CRESTOR (Page 4 of 9)

8.3 Females and Males of Reproductive Potential

Contraception

CRESTOR may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during treatment with CRESTOR.

8.4 Pediatric Use

In children and adolescents 8 to 17 years of age with heterozygous familial hypercholesterolemia, the safety and effectiveness of CRESTOR as an adjunct to diet to reduce total cholesterol, LDL-C, and ApoB levels when, after an adequate trial of diet therapy, LDL-C exceeds 190 mg/dL or when LDL-C exceeds 160 mg/dL and there is a positive family history of premature CVD or two or more other CVD risk factors, were established in one controlled trial and in one open-label, uncontrolled trial [see Clinical Studies (14.7)]. The long-term efficacy of CRESTOR therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

The safety and effectiveness of CRESTOR in children and adolescents 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. There was no detectable effect of CRESTOR on growth, weight, BMI (body mass index), or sexual maturation [see Clinical Studies (14.7)] in children and adolescents (10 to 17 years of age).

CRESTOR has not been studied in controlled clinical trials involving prepubertal patients or patients younger than 10 years of age with heterozygous familial hypercholesterolemia. However, the safety and effectiveness of CRESTOR were evaluated in a two year open-label uncontrolled trial that included children and adolescents 8 to 17 years of age with heterozygous familial hypercholesterolemia [see Clinical Studies (14.7)]. The safety and efficacy of CRESTOR in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design.

Children and adolescents 7 to 15 years of age with homozygous familial hypercholesterolemia were studied in a 6-week randomized, placebo-controlled, cross-over study with CRESTOR 20 mg once daily followed by 12 weeks of open-label treatment [see Clinical Studies (14.6) ]. In general, the safety profile in this trial was consistent with that of the previously established safety profile in adults.

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. Adolescent females should be counseled on appropriate contraceptive methods while on CRESTOR therapy [see Use in Specific Populations (8.1)].

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)].

8.6 Renal Impairment

Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CLcr ≥ 30 mL/min/1.73 m2). Exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) who are not receiving hemodialysis and dose adjustment is required [see Dosage and Administration (2.5), Warnings and Precautions (5.1)and Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment

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 (4) , Warning and Precautions (5.2), and Clinical Pharmacology (12.3)].

8.8 Asian Patients

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 (2.3) and Clinical Pharmacology (12.3) ].

10 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.

11 DESCRIPTION

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:

strucural formula
(click image for full-size original)

The empirical formula for rosuvastatin calcium is (C22 H27 FN3 O6 S)2 Ca 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.

CRESTOR Tablets for oral administration contain 5, 10, 20, or 40 mg of rosuvastatin and the following 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.

12 CLINICAL PHARMACOLOGY

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.

12.3 Pharmacokinetics

Absorption

In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to CRESTOR dose. The absolute bioavailability of rosuvastatin is approximately 20%.

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

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 the parent compound. Overall, greater than 90% of active plasma HMG‑CoA reductase inhibitory activity is accounted for by the parent compound.

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.

Specific 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, including one conducted in the US, have demonstrated an approximate 2‑fold elevation in median exposure (AUC and Cmax ) in Asian subjects when compared with a Caucasian control group.

Gender

There were no differences in plasma concentrations of rosuvastatin between men and women.

Pediatric

In a population pharmacokinetic analysis of two pediatric trials involving patients with heterozygous familial hypercholesterolemia 10 to 17 years of age and 8 to 17 years of age, respectively, rosuvastatin exposure appeared comparable to or lower than rosuvastatin exposure in adult patients.

Geriatric

There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).

Renal Impairment

Mild to moderate renal impairment (CLcr ≥ 30 mL/min/1.73 m2) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3‑fold) in patients with severe renal impairment (CLcr < 30 mL/min/1.73 m2) not receiving hemodialysis compared with healthy subjects (CLcr > 80 mL/min/1.73 m2).

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 Impairment

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.

Drug-Drug Interactions

Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent.

Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter organic anion-transporting polyprotein 1B1 (OATP1B1) and efflux transporter breast cancer resistance protein (BCRP). Concomitant administration of CRESTOR with medications that are inhibitors of these transporter proteins (e.g. cyclosporine, certain HIV protease inhibitors) may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy [see Dosage and Administration (2.4)]. It is recommended that prescribers consult the relevant product information when considering administration of such products together with CRESTOR.

Table 4. Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure
*
Single dose unless otherwise noted.
Clinically significant [see Dosage and Administration (2) and Warnings and Precautions (5) ]
Mean ratio with 90% CI (with/without coadministered drug, e.g., 1 = no change, 0.7 = 30% decrease, 11 = 11 fold increase in exposure)

Coadministered drug and dosing regimen

Rosuvastatin

Mean Ratio (ratio with/without coadministered drug) No Effect = 1.0

Dose (mg) *

Change in AUC

Change in Cmax

Cyclosporine – stable dose required (75 mg – 200 mg BID)

10 mg QD for 10 days

7.1

11

Atazanavir/ritonavir combination 300 mg/100 mg QD for 8 days

10 mg

3.1

7

Simeprevir 150 mg QD, 7 days

10 mg, single dose

2.8(2.3-3.4)

3.2
(2.6-3.9)

Lopinavir/ritonavir combination 400 mg/100 mg BID for 17 days

20 mg QD for 7 days

2.1

(1.7-2.6)

5
(3.4-6.4)

Gemfibrozil 600 mg BID for 7 days

80 mg

1.9(1.6-2.2)

2.2
(1.8-2.7)

Eltrombopag 75 mg QD, 5 days

10 mg

1.6

(1.4-1.7)

2
(1.8-2.3)

Darunavir 600 mg/ritonavir 100 mg BID, 7 days

10 mg QD for 7 days

1.5

(1.0-2.1)

2.4
(1.6-3.6)

Tipranavir/ritonavir combination 500 mg/200mg BID for 11 days

10 mg

1.4

(1.2-1.6)

2.2
(1.8-2.7)

Dronedarone 400 mg BID

10 mg

1.4

Itraconazole 200 mg QD, 5 days

10 mg or 80 mg

1.4

(1.2-1.6)

1.3

(1.1-1.4)

1.4
(1.2-1.5)
1.2
(0.9-1.4)

Ezetimibe 10 mg QD, 14 days

10 mg QD for 14 days

1.2
(0.9-1.6)
1.2

(0.8-1.6)

Fosamprenavir/ritonavir 700 mg/100 mg BID for 7 days

10 mg

1.1

1.5

Fenofibrate 67 mg TID for 7 days

10 mg

1.2
(1.1-1.3)

Rifampicin 450 mg QD, 7 days

20 mg

Aluminum & magnesium hydroxide combination antacid

Administered simultaneouslyAdministered 2 hours apart

40 mg40 mg

0.5

(0.4-0.5)

0.8

(0.7-0.9)

0.5
(0.4-0.6)
0.8
(0.7-1.0)

Ketoconazole 200 mg BID for 7 days

80 mg

1.0

(0.8-1.2)

1.0

(0.7-1.3)

Fluconazole 200 mg QD for 11 days

80 mg

1.1

(1.0-1.3)

1.1

(0.9-1.4)

Erythromycin 500 mg QID for 7 days

80 mg

0.8

(0.7-0.9)

0.7

(0.5-0.9)

Table 5. Effect of Rosuvastatin Coadministration on Systemic Exposure to Other Drugs
Rosuvastatin Dosage Regimen Coadministered Drug
Mean Ratio (ratio with/without coadministered drug) No Effect = 1.0
Name and Dose Change in AUC Change in Cmax
*
Clinically significant pharmacodynamic effects [see Warnings and Precautions (5.3) ]
Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7=30% decrease, 11=11-fold increase in exposure)

40 mg QD for 10 days

Warfarin *

25 mg single dose

R- Warfarin 1.0

(1.0-1.1)

S-Warfarin 1.1

(1.0-1.1)

R-Warfarin 1.0

(0.9-1.0)

S-Warfarin 1.0

(0.9-1.1)

40 mg QD for 12 days

Digoxin

0.5 mg single dose

1.0

(0.9-1.2)

1.0

(0.9-1.2)

40 mg QD for 28 days

Oral Contraceptive

(ethinyl estradiol 0.035 mg & norgestrel 0.180, 0.215 and 0.250 mg) QD for 21 Days

EE 1.3

(1.2-1.3)

NG 1.3

(1.3-1.4)

EE 1.3

(1.2-1.3)

NG 1.2

(1.1-1.3)

EE = ethinyl estradiol, NG = norgestrel

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