Prescription Drug Information: Rosuvastatin Calcium (Page 5 of 8)

11 DESCRIPTION

Rosuvastatin calcium, USP is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)-reductase inhibitor.

The chemical name for rosuvastatin calcium, USP 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:

structure
(click image for full-size original)

The empirical formula for rosuvastatin calcium, USP is (C22 H27 FN3 O6 S)2 Ca and the molecular weight is 1001.14. Rosuvastatin calcium, USP is a white to off-white powder that is very slightly soluble in water, insoluble in methanol and ethanol. Rosuvastatin calcium, USP is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.0.

Rosuvastatin Tablets, USP for oral use contain 5 mg, 10 mg, 20 mg, or 40 mg (equivalent to 5.2 mg, 10.4 mg, 20.8 mg, and 41.6 mg rosuvastatin calcium) and the following inactive ingredients: crospovidone, ferric oxide red, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium bicarbonate, titanium dioxide and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rosuvastatin is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol.

12.2 Pharmacodynamics

Inhibition of HMG-CoA reductase by rosuvastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of rosuvastatin is usually achieved by 4 weeks and is maintained after that.

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%. The AUC of rosuvastatin does not differ following evening or morning drug administration.

Effect of food

Administration of rosuvastatin with food did not affect the AUC of rosuvastatin.

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

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. The elimination half-life of rosuvastatin is approximately 19 hours.

Specific Populations

Geriatric Patients

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

Pediatric Patients

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.

Male and Female Patients

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

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.

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).

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 (2.6) and Drug Interactions (7.1)].

Table 8: Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure

Coadministered drug and dosing regimen Rosuvastatin
Mean Ratio (ratio with/without coadministered drug)
No Effect=1
Dose (mg)1 Change in AUC Change in Cmax

Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + Voxilaprevir (100 mg) once daily for 15 days

10 mg, single dose

7.392

(6.68 to 8.18)3

18.882

(16.23 to 21.96)3

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

10 mg, QD for

10 days

7.12

112

Darolutamide 600 mg BID, 5 days

5 mg, single dose

5.22

~52

Regorafenib 160 mg QD, 14 days

5 mg, single dose

3.82

4.62

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

10 mg

3.12

72

Simeprevir 150 mg QD, 7 days

10 mg, single

dose

2.82

(2.3 to 3.4)3

3.22

(2.6 to 3.9)3

Velpatasvir 100 mg once daily

10 mg, single dose

2.692

(2.46 to 2.94)3

2.612

(2.32 to 2.92)3

Ombitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100mg + dasabuvir 400mg BID

5 mg, single dose

2.592

(2.09 to 3.21)3

7.132

(5.11 to 9.96)3

Teriflunomide

Not available

2.512

2.652

Enasidenib 100 mg QD, 28 days

10 mg, single

dose

2.44

3.66

Elbasvir 50 mg/grazoprevir 200 mg once daily

10 mg single dose

2.262

(1.89 to 2.69)3

5.492

(4.29 to 7.04)3

Glecaprevir 400 mg/pibrentasvir 120 mg once daily

5 mg, once daily

2.152

(1.88 to 2.46)3

5.622

(4.80 to 6.59)3

Lopinavir/ritonavir combination

400 mg/100 mg BID for 17 days

20 mg, QD

for 7 days

2.12

(1.7 to 2.6)3

52

(3.4 to 6.4) 3

Capmatinib 400 mg BID

10 mg, single dose

2.082

(1.56 to 2.76)3

3.042

(2.36 to 3.92)3

Fostamatinib 100 mg BID

20 mg, single dose

1.962

(1.77-2.15)3

1.882

(1.69-2.09) 3

Febuxostat 120 mg QD for 4 days

10 mg, single dose

1.92

(1.5-2.5) 3

2.12

(1.8-2.6) 3

Gemfibrozil 600 mg BID for 7 days

80 mg

1.92

(1.6 to 2.2)3

2.22

(1.8 to 2.7)3

Tafamidis 61 mg BID on Days 1 & 2, followed by QD on Days 3 to 9

10 mg

1.972

(1.68-2.31)3

1.862

(1.59-2.16)3

Eltrombopag 75 mg QD, 5 days

10 mg

1.6

(1.4 to 1.7) 3

2

(1.8 to 2.3) 3

Darunavir 600 mg/ritonavir

100 mg BID, 7 days

10 mg, QD

for 7 days

1.5

(1 to 2.1)3

2.4

(1.6 to 3.6)3

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

10 mg

1.4

(1.2 to 1.6)3

2.2

(1.8 to 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 to 1.6)3

1.3

(1.1 to 1.4)3

1.4

(1.2 to 1.5)3

1.2

(0.9 to 1.4)3

Ezetimibe 10 mg QD, 14 days

10 mg, QD for 14 days

1.2

(0.9 to 1.6) 3

1.2

(0.8 to 1.6) 3

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 to 1.3)3

Rifampicin 450 mg QD, 7 days

20 mg

Aluminum & magnesium hydroxide combination antacid

Administered simultaneously Administered 2 hours apart

40 mg

40 mg

0.52

(0.4 to 0.5)3

0.8

(0.7 to 0.9)3

0.52

(0.4 to 0.6)3

0.8

(0.7 to 1)3

Ketoconazole 200 mg BID for 7 days

80 mg

1

(0.8 to 1.2)3

1

(0.7 to 1.3)3

Fluconazole 200 mg QD for 11 days

80 mg

1.1

(1 to 1.3)3

1.1

(0.9 to 1.4)3

Erythromycin 500 mg QID for 7 days

80 mg

0.8

(0.7 to 0.9)3

0.7

(0.5 to 0.9)3

QD= Once daily, BID= Twice daily, TID= Three times daily, QID= Four times daily
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 9: 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
Name and Dose Change in AUC Change in Cmax

40 mg QD for 10 days

Warfarin 1

25 mg single dose

R-Warfarin

1

(1 to 1.1)2

S-Warfarin

1.1

(1 to 1.1)2

R-Warfarin

1

(0.9 to 1)2

S-Warfarin

1

(0.9 to 1.1)2

40 mg QD for 12 days

Digoxin

0.5 mg single dose

1

(0.9 to 1.2)2

1

(0.9 to 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 to 1.3)2

NG 1.3

(1.3 to 1.4)2

EE 1.3

(1.2 to 1.3)2

NG 1.2

(1.1 to 1.3)2

EE = ethinyl estradiol, NG = norgestrel, QD= Once daily

1 Clinically significant pharmacodynamic effects [see Drug Interactions (7.3)]

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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