Pravastatin Sodium 20 mg Tablet, 500-count — NDC 60505-0169-5 (Billing 60505-0169-05)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Pravastatin is a reversible inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

12.2Pharmacodynamics Inhibition of HMG-CoA reductase by pravastatin 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 pravastatin is usually achieved by 4 weeks and is maintained after that.

12.3Pharmacokinetics Absorption Pravastatin is administered orally in the active form. Peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%.

While the presence of food in the gastrointestinal tract reduces area under the concentration-time curve (AUC) and C max by 31% and 49%, respectively, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals. Pravastatin plasma concentrations, including AUC, C max , and steady-state minimum (C min ), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose.

Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose. The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin C max and AUC following a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively.

Steady-state AUCs, C max , and C min plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin tablets. Distribution Approximately 50% of the circulating drug is bound to plasma proteins. Elimination Metabolism The major biotransformation pathways for pravastatin are: (a) isomerization to 6-­epi pravastatin and the 3α-hydroxy isomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945.

The 3α-hydroxy isomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66). Excretion Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces.

After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation). Following single dose oral administration of 14 C-pravastatin, the radioactive elimination t ½ for pravastatin is 1.8 hours in humans and the elimination half-life (t ½ ) for total radioactivity (pravastatin plus metabolites) is 77 hours. Specific Populations Renal Impairment A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance).

No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and C max values, respectively, and a 0.61 hour shorter t ½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945) [see Use in Specific Populations ( 8.6 )] . Hepatic Impairment In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold i… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Pravastatin is a reversible inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

12.3Pharmacokinetics Absorption Pravastatin is administered orally in the active form. Peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%.

While the presence of food in the gastrointestinal tract reduces area under the concentration-time curve (AUC) and C max by 31% and 49%, respectively, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals. Pravastatin plasma concentrations, including AUC, C max , and steady-state minimum (C min ), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose.

Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose. The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin C max and AUC following a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively.

Steady-state AUCs, C max , and C min plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin tablets. Distribution Approximately 50% of the circulating drug is bound to plasma proteins. Elimination Metabolism The major biotransformation pathways for pravastatin are: (a) isomerization to 6-­epi pravastatin and the 3α-hydroxy isomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945.

The 3α-hydroxy isomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66). Excretion Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces.

After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation). Following single dose oral administration of 14 C-pravastatin, the radioactive elimination t ½ for pravastatin is 1.8 hours in humans and the elimination half-life (t ½ ) for total radioactivity (pravastatin plus metabolites) is 77 hours. Specific Populations Renal Impairment A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance).

No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and C max values, respectively, and a 0.61 hour shorter t ½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945) [see Use in Specific Populations ( 8.6 )] . Hepatic Impairment In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects.

Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects [see Use in Specific Populations ( 8.6 )]. Geriatric In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 t… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES Prevention of Coronary Heart Disease In the Pravastatin Primary Prevention Study (WOS), the effect of pravastatin on fatal and nonfatal CHD was assessed in 6,595 male patients 45 to 64 years of age, without a previous MI, and with LDL-C levels between 156 to 254 mg/dL. In this randomized, double-blind, placebo-controlled study, patients were treated with standard care, including dietary advice, and either pravastatin 40 mg daily (N=3,302) or placebo (N=3,293) and followed for a median duration of 4.8 years.

Median (25 th , 75 th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7), −27.7 (−36, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively. Pravastatin significantly reduced the rate of first coronary events (either CHD death or nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus 174 events in the pravastatin group [CHD death=31, nonfatal MI=143], p=0.0001 [see figure below]). The risk reduction with pravastatin was similar across the age range studied and throughout the range of baseline LDL cholesterol levels.

Pravastatin also decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients). Cardiovascular deaths were decreased by 32% (73 vs 50) and there was no increase in death from non-cardiovascular causes. Secondary Prevention of Cardiovascular Events In the LIPID study, the effect of pravastatin, 40 mg daily, was assessed in 9,014 patients (7,498 men; 1,516 women; 3,514 patients ≥65 years; 782 patients with diabetes) who had experienced either an MI (5,754 patients) or had been hospitalized for unstable angina pectoris (3,260 patients) in the preceding 3 to 36 months.

Patients in this multicenter, double-blind, placebo-controlled study participated for an average of 5.6 years (median of 5.9 years) and at randomization had Total-C between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between 46 and 274 mg/dL (mean 150 mg/dL), TG between 35 and 2,710 mg/dL (mean 160 mg/dL), and HDL-C between 1 and 103 mg/dL (mean 37 mg/dL). At baseline, 82% of patients were receiving aspirin and 76% were receiving antihypertensive medication. Treatment with pravastatin significantly reduced the risk for total mortality by reducing coronary death (see Table 7 ).

The risk reduction due to treatment with pravastatin on CHD mortality was consistent regardless of age. Pravastatin significantly reduced the risk for total mortality (by reducing CHD death) and CHD events (CHD mortality or nonfatal MI) in patients who qualified with a history of either MI or hospitalization for unstable angina pectoris. Table 7: LIPID - Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin 40 mg (N=4,512) Placebo (N=4,502) Risk Reduction p -value Primary Endpoint CHD mortality 287 (6.4) 373 (8.3) 24% 0.0004 Secondary Endpoints Total mortality 498 (11.0) 633 (14.1) 23% <0.0001 CHD mortality or nonfatal MI 557 (12.3) 715 (15.9) 24% <0.0001 Myocardial revascularization procedures (CABG or PTCA) 584 (12.9) 706 (15.7) 20% <0.0001 Stroke All-cause 169 (3.7) 204 (4.5) 19% 0.0477 Non-hemorrhagic 154 (3.4) 196 (4.4) 23% 0.0154 Cardiovascular mortality 331 (7.3) 433 (9.6) 25% <0.0001 In the CARE study, the effect of pravastatin, 40 mg daily, on CHD death and nonfatal MI was assessed in 4,159 patients (3,583 men and 576 women) who had experienced a MI in the preceding 3 to 20 months and who had normal (below the 75 th percentile of the general population) plasma total cholesterol levels.

Patients in this double-blind, placebo-controlled study participated for an average of 4.9 years and had a mean baseline Total-C of 209 mg/dL. LDL-C levels in this patient population ranged from 101 to 180 mg/dL (mean 139 mg/dL). At baseline, 84% of patients were receiving aspiri… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m 2 ) and at approximately 4 times the HD, based on AUC. In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001).

At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors.

No evidence of mutagenicity was observed in vitro , with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli ; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae . In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice. In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance.

No adverse effects were seen in juvenile rats dosed with 5 mg/kg/day pravastatin (5 times plasma exposure at the maximum recommended human dose [MRHD] of 80 mg based on AUC) in a study of pravastatin administered from postnatal days (PND) 4 through 80 at 5, 15 and 45 mg/kg/day. A PND 4 rat is generally comparable to a 3rd trimester human fetus with regards to neurologic development/myelination. At ≥ 15 mg/kg/day (≥ 20 times the MRHD), decreased body-weight gain was observed during the pre-weaning period and slight thinning of the corpus callosum was observed at the end of the drug-free recovery period (PND 132).

Thinning of the corpus callosum was not associated with any inflammatory or degenerative changes in the brain. Impacts on neurobehavioral and learning endpoints were detected only at very high exposures (43 times the MRHD). No thinning of the corpus callosum was observed in rats dosed with pravastatin for 3 months beginning on PND 35 at ≥ 250 mg/kg/day.

PND 35 in a rat is approximately equivalent to an 8 to 12-year-old human child.