Pravachol - Clinical Pharmacology

(Page 5)

Median (25 th , 75 th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total C, LDL-C, TG, and HDL were -20.3 (-26.9, -11.7), -27.7 (-36.0, -16.9), -9.1 (-27.6, 12.5), and 6.7 (-2.1, 15.6), respectively. PRAVACHOL significantly reduced the rate of first coronary events (either coronary heart disease [CHD] death or nonfatal MI) by 31% [248 events in the placebo group (CHD death= 44, nonfatal MI= 204) vs 174 events in the PRAVACHOL group (CHD death= 31, nonfatal MI= 143), p= 0.0001 (see figure below)].

The risk reduction with PRAVACHOL was similar and significant throughout the entire range of baseline LDL cholesterol levels. This reduction was also similar and significant across the age range studied with a 40% risk reduction for patients younger than 55 years and a 27% risk reduction for patients 55 years and older. The Pravastatin Primary Prevention Study included only men and therefore it is not clear to what extent these data can be extrapolated to a similar population of female patients.

PRAVACHOL also significantly decreased the risk for undergoing myocardial revasculariza-tion procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients, p= 0.009) and coronary angiography by 31% (128 vs 90, p= 0.007). Cardiovascular deaths were decreased by 32% (73 vs 50, p= 0.03) and there was no increase in death from non-cardiovascular causes.

Secondary Prevention of Cardiovascular Events

In the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) 2 study, the effect of PRAVACHOL (pravastatin sodium), 40 mg daily, was assessed in 9014 patients (7498 men; 1516 women; 3514 elderly patients [age 65 years]; 782 diabetic patients) who had experi-enced either an MI (5754 patients) or had been hospitalized for unstable angina pectoris (3260 patients) in the preceding 3-36 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 cholesterol between 114 and 563 mg/ dL (mean 219 mg/ dL), LDL-C between 46 and 274 mg/ dL (mean 150 mg/ dL), triglycerides 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 PRAVACHOL significantly reduced the risk for total mortality by reducing coro-nary death (see Table 1). The risk reduction due to treatment with PRAVACHOL on CHD mor-tality was consistent regardless of age. PRAVACHOL 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 1: LIPID Ð Primary and Secondary Endpoints

Number (%) of Subjects Pravastatin 40 mg Placebo Risk

Event (N= 4512) (N= 4502) 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 non-fatal 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 Cholesterol and Recurrent Events (CARE) 3 study the effect of PRAVACHOL, 40 mg daily, on coronary heart disease death and nonfatal MI was assessed in 4159 patients (3583 men and 576 women) who had experienced a myocardial infarction in the preceding 3-20 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 cholesterol of 209 mg/ dL. LDL choles-terol levels in this patient population ranged from 101 mg/ dL-180 mg/ dL (mean= 139 mg/ dL). At baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive medications. Median (25 th , 75 th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total C, LDL-C, TG, and HDL were -22.0 (-28.4, -14.9), -32.4 (-39.9, -23.7), -11.0 (-26.5, 8.6), and 5.1 (-2.9, 12.7), respectively. Treatment with PRAVACHOL 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 transient ischemic attack (TIA) (see Table 2).

Table 2: CARE Ð Primary and Secondary Endpoints

Number (%) of Subjects Pravastatin 40 mg Placebo Risk

Event (N= 2081) (N= 2078) Reduction P-value

Primary Endpoint CHD mortality or non-fatal MI* 212 (10.2) 274 (13.2) 24% 0.003

Secondary Endpoints Myocardial revascularization 294 (14.1) 391 (18.8) 27% < 0.001

procedures (CABG or PTCA) Stroke or TIA 93 (4.5) 124 (6.0) 26% 0.029

* The risk reduction due to treatment with PRAVACHOL was consistent in both sexes.

In the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I) 4 study, the effect of pravastatin therapy on coronary atherosclerosis was assessed by coronary angiogra-phy in patients with coronary disease and moderate hypercholesterolemia (baseline LDL-C range= 130-190 mg/ dL). In this double-blind, multicenter, controlled clinical trial angiograms were evaluated at baseline and at three years in 264 patients. Although the difference between pravastatin and placebo for the primary endpoint (per-patient change in mean coronary artery diameter) and one of two secondary endpoints (change in percent lumen diameter stenosis) did not reach statistical significance, for the secondary endpoint of change in mini-mum lumen diameter, statistically significant slowing of disease was seen in the pravastatin treatment group (p= 0.02).

In the Regression Growth Evaluation Statin Study (REGRESS) 5 , the effect of pravastatin on coronary atherosclerosis was assessed by coronary angiography in 885 patients with angina pectoris, angiographically documented coronary artery disease and hypercholesterolemia (baseline total cholesterol range= 160-310 mg/ dL). In this double-blind, multicenter, con-trolled clinical trial, angiograms were evaluated at baseline and at two years in 653 patients (323 treated with pravastatin).

Progression of coronary atherosclerosis was significantly slowed in the pravastatin group as assessed by changes in mean segment diameter (p= 0.037) and minimum obstruction diameter (p= 0.001). Analysis of pooled events from PLAC I, the Pravastatin, Lipids and Atherosclerosis in the Carotids Study (PLAC II) 6 , REGRESS, and the Kuopio Atherosclerosis Prevention Study (KAPS) 7 (combined N= 1891) showed that treatment with pravastatin was associated with a statistically significant reduction in the composite event rate of fatal and nonfatal myocardial infarction (46 events or 6.4% for placebo versus 21 events or 2.4% for pravastatin, p= 0.001). The pre-dominant effect of pravastatin was to reduce the rate of nonfatal myocardial infarction.

Primary Hypercholesterolemia (Fredrickson Type IIa and IIb) PRAVACHOL (pravastatin sodium) is highly effective in reducing Total-C, LDL-C and

Triglycerides (TG) in patients with heterozygous familial, presumed familial combined and non-familial (non-FH) forms of primary hypercholesterolemia, and mixed dyslipidemia. A therapeutic response is seen within 1 week, and the maximum response usually is achieved within 4 weeks. This response is maintained during extended periods of therapy.

In addition, PRAVACHOL is effective in reducing the risk of acute coronary events in hypercholesterolemic patients with and without previous myocardial infarction. A single daily dose is as effective as the same total daily dose given twice a day. In multi-center, double-blind, placebo-controlled studies of patients with primary hypercholes-terolemia, treatment with pravastatin in daily doses ranging from 10 mg to 40 mg consistently and significantly decreased Total-C, LDL-C, TG, and Total-C/ HDL-C and LDL-C/ HDL-C ratios (see Table 3).

In a pooled analysis of two multicenter, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin at a daily dose of 80 mg (N= 277) significantly decreased Total-C, LDL-C, and TG. The 25 th and 75 th percentile changes from baseline in LDL-C for pravastatin 80 mg were -43% and -30%. The efficacy results of the individual studies were consistent with the pooled data (see Table 3). Treatment with PRAVACHOL modestly decreased VLDL-C and PRAVACHOL across all doses produced variable increases in HDL-C (see Table 3).

Table 3: Primary Hypercholesterolemia Studies: Dose Response of PRAVACHOL

Once Daily Administration

Dose Total-C LDL-C HDL-C TG

Mean Percent Changes From Baseline After 8 Weeks*

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 Weeks**

Placebo (N= 162) 0% -1% -1% +1%

80 mg (N= 277) -27% -37% +3% -19%

*a multicenter, double-blind, placebo-controlled study ** pooled analysis of 2 multicenter, double-blind, placebo-controlled studies

In another clinical trial, patients treated with pravastatin in combination with cholestyra-mine (70% of patients were taking cholestyramine 20 or 24 g per day) had reductions equal to or greater than 50% in LDL-C. Furthermore, pravastatin attenuated cholestyramine-induced increases in TG levels (which are themselves of uncertain clinical significance).

Hypertriglyceridemia (Fredrickson Type IV) The response to pravastatin in patients with Type IV hyperlipidemia (baseline TG > 200 mg/ dL and LDL-C < 160 mg/ dL) was evaluated in a subset of 429 patients from the Cholesterol and Recurrent Events (CARE) study. For pravastatin-treated subjects, the median (min, max) base-line triglyceride level was 246.0 (200.5, 349.5) mg/ dL (see Table 4).

Table 4: Patients With Fredrickson Type IV Hyperlipidemia Median (25 th , 75 th percentile) Percent Change From Baseline

Pravastatin 40 mg (N= 429) Placebo (N= 430)

Triglycerides -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 (-9.0, 10.0) HDL-C 7.4 (-1.2, 17.7) 2.8 (-5.7, 11.7)

Non-HDL-C -27.2 (-34.0, -18.5) -0.8 (-8.2, 7.0)

Dysbetalipoproteinemia (Fredrickson Type III) The response to pravastatin in two double-blind crossover studies of 46 patients with geno-type

E2/ E2 and Fredrickson Type III dysbetalipoproteinemia is shown in Table 5.

Table 5: Patients With Fredrickson Type III Dysbetalipoproteinemia Median (min, max) Percent Change From Baseline

Median (min, max) at Median % Change (min, max) Baseline (mg/ dL) Pravastatin 40 mg (N= 20)

Study 1 Total-C 386.5 (245.0, 672.0) -32.7 (-58.5, 4.6)

Triglycerides 443.0 (275.0, 1299.0) -23.7 (-68.5, 44.7) VLDL-C* 206.5 (110.0, 379.0) -43.8 (-73.1, -14.3)

LDL-C* 117.5 (80.0, 170.0) -40.8 (-63.7, 4.6) HDL-C 30.0 (18.0, 88.0) 6.4 (-45.0, 105.6)

Non-HDL-C 344.5 (215.0, 646.0) -36.7 (-66.3, 5.8) *N= 14

Median (min, max) at Median % Change (min, max) Baseline (mg/ dL) Pravastatin 40 mg (N= 26)

Study 2 Total-C 340.3 (230.1, 448.6) -31.4 (-54.5, -13.0)

Triglycerides 343.2 (212.6, 845.9) -11.9 (-56.5, 44.8) VLDL-C 145.0 (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, 58.0) 5.0 (-17.7, 66.7)

Non-HDL-C 295.8 (195.3, 421.5) -35.5 (-81.0, -13.5)

Pediatric Clinical Study

A double-blind placebo-controlled study in 214 patients (100 boys and 114 girls) with heterozy-gous familial hypercholesterolemia (HeFH), aged 8-18 years was conducted for two (2) years. The children (aged 8-13 years) were randomized to placebo (n= 63) or 20 mg of pravastatin daily (n= 65) and the adolescents (aged 14-18 years) were randomized to placebo (n= 45) or 40 mg of pravastatin daily (n= 41). Inclusion in the study required LDL-C level >95 th percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercho-lesterolemia. The mean baseline LDL-C value was 239 mg/ dL and 237 mg/ dL in the pravastatin (range: 151-405 mg/ dL) and placebo (range: 154-375 mg/ dL) groups, respectively. Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and apolipoprotein B in both children and adolescents (see Table 6). The effect of pravastatin treatment in the two age groups was similar.

Table 6: Lipid-Lowering Effects of Pravastatin in Pediatric Patients with Heterozygous Familial Hypercholesterolemia:

Least-Squares Mean Percent Change from Baseline at Month 24 (Last Observation Carried Forward: Intent-to-Treat)*

95% CI of the Pravastatin Pravastatin Combined Combined Difference

20 mg 40 mg Pravastatin Placebo Between (Aged 8-13 (Aged 14-18 (Aged 8-18 (Aged 8-18 Combined years) years) years) years) Pravastatin N= 65 N= 41 N= 106 N= 108 and Placebo

LDL-C -26.04** -21.07** -24.07** -1.52 (-26.74, -18.86)

TC -20.75** -13.08** -17.72** -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 -23.16** -18.08** -21.11** -0.97 (-24.29, -16.18) (N) (61) (39) (100) (106)

*The above least-squares mean values were calculated based on log-transformed lipid values.

** Significant at p 0.0001 when compared with placebo.

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

The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in children. The long-term efficacy of pravastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

INDICATIONS AND USAGE

Therapy with PRAVACHOL (pravastatin sodium) should be considered in those individuals at increased risk for atherosclerosis-related clinical events as a function of cholesterol level, the presence or absence of coronary heart disease, and other risk factors.

Primary Prevention of Coronary Events

In hypercholesterolemic patients without clinically evident coronary heart disease, PRAVACHOL is indicated to: Ð Reduce the risk of myocardial infarction Ð Reduce the risk of undergoing myocardial revascularization procedures Ð Reduce the risk of cardiovascular mortality with no increase in death from non-cardio-vascular causes. Secondary Prevention of Cardiovascular Events In patients with clinically evident coronary heart disease, PRAVACHOL is indicated to:

Reduce the risk of total mortality by reducing coronary death Ð Reduce the risk of myocardial infarction

Reduce the risk of undergoing myocardial revascularization procedures

Reduce the risk of stroke and stroke/ transient ischemic attack (TIA)

Slow the progression of coronary atherosclerosis.

Hyperlipidemia PRAVACHOL is indicated as an adjunct to diet to reduce elevated Total-C, LDL-C, Apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dys-lipidemia (Fredrickson Type IIa and IIb). 8 PRAVACHOL is indicated as adjunctive therapy to diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson Type IV). PRAVACHOL is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.

PRAVACHOL is indicated as an adjunct to diet and life-style modification for treatment of HeFH in children and adolescent patients ages 8 years and older if after an adequate trial of diet the following findings are present. 1. LDL-C remains 190 mg/ dL or 2. LDL-C remains 160 mg/ dL and; Ð there is a positive family history of premature cardiovascular disease or Ð two or more other CVD risk factors are present in the patient.

Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when the response to diet and other nonpharmacological measures alone has been inadequate (see NCEP Guidelines below). Prior to initiating therapy with pravastatin, secondary causes for hypercholesterolemia (e. g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure Total-C, HDL-C, and TG. For patients with triglycerides (TG) < 400 mg/ dL ( 4.5 mmol/ L), LDL-C can be estimated using the following equation:

LDL-C= Total-C -HDL-C -¹ TG

For TG levels > 400 mg/ dL ( 4.5 mmol/ L), this equation is less accurate and LDL-C con-centrations should be determined by ultracentrifugation. In many hypertriglyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such cases, HMG-CoA reductase inhibitors are not indicated.

Lipid determinations should be performed at intervals of no less than four weeks and dosage adjusted according to the patient's response to therapy.

The National Cholesterol Education Program's Treatment Guidelines are summarized below: NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories

LDL Levels at Which to Initiate Therapeutic LDL Level at Which to

LDL Goal Lifestyle Changes Consider Drug Therapy Risk Category (mg/ dL) (mg/ dL) (mg/ dL)

CHD a or CHD Risk <100 100 130 equivalents (100-129: drug optional) b

(10-year risk >20%)

<130 130 10-year risk 10%-20%: 2+ Risk factors

130 (10-year risk 20%) 10-year risk <10%:

160 0-1 Risk factor c <160 160 190

(160-189: LDL-lowering drug optional)

a CHD, coronary heart disease.

b Some authorities recommend the use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/ dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e. g., nicotinic acid or fibrate. Clinical judgement also may call for deferring drug therapy in this subcategory. c Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary. After the LDL-C goal has been achieved, if the TG is still 200 mg/ dL, non-HDL-C (Total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/ dL higher than LDL-C goals for each risk category.

At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is 130 mg/ dL (see NCEP Treatment Guidelines, above). Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the Total-C be used to monitor therapy. As with other lipid-lowering therapy, PRAVACHOL (pravastatin sodium) is not indicated when hypercholesterolemia is due to hyperalphalipoproteinemia (elevated HDL-C). The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below:

Category Total-C (mg/ dL) LDL-C (mg/ dL)

Acceptable <170 <110 Borderline 170-199 110-129

High 200 130