Rosuvastatin Calcium 5 mg Tablet, Film Coated, 500-count — NDC 27808-155-03 (Billing 27808-0155-03)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics 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.

12.3Pharmacokinetics A bsorption 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 dose. The absolute bioavailability of rosuvastatin is approximately 20%.

The AUC of rosuvastatin does not differ following evening or morning drug administration. E ffect of food Administration of rosuvastatin with food did not affect the AUC of rosuvastatin. D istribution 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. E limination Me tabolism 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. Exc retion 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 Ge riatric Patients There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).

Pe diatric Patients In a population pharmacokinetic analysis of two pediatric trials involving patients with HeFH 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. M ale and Female Patients There were no differences in plasma concentrations of rosuvastatin between males and females. R acial or Ethnic Groups A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among White, Hispanic or Latino ethnicity, 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 C max ) in Asian subjects when compared with a White control group. P atients with Renal Impairment Mild to moderate renal impairment (CL cr ≥30 mL/min/1.73 m 2 ) 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 2 ) not receiving hemodialysis compared with healthy subjects (CL cr >80 mL/min/1.73 m 2 ).

Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function. P atients with Hepatic Impairment In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased. In… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.5Pharmacogenomics Disposition of rosuvastatin, involves OATP1B1 and other transporter proteins. Higher plasma concentrations of rosuvastatin have been reported in very small groups of patients (n=3 to 5) who have two reduced function alleles of the gene that encodes OATP1B1 ( SLCO1B1 521T > C). The frequency of this genotype (i.e., SLCO1B1 521 C/C) is generally lower than 5% in most racial/ethnic groups.

The impact of this polymorphism on efficacy and/or safety of rosuvastatin has not been clearly established.

12.3Pharmacokinetics A bsorption 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 dose. The absolute bioavailability of rosuvastatin is approximately 20%.

The AUC of rosuvastatin does not differ following evening or morning drug administration. E ffect of food Administration of rosuvastatin with food did not affect the AUC of rosuvastatin. D istribution 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. E limination Me tabolism 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. Exc retion 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 Ge riatric Patients There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).

Pe diatric Patients In a population pharmacokinetic analysis of two pediatric trials involving patients with HeFH 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. M ale and Female Patients There were no differences in plasma concentrations of rosuvastatin between males and females. R acial or Ethnic Groups A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among White, Hispanic or Latino ethnicity, 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 C max ) in Asian subjects when compared with a White control group. P atients with Renal Impairment Mild to moderate renal impairment (CL cr ≥30 mL/min/1.73 m 2 ) 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 2 ) not receiving hemodialysis compared with healthy subjects (CL cr >80 mL/min/1.73 m 2 ).

Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function. P atients 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. Dr ug Interaction 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 administr… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES P rimary Prevention of CV Disease In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of rosuvastatin on the occurrence of major (CV) disease events was assessed in 17,802 males (≥50 years) and females (≥60 years) who had no clinically evident CV disease, LDL-C levels <130 mg/dL and hsCRP levels ≥2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.6% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL-C levels (23%), cigarette smoking (16%), or a family history of premature CHD (12%).

Patients had a median baseline LDL-C of 108 mg/dL and hsCRP of 4.3 mg/L. Patients were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean duration of 2 years. The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in rosuvastatin-treated subjects.

The primary end point was a composite end point consisting of the time-to-first occurrence of any of the following major CV events: CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina or an arterial revascularization procedure. Rosuvastatin significantly reduced the risk of major CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p<0.001) relative risk reduction of 44% and absolute risk reduction of 1.2% (see Figure 1).

The risk reduction for the primary end point was consistent across the following predefined subgroups: age, sex, race, smoking status, family history of premature CHD, body mass index, LDL-C, HDL-C, and hsCRP levels. F igure 1. Time to First Occurrence of Major CV Events in JUPITER The individual components of the primary end point are presented in Figure 3.

Rosuvastatin significantly reduced the risk of nonfatal myocardial infarction, nonfatal stroke, and arterial revascularization procedures. There were no significant treatment differences between the rosuvastatin and placebo groups for death due to CV causes or hospitalizations for unstable angina. Rosuvastatin significantly reduced the risk of myocardial infarction (6 fatal events and 62 nonfatal events in placebo-treated subjects vs.

9 fatal events and 22 nonfatal events in rosuvastatin-treated subjects) and the risk of stroke (6 fatal events and 58 nonfatal events in placebo-treated subjects vs. 3 fatal events and 30 nonfatal events in rosuvastatin-treated subjects). In a post-hoc subgroup analysis of JUPITER subjects (rosuvastatin=725, placebo=680) with a hsCRP ≥2 mg/L and no other traditional risk factors (smoking, BP ≥140/90 or taking antihypertensives, low HDL-C) other than age, after adjustment for high HDL-C, there was no significant treatment benefit with rosuvastatin treatment.

F igure 2. Major CV Events by Treatment Group in JUPITER At one year, rosuvastatin increased HDL-C and reduced LDL-C, hsCRP, total cholesterol and serum triglyceride levels (p<0.001 for all versus placebo). Primary Hyperlipidemia in Adults Rosuvastatin reduces Total-C, LDL-C, ApoB, non-HDL-C, and TG, and increases HDL-C, in adult patients with hyperlipidemia and mixed dyslipidemia.

In a multicenter, double-blind, placebo-controlled study in patients with hyperlipidemia, rosuvastatin given as a single daily dose (5 to 40 mg) for 6 weeks significantly reduced Total-C, LDL-C, non-HDL-C, and ApoB, across the dose range (Table 10). Table 10: Lipid-Modifying Effect of Rosuvastatin in Adult Patients with Hyperlipidemia (Adjusted Mean % Change from Baseline at Week 6) D o se N T otal-C L D L -C N on -HDL-C A p oB TG H D L -C Placebo 13 -5 -7 -7 -3 -3 3 Rosuvastatin 5 mg 17 -33 -45 -44 -38 -35 13 Rosuvastatin 10 mg 17 -36 -52 -48 -42 -10 14 Rosuvastatin 20 mg 17 -40 -55 -51… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses. In a 107-week carcinogenicity study in mice given 10, 60, or 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC.

An increased incidence of hepatocellular tumors was not seen at lower doses. Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli , the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.

In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen.

Spermatidic giant cells were observed in monkeys after 6-month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class.