Pravastatin Sodium (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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/m2) 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.

14 CLINICAL STUDIES

Prevention of Coronary Heart Disease

In the Pravastatin Primary Prevention Study (WOS), the effect of pravastatin sodium on fatal and nonfatal CHD was assessed in 6595 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 sodium 40 mg daily (N=3302) or placebo (N=3293) and followed for a median duration of 4.8 years. Median (25th , 75th 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 sodium 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 sodium group [CHD death=31, nonfatal MI=143], p=0.0001 [see figure below]). The risk reduction with pravastatin sodium was similar across the age range studied and throughout the range of baseline LDL cholesterol levels.

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Pravastatin sodium 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 sodium, 40 mg daily, was assessed in 9014 patients (7498 men; 1516 women; 3514 patients ≥65 years; 782 patients with diabetes) who had experienced either an MI (5754 patients) or had been hospitalized for unstable angina pectoris (3260 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 2710 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 sodium significantly reduced the risk for total mortality by reducing coronary death (see Table 7). The risk reduction due to treatment with pravastatin sodium on CHD mortality was consistent regardless of age. Pravastatin sodium 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 Sodium 40 mg (N=4512) Placebo (N=4502) Risk Reduction p -value

Primary Endpoint

CHD mortality

287 (6.4)

373 (8.3)

24%

0.0004

Secondary Endpoints

Total mortality

498 (11)

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 sodium, 40 mg daily, on CHD death and nonfatal MI was assessed in 4159 patients (3583 men and 576 women) who had experienced a MI in the preceding 3 to 20 months and who had normal (below the 75th 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 aspirin and 82% were taking antihypertensive medications. Median (25th , 75th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −22 (−28.4, −14.9), −32.4 (−39.9, −23.7), −11 (−26.5, 8.6), and 5.1 (−2.9, 12.7), respectively. Treatment with pravastatin sodium significantly reduced the rate of first recurrent coronary events (either CHD death or nonfatal MI), the risk of undergoing revascularization procedures (PTCA, CABG), and the risk for stroke or TIA (see Table 8).

Table 8: CARE — Primary and Secondary Endpoints
Number (%) of Subjects
Event Pravastatin Sodium 40 mg (N=2081) Placebo (N=2078) Risk Reduction p -value
a The risk reduction due to treatment with pravastatin sodium was consistent in both sexes.

Primary Endpoint

CHD mortality or nonfatal MIa

212 (10.2)

274 (13.2)

24%

0.003

Secondary Endpoints

Myocardial revascularization procedures (CABG or PTCA)

294 (14.1)

391 (18.8)

27%

<0.001

Stroke or TIA

93 (4.5)

124 (6)

26%

0.029

Primary Hyperlipidemia

In multicenter, double-blind, placebo-controlled studies of patients with primary hyperlipidemia, treatment with pravastatin sodium in daily doses ranging from 10 to 40 mg consistently and significantly decreased Total-C, LDL-C, and TG (see Table 9).

In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with primary hyperlipidemia, treatment with pravastatin sodium at a daily dose of 80 mg (N=277) significantly decreased Total-C, LDL-C, and TG. The 25th and 75th percentile changes from baseline in LDL-C for pravastatin sodium 80 mg were −43% and −30%. The efficacy results of the individual studies were consistent with the pooled data (see Table 9).

Table 9: Primary Hyperlipidemia Trials: Dose Response of Pravastatin Sodium Once Daily Administration
a A multicenter, double-blind, placebo-controlled study.b Pooled analysis of 2 multicenter, double-blind, placebo-controlled studies.

Dose

Total-C

LDL-C

HDL-C

TG

Mean Percent Changes From Baseline After 8 Weeksa

Placebo (N=36)

−3%

−4%

+1%

−4%

10 mg (N=18)

−16%

−22%

+7%

−15%

20 mg (N=19)

−24%

−32%

+2%

−11%

40 mg (N=18)

−25%

−34%

+12%

−24%

Mean Percent Changes From Baseline After 6 Weeksb

Placebo (N=162)

0%

−1%

−1%

+1%

80 mg (N=277)

−27%

−37%

+3%

−19%

Hypertriglyceridemia

The response to pravastatin sodium in patients with hypertriglyceridemia (baseline TG >200 mg/dL and LDL-C <160 mg/dL) was evaluated in a subset of 429 patients from the CARE study. For pravastatin-treated subjects, the median (min, max) baseline TG level was 246 (200.5, 349.5) mg/dL (see Table 10).

Table 10: Patients with Hypertriglyceridemia Median (25th , 75th percentile) % Change from Baseline

Pravastatin 40 mg (N=429)

Placebo (N=430)

TG

−21.1 (−34.8, 1.3)

−6.3 (−23.1, 18.3)

Total-C

−22.1 (−27.1, −14.8)

0.2 (−6.9, 6.8)

LDL-C

−31.7 (−39.6, −21.5)

0.7 (−9, 10)

HDL-C

7.4 (−1.2, 17.7)

2.8 (−5.7, 11.7)

Non-HDL-C

−27.2 (−34, −18.5)

−0.8 (−8.2, 7)

Dysbetalipoproteinemia

The response to pravastatin sodium in two double-blind crossover studies of 46 patients with genotype E2/E2 and dysbetalipoproteinemia is shown in Table 11.

Table 11: Patients with Dysbetalipoproteinemia Median (min, max) % Change from Baseline

Median (min, max)at Baseline (mg/dL)

Median % Change (min, max)Pravastatin 40 mg (N=20)

Study 1

Total-C

386.5 (245, 672)

−32.7 (−58.5, 4.6)

TG

443 (275, 1299)

−23.7 (−68.5, 44.7)

VLDL-Ca

206.5 (110, 379)

−43.8 (−73.1, −14.3)

LDL-Ca

117.5 (80, 170)

−40.8 (−63.7, 4.6)

HDL-C

30 (18, 88)

6.4 (−45, 105.6)

Non-HDL-C

344.5 (215, 646)

−36.7 (−66.3, 5.8)

a N=14

Median (min, max)at Baseline (mg/dL)

Median % Change (min, max)Pravastatin 40 mg (N=26)

Study 2

Total-C

340.3 (230.1, 448.6)

−31.4 (−54.5, −13)

TG

343.2 (212.6, 845.9)

−11.9 (−56.5, 44.8)

VLDL-C

145 (71.5, 309.4)

−35.7 (−74.7, 19.1)

LDL-C

128.6 (63.8, 177.9)

−30.3 (−52.2, 13.5)

HDL-C

38.7 (27.1, 58)

5 (−17.7, 66.7)

Non-HDL-C

295.8 (195.3, 421.5)

−35.5 (−81, −13.5)

HeFH in Pediatric Patients Aged 8 Years and Above

A double-blind, placebo-controlled study in 214 pediatric patients (100 males and 114 females) with heterozygous familial hypercholesterolemia (HeFH), aged 8 to 18 years was conducted for 2 years. The pediatric patients aged 8 to 13 years were randomized to placebo (N=63) or 20 mg of pravastatin sodium daily (N=65) and the pediatric patients aged 14 to 18 years were randomized to placebo (N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C level >95th percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercholesterolemia. The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL in the pravastatin (range: 151 to 405 mg/dL) and placebo (range: 154 to 375 mg/dL) groups, respectively.

Pravastatin sodium significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both pediatric age groups (see Table 12). The effect of pravastatin sodium treatment in the 2 age groups was similar.

Table 12: Lipid-Lowering Effects of Pravastatin Sodium in Pediatric Patients with Heterozygous Familial Hypercholesterolemia: Least-Squares Mean % Change from Baseline at Month 24 (Last Observation Carried Forward: Intent-to-Treat)a
Pravastatin 20 mg (Aged 8 to 13 years) N=65 Pravastatin 40 mg (Aged 14 to 18 years) N=41 Combined Pravastatin (Aged 8 to 18 years) N=106 Combined Placebo (Aged 8 to 18 years) N=108 95% CI of the Difference Between Combined Pravastatin and Placebo
a The above least-squares mean values were calculated based on log-transformed lipid values.b Significant at p≤0.0001 when compared with placebo.

LDL-C

−26.04b

−21.07b

−24.07b

−1.52

(−26.74, −18.86)

TC

−20.75b

−13.08b

−17.72b

−0.65

(−20.40, −13.83)

HDL-C

1.04

13.71

5.97

3.13

(−1.71, 7.43)

TG

−9.58

−0.30

−5.88

−3.27

(−13.95, 10.01)

ApoB(N)

−23.16b (61)

−18.08b (39)

−21.11b (100)

−0.97(106)

(−24.29, −16.18)

The mean achieved LDL-C was 186 mg/dL (range: 67 to 363 mg/dL) in the pravastatin sodium group k to 236 mg/dL (range: 105 to 438 mg/dL) in the placebo group.

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