Rosuvastatin (Page 4 of 7)

8.3 Females and Males of Reproductive Potential

Contraception
Rosuvastatin 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 rosuvastatin.

8.4 Pediatric Use

Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

Of the 10,275 patients in clinical studies with rosuvastatin, 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 rosuvastatin 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

Rosuvastatin 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; rosuvastatin should be used with caution in these patients [see Contraindications (4), Warnings 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. Rosuvastatin 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

Rosuvastatin calcium is a synthetic lipid-lowering agent for oral administration.
The chemical name for rosuvastatin calcium is (3R, 5S, 6E) -7-[4-(4-Fluorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid calcium salt with the following structural formula:

rosuvastatinstructure

The empirical formula for rosuvastatin calcium is (C22 H27 FN3 O6 S)2 Ca and the molecular weight is 1001.14. Rosuvastatin calcium USP is a white or almost white hygroscopic powder that is sparingly soluble in methanol, slightly soluble in water, practically insoluble in anhydrous ethanol.
Rosuvastatin tablets USP for oral administration contain 5, 10, 20, or 40 mg of rosuvastatin and the following inactive ingredients: Each tablet contains: crospovidone, FD&C blue #2/indigo carmine aluminum lake, FD&C red #40/allura red AC aluminum lake, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium bicarbonate, talc, titanium dioxide and triacetin. Additionally 5 mg tablets contain FD&C yellow #5/tartrazine aluminum lake and 10 mg, 20 mg and 40 mg tablets contain FD&C yellow #6/sunset yellow FCF aluminum lake.
USP Dissolution test is pending.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

Rosuvastatin dose dependently reduces elevated LDL-cholesterol and reduces total cholesterol and triglycerides and increases HDL-cholesterol [see Clinical Studies (14)]. A therapeutic response to rosuvastatin is evident within 1 week of commencing therapy and 90% of maximum response is usually achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that. Individualization of drug dosage should be based on the therapeutic response [see Dosage and Administration (2)].

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 rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%.
Administration of rosuvastatin 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.
Elimination
Rosuvastatin is primarily eliminated by excretion in the feces. The elimination half-life of rosuvastatin is approximately 19 hours.
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%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.
Specific Populations
Racial or Ethnic Groups
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.
Male and Female Patients
There were no differences in plasma concentrations of rosuvastatin between men and women.
Pediatric use information for patients ages 8 to less than 10 years is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
Geriatric Patients
There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).
Patients with 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.
Patients with 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 Interactions Studies
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 rosuvastatin with medications that are inhibitors of these transporter proteins (e.g. cyclosporine, certain HIV protease inhibitors) may result in increased rosuvastatin plasma concentrations [see Dosage and Administration (2.4) and Drug Interactions (7.1, 7.3)].

Table 4. Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure

Coadministered drug and dosing regimen

Rosuvastatin

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

Dose (mg)1

Change in AUC

Change inCmax

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

10 mg QD for10 days

7.12

112

Atazanavir/ritonavir combination300 mg/100 mg QD for 8 days

10 mg

3.12

72

Simeprevir150 mg QD, 7 days

10 mg, single dose

2.82 (2.3-3.4)3

3.22 (2.6-3.9)3

Lopinavir/ritonavir combination400 mg/100 mg BID for 17 days

20 mg QD for7 days

2.12 (1.7-2.6)3

52 (3.4-6.4)3

Gemfibrozil 600 mg BID for 7 days

80 mg

1.92 (1.6-2.2) 3

2.2‑2 (1.8-2.7) 3

Eltrombopag 75 mg QD, 5 days

10 mg

1.6(1.4-1.7)3

2(1.8-2.3) 3

Darunavir 600 mg/ritonavir 100 mg BID, 7 days

10 mg QD for7 days

1.5(1.0-2.1) 3

2.4(1.6-3.6) 3

Tipranavir/ritonavir combination500 mg/200 mg BID for 11 days

10 mg

1.4(1.2-1.6) 3

2.2(1.8-2.7) 3

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) 3 1.3(1.1-1.4) 3

1.4(1.2-1.5) 3 1.2(0.9-1.4)3

Ezetimibe 10 mg QD, 14 days

10 mg QD for14 days

1.2(0.9-1.6)3

1.2(0.8-1.6)3

Fosamprenavir/ritonavir700 mg/100 mg BID for 7 days

10 mg

1.1

1.5

Fenofibrate 67 mg TID for 7days

10 mg

1.2(1.1-1.3)3

Rifampicin 450 mg QD, 7 days

20 mg

Aluminum & magnesium hydroxide combination antacid Administered simultaneously Administered 2 hours apart

40 mg40 mg

0.52 (0.4-0.5)3 0.8(0.7-0.9)3

0.52 (0.4-0.6)3 0.8(0.7-1.0)3

Ketoconazole 200 mg BID for 7 days

80 mg

1.0(0.8-1.2)3

1.0(0.7-1.3)3

Fluconazole 200 mg QD for 11 days

80 mg

1.1(1.0-1.3)3

1.1(0.9-1.4)3

Erythromycin 500 mg QID for 7 days

80 mg

0.8(0.7-0.9)3

0.7(0.5-0.9)3

2

1 Single dose unless otherwise noted.
2 Clinically significant [see Dosage and Administration (2) and 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) 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

40 mg QD for 10 days

Warfarin 1 25 mg single dose

R-Warfarin 1.0 (1.0-1.1)2 S-Warfarin 1.1 (1.0-1.1)2

R-Warfarin 1.0 (0.9-1.0)2 S-Warfarin 1.0 (0.9-1.1)2

40 mg QD for 12 days

Digoxin 0.5 mg single dose

1.0 (0.9-1.2)2

1.0 (0.9-1.2)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)2 NG 1.3 (1.3-1.4)2

EE 1.3 (1.2-1.3)2 NG 1.2 (1.1-1.3)2

EE = ethinyl estradiol, NG = norgestrel
1 Clinically significant pharmacodynamic effects [see Warnings and Precautions (5.3)]
2 Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7=30% decrease, 11=11-fold increase in exposure)

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