Shandong Luoxin Pharmaceutical

ROSUVASTATIN CALCIUM

rosuvastatin calcium

Post-LOE

ORAL · TABLET

12.1 Mechanism of Action Rosuvastatin tablets are inhibitors 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 tablets 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 C max and AUC increased in approximate proportion to rosuvastatin tablets 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 tablets 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 (CL cr ≥30 mL/min/1.73 m ) 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 (CL cr <30 mL/min/1.73 m ) not receiving hemodialysis compared with healthy subjects (CL cr >80 mL/min/1.73 m ). 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, C max and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, C max 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 tablets 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

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