Rosuvastatin Calcium

Hyperlipidemia And Mixed Dyslipidemia

Sections or subsections omitted from the full prescribing information are not listed. CRESTOR is indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C, ApoB, nonHDLC, and triglycerides and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and nonpharmacological interventions alone has been inadequate.

Pediatric Patients With Familial Hypercholesterolemia

CRESTOR is indicated as an adjunct to diet to:

• reduce Total-C, LDL-C and ApoB levels in children and adolescents 8 to 17 years of age with heterozygous familial hypercholesterolemia 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 two or more other CVD risk factors.
• reduce LDL-C, Total-C, nonHDL-C and ApoB in children and adolescents 7 to 17 years of age with homozygous familial hypercholesterolemia, either alone or with other lipid-lowering treatments (e.g., LDL apheresis).

Hypertriglyceridemia

CRESTOR is indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

CRESTOR is indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).

Adult Patients With Homozygous Familial Hypercholesterolemia

CRESTOR is indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDLC, TotalC, and ApoB in adult patients with homozygous familial hypercholesterolemia.

Slowing Of The Progression Of Atherosclerosis

CRESTOR is indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower TotalC and LDLC to target levels.

Primary Prevention Of Cardiovascular Disease

In individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease based on age ≥ 50 years old in men and ≥ 60 years old in women, hsCRP ≥ 2 mg/L, and the presence of at least one additional cardiovascular disease risk factor such as hypertension, low HDLC, smoking, or a family history of premature coronary heart disease, CRESTOR is indicated to:

• reduce the risk of stroke
• reduce the risk of myocardial infarction
• reduce the risk of arterial revascularization procedures

Limitations Of Use

CRESTOR has not been studied in Fredrickson Type I and V dyslipidemias.

Included as part of the PRECAUTIONS section.

You should not take rosuvastatin if you are allergic to it, if you are pregnant or breast-feeding, or if you have liver disease.

Stop taking this medication and tell your doctor right away if you become pregnant.

Before taking rosuvastatin, tell your doctor if you have ever had liver or kidney disease, diabetes, or a thyroid disorder, if you are of Chinese descent, or if you drink more than 2 alcoholic beverages daily.

In rare cases, rosuvastatin can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

Avoid eating foods that are high in fat or cholesterol. Rosuvastatin will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan.

Avoid drinking alcohol. It can raise triglyceride levels and may increase your risk of liver damage.

There are many other drugs that can increase your risk of serious medical problems if you take them together with rosuvastatin. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Rosuvastatin is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.

Avoid using antacids without your doctor's advice. Use only the type of antacid your doctor recommends, and do not take it within 2 hours after taking rosuvastatin. Some antacids can make it harder for your body to absorb rosuvastatin.

Avoid eating foods that are high in fat or cholesterol. Rosuvastatin will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan.

Avoid drinking alcohol. It can raise triglyceride levels and may increase your risk of liver damage.

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis) [see WARNINGS AND PRECAUTIONS]
• Liver enzyme abnormalities [see WARNINGS AND PRECAUTIONS]

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

In the CRESTOR controlled clinical trials database (placebo or active-controlled) of 5394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were:

• myalgia
• abdominal pain
• nausea

The most commonly reported adverse reactions (incidence ≥ 2%) in the CRESTOR controlled clinical trial database of 5394 patients were:

• headache
• myalgia
• abdominal pain
• asthenia
• nausea

Adverse reactions reported in ≥ 2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks.

Table 1: Adverse Reactions Reported in ≥ 2% of Patients Treated with CRESTOR and > Placebo in Placebo-Controlled Trials (% of Patients )

Adverse Reactions	CRESTOR 5 mg N=291	CRESTOR 10 mg N=283	CRESTOR 20 mg N=64	CRESTOR 40 mg N=106	Total CRESTOR 5 mg D40 mg N=744	Placebo N=382
Headache	5.5	4.9	3.1	8.5	5.5	5.0
Nausea	3.8	3.5	6.3	0	3.4	3.1
Myalgia	3.1	2.1	6.3	1.9	2.8	1.3
Asthenia	2.4	3.2	4.7	0.9	2.7	2.6
Constipation	2.1	2.1	4.7	2.8	2.4	2.4
*Adverse reactions by COSTART preferred term.

Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria [see WARNINGS AND PRECAUTIONS]; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities.

In the METEOR study, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with CRESTOR versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea [see Clinical Studies].

Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 2.

Table 2: Adverse Reactions Reported in ≥ 2% of Patients Treated with CRESTOR and > Placebo in the METEOR Trial (% of Patients )

Adverse Reactions	CRESTOR 40 mg N=700	Placebo N=281
Myalgia	12.7	12.1
Arthralgia	10.1	7.1
Headache	6.4	5.3
Dizziness	4.0	2.8
Increased CPK	2.6	0.7
Abdominal pain	2.4	1.8
ALT > 3x ULN†	2.2	0.7
*Adverse reactions by MedDRA preferred term. †Frequency recorded as abnormal laboratory value

In the JUPITER study, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation.

In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c > 6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebotreated patients [see WARNINGS AND PRECAUTIONS and Clinical Studies].

Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 3.

Table 3: Adverse Reactions* Reported in ≥ 2% of Patients Treated with CRESTOR and > Placebo in the JUPITER Trial (% of Patients )

Adverse Reactions	CRESTOR 20 mg N=8901	Placebo N=8901
Myalgia	7.6	6.6
Arthralgia	3.8	3.2
Constipation	3.3	3.0
Diabetes mellitus	2.8	2.3
Nausea	2.4	2.3
* Treatment-emergent adverse reactions by MedDRA preferred term.

Pediatric Patients With Heterozygous Familial Hypercholesterolemia

In a 12-week controlled study in boys and postmenarcheal girls 10 to 17 years of age with heterozygous familial hypercholesterolemia with CRESTOR 5 to 20 mg daily [see Use in Specific Populations and Clinical Studies], elevations in serum creatine phosphokinase (CK) > 10 x ULN were observed more frequently in rosuvastatin compared with placebo-treated children. Four of 130 (3%) children treated with rosuvastatin (2 treated with 10 mg and 2 treated with 20 mg) had increased CK > 10 x ULN, compared to 0 of 46 children on placebo.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of CRESTOR: arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares), peripheral neuropathy and gynecomastia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see WARNINGS AND PRECAUTIONS].

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

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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

• Manufacturer recommends obtaining lipoprotein concentrations within 2–4 weeks following initiation and/or titration of rosuvastatin and adjusting dosage accordingly.1 ACC/AHA cholesterol management guideline recommends obtaining lipoprotein concentrations within 4–12 weeks following initiation of statin therapy (to assess response and adherence) and monitoring every 3–12 months thereafter as clinically indicated.350

• Periodically reinforce adherence to lifestyle modifications.350

Administration

Oral Administration

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

Do not take 2 doses within 12 hours of each other.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 8 to <10 years of age: Recommended dosage range is 5–10 mg once daily.1

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

Adjust dosage at intervals of ≥4 weeks.1

Homozygous Familial Hypercholesterolemia Oral

Children and adolescents 7–17 years of age: Recommended dosage is 20 mg once daily.1

Adults

Prevention of Cardiovascular Events

Select appropriate statin intensity to achieve optimal ASCVD risk reduction.350 Giving maximally tolerated statin intensity is preferred over giving lower statin dosages in combination with nonstatin drugs, a strategy not yet shown to reduce ASCVD risk.350

Although dosages of 5 and 40 mg once daily are FDA-labeled dosages, these dosages were not evaluated in randomized controlled studies reviewed by the ACC/AHA expert panel.350

Primary Prevention in Patients with LDL-cholesterol Concentrations ≥190 mg/dL (≥21 years of age) Oral

ACC/AHA cholesterol management guideline recommends initiating high-intensity statin therapy (e.g., rosuvastatin 20–40 mg once daily); if not well tolerated, use maximum tolerated statin intensity.350

Intensify statin therapy to achieve ≥50% reduction in LDL-cholesterol concentrations.350

In patients currently receiving maximum intensity of statin therapy, consider adding a nonstatin drug to further reduce LDL-cholesterol concentrations; however, consider potential benefits, adverse effects, drug interactions, and patient preferences.350

Primary Prevention in Patients with Type 1 or 2 Diabetes Mellitus† (40–75 years of age) Oral

ACC/AHA cholesterol management guideline recommends moderate-intensity statin therapy (e.g., rosuvastatin 5–10 mg once daily).350

If estimated 10-year ASCVD risk ≥7.5%, consider high-intensity statin therapy (e.g., rosuvastatin 20–40 mg once daily).350

In patients <40 or >75 years of age, consider potential benefits, adverse effects, drug interactions, and patient preferences when deciding to initiate, continue, or intensify statin therapy.350

Primary Prevention in Patients with LDL-cholesterol Concentrations 70–189 mg/dL and Elevated ASCVD Risk (40–75 years of age) Oral

Estimated 10-year ASCVD risk ≥7.5%: ACC/AHA cholesterol management guideline recommends moderate- (e.g., rosuvastatin 5–10 mg once daily) to high-intensity statin therapy (e.g., rosuvastatin 20–40 mg once daily).350

Estimated 10-year ASCVD risk of 5 to <7.5%: ACC/AHA cholesterol management guideline recommends moderate-intensity statin therapy.350

Consider potential benefits, adverse effects, drug interactions, and patient preferences before initiating statin therapy.350

Secondary Prevention† in Patients with Clinical ASCVD (i.e., acute coronary syndromes; history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin) (21–75 years of age) Oral

ACC/AHA cholesterol management guideline recommends high-intensity statin therapy (e.g., rosuvastatin 20–40 mg once daily) unless contraindicated.350

In patients at increased risk for developing statin-associated adverse effects or in whom high-intensity statin therapy is inappropriate or contraindicated, consider moderate-intensity statin therapy (e.g., rosuvastatin 5–10 mg once daily) if tolerated.350

Patients >75 years of age: Individualize therapy based on potential benefits, adverse effects, drug interactions, and patient preferences; may consider moderate-intensity statin therapy if tolerated.350

Dyslipidemias General Dosage Oral

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

Dosage range is 5–40 mg once daily.1 Reserve maximum 40-mg daily dosage for patients who have not achieved adequate response with the 20-mg daily dosage.1

Homozygous Familial Hypercholesterolemia Oral

Usual initial dosage is 20 mg once daily.1

Dosage Modification Oral

ACC/AHA cholesterol management guideline states may consider decreasing statin dosage when LDL-cholesterol concentrations are <40 mg/dL on 2 consecutive measurements; however, no data to suggest that LDL-cholesterol concentrations <40 mg/dL increase risk of adverse effects.350

Dosage modifications may be necessary when used concomitantly with certain drugs (see Specific Drugs under Interactions).1

Prescribing Limits

Pediatric Patients

Dyslipidemias Oral

Maximum 20 mg once daily.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.)

Consider increased systemic exposure when treating Asian patients not adequately controlled at dosages up to 20 mg daily.1

Geriatric Patients

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

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

Drugs Affecting Transport Systems

Substrate for organic anion transport protein (OATP) 1B1 and breast cancer resistance protein (BCRP).1 Concomitant use with drugs that inhibit these transport proteins potentially may increase plasma concentrations of rosuvastatin and increase risk of myopathy.1 Consult relevant prescribing information of such drugs when considering concomitant use.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: Rosuvastatin peak plasma concentration and AUC unaffected1
Colchicine	Myopathy, including rhabdomyolysis, reported1	Use concomitantly with caution1
Cyclosporine	Increased rosuvastatin peak plasma concentration and AUC1 339 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
Dronedarone	Increased rosuvastatin AUC1
Eltrombopag	Increased rosuvastatin peak plasma concentration and AUC1
Erythromycin	Decreased rosuvastatin concentrations1
Ezetimibe	Increased rosuvastatin peak plasma concentration and AUC1
Fibric acid derivatives (fenofibrate, gemfibrozil)	Increased risk of myopathy and/or rhabdomyolysis1 Fenofibrate: Modest increase in rosuvastatin peak plasma concentration, rosuvastatin AUC unaffected; not considered clinically important1 Gemfibrozil: Increased rosuvastatin peak plasma concentration and AUC1	Fenofibrate: Use concomitantly with caution1 Gemfibrozil: Avoid concomitant use; if concomitant use cannot be avoided, initiate rosuvastatin at 5 mg once daily and do not exceed 10 mg daily1
HCV protease inhibitors	Simeprevir: Increased risk of myopathy; increased rosuvastatin peak plasma concentration and AUC1	Use concomitantly with caution1 Simeprevir: Initiate rosuvastatin at 5 mg once daily and do not exceed 10 mg once daily1
HIV protease inhibitors	Increased risk of myopathy1 Ritonavir-boosted atazanavir or lopinavir/ritonavir: Increased rosuvastatin peak plasma concentration and AUC1 Ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, or ritonavir-boosted tipranavir: Minimal to no change in exposure to rosuvastatin1	Use concomitantly with caution1 Ritonavir-boosted atazanavir or lopinavir/ritonavir: Initiate rosuvastatin at 5 mg once daily and do not exceed 10 mg once daily1
Lomitapide	Slight increases in peak plasma concentration and AUC of rosuvastatin374	Dosage adjustment of rosuvastatin not required374
Niacin (antilipemic dosages [≥1 g daily])	Increased risk of severe adverse effects (disturbances in glycemic control requiring hospitalization, development of diabetes mellitus, adverse GI effects, myopathy, gout, rash, skin ulceration, infection, bleeding) with concomitant use of niacin (1.5–2 g daily) and simvastatin (40–80 mg daily, with or without ezetimibe)369 371	Use concomitantly with caution1
Omega-3-acid ethyl esters	No effect on rate or extent of exposure to rosuvastatin at steady state373
Oral contraceptives	Increased concentrations of ethinyl estradiol and norgestrel1
Rifampin	Rosuvastatin AUC unaffected1
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 339

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: Exposure in children and adolescents (8–17 years of age) is similar to or less than that observed in adults.1 377

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

Genetic polymorphism of the OATP1B1 gene may affect rosuvastatin exposure.1 Higher plasma concentrations reported in a limited number of patients with 2 reduced-function variant OATP1B1 alleles.1 Frequency of this genotype is <5% in most populations; effect on efficacy and safety not established.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

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

Rosuvastatin Calcium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	5 mg (of rosuvastatin)*	Crestor	AstraZeneca
			Rosuvastatin Tablets
		10 mg (of rosuvastatin)*	Crestor	AstraZeneca
			Rosuvastatin Tablets
		20 mg (of rosuvastatin)*	Crestor	AstraZeneca
			Rosuvastatin Tablets
		40 mg (of rosuvastatin)*	Crestor	AstraZeneca
			Rosuvastatin Tablets