more common in adults who take rosuvastatin 40mg daily.
  • These symptoms are usually temporary and do not cause a decline in renal function.
  • If persistent hematuria or proteinuria is not explained, you may consider reducing your dosage.

• Hepatotoxicity:

  • Rarely are postmarketing reports of fatal or nonfatal liver failure.
  • Stop treatment if you experience severe hepatotoxicity, clinical signs and/or hyperbilirubinemia/ jaundice.
  • Do not take rosuvastatin if an alternative etiology has not been discovered.
  • At baseline, liver enzyme tests should be performed. However, routine periodic monitoring of liver enzymes may not be necessary.

• Hypersensitivity

  • Reports of hypersensitivity reactions including angioedema, pruritus and urticaria have been made.

• Myopathy/rhabdomyolysis:

  • Patients should be monitored closely for rhabdomyolysis and acute renal failure due to myoglobinuria or myopathy.
  • 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 required, consider lower starting and maintenance doses of rosuvastatin.
  • Patients with hypothyroidism that has not been properly treated, patients who are taking colchicine, >=65 years old, and women should be cautious. These patients are more likely to develop myopathy.
  • It has been reported that immuno-mediated necrotizing myopathy (IMNM), associated with HMG–CoA reductase inhibitors, is also possible.
  • Patients should be taught to report any unexplained pain, tenderness, weakness or brown urine, particularly if it is accompanied by malaise, fever, or other symptoms.
  • If CPK levels are elevated or myopathy is suspected/diagnosed, discontinue therapy.

• Hepatic impairment, ethanol and/or ethanol abuse:

  • Patients who have had liver disease or are prone to excessive consumption of ethanol should be cautious.
  • It is not recommended for use in the presence of active liver disease, or undiagnosed transaminase elevations.

• Renal impairment

  • Adjustment of dosage is necessary.

Rosuvastatin: Drug Interaction

Monitoring parameters:

ACC/AHA Blood Cholesterol Guideline recommendations:

Lipid panel (total cholesterol, HDL, LDL, triglycerides):

• Lipid profile (fasting or nonfasting) before starting treatment.
• Repeat 1 to 3 months after initiating therapy and every 3 to 12 months subsequently.
• If 2 consecutive LDL levels are <40 mg/dL, consider reducing 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: 

• 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).

Diabetes:

• 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 smoking cessation.

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

How to administer Rosuvastatin (Crestor)?

Capsule:

• Oral:
  • Administer with or without food, at any time of the day.
  • Swallow the capsule whole; do not crush or chew.
  • The capsule may be opened and contents emptied onto 1 teaspoonful of applesauce; swallow immediately, do not chew.
• Nasogastric tube:
  • Capsule may be opened and mixed with 40 mL of water for administering via NGT; flush NG tube with an additional 20 mL of water.

Tablet:

• Administer with or without food at any time of the day;
• Swallow the tablet whole.

Mechanism of action of Rosuvastatin (Crestor):

• It inhibits the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis.
• This causes a compensatory rise in LDL receptor expression on hepatocyte membranes, and stimulates LDL catabolism. HMG-CoA inhibitors are able to lower high-sensitivity CRP (hsCRP) levels.
• They also improve endothelial function and reduce inflammation at the site.

Notice:

• Maximum serum concentrations and AUC were similar in pediatric patients (ages 10-17 years) to adult values.

The onset of action:

• Within 1 week;
• maximal at 4 weeks

Protein binding:

• 88%

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)

Bioavailability:

• 20% (high first-pass extraction by liver)

Half-life elimination:

• 19 hours

Time to peak plasma:

• 3 to 5 hours

Excretion:

• Feces (90%), primarily as unchanged drug

International Brand Names of Rosuvastatin:

• Crestor
• Ezallor Sprinkle
• ACH-Rosuvastatin
• ACT Rosuvastatin
• AG-Rosuvastatin
• APO-Rosuvastatin
• AuroRosuvastatin
• BIO-Rosuvastatin
• Crestor
• DOM-Rosuvastatin
• JAMP-Rosuvastatin
• MarRosuvastatin
• MED-Rosuvastatin
• MINT-Rosuvastatin
• MYLAN-Rosuvastatin
• NRARosuvastatin
• PMS-Rosuvastatin
• Priva-Rosuvastatin
• RIVA-Rosuvastatin
• SANDOZ Rosuvastatin
• SunPharma Rosuvastatin
• TEVA-Rosuvastatin
• Advochol
• Alvostat
• Astende
• Cemicresto
• Cholestor 10
• Clivas
• Creazin
• Cresadex
• Crestat
• Crestor
• Creva
• Delorin
• Devastin
• Fortius
• Justechol
• K-Zuva
• Lipichek
• Merovast
• Neustatin-R
• Recansa
• Robestar
• Rolip
• Romazic
• Rosart
• Rosca
• Rosetor
• Rossuwell
• Rostab
• Rostatin
• Rostin
• Rosu
• Rosucard
• Rosucol
• Rosucor
• Rosucrest
• Rosufer
• Rosunor
• Rosuterol
• Rosuva
• Rosuvas
• Rosuvaz
• Rosuxl
• Roswin
• Roswiss
• Rotip
• Rotorlip
• Rovartal
• Rovas
• Rovasto
• Rovastor
• Rovasyn
• Rovatitan
• Rovetin
• Rovista
• Rovitan
• Rozavas
• Rozinin
• Rupilip
• Rustor
• RVS
• Sinlip
• Softan
• Statinor
• Stator
• Surotin
• Tintaros
• Vaptor
• Vastrol
• Visacor
• Vivacor
• Zyrova

Rosuvastatin Brand Names in Pakistan: