CRESTOR- rosuvastatin calcium_tablet, film coated

CRESTOR is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In vivo in vitro in vivo in vitro Absorption: max Administration of CRESTOR with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration. Distribution: Metabolism: in vitro Excretion: 1/2 After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. Race: max Gender: Geriatric: Renal Impairment: cr 2 cr 2 cr 2 Hemodialysis: Hepatic Impairment: In patients with Child-Pugh A disease, C max max Drug-Drug Interactions: Cytochrome P450 3A4 Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure Coadministered drug and dosing regimen Rosuvastatin Dose (mg) Single dose unless otherwise noted Change in AUC Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of up arrow and down arrow indicate the exposure increase and decrease, respectively. Change in C max Cyclosporine en dash stable dose required (75 mg en dash 200 mg BID) 10 mg QD for 10 days up arrow 7-fold Clinically significant [ see Dosage and Administration 2 Warnings and Precautions 5 up arrow 11-fold Gemfibrozil 600 mg BID for 7 days 80 mg up arrow 1. 9-fold up arrow 2. 2-fold Lopinavir/ritonavir combination 400 mg/100 mg BID for 10 days 20 mg QD for 7 days up arrow 2-fold up arrow 5-fold Atazanavir/ritonavir combination 300 mg/100 mg QD for 7 days 10 mg up arrow 3-fold up arrow 7-fold Tipranavir/ritonavir combination 500 mg/200mg BID for 11 days 10 mg up arrow 26% up arrow 2-fold Fosamprenavir/ritonavir 700 mg/100 mg BID for 7 days 10 mg up arrow 8% up arrow 45% Fenofibrate 67 mg TID for 7 days 10 mg up arrow 7% up arrow 21% Aluminum & magnesium hydroxide combination antacid Administered simultaneously Administered 2 hours apart 40 mg 40 mg down arrow 54% down arrow 22% down arrow 50% down arrow 16% Erythromycin 500 mg QID for 7 days 80 mg down arrow 20% down arrow 31% Ketoconazole 200 mg BID for 7 days 80 mg up arrow 2% down arrow 5% Itraconazole 200 mg QD for 5 days 10 mg 80 mg up arrow 39% up arrow 28% up arrow 36% up arrow 15% Fluconazole 200 mg QD for 11 days 80 mg up arrow 14% up arrow 9% Table 5. Effect of Rosuvastatin Coadministration on Systemic Exposure To Other Drugs Rosuvastatin Dosage Regimen Coadministered Drug Name and Dose Change in AUC Change in C max 40 mg QD for 10 days Warfarin Clinically significant pharmacodynamic effects [ see Warnings and Precautions 5. 4 25 mg single dose R- Warfarin up arrow 4% S-Warfarin up arrow6% R-Warfarin down arrow 1% S-Warfarin 0% 40 mg QD for 12 days Digoxin 0. 5 mg single dose up arrow 4% up arrow 4% 40 mg QD for 28 days Oral Contraceptive (ethinyl estradiol 0. 035 mg & norgestrel 0. 250 mg) QD for 21 Days EE up arrow 26% NG up arrow 34% EE up arrow 25% NG up arrow 23% EE = ethinyl estradiol, NG = norgestrel.

CRESTOR is an HMG Co-A reductase inhibitor indicated for: patients with primary hyperlipidemia and mixed dyslipidemia as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TG levels and to increase HDL-C (1. 1) patients with hypertriglyceridemia as an adjunct to diet (1. 2) patients with primary dysbetalipoproteinemia (Type III hyperlipoproteinemia) as an adjunct to diet (1. 3) patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C, total-C, and ApoB (1. 4) slowing the progression of atherosclerosis as part of a treatment strategy to lower total-C and LDL-C as an adjunct to diet (1. 5) pediatric patients 10 to 17 years of age with heterozygous familial hypercholesterolemia (HeFH) to reduce elevated total-C, LDL-C and ApoB after failing an adequate trial of diet therapy (1. 1) risk reduction of MI, stroke, and arterial revascularization procedures in patients without clinically evident CHD, but with multiple risk factors (1. 6) Limitations of use (1. 7): CRESTOR has not been studied in Fredrickson Type I and V dyslipidemias. CRESTOR is indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C, ApoB, nonHDL-C, 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 10 to 17 years of age with Heterozygous Familial Hypercholesterolemia (HeFH) Adjunct to diet to reduce Total-C, LDL-C and ApoB levels in adolescent boys and girls, who are at least one year post-menarche, 10-17 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 and there is a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors. CRESTOR is indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia. CRESTOR is indicated as an adjunct to diet for the treatment of patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia). CRESTOR is indicated as adjunctive therapy to other lipid-lowering treatments (e. , LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, Total-C, and ApoB in adult patients with homozygous familial hypercholesterolemia. 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 Total-C and LDL-C to target levels. 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 HDL-C, 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 CRESTOR has not been studied in Fredrickson Type I and V dyslipidemias.

CRESTOR can be taken with or without food, at any time of day. 1) Dose range: 5-40 mg once daily. Use 40 mg dose only for patients not reaching LDL-C goal with 20 mg. 1) HoFH: In pediatric patients 10 to 17 years of age with HeFH, the usual dose range is 5-20 mg/day; doses greater than 20 mg have not been studied in this patient population. 2) The dose range for CRESTOR is 5 to 40 mg orally once daily. The usual starting dose is 10-20 mg. CRESTOR can be administered as a single dose at any time of day, with or without food. When initiating CRESTOR therapy or switching from another HMG-CoA reductase inhibitor therapy, the appropriate CRESTOR starting dose should first be utilized, and only then titrated according to the patient’s response and individualized goal of therapy. After initiation or upon titration of CRESTOR, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly. The 40 mg dose of CRESTOR should be used only for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose [ see Warnings and Precautions The usual dose range of CRESTOR is 5-20 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy [ see Clinical Pharmacology Indications and Usage The recommended starting dose of CRESTOR is 20 mg once daily. Response to therapy should be estimated from preapheresis LDL-C levels. Initiation of CRESTOR therapy with 5 mg once daily should be considered for Asian patients [ see Use in Specific Populations Clinical Pharmacology In patients taking cyclosporine, the dose of CRESTOR should be limited to 5 mg once daily [ see Warnings and Precautions and Drug Interactions see Warnings and Precautions Drug Interactions For patients with severe renal impairment (CL cr 2 see Use in Specific Populations Clinical Pharmacology.

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 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 Most frequent adverse reactions (rate > To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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. 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. Adverse Reactions Adverse reactions by COSTART preferred term. 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 en dash 40 mg N=744 Placebo N=382 Headache 5. 1 Myalgia 3. 3 Asthenia 2. 6 Constipation 2. 4 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 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. 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. Adverse Reactions Adverse reactions by MedDRA preferred term. Adverse Reactions CRESTOR 40 mg Placebo Myalgia 12. 1 Arthralgia 10. 1 Headache 6. 3 Dizziness 4. 8 Increased CPK 2. 7 Abdominal pain 2. 8 Frequency recorded as abnormal laboratory value. 7 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. 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. 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 placebo-treated patients [ see Warnings and Precautions Clinical Studies Adverse reactions reported in >= 2% of patients and at a rate greater than placebo are shown in Table 3. Adverse Reactions Treatment-emergent adverse reactions by MedDRA preferred term. Adverse Reactions CRESTOR 20 mg N=8901 Placebo N=8901 Myalgia 7. 6 Arthralgia 3. 2 Constipation 3. 3 In a 12-week controlled study in boys and postmenarchal girls, the safety and tolerability profile of CRESTOR 5 to 20 mg daily was generally similar to that of placebo [ see Clinical Studies Use in Specific Populations, Pediatric Use However, 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. The following adverse reactions have been identified during postapproval use of CRESTOR: arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, depression, and sleep disorders (including insomnia and nightmares). 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 postmarketing reports of cognitive impairment (e. , 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).

CRESTOR is contraindicated in the following conditions: Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with CRESTOR [ see Adverse Reactions Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [ see Warnings and Precautions Women who are pregnant or may become pregnant. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, CRESTOR may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy [ see Use in Specific Populations Nonclinical Toxicology Nursing mothers. Because another drug in this class passes into breast milk, and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require CRESTOR treatment should be advised not to nurse their infants [ see Use in Specific Populations Known hypersensitivity to product components (4) Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels (4) Women who are pregnant or may become pregnant (4, 8. 1) Nursing mothers (4, 8.

Severe renal impairment (not on hemodialysis): Asian population: CRESTOR is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol products are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy [ see Contraindications There are no adequate and well-controlled studies of CRESTOR in pregnant women. There have been rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-fourfold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified. Rosuvastatin crosses the placenta in rats and rabbits. In rats, CRESTOR was not teratogenic at systemic exposures equivalent to a human therapeutic dose of 40 mg/day. At 10-12 times the human dose of 40 mg/day, there was decreased pup survival, decreased fetal body weight among female pups, and delayed ossification. In rabbits, pup viability decreased and maternal mortality increased at doses equivalent to the human dose of 40 mg/day [ see Nonclinical Toxicology CRESTOR may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking CRESTOR, the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during pregnancy. It is not known whether rosuvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. In rats, breast milk concentrations of rosuvastatin are three times higher than plasma levels; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because HMG-CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants, women who require CRESTOR treatment should be advised not to nurse their infants [ see Contraindications The safety and effectiveness of CRESTOR in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia were evaluated in a controlled clinical trial of 12 weeks duration followed by 40 weeks of open-label exposure. Patients treated with 5 mg, 10 mg, and 20 mg daily CRESTOR had an adverse experience profile generally similar to that of patients treated with placebo [ see Adverse Reactions see Clinical Studies see Use in Specific Populations In children and adolescents with homozygous familial hypercholesterolemia experience is limited to eight patients (aged 8 years and above). In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10 to 17 years of age with heterozygous FH received single and multiple oral doses of CRESTOR. Both C max Of the 10,275 patients in clinical studies with CRESTOR, 3159 (31%) were 65 years and older, and 698 (6. 8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients are at higher risk of myopathy and CRESTOR should be prescribed with caution in the elderly [ see Warnings and Precautions Clinical Pharmacology Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CL cr 2 cr 2 see Dosage and Administration Warnings and Precautions Clinical Pharmacology CRESTOR is contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is known to increase rosuvastatin exposure; CRESTOR should be used with caution in these patients [ see Contraindications Warning and Precautions Clinical Pharmacology Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. CRESTOR dosage should be adjusted in Asian patients [ see Dosage and Administration Clinical Pharmacology.

Cyclosporine: Gemfibrozil: Lopinavir/Ritonavir or atazanavir/ritonavir: Coumarin anticoagulants: Concomitant lipid-lowering therapies: Cyclosporine significantly increased rosuvastatin exposure. Therefore, in patients taking cyclosporine, therapy should be limited to CRESTOR 5 mg once daily [ see Dosage and Administration Warnings and Precautions Clinical Pharmacology Gemfibrozil significantly increased rosuvastatin exposure. Therefore, combination therapy with CRESTOR and gemfibrozil should be avoided. If used, do not exceed CRESTOR 10 mg once daily [ see Clinical Pharmacology Coadministration of rosuvastatin with certain protease inhibitors given in combination with ritonavir has differing effects on rosuvastatin exposure. The protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase rosuvastatin exposure (AUC) up to threefold [ see Table 3 en dash Clinical Pharmacology see Dosage and Administration Warnings and Precautions Clinical Pharmacology CRESTOR significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with CRESTOR. In patients taking coumarin anticoagulants and CRESTOR concomitantly, INR should be determined before starting CRESTOR and frequently enough during early therapy to ensure that no significant alteration of INR occurs [ see Warnings and Precautions Clinical Pharmacology The risk of skeletal muscle effects may be enhanced when CRESTOR is used in combination with lipid-modifying doses (>=1 g/day) of niacin; caution should be used when prescribing with CRESTOR [ see Warnings and Precautions When CRESTOR was coadministered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with CRESTOR [ see Warnings and Precautions Clinical Pharmacology.

OVERDOSAGE
There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.
NONCLINICAL TOXICOLOGY
In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses. In a 107-week carcinogenicity study in mice given 10, 60, 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses. Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium Escherichia coli in vivo In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6-month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class. Embryo-fetal Development Rosuvastatin crosses the placenta and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18. In female rats given oral gavage doses of 5, 15, 50 mg/kg/day rosuvastatin before mating and continuing through day 7 postcoitus results in decreased fetal body weight (female pups) and delayed ossification at the high dose (systemic exposures 10 times the human exposure at 40 mg/day based on AUC). In pregnant rats given oral gavage doses of 2, 10, 50 mg/kg/day from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred in groups given 50 mg/kg/day, systemic exposures >= 12 times the human exposure at 40 mg/day based on body surface area. In pregnant rabbits given oral gavage doses of 0. 3, 1, 3 mg/kg/day from gestation day 6 to lactation day 18 (weaning), exposures equivalent to the human exposure at 40 mg/day based on body surface area, decreased fetal viability and maternal mortality was observed. Rosuvastatin was not teratogenic in rats at <= 25 mg/kg/day or in rabbits <= 3 mg/kg/day (systemic exposures equivalent to the human exposure at 40 mg/day based on AUC or body surface area, respectively). Central Nervous System Toxicity CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Edema, hemorrhage, and partial necrosis in the interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Doses <=30 mg/kg/day (systemic exposures <=60 times the human exposure at 40 mg/day based on AUC) did not reveal retinal findings during treatment for up to one year.
CLINICAL STUDIES
CRESTOR reduces Total-C, LDL-C, ApoB, nonHDL-C, and TG, and increases HDL-C, in adult patients with hyperlipidemia and mixed dyslipidemia. Dose-Ranging Study: Table 6. Dose-Response in Patients With Hyperlipidemia (Adjusted Mean % Change From Baseline at Week 6) Dose N Total-C LDL-C Non-HDL-C ApoB TG HDL-C Placebo 13 -5 -7 -7 -3 -3 3 CRESTOR 5 mg 17 -33 -45 -44 -38 -35 13 CRESTOR 10 mg 17 -36 -52 -48 -42 -10 14 CRESTOR 20 mg 17 -40 -55 -51 -46 -23 8 CRESTOR 40 mg 18 -46 -63 -60 -54 -28 10 Active-Controlled Study: Figure 1. Percent LDL-C Change by Dose of CRESTOR, Atorvastatin, Simvastatin, and Pravastatin at Week 6 in Patients with Hyperlipidemia or Mixed Dyslipidemia Box plots are a representation of the 25th, 50th, and 75th percentile values, with whiskers representing the 10th and 90th percentile values. Mean baseline LDL-C: 189 mg/dL Table 7. Percent Change in LDL-C From Baseline to Week 6 (LS Mean Corresponding standard errors are approximately 1. 00 Treatment Daily Dose Treatment 10 mg 20 mg 40 mg 80 mg CRESTOR -46 CRESTOR 10 mg reduced LDL-C significantly more than atorvastatin 10 mg; pravastatin 10 mg, 20 mg, and 40 mg; simvastatin 10 mg, 20 mg, and 40 mg. 002) -52 CRESTOR 20 mg reduced LDL-C significantly more than atorvastatin 20 mg and 40 mg; pravastatin 20 mg and 40 mg; simvastatin 20 mg, 40 mg, and 80 mg. 002) -55 CRESTOR 40 mg reduced LDL-C significantly more than atorvastatin 40 mg; pravastatin 40 mg; simvastatin 40 mg, and 80 mg. 002) --- Atorvastatin -37 -43 -48 -51 Simvastatin -28 -35 -39 -46 Pravastatin -20 -24 -30 --- figure one Active-Controlled Study Table 8. Mean LDL-C Percentage Change from Baseline CRESTOR (n=435) LS Means are least square means adjusted for baseline LDL-C Atorvastatin (n=187) Week 6 20mg -47% (-49%, -46%) -38% (-40%, -36%) Week 12 40mg -55% (-57%, -54%) -47% (-49%, -45%) Week 18 80mg NA -52% (-54%, -50%) Dose-Response Study: Table 9. Dose-Response in Patients With Primary Hypertriglyceridemia Over 6 Weeks Dosing Median (Min, Max) Percent Change From Baseline Dose Placebo CRESTOR CRESTOR CRESTOR CRESTOR Triglycerides 1 (-40, 72) -21 (-58, 38) -37 (-65, 5) -37 (-72, 11) -43 (-80, -7) nonHDL-C 2 (-13, 19) -29 (-43, -8) -49 (-59, -20) -43 (-74, 12) -51 (-62, -6) VLDL-C 2 (-36, 53) -25 (-62, 49) -48 (-72, 14) -49 (-83, 20) -56 (-83, 10) Total-C 1 (-13, 17) -24 (-40, -4) -40 (-51, -14) -34 (-61, -11) -40 (-51, -4) LDL-C 5 (-30, 52) -28 (-71, 2) -45 (-59, 7) -31 (-66, 34) -43 (-61, -3) HDL-C -3 (-25, 18) 3 (-38, 33) 8 (-8, 24) 22 (-5, 50) 17 (-14, 63) In a randomized, multicenter, double-blind crossover study, 32 patients (27 with є2/є2 and 4 with apo E mutation [Arg145Cys] with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia) entered a 6-week dietary lead-in period on the NCEP Therapeutic Lifestyle Change (TLC) diet. Following dietary lead-in, patients were randomized to a sequence of treatments in conjunction with the TLC diet for 6 weeks each: rosuvastatin 10 mg followed by rosuvastatin 20 mg or rosuvastatin 20 mg followed by rosuvastatin 10 mg. CRESTOR reduced nonHDL-C (primary end point) and circulating remnant lipoprotein levels. Results are shown in the table below. Lipid-modifying Effects of Rosuvastatin 10 mg and 20 mg in Primary Dysbetalipoproteinemia (Type III hyperlipoproteinemia) after Six weeks by Median Percent Change (95% CI) from Baseline (N=32) Median at Baseline (mg/dL) Median percent change from baseline (95% CI) CRESTOR 10 mg Median percent change from baseline (95% CI) CRESTOR 20 mg Total-C 342. 5 en dash 43. 9, en dash 37. 8) Triglycerides 503. 1) NonHDL-C 294. 5) VLDL-C + IDL-C 209. 7) LDL-C 112. 1) HDL-C 35. 5) RLP-C 82. 6) Apo-E 16. 6) Dose-Titration Study: In a double-blind, randomized, multicenter, placebo-controlled, 12-week study, 176 (97 male and 79 female) children and adolescents with heterozygous familial hypercholesterolemia were randomized to rosuvastatin 5, 10 or 20 mg or placebo daily. Patients ranged in age from 10 to 17 years (median age of 14 years) with approximately 30% of the patients 10 to 13 years and approximately 17%, 18%, 40%, and 25% at Tanner stages II, III, IV, and V, respectively. Females were at least 1 year postmenarche. Mean LDL-C at baseline was 233 mg/dL (range of 129 to 399). The 12-week double-blind phase was followed by a 40-week open-label dose-titration phase, where all patients (n=173) received 5 mg, 10 mg or 20 mg rosuvastatin daily. Rosuvastatin significantly reduced LDL-C (primary end point), total cholesterol and ApoB levels at each dose compared to placebo. Results are shown in Table 11 below. Table 11 en dash Lipid-modifying effects of rosuvastatin in pediatric patients 10 to 17 years of age with heterozygous familial hypercholesterolemia (least-squares mean percent change from baseline to week 12) Dose (mg) N LDL-C HDL-C Total-C TG Median percent change ApoB Placebo 46 -1% +7% 0% -7% -2% 5 42 -38% +4% Difference from placebo not statistically significant -30% -13% -32% 10 44 -45% +11% -34% -15% -38% 20 44 -50% +9% -39% 16% -41% At the end of the 12-week, double-blind treatment period, the percentage of patients achieving the LDL-C goal of less than 110 mg/dL (2. 8 mmol/L) was 0% for placebo, 12% for rosuvastatin 5 mg, 41% for rosuvastatin 10 mg and 41% for rosuvastatin 20 mg. For the 40-week, open-label phase, 71% of the patients were titrated to the maximum dose of 20 mg and 41% of the patients achieved the LDL-C goal of 110 mg/dL. The long-term efficacy of rosuvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established. In the Measuring Effects on Intima Media Thickness: an Evaluation Of Rosuvastatin 40 mg (METEOR) The annualized rate of change from baseline for the placebo group was +0. 0131 mm/year (p<0. The annualized rate of change from baseline for the group treated with CRESTOR was -0. 0014 mm/year (p=0. At an individual patient level in the group treated with CRESTOR, 52. 1% of patients demonstrated an absence of disease progression (defined as a negative annualized rate of change), compared to 37. 7% of patients in the placebo group. In the J U P I T E R The primary end point was a composite end point consisting of the time-to-first occurrence of any of the following major CV events: CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina or an arterial revascularization procedure. Rosuvastatin significantly reduced the risk of major CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p<0. 001) relative risk reduction of 44% and absolute risk reduction of 1. 2% (see Figure 2). The risk reduction for the primary end point was consistent across the following predefined subgroups: age, sex, race, smoking status, family history of premature CHD, body mass index, LDL-C, HDL-C, and hsCRP levels. Time to first occurrence of major cardiovascular events in JUPITER The individual components of the primary end point are presented in Figure 3. Rosuvastatin significantly reduced the risk of nonfatal myocardial infarction, nonfatal stroke, and arterial revascularization procedures. There were no significant treatment differences between the rosuvastatin and placebo groups for death due to cardiovascular causes or hospitalizations for unstable angina. Rosuvastatin significantly reduced the risk of myocardial infarction (6 fatal events and 62 nonfatal events in placebo-treated subjects vs. 9 fatal events and 22 nonfatal events in rosuvastatin-treated subjects) and the risk of stroke (6 fatal events and 58 nonfatal events in placebo-treated subjects vs. 3 fatal events and 30 nonfatal events in rosuvastatin-treated subjects). In a post-hoc subgroup analysis of JUPITER subjects (n=1405; rosuvastatin=725, placebo=680) with a hsCRP >=2 mg/L and no other traditional risk factors (smoking, BP >=140/90 or taking antihypertensives, low HDL-C) other than age, after adjustment for high HDL-C, there was no significant treatment benefit with rosuvastatin treatment. Major CV events by treatment group in JUPITER At one year, rosuvastatin increased HDL-C and reduced LDL-C, hsCRP, total cholesterol and serum triglyceride levels (p<0. 001 for all versus placebo). figure two figure three.
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