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:
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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