Generic Name: ROSUVASTATIN CALCIUM
Brand Name: CRESTOR
- Substance Name(s):
- ROSUVASTATIN CALCIUM
DRUG INTERACTIONS
7 Cyclosporine: Combination increases rosuvastatin exposure. Limit CRESTOR dose to 5 mg once daily. (2.5, 7.1) Gemfibrozil: Combination should be avoided. If used together, limit CRESTOR dose to 10 mg once daily. (2.6, 5.1, 7.2) Lopinavir/Ritonavir or atazanavir/ritonavir: Combination increases rosuvastatin exposure. Limit CRESTOR dose to 10 mg once daily. (2.5, 5.1, 7.3) Coumarin anticoagulants: Combination prolongs INR. Achieve stable INR prior to starting CRESTOR. Monitor INR frequently until stable upon initiation or alteration of CRESTOR therapy. (5.3, 7.4) Concomitant lipid-lowering therapies: Use with fibrates and niacin products may increase the risk of skeletal muscle effects. (2.6, 5.1, 7.5, 7.6) 7.1 Cyclosporine Cyclosporine significantly increased rosuvastatin exposure. Therefore, in patients taking cyclosporine, therapy should be limited to CRESTOR 5 mg once daily [see Dosage and Administration (2.5), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. 7.2 Gemfibrozil 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 Dosage and Administration (2.6) and Clinical Pharmacology (12.3)]. 7.3 Protease Inhibitors 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 – Clinical Pharmacology (12.3)]. For these combinations the dose of CRESTOR should be limited to 10 mg. The combinations of tipranavir/ritonavir or fosamprenavir/ritonavir produce little or no change in rosuvastatin exposure. Caution should be exercised when rosuvastatin is coadministered with protease inhibitors given in combination with ritonavir [see Dosage and Administration (2.5), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 7.4 Coumarin Anticoagulants 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 (5.3) and Clinical Pharmacology (12.3)]. 7.5 Niacin The risk of skeletal muscle effects may be enhanced when CRESTOR is used in combination with niacin; a reduction in CRESTOR dosage should be considered in this setting [see Warnings and Precautions (5.1)]. 7.6 Fenofibrate When CRESTOR was coadministered with fenofibrate no clinically significant increase in the AUC of rosuvastatin or fenofibrate, was observed. The benefit of further alterations in lipid levels by the combined use of CRESTOR with fibrates should be carefully weighed against the potential risks of this combination [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
OVERDOSAGE
10 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.
DESCRIPTION
11 CRESTOR (rosuvastatin calcium) is a synthetic lipid-lowering agent for oral administration. The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with the following structural formula: The empirical formula for rosuvastatin calcium is (C22H27FN3O6S)2Ca and the molecular weight is 1001.14. Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.0. Inactive Ingredients: Each tablet contains: microcrystalline cellulose NF, lactose monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF, hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide, and red ferric oxide NF.
CLINICAL STUDIES
14 14.1 Hyperlipidemia and Mixed Dyslipidemia 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: In a multicenter, double-blind, placebo-controlled, dose-ranging study in patients with hyperlipidemia CRESTOR given as a single daily dose for 6 weeks significantly reduced Total-C, LDL-C, nonHDL-C, and ApoB, across the dose range (Table 6). 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: CRESTOR was compared with the HMG-CoA reductase inhibitors atorvastatin, simvastatin, and pravastatin in a multicenter, open-label, dose-ranging study of 2240 patients with hyperlipidemia or mixed dyslipidemia. After randomization, patients were treated for 6 weeks with a single daily dose of either CRESTOR, atorvastatin, simvastatin, or pravastatin (Figure 1 and Table 7). 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 MeanCorresponding standard errors are approximately 1.00) by Treatment Group (sample sizes ranging from 156–167 patients per group) Treatment Daily Dose Treatment 10 mg 20 mg 40 mg 80 mg CRESTOR -46CRESTOR 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. (p<0.002) -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. (p<0.002) -55CRESTOR 40 mg reduced LDL-C significantly more than atorvastatin 40 mg; pravastatin 40 mg; simvastatin 40 mg, and 80 mg. (p<0.002) — Atorvastatin -37 -43 -48 -51 Simvastatin -28 -35 -39 -46 Pravastatin -20 -24 -30 — 14.2 Heterozygous Familial Hypercholesterolemia Active-Controlled Study: In a study of patients with heterozygous FH (baseline mean LDL of 291), patients were randomized to CRESTOR 20 mg or atorvastatin 20 mg. The dose was increased by 6-week intervals. Significant LDL-C reductions from baseline were seen at each dose in both treatment groups (Table 8). Table 8. Mean LDL-C Percentage Change from Baseline CRESTOR (n=435) LS Mean LS Means are least square means adjusted for baseline LDL-C (95% CI) Atorvastatin (n=187) LS Mean (95% CI) 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%) 14.3 Hypertriglyceridemia Dose-Response Study: In a double-blind, placebo-controlled dose-response study in patients with baseline TG levels from 273 to 817 mg/dL, CRESTOR given as a single daily dose (5 to 40 mg) over 6 weeks significantly reduced serum TG levels (Table 9). Table 9. Dose-Response in Patients With Primary Hypertriglyceridemia Over 6 Weeks Dosing Median (Min, Max) Percent Change From Baseline Dose Placebo (n=26) CRESTOR 5 mg (n=25) CRESTOR 10 mg (n=23) CRESTOR 20 mg (n=27) CRESTOR 40 mg (n=25) 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) 14.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) 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. Table 10. 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 – 43.3 (-46.9, – 37.5) -47.6 (-51.6,-42.8) Triglycerides 503.5 -40.1 (-44.9, -33.6) -43.0 (-52.5, -33.1) NonHDL-C 294.5 -48.2 (-56.7, -45.6) -56.4 (-61.4, -48.5) VLDL-C + IDL-C 209.5 -46.8 (-53.7, -39.4) -56.2 (-67.7, -43.7) LDL-C 112.5 -54.4 (-59.1, -47.3) -57.3 (-59.4, -52.1) HDL-C 35.5 10.2 (1.9, 12.3) 11.2 (8.3, 20.5) RLP-C 82.0 -56.4 (-67.1, -49.0) -64.9 (-74.0, -56.6) Apo-E 16.0 -42.9 (-46.3, -33.3) -42.5 (-47.1, -35.6) 14.5 Homozygous Familial Hypercholesterolemia Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40, 8-63 years) were evaluated for their response to CRESTOR 20 to 40 mg titrated at a 6-week interval. In the overall population, the mean LDL-C reduction from baseline was 22%. About one-third of the patients benefited from increasing their dose from 20 mg to 40 mg with further LDL lowering of greater than 6%. In the 27 patients with at least a 15% reduction in LDL-C, the mean LDL-C reduction was 30% (median 28% reduction). Among 13 patients with an LDL-C reduction of <15%, 3 had no change or an increase in LDL-C. Reductions in LDL-C of 15% or greater were observed in 3 of 5 patients with known receptor negative status. 14.6 Pediatric Patients with Heterozygous Familial Hypercholesterolemia 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 – 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 TGMedian 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. 14.7 Slowing of the Progression of Atherosclerosis In the Measuring Effects on Intima Media Thickness: an Evaluation Of Rosuvastatin 40 mg (METEOR) study, the effect of therapy with CRESTOR on carotid atherosclerosis was assessed by B-mode ultrasonography in patients with elevated LDL-C, at low risk (Framingham risk <10% over ten years) for symptomatic coronary artery disease and with subclinical atherosclerosis as evidenced by carotid intimal-medial thickness (cIMT). In this double-blind, placebo-controlled clinical study 984 patients were randomized (of whom 876 were analyzed) in a 5:2 ratio to CRESTOR 40 mg or placebo once daily. Ultrasonograms of the carotid walls were used to determine the annualized rate of change per patient from baseline to two years in mean maximum cIMT of 12 measured segments. The estimated difference in the rate of change in the maximum cIMT analyzed over all 12 carotid artery sites between patients treated with CRESTOR and placebo-treated patients was -0.0145 mm/year (95% CI –0.0196, –0.0093; p<0.0001). The annualized rate of change from baseline for the placebo group was +0.0131 mm/year (p<0.0001). The annualized rate of change from baseline for the group treated with CRESTOR was -0.0014 mm/year (p=0.32). 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. 14.8 Primary Prevention of Cardiovascular Disease In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of CRESTOR (rosuvastatin calcium) on the occurrence of major cardiovascular (CV) disease events was assessed in 17,802 men (≥50 years) and women (≥60 years) who had no clinically evident cardiovascular disease, LDL-C levels <130 mg/dL (3.3 mmol/l) and hs-CRP levels ≥2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.6% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL-C levels (23%), cigarette smoking (16%), or a family history of premature CHD (12%). Study participants had a median baseline LDL-C of 108 mg/dL and hsCRP of 4.3 mg/L. Study participants were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean duration of 2 years. The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in rosuvastatin-treated subjects. 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. Figure 2. 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. Figure 3. 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).
RECENT MAJOR CHANGES
Recent Major Changes Indications and Usage, Pediatric Patients 10 to 17 years of age with Heterozygous Familial Hypercholesterolemia (HeFH) (1.1) 10/2009 Dosage and Administration, HeFH in Pediatric Patients (10 to 17 years of age) (2.2) 10/2009 Dosage and Administration, Use with Cyclosporine, Lopinavir/Ritonavir or Atazanavir/Ritonavir (2.5) 01/2010 Warnings and Precautions, Skeletal muscle effects (e.g., myopathy and rhabdomyolysis) (5.1) 01/2010 Indications and Usage, Primary Prevention of Cardiovascular Disease (1.6) 02/2010
GERIATRIC USE
8.5 Geriatric Use 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 (5.1) and Clinical Pharmacology (12.3)].
MECHANISM OF ACTION
12.1 Mechanism of Action 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 studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.
INDICATIONS AND USAGE
1 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. 1.1 Hyperlipidemia and Mixed Dyslipidemia 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. 1.2 Hypertriglyceridemia CRESTOR is indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia. 1.3 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) CRESTOR is indicated as an adjunct to diet for the treatment of patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia). 1.4 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 LDL-C, Total-C, and ApoB in adult patients with homozygous familial hypercholesterolemia. 1.5 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 Total-C and LDL-C to target levels. 1.6 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 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 1.7 Limitations of Use CRESTOR has not been studied in Fredrickson Type I and V dyslipidemias.
PEDIATRIC USE
8.4 Pediatric Use 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 (6.2)]. Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. There was no detectable effect of CRESTOR on growth, weight, BMI (body mass index), or sexual maturation [see Clinical Studies (14.5)] in pediatric patients (10 to 17 years of age). Adolescent females should be counseled on appropriate contraceptive methods while on CRESTOR therapy [see Use in Specific Populations (8.1)]. CRESTOR has not been studied in controlled clinical trials involving prepubertal patients or patients younger than 10 years of age. Doses of CRESTOR greater than 20 mg have not been studied in the pediatric population. 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 Cmax and AUC of rosuvastatin were similar to values observed in adult subjects administered the same doses.
PREGNANCY
8.1 Pregnancy Teratogenic effects: Pregnancy Category X. 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 (4)]. 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 (13.2)]. 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.
NUSRING MOTHERS
8.3 Nursing Mothers 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 (4)].
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with use of 40 mg dose, advanced age (>65), hypothyroidism, renal impairment, and combination use with cyclosporine, lopinavir/ritonavir, atazanavir/ritonavir, or certain other lipid-lowering drugs. Advise patients to promptly report unexplained muscle pain, tenderness, or weakness and discontinue CRESTOR if signs or symptoms appear (5.1) Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminases can occur. Monitor liver enzymes before and during treatment. (5.2) 5.1 Skeletal Muscle Effects Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including CRESTOR. These risks can occur at any dose level, but are increased at the highest dose (40 mg). CRESTOR should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment). The risk of myopathy during treatment with CRESTOR may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, lopinavir/ritonavir, or atazanavir/ritonavir [see Dosage and Administration (2) and Drug Interactions (7)]. CRESTOR therapy should be discontinued if markedly elevated creatinine kinase levels occur or myopathy is diagnosed or suspected. CRESTOR therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). All patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. 5.2 Liver Enzyme Abnormalities and Monitoring It is recommended that liver enzyme tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG-CoA reductase inhibitors, including CRESTOR. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to CRESTOR therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials. In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking CRESTOR versus 0.5% of patients treated with placebo. Patients who develop increased transaminase levels should be monitored until the abnormalities have resolved. Should an increase in ALT or AST of >3 times ULN persist, reduction of dose or withdrawal of CRESTOR is recommended. CRESTOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease [see Clinical Pharmacology (12.3)]. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of CRESTOR [see Contraindications (4)]. 5.3 Concomitant Coumarin Anticoagulants Caution should be exercised when anticoagulants are given in conjunction with CRESTOR because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. 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 Drug Interactions (7.4)]. 5.4 Proteinuria and Hematuria In the CRESTOR clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among CRESTOR treated patients. These findings were more frequent in patients taking CRESTOR 40 mg, when compared to lower doses of CRESTOR or comparator HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on CRESTOR therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing. 5.5 Endocrine Effects Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including CRESTOR [see Adverse Reactions (6.1)]. Although clinical studies have shown that CRESTOR alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if CRESTOR is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION 17.1 Skeletal Muscle Effects Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. 17.2 Concomitant Use of Antacids When taking CRESTOR with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after CRESTOR administration. 17.3 Pregnancy 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. 17.4 Liver Enzymes It is recommended that liver enzymes be checked before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. CRESTOR is a trademark of the AstraZeneca group of companies. © AstraZeneca 2003, 2005, 2007, 2008, 2009, 2010 Licensed from SHIONOGI & CO., LTD., Osaka, Japan Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 ASTRAZENECA Rev. June 2010 PATIENT INFORMATION CRESTOR® (rosuvastatin calcium) Tablets (Kres-tor) Read this information carefully before you start taking CRESTOR. Each time you refill your prescription for CRESTOR, read the patient information, as there may be new information. This summary does not include everything there is to know about CRESTOR and does not take the place of talking with your health care professional about your medical condition or treatment. If you have any questions about CRESTOR, ask your health care professional. Only your health care professional can tell you if CRESTOR is right for you. What is CRESTOR? CRESTOR is a prescription medicine that belongs to a group of cholesterol-lowering medicines called statins. Along with diet, CRESTOR lowers “bad” cholesterol (LDL-C), increases “good” cholesterol (HDL-C). If bad cholesterol levels are left untreated, fatty deposits (plaque) can build up in the walls of the blood vessels. This plaque buildup over time, can lead to narrowing of these vessels. This is one of the most common causes of heart disease. By lowering bad cholesterol in your blood, CRESTOR can slow this plaque buildup in the walls of blood vessels. CRESTOR has been proven to reduce the risk of heart attacks and strokes in older adults without known heart disease. What is Cholesterol? Cholesterol is a fatty substance, also called a lipid, normally found in your bloodstream. Your body needs a certain amount of cholesterol to function properly. But high cholesterol can lead to health problems. LDL-C is called bad cholesterol because if you have too much in your bloodstream, it can become a danger to your health and can lead to potentially serious conditions. HDL-C is known as good cholesterol because it may help remove excess cholesterol. Common health factors such as diabetes, high blood pressure, smoking, obesity, family history of early heart disease, and age can make controlling your cholesterol even more important. What is Atherosclerosis? Atherosclerosis is the progressive buildup of plaque in the arteries over time. One major cause is high levels of LDL-C. Other health factors, such as family history, diabetes, high blood pressure, or if you smoke, or are overweight, may also play a role in the formation of plaque in arteries. Often this plaque starts building up in arteries in early adulthood and gets worse over time. How Does CRESTOR Work? Most of the cholesterol in your blood is made in the liver. CRESTOR works by reducing cholesterol in two ways: CRESTOR blocks an enzyme in the liver causing the liver to make less cholesterol, and CRESTOR increases the uptake and breakdown by the liver of cholesterol already in the blood. Who Should Not Take CRESTOR? Do not take CRESTOR if you: are pregnant or think you may be pregnant, or are planning to become pregnant. CRESTOR may harm your unborn baby. If you become pregnant, stop taking CRESTOR and call your health care professional right away are breast-feeding. CRESTOR can pass into your breast milk and may harm your baby have liver problems have had an allergic reaction to CRESTOR or are allergic to any of its ingredients. The active ingredient is rosuvastatin calcium. The inactive ingredients are: microcrystalline cellulose, lactose monohydrate, tribasic calcium phosphate, crospovidone, magnesium stearate, hypromellose, triacetin, titanium dioxide, yellow ferric oxide, and red ferric oxide The safety and effectiveness of CRESTOR have not been established in pediatric patients under the age of 10. What should I tell my health care professional before taking CRESTOR? Tell your health care professional if you: have a history of muscle pain or weakness are pregnant or think you may be pregnant, or are planning to become pregnant are breast-feeding drink more than 2 glasses of alcohol daily have liver problems have kidney problems have thyroid problems are Asian or of Asian descent Tell your health care professional about all medicines you take or plan to take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may interact with CRESTOR, causing side effects. It is particularly important to tell your health care professional if you are taking or plan to take medicines for: -your immune system -cholesterol/triglycerides -blood thinning -HIV/AIDS -preventing pregnancy Know all of the medicines you take and what they look like. It’s always a good idea to check that you have the right prescription before you leave the pharmacy and before you take any medicine. Keep a list of your medicines with you to show your health care professional. If you need to go to the hospital or have surgery, tell all of your health care professionals about all medicines that you are taking. How Should I Take CRESTOR? Take CRESTOR exactly as prescribed by your health care professional. Do not change your dose or stop CRESTOR without talking to your health care professional, even if you are feeling well. Your health care professional may do blood tests to check your cholesterol levels before and during your treatment with CRESTOR. Your dose of CRESTOR may be changed based on these blood tests results. CRESTOR can be taken at any time of day, with or without food. Swallow the tablets whole. Your health care professional may start you on a cholesterol lowering diet before giving you CRESTOR. Stay on this diet when you take CRESTOR. Wait at least 2 hours after taking CRESTOR to take an antacid that contains a combination of aluminum and magnesium hydroxide. If you miss a dose of CRESTOR, take it as soon as you remember. However, do not take 2 doses of CRESTOR within 12 hours of each other. If you take too much CRESTOR or overdose, call your health care professional or a Poison Control Center right away or go to the nearest emergency room. What Should I Avoid While Taking CRESTOR? Talk to your health care professional before you start any new medicines. This includes prescription and nonprescription medicines, vitamins, and herbal supplements. CRESTOR and certain other medicines can interact, causing serious side effects. Talk to your health care professional if you are pregnant or plan to become pregnant. Do not use CRESTOR if you are pregnant, trying to become pregnant or suspect that you are pregnant. If you become pregnant while taking CRESTOR, stop taking it and contact your health care professional immediately. What are the Possible Side Effects of CRESTOR? CRESTOR can cause side effects in some people. Serious side effects may include: Muscle Problems. Call your health care professional right away if you experience unexplained muscle pain, tenderness, or weakness especially with fever. This may be an early sign of a rare muscle problem that could lead to serious kidney problems. The risk of muscle problems is greater in people who are 65 years of age or older, or who already have thyroid or kidney problems. The chance of muscle problems may be increased if you are taking certain other medicines with CRESTOR. Liver problems. Your health care professional should do blood tests before you start taking CRESTOR and during treatment to check for signs of possible liver problems. The most common side effects may include: Headache, muscle aches and pains, abdominal pain, weakness, and nausea. This is not a complete list of side effects of CRESTOR. Talk to your health care professional for a complete list or if you have side effects that bother you or that do not go away. How Do I Store CRESTOR? Store CRESTOR at room temperature, 68 to 77°F (20 to 25°C) and in a dry place. If your health care professional tells you to stop treatment or if your medicine is out of date, throw the medicine away. Keep CRESTOR and all medicines in a secure place and out of the reach of children. What are the Ingredients in CRESTOR? Active Ingredient: rosuvastatin calcium Inactive Ingredients: microcrystalline cellulose NF, lactose monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF, hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide, and red ferric oxide NF. General Information About CRESTOR It is important to take CRESTOR as prescribed and to discuss any health changes you experience while taking CRESTOR with your health care professional. Do not use CRESTOR for a condition for which it was not prescribed. Do not give CRESTOR to other people, even if they have the same medical condition you have. It may harm them. This leaflet summarizes important information about CRESTOR. If you would like more information about CRESTOR, ask your health care professional. You can also go to the CRESTOR website at www.crestor.com or call 1-800-CRESTOR. CRESTOR is a trademark of the AstraZeneca group of companies. © AstraZeneca 2003, 2005, 2007, 2008, 2009, 2010 Licensed from SHIONOGI & CO., LTD., Osaka, Japan Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 ASTRAZENECA Rev. June 2010
DOSAGE AND ADMINISTRATION
2 CRESTOR can be taken with or without food, at any time of day. (2.1) Dose range: 5-40 mg once daily. Use 40 mg dose only for patients not reaching LDL-C goal with 20 mg. (2.1) HoFH: Starting dose 20 mg. (2.3) 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. (2.2) 2.1 General Dosing Information 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 (5.1)]. 2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 years of age) 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 (12) and Indications and Usage (1.2)]. Adjustments should be made at intervals of 4 weeks or more. 2.3 Homozygous Familial Hypercholesterolemia The recommended starting dose of CRESTOR is 20 mg once daily. Response to therapy should be estimated from preapheresis LDL-C levels. 2.4 Dosage in Asian Patients Initiation of CRESTOR therapy with 5 mg once daily should be considered for Asian patients [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)]. 2.5 Use with Cyclosporine, Lopinavir/Ritonavir or Atazanavir/Ritonavir In patients taking cyclosporine, the dose of CRESTOR should be limited to 5 mg once daily [see Warnings and Precautions (5.1) and Drug Interactions (7.1)]. In patients taking a combination of lopinavir and ritonavir or atazanavir and ritonavir, the dose of CRESTOR should be limited to 10 mg once daily [see Warnings and Precautions (5.1) and Drug Interactions (7.3)]. 2.6 Concomitant Lipid-Lowering Therapy The risk of skeletal muscle effects may be enhanced when CRESTOR is used in combination with niacin or fenofibrate; a reduction in CRESTOR dosage should be considered in this setting [see Warnings and Precautions (5.1) and Drug Interactions (7.5, 7.6)]. Combination therapy with gemfibrozil should be avoided because of an increase in CRESTOR exposure with concomitant use; if CRESTOR is used in combination with gemfibrozil, the dose of CRESTOR should be limited to 10 mg once daily [see Warnings and Precautions (5.1) and Drug Interactions (7.2)]. 2.7 Dosage in Patients With Severe Renal Impairment For patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) not on hemodialysis, dosing of CRESTOR should be started at 5 mg once daily and not exceed 10 mg once daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].