CRESTOR (rosuvastatin calcium) is indicated as an adjunct to diet, at least equivalent to the Adult Treatment Panel III (ATP III TLC diet), for the reduction of elevated total cholesterol (Total-C), LDL-C, ApoB, the Total-C/HDL-C ratio and triglycerides (TG) and for increasing HDL-C; in hyperlipidemic and dyslipidemic conditions, when response to diet and exercise alone has been inadequate including:

• Primary hypercholesterolemia (Type IIa including heterozygous familial hypercholesterolemia and severe non-familial hypercholesterolemia)

  
  

• Combined (mixed) dyslipidemia (Type IIb)

  
  

• Homozygous familial hypercholesterolemia where CRESTOR is used either alone or as an adjunct to diet and other lipid lowering treatment such as apheresis

  
  

 

CRESTOR is contraindicated:

• In patients who are hypersensitive to any component of this medication (see Dosage Forms, Composition and Packaging).

  
  

• In patients with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal (see Warnings and Precautions).

  
  

• In pregnant and nursing mothers.

  
  

  Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). CRESTOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the possible harm. If the patient becomes pregnant while taking CRESTOR, the drug should be discontinued immediately and the patient apprised of the potential harm to the fetus. Atherosclerosis being a chronic process, discontinuation of lipid metabolism regulating drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia (see Warnings and Precautions, Special Populations, Pregnant Women, Nursing Women).

  
  

• In patients using concomitant cyclosporine (see Drug Interactions).

  
  

 

CRESTOR 40 mg is contraindicated in:

• Asian patients

  
  

• Patients with pre-disposing factors for myopathy/rhabdomyolysis such as:

  • Personal or family history of hereditary muscular disorders

    
    

  • Previous history of muscle toxicity with another HMG-CoA reductase inhibitor

    
    

  • Concomitant use of a fibrate or niacin

    
    

  • Severe hepatic impairment

    
    

  • Severe renal impairment (CrCl <30 mL/min/1.73 m²) (see Dosage and Administration, Patients with Renal Impairment)

    
    

  • Hypothyroidism

    
    

  • Alcohol abuse

    
    

  • Situations where an increase in rosuvastatin plasma levels may occur

    
    

   

  
  

 

Before instituting therapy with CRESTOR (rosuvastatin calcium), an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in overweight patients, and to treat other underlying medical problems and associated cardiovascular risk factors. The patient should be advised to inform subsequent physicians of the prior use of CRESTOR or any other lipid-lowering agent.

Ubiquinone levels were not measured in CRESTOR clinical trials. Significant decreases in circulating ubiquinone levels in patients treated with other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Rosuvastatin demonstrated no effect upon nonstimulated cortisol levels and no effect on thyroid metabolism as assessed by TSH plasma concentration. In CRESTOR treated patients, there was no impairment of adrenocortical reserve and no reduction in plasma cortisol concentrations. Clinical studies with other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma testosterone concentration. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with rosuvastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone or cimetidine) that may decrease the levels of endogenous steroid hormones.

In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lipoprotein(a) [LP(a)] concentrations. Present knowledge suggests the importance of high LP(a) levels as an emerging risk factor for coronary heart disease. It is thus desirable to maintain and reinforce lifestyle changes in high risk patients placed on rosuvastatin therapy.

CRESTOR is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal.

As with other HMG-CoA reductase inhibitors, it is recommended that a liver function test be carried out prior to, and 3 months following, the initiation of CRESTOR or if the patient is titrated to the dose of 40 mg. CRESTOR should be discontinued or the dose reduced if the level of transaminases is greater than 3 times the upper limit of normal.

CRESTOR, as well as other HMG-CoA reductase inhibitors should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.

As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin (<0.5%); the majority of cases were mild, asymptomatic and transient.

In subjects with varying degrees of hepatic impairment there was no evidence of increased exposure to rosuvastatin other than in 2 subjects with the most severe liver disease (Child-Pugh scores of 8 and 9). In these subjects, systemic exposure was increased by at least 2-fold compared to subjects with lower Child-Pugh scores (see Dosage and Administration, Patients with Hepatic Impairment).

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria, have been reported with CRESTOR and with other HMG-CoA reductase inhibitors.

Effects on skeletal muscle such as myalgia, myopathy and, rarely, rhabdomyolysis have been reported in patients treated with CRESTOR at all doses and in particular with the 40 mg dose.

Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine kinase (CK) values to greater than ten times the upper limit of normal, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. CRESTOR therapy should be discontinued if markedly elevated CK levels (>10×ULN) are measured or myopathy is diagnosed or suspected.

CRESTOR, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include: personal or family history of hereditary muscular disorders; previous history of muscular toxicity with another HMG-CoA reductase inhibitor; concomitant use of a fibrate or niacin; hypothyroidism; alcohol abuse; excessive physical exercise; age >70 years; renal impairment; hepatic impairment; diabetes with hepatic fatty change; surgery and trauma; frailty; situations where an increase in plasma levels of rosuvastatin may occur.

In CRESTOR trials there was no evidence of increased skeletal muscle effects when CRESTOR was dosed with concomitant therapy such as fibric acid derivatives (including fenofibrate and gemfibrozil), nicotinic acid, azole antifungals and macrolide antibiotics. However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with these medicines.

CRESTOR therapy should be temporarily withheld or discontinued in any patient with an acute serious condition suggestive of myopathy or predisposing to the development of rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic endocrine and electrolyte disorders, or uncontrolled seizures).

Subjects with severe renal impairment (CrCl <30 mL/min/1.73 m²) had a 3-fold increase in plasma concentration of rosuvastatin compared to healthy volunteers and, therefore, CRESTOR 40 mg is contraindicated in these patients (see Contraindications, and Dosage and Administration, Patients with Renal Impairment).

In subjects with varying degrees of renal impairment, mild to moderate renal disease had little influence on plasma concentrations of rosuvastatin.

During the clinical development program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin-treated patients, predominantly in patients dosed above the recommended dose range (i.e. 80 mg). Abnormal urinalysis testing (dipstick-positive proteinuria) has been seen in patients taking CRESTOR and other HMG-CoA reductase inhibitors. This finding was more frequent in patients taking 40 mg when compared to lower doses of rosuvastatin or comparator statins. Shifts in urine protein from none or trace to ++ (dipstick) or more were seen in <1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. The protein detected was mostly tubular in origin. In most cases, proteinuria was generally transient and it decreased or disappeared spontaneously on continued therapy. It has not been shown to be predictive of acute or progressive renal disease.

Nevertheless, a dose reduction may be considered for patients with unexplained persistent proteinuria during routine testing.

An apparent hypersensitivity syndrome has been reported rarely with other HMG-CoA reductase inhibitors. This has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive antinuclear antibody (ANA), erythrocyte sedimentation rate (ESR) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme including Stevens-Johnson syndrome. Treatment should be discontinued if hypersensitivity is suspected (see Contraindications).

CRESTOR is contraindicated during pregnancy (see Contraindications).

It is not known whether rosuvastatin is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking CRESTOR should not breast-feed (see Contraindications).

Treatment experience with CRESTOR in a pediatric population is limited to 8 patients with homozygous familial hypercholesterolemia. None of these patients was below 8 years of age (see Dosage and Administration, Use in Children).

There were no clinically significant pharmacokinetic differences between young and elderly patients (≥65 years) (see Dosage and administration, Use in Elderly). However, elderly patients may be more susceptible to myopathy (see Warnings and Precautions, Muscle Effects, Pre-disposing Factors for Myopathy/Rhabdomyolysis).

Results of pharmacokinetic studies, including a large study conducted in North America, have demonstrated an approximate 2-fold elevation in median exposure in Asian subjects (having either Filipino, Chinese, Japanese, Korean, Vietnamese or Asian-Indian origin) when compared with a Caucasian control group. This increase should be considered when making rosuvastatin dosing decisions for Asian patients and the dose of 40 mg is contraindicated in these patients (see Action and Clinical Pharmacology, Pharmacokinetics, and Contraindications, and Dosage and Administration, Race).

CRESTOR is generally well tolerated. The adverse events seen with CRESTOR are generally mild and transient. CRESTOR clinical trial experience is extensive, involving 1290 patients within placebo controlled trials (768 of which were treated with rosuvastatin) and 11 641 patients within controlled clinical trials (5319 of which were treated with rosuvastatin). In controlled clinical trials, 3.2% of patients were withdrawn from CRESTOR therapy due to adverse events. This withdrawal rate was comparable to that reported in placebo-controlled studies.

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Associated adverse events occurring at an incidence >2% in patients participating in placebo-controlled clinical studies of rosuvastatin, are shown in Table 1.

Table 1: CRESTOR

Number (%) of Subjects with Associated Adverse Events Occurring with >2% Incidence in at least 2 Subjects in any Treatment Group: Placebo Controlled Pool

Body System/ Adverse Event	Placebo (%) (N=367)	Total rosuvastatin (%) (N=768)
Whole Body
Headache	2.2	1.4
Digestive
Abdominal Pain	2.2	1.7
Flatulence	2.7	1.8
Nausea	1.6	2.2

The frequency of adverse events in all clinical trials and considered possibly, probably or definitely drug related are as follows:

Common (1%-10%): headache, myalgia, asthenia, constipation, dizziness, nausea, abdominal pain.

Uncommon (0.1%-1%): pruritus, rash and urticaria.

Rare (0.01%-0.1%): myopathy (including myositis), rhabdomyolysis, pancreatitis and hypersensitivity reactions including angioedema.

The following additional adverse events were reported in controlled clinical trials, regardless of causality: accidental injury, back, chest and general pain, flu syndrome, infection, urinary tract infection, diarrhea, flatulence, gastroenteritis, dyspepsia, hypertonia, insomnia, paresthesia, bronchitis, increased cough, rhinitis, pharyngitis and sinusitis.

In long-term controlled clinical trials CRESTOR was shown to have no harmful effect on the ocular lens.

In addition to the events reported above, the following adverse events have been reported during post-marketing experience with CRESTOR, regardless of causality assessment.

Very rare: arthralgia. It has been observed that as with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis in post-marketing use is higher at the highest marketed dose.

Very rare: jaundice, hepatitis.

Very rare: memory loss.

Very rare: gynecomastia.

In CRESTOR clinical trials there was no evidence of increased skeletal muscle effects when rosuvastatin was dosed with any concomitant therapy. However, CRESTOR and other HMG-CoA reductase inhibitors may cause dose-related increases in serum transaminases and CK levels. An increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors with cyclosporine, fibric acid derivatives (including gemfibrozil), nicotinic acid, azole antifungals and macrolide antibiotics.

In vitro and in vivo data indicate that rosuvastatin has no clinically significant cytochrome P450 interactions (as substrate, inhibitor or inducer). Consequently, there is little potential for drug-drug interactions upon co-administration with agents that are metabolised by cytochrome P450. Rosuvastatin clearance is not dependent on metabolism by cytochome P450 3A4 to a clinically significant extent. This has been confirmed in studies with known cytochrome P450 3A4 inhibitors (ketoconazole, erythromycin, itraconazole).

Co-administration of fenofibrate and CRESTOR 10 mg did not lead to a clinically significant change in the plasma concentrations of either drug. In addition, neither myopathy nor marked CK elevations (>10×ULN) were observed in a study of 128 patients who received CRESTOR 10, 20 and 40 mg plus extended-release niacin or in a second study of 103 patients who received CRESTOR 5 and 10 mg plus fenofibrate. Based on the above data, no pharmacokinetic or pharmacodynamic interaction was observed. No data is available with other fibrates.

Based on post-marketing surveillance, gemfibrozil, fenofibrate, other fibrates and lipid lowering doses of niacin (nicotinic acid) may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone (see Warnings and Precautions, Muscle Effects, Pre-disposing Factors for Myopathy/Rhabdomyolysis). Therefore, combined drug therapy should be approached with caution.

In a pharmacokinetic study, co-administration of CRESTOR and a combination product of two protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers was associated with an approximately two-fold and five-fold increase in rosuvastatin steady-state AUC_(0-24) and C_max respectively. Accordingly, the benefits of lipid lowering with CRESTOR in HIV patients receiving lopinavir/ritonavir must be balanced against the risks of the resulting increased exposure to rosuvastatin when initiating and up-titrating CRESTOR treatment.

Any interaction between CRESTOR and other protease inhibitors has not been examined. (See Warnings and Precautions, Muscle Effects, Pre-disposing Factors for Myopathy/Rhabdomyolysis.)

CRESTOR can be used in combination with bile acid sequestrant (e.g. cholestyramine).

Coadministration of ketoconazole with CRESTOR resulted in no change in plasma concentrations of rosuvastatin.

Coadministration of erythromycin with CRESTOR resulted in small decreases in plasma concentrations of rosuvastatin. These reductions were not considered clinically significant.

Coadministration of itraconazole with CRESTOR resulted in a 28% increase in the AUC of rosuvastatin. This small increase was not considered clinically significant.

Coadministration of fluconazole with CRESTOR resulted in a 14% increase in the AUC of rosuvastatin. This small increase was not considered clinically significant.

Coadministration of digoxin and CRESTOR did not lead to any clinically significant interactions.

Although specific interaction studies were not performed, CRESTOR has been studied in over 5300 patients in clinical trials. Many patients were receiving a variety of medications including antihypertensive agents (beta-adrenergic blocking agents, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and diuretics), antidiabetic agents (biguanides, sulfonylureas, alpha glucosidase inhibitors, and thiazolidinediones), and hormone replacement therapy without evidence of clinically significant adverse interactions.

The drugs listed in Table 2 are based on either drug interaction case reports or studies or potential interactions due to the expected magnitude and seriousness of the interaction (i.e. those identified as contraindicated).

Table 2: CRESTOR

Established or Potential Drug-Drug Interactions

Proper Name	Effect	Clinical Comment
Gemfibrozil	Co-administration of a single rosuvastatin dose (10 mg) to healthy volunteers on gemfibrozil (600 mg bid) resulted in a 2.2- and 1.9-fold increase in mean Cmax and mean AUC of rosuvastatin respectively.	Patients taking this combination should not exceed a dose of CRESTOR 20 mg once daily and the concomitant use of CRESTOR 40 mg once daily is contraindicated.
Coumarin Anticoagulants	As with other HMG-CoA reductase inhibitors, co-administration of CRESTOR and coumarin (e.g. warfarin) may result in a rise in International Normalized Ratio (INR) compared to coumarin alone. In healthy subjects, the co administration of rosuvastatin 40 mg (10 days) and warfarin 25 mg (single dose) produced a higher mean maxINR and AUC-INR than achieved with warfarin alone. Coadministration of CRESTOR 10 and 80 mg to patients on stable warfarin therapy resulted in clinically significant rises in INR (>4, baseline 2-3). The mechanism for this effect is unknown, but is likely due to a pharmacodynamic interaction with warfarin rather than a pharmacokinetic interaction as no relevant differences in the pharmacokinetics of either drug was observed.	In patients taking coumarin, monitoring of INR is recommended at initiation or cessation of therapy with rosuvastatin or following dose adjustment. Rosuvastatin therapy has not been associated with bleeding or changes in INR in patients not taking anticoagulants.
Antacids	Simultaneous dosing of CRESTOR with an antacid suspension containing aluminium and magnesium hydroxide resulted in a decrease of rosuvastatin plasma concentration by approximately 50%.	The clinical relevance of this interaction has not been studied. However, the effect was mitigated when the antacid was dosed 2 hours after CRESTOR. This interaction should not be clinically relevant in patients using this type of antacid infrequently. A frequent antacid user should be instructed to take CRESTOR at a time of day when they are less likely to need the antacid.
Oral Contraceptives	When CRESTOR 40 mg was coadministered with a representative oral contraceptive (ethinyl estradiol [35 µg] and norgestrel [180 µg on days 1 to 7, 215 µg on days 8 to 15, and 250 µg on days 16 to 21]) no reduction in contraceptive efficacy was observed. An increase in plasma concentrations (AUC) of ethinyl estradiol (26%) and norgestrel (34%) occurred.	These increased plasma levels should be considered when selecting oral contraceptive doses.
Immunosuppressants (Including Cyclosporine)	CRESTOR 10 and 20 mg were administered to cardiac transplant patients (at least 6 months post-transplant) whose concomitant medication included cyclosporine, prednisone and azathioprine. Results showed that cyclosporine pharmacokinetics were not affected by rosuvastatin. However, cyclosporine did increase the systemic exposure of rosuvastatin by 11-fold (Cmax) and 7-fold (AUC [0-24]) compared with historical data in healthy individuals.	The concomitant use of CRESTOR and cyclosporine is contraindicated (see Contraindications).

CRESTOR can be taken with or without food (see Dosage and Administration).

Patients should be placed on a standard cholesterol-lowering diet (at least equivalent to the Adult Treatment Panel III (ATP III TLC diet)) before receiving CRESTOR (rosuvastatin calcium), and should continue on this diet during treatment with CRESTOR. If appropriate, a program of weight control and physical exercise should be implemented.

Prior to initiating therapy with CRESTOR, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed.

The dose range of CRESTOR is 5 to 40 mg orally once a day. The recommended starting dose of CRESTOR in most patients is 10 mg orally once daily. The majority of patients are controlled at the 10 mg dose. If necessary, dose adjustment can be made at 2-4 week intervals. The maximum response is usually achieved within 2-4 weeks and is maintained during chronic therapy.

CRESTOR may be taken in the morning or evening, with or without food.

Initiation of therapy with CRESTOR 5 mg once daily may be considered for patients requiring less aggressive LDL-C reductions or who have predisposing factors for myopathy (see Warnings and Precautions, Muscle Effects).

Patients who are switched to CRESTOR from treatment with another HMG-CoA reductase inhibitor should be started on 10 mg even if they were on a high dose of the previous HMG-CoA reductase inhibitor. A switch dose of 20 mg may be considered for patients with severe hypercholesterolemia.

For patients with severe hypercholesterolemia (including those with familial hypercholesterolemia), a 20 mg start dose may be considered. These patients should be carefully followed.

A dose of 40 mg once daily should only be used in patients with severe hypercholesterolemia who do not achieve their target treatment on 20 mg and have no predisposing factors for myopathy/rhabdomyolysis (see Dosage and Administration). Consultation with a specialist is recommended when initiating CRESTOR 40 mg dose.

The dosage of CRESTOR should be individualized according to baseline LDL-C, total C/HDL-C ratio and/or TG levels to achieve the recommended target lipid values at the lowest possible dose (see Recommendations for the Management of Dyslipidemia and the Prevention of Cardiovascular Disease [Canada] (summarized below in Table 3), and/or the Third Report of the U.S. National Cholesterol Education Program [NCEP Adult Treatment Panel III]) and the patient response.

Lipid levels should be monitored periodically and, if necessary, the dose of CRESTOR adjusted based on target lipid levels recommended by guidelines.

Table 3: CRESTOR

Canadian Recommendations for Target Lipid Values Based on Level of Risk

Risk Category	Target Levels
	LDL-C (mmol/L)		Total-C/HDL-C ratio
High a (10-year risk of CAD ≥20% or a history of diabetes mellitusb or any atherosclerotic disease)	<2.5	and	<4.0
Moderate (10-year risk 11-19%)	<3.5	and	<5.0
Low c (10-year risk ≤10%)	<4.5	and	<6.0

^a. Apolipoprotein B can be used as an alternative measurement, particularly for follow-up of patients treated with statins. An optimal level of apolipoprotein B in a patient at high risk is <0.9 g/L, in a patient at moderate risk <1.05 g/L and in a patient at low risk <1.2 g/L.
^b. Includes patients with chronic kidney disease and those undergoing long-term dialysis.
^c. In the 'very low' risk stratum, treatment may be deferred if the 10-year estimate of cardiovascular disease is <5% and the LDL-C level is <5.0 mmol/L.

Legend:

The following reductions in total cholesterol, LDL-C, TG, Total-C/HDL and increases in HDL-C have been observed in a dose-response study, and may serve as a guide to treatment of patients with mild to moderate hypercholesterolemia: see Table 4.

Table 4: CRESTOR

Dose-Response in Patients with Mild to Moderate Hypercholesterolemia (Mean Percent Change from Baseline)

CRESTOR Dose (mg/day)	N	Total-C	LDL-C	TG	HDL-C	Total-C /HDL-C	Apo B
Placebo	13	−5	−7	−3	3	−8	−3
5	17	−33	−45	−35	13	−41	−38
10	17	−36	−52	−10	14	−43	−42
20	17	−40	−55	−23	8	−44	−46
40	18	−46	−63	−28	10	−51	−54

The usual dose range applies in patients with mild to moderate hepatic impairment. Increased systemic exposure has been observed in patients with severe hepatic impairment and, therefore, in these patients the dose of CRESTOR should not exceed 20 mg once daily (see Contraindications, and Warnings and Precautions, Hepatic/Biliary/Pancreatic, Hepatic Impairment).

The usual dose range applies in patients with mild to moderate renal impairment. Increased systemic exposure to rosuvastatin has been observed in patients with severe renal impairment. For patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m²) the starting dose of CRESTOR should be 5 mg and not exceed 10 mg once daily (see Contraindications, and Warnings and Precautions, Renal, Renal Impairment).

The initial dose of CRESTOR, in Asian patients, should be 5 mg once daily. The potential for increases in systemic exposure must be considered when making treatment decisions. The maximum dose should not exceed CRESTOR 20 mg once daily (see Contraindications, and Warnings and Precautions, Special Populations, Race).

Pediatric experience is limited to a very small number of children (aged 8 years and above) with homozygous familial hypercholesterolemia. Use in children should be supervised by specialists (see Warnings and Precautions, Special Populations, Pediatrics (≤18 years of age)).

No dose adjustment is necessary in the elderly (see Warnings and Precautions, Special Populations, Geriatrics (≥65 years of age).

See Warnings and Precautions, and Drug-Food Interactions.

There is no specific treatment in the event of over dosage. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.

CRESTOR (rosuvastatin calcium) is a synthetic, enantiomerically pure lipid-lowering agent. It is a selective, potent and competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyses the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in cholesterol biosynthesis.

Studies have shown that CRESTOR lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver by increasing the number of hepatic Low Density Lipoprotein (LDL) receptors on the cell-surface for enhanced uptake and catabolism of LDL. Additionally, CRESTOR inhibits the hepatic synthesis of Very Low Density Lipoprotein (VLDL), thereby reducing the total number of VLDL and LDL particles.

Epidemiologic, clinical and experimental studies have established that high LDL-C, low HDL-C and high plasma TG promote human atherosclerosis and are risk factors for developing cardiovascular disease. Some studies have also shown that the total-C/HDL-C ratio is the best predictor of coronary artery disease. In contrast, increased levels of HDL-C are associated with decreased cardiovascular risk. Drug therapies that reduce levels of LDL-C or decrease TG while simultaneously increasing HDL-C have demonstrated reductions in rates of cardiovascular mortality and morbidity.

CRESTOR is administered orally following which rosuvastatin, the active moiety, is rapidly absorbed, reaching peak plasma concentration 3 to 5 hours after dosing.

Both peak concentration (C_max) and area under the plasma concentration-time curve (AUC) increase in proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20% and there is no accumulation on repeated dosing. CRESTOR may be given with or without food. Administration in the morning or evening did not affect the rate and extent of absorption nor the ability of rosuvastatin to reduce LDL-C.

Rosuvastatin undergoes first pass extraction in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The mean volume of distribution at steady state of rosuvastatin is approximately 134 L. Rosuvastatin is approximately 90% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

Rosuvastatin is not extensively metabolised with approximately 10% of a radiolabeled dose recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9, and in in vitro studies has demonstrated to have approximately one-half the HMG-CoA reductase inhibitory activity of rosuvastatin. The parent compound accounts for greater than 87% of the circulating active HMG-CoA reductase inhibitor activity.

Following an oral dose, rosuvastatin and its metabolites are primarily excreted in the faeces (90%) with the remainder being excreted in the urine. Fecal recovery represents absorbed drug, metabolites in the bile, and unabsorbed drug. The elimination half-life (t_½) of rosuvastatin is approximately 19 hours and does not increase with increasing doses.

A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups. However, pharmacokinetic studies with rosuvastatin, including one conducted in North America, have demonstrated an approximate 2-fold elevation in median exposure (AUC and C_max) in Asian subjects when compared with a Caucasian control group (see Contraindications, and Warnings and Precautions, Special Populations, Race, and Dosage and Administration, Race).

Store between 15 and 30°C.

Crestor.

Each yellow, round, biconvex, film-coated tablet, printed “5” and “ZD4522” on one side, contains: rosuvastatin 5 mg as rosuvastatin calcium. Nonmedicinal ingredients: calcium phosphate, crospovidone, ferric oxide red, ferric oxide yellow, glycerol triacetate, hydroxypropyl methylcellulose, lactose monohydrate, microcrystalline cellulose, magnesium stearate and titanium dioxide. Blisters of 3×10.

Each pink, round, biconvex, film-coated tablet, printed “10” and “ZD4522” on one side, contains: rosuvastatin 10 mg as rosuvastatin calcium. Nonmedicinal ingredients: calcium phosphate, crospovidone, ferric oxide red, ferric oxide yellow, glycerol triacetate, hydroxypropyl methylcellulose, lactose monohydrate, microcrystalline cellulose, magnesium stearate and titanium dioxide. Blisters of 3×10.

Each pink, round, biconvex, film-coated tablet, printed “20” and “ZD4522” on one side, contains: rosuvastatin 20 mg as rosuvastatin calcium. Nonmedicinal ingredients: calcium phosphate, crospovidone, ferric oxide red, ferric oxide yellow, glycerol triacetate, hydroxypropyl methylcellulose, lactose monohydrate, microcrystalline cellulose, magnesium stearate and titanium dioxide. Blisters of 3×10.

Each pink, oval, biconvex, film-coated tablet, printed “40” on one side and “ZD4522” on the other, contains: rosuvastatin 40 mg as rosuvastatin calcium. Nonmedicinal ingredients: calcium phosphate, crospovidone, ferric oxide red, ferric oxide yellow, glycerol triacetate, hydroxypropyl methylcellulose, lactose monohydrate, microcrystalline cellulose, magnesium stearate and titanium dioxide. Blisters of 3×10.