Dosing and uses of Crestor (rosuvastatin)
Adult dosage forms and strengths
tablet
- 5mg
- 10mg
- 20mg
- 40mg
Hypercholesterolemia
Hypertriglyceridemia, hyperlipidemia, mixed dyslipidemia, slowing progression of atherosclerosis, primary dysbetalipoproteinemia
10-20 mg PO qDay initially; may titrate; not to exceed 40 mg/day
Dosage range: 5-40 mg/day
Homozygous familial hypercholesterolemia: Initiate with 20 mg PO qDay; may titrate; not to exceed 40 mg/day
Primary Prevention
Primary prevention of cardiovascular disease in individuals with no clinically evident heart disease but who are at risk because of combined effect of risk factors listed below
Approval based on JUPITER trial (Justification for the Use of statins in Prevention: an Intervention Trial Evaluation Rosuvastatin)
Initial: 10-20 mg PO qDay
Dosage range 5-40 mg/day
Cardiovascular disease
- Shown to reduce risk of stroke, MI, and arterial revascularization procedures (including CABG, bypass grafting of peripheral artery or carotid artery, and angioplasty or stent placement)
Risk factors
- Age (>50 yr in men; >60 yr in women), AND
- Elevated high-sensitivity C-reactive protein level (>2 mg/L), AND
- Presence of at least 1 additional cardiovascular risk factor (eg, high blood pressure, low HDL-C, smoking, family history of premature heart disease)
Dosing Considerations
Patients of Asian descent: Initiate with 5 mg/day
Coadministration with other lipid-lowering therapy: Consider dose reduction if combined with niacin or fenofibrate, because of increased risk for skeletal muscle effects
Coadministration with cyclosporine: Not to exceed 5 mg/day
Coadministration with gemfibrozil: Avoid if possible; if used together, do not exceed 10 mg/day
Coadministration with ritonavir, lopinavir/ritonavir, or atazanavir/ritonavir: Not to exceed 10 mg/day
Overdose management
- Adverse drug reactions from overdose may include peripheral neuropathy, diarrhea, increased K+, myopathy, rhabdomyolysis, acute renal failure, elevated LFTs, eye lens opacities
- Treatment is supportive
Dosing Modifications
Renal impairment
- Severe (CrCl <30 mL/min/1.73m²) and not on hemodialysis: Decrease starting dose to 5 mg PO qDay; not to exceed 10 mg PO qDay
- CrCl>30mL/min/1.73m²: Dose adjustment not necessary
- Active liver disease: Use is contraindicated
- Chronic alcoholic liver disease is known to increase rosuvastatin exposure; caution advised
Pediatric dosage forms and strengths
tablet
- 5mg
- 10mg
- 20mg
- 40mg
Heterozygous Familial Hypercholesterolemia (HeFH)
Indicated to reduce total-C, LDL-C, and ApoB levels in children and adolescents aged 8-17 yr if after an adequate trial of diet therapy the following findings are present: LDL-C >190 mg/dL, or >160 mg/dL along with a positive family history of premature cardiovascular disease (CVD) or ≥2 CVD risk factors
<8 years: Safety and efficacy not established
8 to <10 years: 5-10 mg PO qDay
10-17 years: 5-20 mg PO qDay; may adjust dose at intervals of at least 4 wk; not to exceed 20 mg/day
Homozygous Familial Hypercholesterolemia (HoFH)
Indicated to reduce LDL-C, Total-C, nonHDL-C and ApoB in children and adolescents aged 7 to 17 yr with homozygous familial hypercholesterolemia, either alone or with other lipid-lowering treatments (eg, LDL apheresis)
<7 years: Safety and efficacy not established
7-17 years: 20 mg PO qDay
Crestor (rosuvastatin) adverse (side) effects
>10%
Myalgia (3-13%)
1-10%
Arthralgia (10%)
Diabetes mellitus, new onset (3%)
Pharyngitis (9%)
Headache (6%)
Asthenia (up to 5%)
Dizziness (4%)
CPK increased (3%)
Nausea (3%)
Abdominal pain (2%)
ALT increased (2%)
Constipation (2%)
Flulike illness (2%)
UTI (2%)
<1%
Jaundice
Myopathy
Rhabdomyolysis
Postmarketing Reports
Arthralgia
Peripheral neuropathy
Depression and sleep disorders (including insomnia and nightmares)
Fatal and nonfatal hepatic failure, hepatitis, jaundice
Thrombocytopenia
Gynecomastia
Warnings
Contraindications
Hypersensitivity
Active liver disease, elevated LFTs
Pregnancy, lactation
Cautions
Nonserious and reversible cognitive side effects may occur
Increased blood sugar and glycosylated hemoglobin (HbA1c) levels reported with statin intake; in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus
Chronic liver disease
Measure liver enzymes before initiating and if signs or symptoms of liver injury occur
Consider lower initial dose (5 mg qDay) in patients with risk of myopathy
Increased risk of rhabdomyolysis, especially at highest approved dose of 40 mg/day; reserve highest dose only for patients who fail to achieve desired cholesterol level at 20 mg/day
Use 5 mg/day starting dose in people of Asian ancestry, who may build up higher drug levels and be at higher risk of myopathy
Rare reports of immune-mediated necrotizing myopathy (IMNM), characterized by increased serum creatine kinase that persists despite discontinuing statin
Discontinue if CK levels are markedly elevated
Pregnancy and lactation
Pregnancy
Contraindicated
Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol (eg, cell membranes), rosuvastatin may cause fetal harm when administered to pregnant women
Lactation
Contraindicated
Limited data indicate that rosuvastatin is present in human milk; because statins have the potential for serious adverse reactions in nursing infants, women who require rosuvastatin treatment should not breastfeed their infants
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Crestor (rosuvastatin)
Mechanism of action
HMG-CoA reductase inhibitor; inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase
Absorption
Bioavailability: 20%
Peak plasma time: 3-5 hr
Distribution
Vd: 134 L
Protein bound: 88%
Metabolism
Metabolism: ~10% by hepatic CYP2C9
Metabolites: N-desmethyl, lactone
Elimination
Half-Life, Elimination: 19 hr
Excretion: Feces (90%)
Pharmacogenomics
Hepatic influx and efflux transporters (single-nucleotide polymorphisms [SNPs] within the solute carrier organic anion transporter 1B1 (SLCO1B1) gene, encoding the organic anion transporter polypeptide 1B1 (OATP1B1) influx transporter)
SLCO1B1 (OATP1B1) CC genotype significantly increases AUCs of parent drug and metabolites compared with the CT or TT genotypes
This polymorphism is proposed to reduced transport into the liver, the main site of statin metabolism and elimination, resulting in elevated plasma concentrations
SLCO1B1 polymorphism is thought to have a lesser effect on the more hydrophilic statins (eg, rosuvastatin, fluvastatin) compared with those that are more lipophilic (eg, atorvastatin, pravastatin, simvastatin)
Other genetic polymorphisms of elimination (eg, CYP450, P-glycoprotein) for each individual drug must also be considered, to explain variability for statin clearance among patients that exhibit SCLO1B1 polymorphism
SLCO1B1 CC genotype is most common in Caucasians and Asians (15%); decrease dose by 50% in people of Asian descent
Risk of myopathy is 2.6- to 4.3-fold higher if the C allele is present and 16.9-fold higher in CC homozygotes than in TT homozygotes
Genetic testing laboratories
- Optivia Biotechnology, Inc (https://optiviabio.com)
