(8-12-03)
`
`TABLETS
`CRESTOR®
`(rosuvastatin calcium)
`
`PCC 630100
`
`DESCRIPTION
`CRESTOR® (rosuvastatin calcium) is a synthetic lipid-lowering agent. Rosuvastatin is an
`inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme
`catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in
`cholesterol biosynthesis.
`
`bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-
`is
`calcium
`Rosuvastatin
`[methyl(methylsulfonyl)amino]
`pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic
`acid]
`calcium salt. The empirical formula for rosuvastatin calcium is (C22H27FN3O6S)2Ca. Its
`molecular weight is 1001.14. Its structural formula is:
`
`OH OH
`
`O
`
`O
`
`Ca2+
`
`2
`
`F
`
`N
`
`N S
`
`N
`O2Me
`
`Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and
`methanol, and slightly soluble in ethanol. Rosuvastatin is a hydrophilic compound with a
`partition coefficient (octanol/water) of 0.13 at pH of 7.0.
`
`CRESTOR Tablets for oral administration contain 5, 10, 20, or 40 mg of rosuvastatin and the
`following 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.
`
`CLINICAL PHARMACOLOGY
`General: In the bloodstream , cholesterol and triglycerides (TG) circulate as part of
`lipoprotein complexes.
` With ultracentrifugation,
`these complexes separate
`into
`very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density
`lipoprotein (LDL) fractions that contain apolipoprotein B-100 (ApoB-100) and high-density
`lipoprotein (HDL) fractions.
`
`CFAD Exhibit 1046
`
`

`
`Cholesterol and TG synthesized in the liver are incorporated into VLDL and secreted into the
`circulation for delivery to peripheral tissues. TG are removed by the action of lipases, and in a
`series of steps, the modified VLDL is transformed first into IDL and then into cholesterol-rich
`LDL. IDL and LDL are removed from the circulation mainly by high affinity ApoB/E
`receptors, which are expressed to the greatest extent on liver cells. HDL is hypothesized to
`participate in the reverse transport of cholesterol from tissues back to the liver.
`
`Epidemiologic, experimental, and clinical studies have established that high LDL cholesterol
`(LDL-C), low HDL cholesterol (HDL-C), and high plasma TG promote human atherosclerosis
`and are risk factors for developing cardiovascular disease. In contrast, higher levels of HDL-
`C are associated with decreased cardiovascular risk.
`
`Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL, and
`remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently
`found with low HDL-C levels and small LDL particles, as well as in association with
`non-lipid metabolic risk factors for coronary heart disease (CHD). As such, total plasma TG
`has not consistently been shown to be an independent risk factor for CHD. Furthermore, the
`independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular
`morbidity and mortality has not been determined.
`
`Mechanism of Action: Rosuvastatin 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.
`
`Rosuvastatin reduces total cholesterol (total-C), LDL-C, ApoB, and nonHDL-C (total
`cholesterol minus HDL-C) in patients with homozygous and heterozygous familial
`hypercholesterolemia
`(FH), nonfamilial
`forms of hypercholesterolemia, and mixed
`dyslipidemia. Rosuvastatin also reduces TG and produces increases in HDL-C. Rosuvastatin
`reduces total-C, LDL-C, VLDL-cholesterol (VLDL-C), ApoB, nonHDL-C and TG, and
`increases HDL-C in patients with isolated hypertriglyceridemia. The effect of rosuvastatin on
`cardiovascular morbidity and mortality has not been determined.
`
`2
`
`

`
`Pharmacokinetics and Drug Metabolism
`Absorption: In clinical pharmacology studies in man, peak plasma concentrations of
`rosuvastatin were reached 3 to 5 hours following oral dosing. Both peak concentration (Cmax)
`and area under the plasma concentration-time curve (AUC) increased in approximate
`proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately
`20%.
`
`Administration of rosuvastatin with food decreased the rate of drug absorption by 20% as
`assessed by Cmax, but there was no effect on the extent of absorption as assessed by AUC.
`
`Plasma concentrations of rosuvastatin do not differ following evening or morning drug
`administration.
`
`Significant LDL-C reductions are seen when rosuvastatin is given with or without food, and
`regardless of the time of day of drug administration.
`
`Distribution: Mean volume of distribution at steady-state of rosuvastatin is approximately
`134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is
`reversible and independent of plasma concentrations.
`
`Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a
`radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl
`rosuvastatin, which is formed principally by cytochrome P450 2C9, and in vitro studies have
`demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the
`HMG-CoA reductase inhibitory activity of rosuvastatin. Overall, greater than 90% of active
`plasma HMG-CoA reductase inhibitory activity is accounted for by rosuvastatin.
`
`Excretion: Following oral administration, rosuvastatin and its metabolites are primarily
`excreted in the feces (90%). The elimination half-life (t1/2) of rosuvastatin is approximately
`19 hours.
`
`After an intravenous dose, approximately 28% of total body clearance was via the renal route,
`and 72% by the hepatic route.
`
`Special Populations
`Race: A population pharmacokinetic analysis revealed no clinically relevant differences in
`pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups.
`However, pharmacokinetic studies show an approximate 2-fold elevation in median exposure
`(AUC) in Japanese subjects residing in Japan and in Chinese subjects residing in Singapore
`when compared with Caucasians residing in North America and Europe. No studies directly
`examining Asian ethnic populations residing in the U.S. are available, so the contribution of
`environmental and genetic factors to the observed increases in rosuvastatin drug levels have
`not been determined. (See WARNINGS, Myopathy/Rhabdomyolysis, and PRECAUTIONS,
`General.)
`
`3
`
`

`
`Gender: There were no differences in plasma concentrations of rosuvastatin between men
`and women.
`
`Geriatric: There were no differences in plasma concentrations of rosuvastatin between the
`nonelderly and elderly populations (age ≥65 years).
`
`Pediatric: 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 rosuvastatin. Both Cmax and
`AUC of rosuvastatin were similar to values observed in adult subjects administered the same
`doses.
`
`Insufficiency: Mild
`Renal
`(creatinine clearance
`impairment
`renal
`to moderate
`≥ 30 mL/min/1.73m2) had no influence on plasma concentrations of rosuvastatin when oral
`doses of 20 mg rosuvastatin were administered for 14 days. However, plasma concentrations
`of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe
`(CLcr < 30 mL/min/1.73m2)
`renal
`impairment
`compared with
`healthy
`subjects
`(CLcr > 80 mL/min/1.73m2) (see PRECAUTIONS, General).
`
`Hemodialysis: Steady-state plasma concentrations of rosuvastatin in patients on chronic
`hemodialysis were approximately 50% greater compared with healthy volunteer subjects with
`normal renal function.
`
`Hepatic Insufficiency: In patients with chronic alcohol liver disease, plasma concentrations
`of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, Cmax and
`AUC were increased by 60% and 5%, respectively, as compared with patients with normal
`liver function. In patients with Child-Pugh B disease, Cmax and AUC were increased 100% and
`21%,
`respectively,
`compared with patients with normal
`liver
`function
`(see
`CONTRAINDICATIONS and WARNINGS, Liver Enzymes).
`
`Drug-Drug Interactions
`Cytochrome P450 3A4: In vitro and in vivo data indicate that rosuvastatin clearance is not
`dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. This has
`been confirmed in studies with known cytochrome P450 3A4 inhibitors (ketoconazole,
`erythromycin, itraconazole).
`
`Ketoconazole: Coadministration of ketoconazole (200 mg twice daily for 7 days) with
`rosuvastatin (80 mg) resulted in no change in plasma concentrations of rosuvastatin.
`
`Erythromycin: Coadministration of erythromycin (500 mg four times daily for 7 days) with
`rosuvastatin (80 mg) decreased AUC and Cmax of rosuvastatin by 20% and 31%, respectively.
`These reductions are not considered clinically significant.
`
`4
`
`

`
`Itraconazole: Itraconazole (200 mg once daily for 5 days) resulted in a 39% and 28%
`increase in AUC of rosuvastatin after 10 mg and 80 mg dosing, respectively. These increases
`are not considered clinically significant.
`
`Fluconazole: Coadministration of fluconazole (200 mg once daily for 11 days) with
`rosuvastatin (80 mg) resulted in a 14% increase in AUC of rosuvastatin. This increase is not
`considered clinically significant.
`
`Cyclosporine: Coadministration of cyclosporine with rosuvastatin resulted in no significant
`changes in cyclosporine plasma concentrations. However, Cmax and AUC of rosuvastatin
`increased 11- and 7-fold, respectively, compared with historical data in healthy subjects.
`These
`increases are considered
`to be clinically significant (see PRECAUTIONS,
`Drug Interactions, WARNINGS, Myopathy/Rhabdomyolysis,
`and DOSAGE AND
`ADMINISTRATION).
`
`Warfarin: Coadministration of warfarin (20 mg) with rosuvastatin (40 mg) did not change
`warfarin plasma concentrations but increased the International Normalized Ratio (INR) (see
`PRECAUTIONS, Drug Interactions).
`
`Digoxin: Coadministration of digoxin (0.5 mg) with rosuvastatin (40 mg) resulted in no
`change to digoxin plasma concentrations.
`
`Fenofibrate: Coadministration of fenofibrate (67 mg three times daily) with rosuvastatin
`(10 mg) resulted in no significant changes in plasma concentrations of rosuvastatin or
`fenofibrate
`(see
`PRECAUTIONS,
`Drug
`Interactions,
`and WARNINGS,
`Myopathy/Rhabdomyolysis).
`
`Gemfibrozil: Coadministration of gemfibrozil (600 mg twice daily for 7 days) with
`rosuvastatin (80 mg) resulted in a 90% and 120% increase for AUC and Cmax of rosuvastatin,
`respectively. This increase is considered to be clinically significant (see PRECAUTIONS,
`Drug
`Interactions, WARNINGS, Myopathy/Rhabdomyolysis, DOSAGE AND
`ADMINISTRATION).
`
`Antacid: Coadministration of an antacid (aluminum and magnesium hydroxide combination)
`with rosuvastatin (40 mg) resulted in a decrease in plasma concentrations of rosuvastatin by
`54%. However, when the antacid was given 2 hours after rosuvastatin, there were no
`clinically significant changes in plasma concentrations of rosuvastatin (see PRECAUTIONS,
`Information for Patients).
`
`Oral contraceptives: Coadministration of oral contraceptives (ethinyl estradiol and
`norgestrel) with rosuvastatin resulted in an increase in plasma concentrations of ethinyl
`estradiol and norgestrel by 26% and 34%, respectively.
`
`5
`
`

`
`Clinical Studies
`Hypercholesterolemia (Heterozygous Familial and Nonfamilial)
`and Mixed Dyslipidemia (Fredrickson Type IIa and IIb)
`CRESTOR reduces total-C, LDL-C, ApoB, nonHDL-C, and TG, and increases HDL-C, in
`patients with hypercholesterolemia and mixed dyslipidemia. Therapeutic response is seen
`within 1 week, and maximum response is usually achieved within 4 weeks and maintained
`during long-term therapy.
`
`in a wide variety of adult patient populations with
`is effective
`CRESTOR
`hypercholesterolemia, with and without hypertriglyceridemia, regardless of race, gender, or
`age and in special populations such as diabetics or patients with heterozygous FH. Experience
`in pediatric patients has been limited to patients with homozygous FH.
`
`Dose-Ranging Study: In a multicenter, double-blind, placebo-controlled, dose-ranging study
`in patients with hypercholesterolemia, 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 1).
`
`Table 1. Dose-Response in Patients With Primary Hypercholesterolemia
`(Adjusted Mean % Change From Baseline at Week 6)
`
`Dose
`Placebo
`5
`10
`20
`40
`
`N
`13
`17
`17
`17
`18
`
`Total-C
`-5
`-33
`-36
`-40
`-46
`
`LDL-C
`-7
`-45
`-52
`-55
`-63
`
`NonHDL-C
`-7
`-44
`-48
`-51
`-60
`
`ApoB
`-3
`-38
`-42
`-46
`-54
`
`TG
`-3
`-35
`-10
`-23
`-28
`
`HDL-C
`3
`13
`14
`8
`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
`2,240 patients with Type IIa and IIb hypercholesterolemia. After randomization, patients
`were treated for 6 weeks with a single daily dose of either CRESTOR, atorvastatin,
`simvastatin, or pravastatin (Figure 1 and Table 2).
`
`6
`
`

`
`Figure 1. Percent LDL-C Change by Dose of CRESTOR,
` Atorvastatin, Simvastatin, and Pravastatin
` at Week 6 in Patients With Type IIa/IIb Dyslipidemia
`
`Table 2. Percent Change in LDL-C From Baseline to Week 6 (LS means §) by
`Treatment Group (sample sizes ranging from 156-167 patients per group)
`
`Treatment
`
`CRESTOR
`
`Atorvastatin
`
`Pravastatin
`
`Simvastatin
`
`10 mg
`
`-46*
`
`-37
`
`-20
`
`-28
`
`Treatment Daily Dose
`20 mg
`40 mg
`
`80 mg
`
`-52†
`
`-43
`
`-24
`
`-35
`
`-55‡
`
`-48
`
`-30
`
`-39
`
`---
`
`-51
`
`---
`
`-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. (p<0.002)
`† 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)
`‡ CRESTOR 40 mg reduced LDL-C significantly more than atorvastatin 40 mg; pravastatin 40 mg; simvastatin
`40 mg, and 80 mg (p<0.002)
`§ Corresponding standard errors are approximately 1.00
`
`7
`
`

`
`Heterozygous Familial Hypercholesterolemia
`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 3).
`
`Table 3. Mean LDL-C Percentage Change from Baseline
`
`CRESTOR
`(n=435)
`LS Mean* (95% CI)
`-47% (-49%, -46%)
`Week 6 20 mg
`-55% (-57%, -54%)
`Week 12 40 mg
`NA
`Week 18 80 mg
`* LS Means are least square means adjusted for baseline LDL.
`
`Atorvastatin
`(n=187)
`LS Mean (95% CI)
`-38% (-40%, -36%)
`-47% (-49%, -45%)
`-52% (-54%, -50%)
`
`Hypertriglyceridemia
`(Fredrickson Type IIb & IV)
`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 4).
`
`Table 4. Dose-Response in Patients With Primary Hypertriglyceridemia Over 6 Weeks Dosing
`Median (Min, Max) Percent Change From Baseline
`
`CRESTOR
`20 mg
`N=27
`-37 (-72, 11)
`-43 (-74, -12)
`-49 (-83, 20)
`-34 (-61, -11)
`-31 (-66, 34)
`22 (-5, 50)
`
`CRESTOR
`40 mg
`N=25
`-43 (-80, -7)
`-51 (-62, -6)
`-56 (-83, 10)
`-40 (-51, -4)
`-43 (-61, -3)
`17 (-14, 63)
`
`CRESTOR
`CRESTOR
`Placebo
`5 mg
`10 mg
`N=26
`N=25
`N=23
`Triglycerides
`1 (-40, 72)
`-21 (-58, 38)
`-37 (-65, 5)
`NonHDL-C
`2 (-13, 19)
`-29 (-43, -8)
`-49 (-59, -20)
`VLDL-C
`2 (-36, 53)
`-25 (-62, 49)
`-48 (-72, 14)
`Total-C
`1 (-13, 17)
`-24 (-40, -4)
`-40 (-51, -14)
`LDL-C
`5 (-30, 52)
`-28 (-71, 2)
`-45 (-59, 7)
`HDL-C
`-3 (-25, 18)
`3 (-38, 33)
`8 (-8, 24)
`Homozygous Familial Hypercholesterolemia
`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.
`
`Dose
`
`8
`
`

`
`INDICATIONS AND USAGE
`CRESTOR is indicated:
`
`1. as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TG levels
`and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous
`familial and nonfamilial) and mixed dyslipidemia (Fredrickson Type IIa and IIb);
`
`2. as an adjunct to diet for the treatment of patients with elevated serum TG levels
`(Fredrickson Type IV);
`
`3.
`
`in patients with homozygous familial
`total-C, and ApoB
`to reduce LDL-C,
`hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL
`apheresis) or if such treatments are unavailable.
`
`According to NCEP-ATPIII guidelines, therapy with lipid-altering agents should be a
`component of multiple-risk-factor intervention in individuals at increased risk for coronary
`heart disease due to hypercholesterolemia. The two major modalities of LDL-lowering
`therapy are therapeutic lifestyle changes (TLC) and drug therapy. The TLC Diet stresses
`reductions in saturated fat and cholesterol intake. Table 5 defines LDL-C goals and cutpoints
`for initiation of TLC and for drug consideration.
`
`9
`
`

`
`Table 5. NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes
`and Drug Therapy in Different Risk Categories
`
`Risk Category
`
`LDL Goal
`
`CHDa or CHD Risk Equivalent
`(10 year risk > 20%)
`
`<100 mg/dL
`
`LDL level at which
`to initiate TLC
`≥100 mg/dL
`
`LDL level at which to consider
`drug therapy
`≥130 mg/dL
`(100-129 mg/dL:drug optional)b
`
`2+ Risk Factors
`(10-year risk ≤ 20%)
`
`<130 mg/dL
`
`≥130 mg/dL
`
`0-1 Risk Factorc
`
`<160 mg/dL
`
`≥160 mg/dL
`
`≥130 mg/dL
`10-year risk 10-20%
`≥160 mg/dL
`10-year risk <10%
`
`≥190 mg/dL (160-189 mg/dL
`(LDL-lowering drug optional)
`
`a CHD = coronary heart disease.
`b Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C <100 mg/dL cannot be
`achieved by TLC. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic
`acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory.
`c Almost all people with 0-1 risk factor have 10-year risk<10%; thus, 10-year risk assessment in people with
`0-1 risk factor is not necessary.
`
`After the LDL-C goal has been achieved, if the TG is still ≥ 200 mg/dL, nonHDL-C (total-C
`minus HDL-C) becomes a secondary target of therapy. NonHDL-C goals are set 30 mg/dL
`higher than LDL-C goals for each risk category.
`
`At the time of hospitalization for a coronary event, consideration can be given to initiating
`drug therapy at discharge if the LDL-C is ≥ 130 mg/dL (see NCEP Treatment Guidelines,
`above).
`
`Patients >20 years of age should be screened for elevated cholesterol levels every 5 years.
`
`Prior to initiating therapy with CRESTOR, secondary causes for hypercholesterolemia (e.g.,
`poorly-controlled
`diabetes
`mellitus,
`hypothyroidism,
`nephrotic
`syndrome,
`dyslipoproteinemias, obstructive liver disease, other drug therapy, and alcoholism) should be
`excluded, and a lipid profile performed to measure total-C, LDL-C, HDL-C, and TG. For
`patients with TG <400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following
`equation: LDL-C = total-C - (0.20 x [TG] + HDL-C). For TG levels >400 mg/dL
`(>4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined
`by ultracentrifugation.
`
`CRESTOR has not been studied in Fredrickson Type I, III, and V dyslipidemias.
`
`10
`
`

`
`CONTRAINDICATIONS
`CRESTOR is contraindicated in patients with a known hypersensitivity to any component of
`this product.
`
`Rosuvastatin is contraindicated in patients with active liver disease or with unexplained
`persistent elevations of serum transaminases (see WARNINGS, Liver Enzymes).
`
`Pregnancy and Lactation
`Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during
`pregnancy should have little impact on the outcome of long-term therapy of primary
`hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential
`components for fetal development (including synthesis of steroids and cell membranes). Since
`HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of
`other biologically active substances derived from cholesterol, they may cause fetal harm when
`administered
`to pregnant women. Therefore, HMG-CoA
`reductase
`inhibitors are
`contraindicated during pregnancy and in nursing mothers. ROSUVASTATIN SHOULD BE
`ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH
`PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED
`OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug,
`therapy should be discontinued immediately and the patient apprised of the potential hazard to
`the fetus.
`
`WARNINGS
`Liver Enzymes
`HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been
`associated with biochemical abnormalities of liver function. The incidence of persistent
`elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more consecutive
`occasions) in serum transaminases in fixed dose studies was 0.4, 0, 0, and 0.1% in patients
`who received rosuvastatin 5, 10, 20, and 40 mg, respectively. 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 rosuvastatin 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.
`
`It is recommended that liver function 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. Liver enzyme changes generally occur in the first 3 months of
`treatment with rosuvastatin. 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 rosuvastatin is recommended.
`
`Rosuvastatin should be used with caution in patients who consume substantial quantities of
`alcohol and/or have a history of liver disease (see CLINICAL PHARMACOLOGY, Special
`Populations, Hepatic Insufficiency).
` Active liver disease or unexplained persistent
`transaminase elevations are contraindications
`to
`the use of
`rosuvastatin
`(see
`CONTRAINDICATIONS).
`
`11
`
`

`
`Myopathy/Rhabdomyolysis
`Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have
`been reported with rosuvastatin and with other drugs in this class.
`
`Uncomplicated myalgia has been reported in rosuvastatin-treated patients (see ADVERSE
`REACTIONS). Creatine kinase (CK) elevations (>10 times upper limit of normal) occurred in
`0.2% to 0.4% of patients taking rosuvastatin at doses up to 40 mg in clinical studies.
`Treatment-related myopathy, defined as muscle aches or muscle weakness in conjunction with
`increases in CK values >10 times upper limit of normal, was reported in up to 0.1% of patients
`taking rosuvastatin doses of up to 40 mg in clinical studies. Rare cases of rhabdomyolysis
`were seen with higher than recommended doses (80 mg) of rosuvastatin in clinical trials.
`Factors that may predispose patients to myopathy with HMG-CoA reductase inhibitors
`include advanced age (≥65 years), hypothyroidism, and renal insufficiency. The incidence of
`myopathy increased at doses of rosuvastatin above the recommended dosage range.
`
`Consequently:
`
`1. Rosuvastatin should be prescribed with caution in patients with predisposing factors for
`myopathy, such as, renal impairment (see DOSAGE AND ADMINISTRATION),
`advanced age, and hypothyroidism.
`
`2. Patients should be advised to promptly report unexplained muscle pain, tenderness, or
`weakness, particularly if accompanied by malaise or fever. Rosuvastatin therapy should be
`discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
`
`3. The risk of myopathy during treatment with rosuvastatin may be increased with concurrent
`administration of other lipid-lowering therapies or cyclosporine, (see CLINICAL
`PHARMACOLOGY, Drug Interactions, PRECAUTIONS, Drug Interactions, and
`DOSAGE AND ADMINISTRATION). The benefit of further alterations in lipid
`levels by the combined use of rosuvastatin with fibrates or niacin should be carefully
`weighed against the potential risks of this combination. Combination therapy with
`rosuvastatin and gemfibrozil should generally be avoided. (See DOSAGE AND
`ADMINISTRATION and PRECAUTIONS, Drug Interactions).
`
`4. The risk of myopathy during treatment with rosuvastatin may be increased in
`circumstances which
`increase
`rosuvastatin drug
`levels
`(see CLINICAL
`PHARMACOLOGY, Special Populations, Race and Renal Insufficiency, and
`PRECAUTIONS, General).
`
`5. Rosuvastatin 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, major
`
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`
`

`
`surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or
`uncontrolled seizures).
`
`PRECAUTIONS
`General
`Before instituting therapy with rosuvastatin, an attempt should be made to control
`hypercholesterolemia with appropriate diet and exercise, weight reduction in obese patients,
`and treatment of underlying medical problems (see INDICATIONS AND USAGE).
`
`impairment
`to patients with severe renal
`Administration of rosuvastatin 20 mg
`(CLcr <30 mL/min/1.73 m2) resulted in a 3-fold increase in plasma concentrations of
`rosuvastatin compared with healthy volunteers (see WARNINGS, Myopathy/Rhabdomyolysis
`and DOSAGE AND ADMINISTRATION).
`
`Pharmacokinetic studies show an approximate 2-fold elevation in median exposure in
`Japanese subjects residing in Japan and in Chinese subjects residing in Singapore compared
`with Caucasians residing in North America and Europe. The contribution of environmental
`and genetic factors to the difference observed has not been determined. However, these
`increases should be considered when making rosuvastatin dosing decisions for patients of
`Japanese and Chinese ancestry. (See WARNINGS Myopathy/Rhabdomyolysis; CLINICAL
`PHARMACOLOGY, Special Populations, Race.)
`
`Information for Patients
`Patients should be advised to report promptly unexplained muscle pain, tenderness, or
`weakness, particularly if accompanied by malaise or fever.
`
`When taking rosuvastatin with an aluminum and magnesium hydroxide combination antacid,
`the antacid should be taken at least 2 hours after rosuvastatin administration (see CLINICAL
`PHARMACOLOGY, Drug Interactions).
`
`Laboratory Tests
`In the rosuvastatin clinical trial 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). However, this finding was more frequent in
`patients taking rosuvastatin 40 mg, when compared to lower doses of rosuvastatin or
`comparator statins, 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 rosuvastatin 40 mg therapy with unexplained persistent
`proteinuria during routine urinalysis testing.
`
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`
`

`
`Drug Interactions
`Cyclosporine: When rosuvastatin 10 mg was co-administered with cyclosporine in cardiac
`transplant patients, rosuvastatin mean Cmax and mean AUC were increased 11-fold and 7-fold,
`respectively, compared with healthy volunteers. These increases are considered to be
`clinically significant and require special consideration in the dosing of rosuvastatin to patients
`taking concomitant cyclosporine (see WARNINGS, Myopathy/Rhabdomyolysis, and
`DOSAGE AND ADMINISTRATION).
`
`Warfarin: Coadministration of rosuvastatin to patients on stable warfarin therapy resulted in
`clinically significant rises in INR (>4, baseline 2-3). In patients taking coumarin
`anticoagulants and rosuvastatin concomitantly, INR should be determined before starting
`rosuvastatin and frequently enough during early therapy to ensure that no significant alteration
`of INR occurs. Once a stable INR time has been documented, INR can be monitored at the
`intervals usually recommended for patients on coumarin anticoagulants. If the dose of
`rosuvastatin is changed, the same procedure should be repeated. Rosuvastatin therapy has not
`been associated with bleeding or with changes in INR in patients not taking anticoagulants.
`
`Gemfibrozil: Coadministration of a single rosuvastatin dose to healthy volunteers on
`gemfibrozil (600 mg twice daily) resulted in 2.2- and 1.9-fold, respectively, increase in mean
`Cmax and mean AUC of rosuvastatin (see DOSAGE AND ADMINISTRATION).
`
`Endocrine Function
`Although clinical studies have shown that rosuvastatin alone does not reduce basal plasma
`cortisol concentration or impair adrenal reserve, caution should be exercised if any HMG-CoA
`reductase inhibitor or other agent used to lower cholesterol levels is administered
`concomitantly with drugs that may decrease the levels or activity of endogenous steroid
`hormones such as ketoconazole, spironolactone, and cimetidine.
`
`CNS 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 comparisons). 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 comparisons). 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 comparisons). 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 comparisons) following treatment up to one year, did
`not reveal retinal findings.
`
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`
`

`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`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 human exposure at 40 mg/day based on AUC. An increased
`incidence of hepatocellular tumors was