Pravastatin Oral

Reduction in Risk of Cardiovascular Events

Primary Prevention

Pravastatin is used as an adjunct to diet and lifestyle modifications in adults with elevated low density lipoprotein (LDL)-cholesterol_without_ clinical evidence of coronary heart disease (CHD) to reduce the risk of myocardial infarction (MI), to reduce the risk of undergoing myocardial revascularization procedures, and to reduce the risk of cardiovascular mortality.^[1]

Efficacy and safety of pravastatin for this use were established in a randomized, placebo-controlled study (Pravastatin Primary Prevention StudyWest of Scotland [WOSCOPS])in men with LDL-cholesterol levels between 156 to 254 mg/dL and no history of MI.^[1][12] Therapy with pravastatin sodium (40 mg daily) for a median of 4.8 years lowered plasma total and LDL-cholesterol by 20 and 28%, respectively, and reduced the incidence of nonfatalMI and death from cardiovascular causes by approximately 31%; the risk of undergoing myocardial revascularization procedures(coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty) also was reduced by 37%.^[1] No baseline LDL-cholesterol- or age-based differences in outcomes were reported.^[1] Cardiovascular deaths were decreased by 32% and there was no increase in death from non-cardiovascular causes.^[1]

Despite favorable findings from the WOSCOPSstudy, clinical benefit (i.e., reduction in CHD-related morbidity or all-cause mortality) was not observed in a randomized, open-label study, the lipid lowering trial (LLT), in a subset of patients from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).^[67][68] In this study (ALLHAT-LLT) in patients 55 years of age or older with well-controlled hypertension and moderately elevated LDL-cholesterol concentrations (mean baseline 145 mg/dL), the incidence of all-cause mortality or CHD-related adverse events (i.e., CHD death, nonfatal MI, stroke, congestive heart failure) was similar among patients receiving pravastatin sodium (40 mg daily) or usual care (i.e., moderate LDL-cholesterol lowering according to the discretion of the patient's primary care physician) for a mean duration of 4.8 years.^[67] The lack of clinical benefit may be attributable to the modest difference in total and LDL-cholesterol reduction between pravastatin and usual care recipients (17 versus 8% reduction in total cholesterol and 28 versus 11% reduction in LDL-cholesterol, respectively) compared with the differences reported in other statin trials.^[67][68] This modest difference may have resulted from poor adherence to initially prescribed therapy;^[68] at year 6 of follow-up, only 70% of patients randomized to receive pravastatin sodium were still taking the protocol-specified dosage (40 mg daily), while 28.5% of patients randomized to receive usual care were receiving antilipemic therapy (26.1% with a statin).^[67][68] Despite the reported lack of clinical benefit, the study results are consistent with previous findings indicating that lesser degrees of cholesterol lowering are associated with less clinical benefit.^[68] Adherence to treatment should be particularly emphasized when antilipemic therapy is implemented in routine clinical practice in order to achieve adequate reductions in LDL-cholesterol concentrations. ^[67][68]

Reducing Progression of Coronary Atherosclerosis (Secondary Prevention)

Pravastatin is used as an adjunct to diet and lifestyle modifications in adults with clinical evidence of CHD to reduce the risk ofcoronary death, MI,myocardial revascularization procedures, stroke or transient ischemic attack (TIA), and to slow the progression of coronary atherosclerosis.^[1]

Several clinical trials designed to evaluate the benefits of pravastatin for secondary prevention of cardiovascular disease in patients with established CHD, including prior MI and angina pectoris, have reported improvements in cardiovascular risk status, as evidenced by reductions in the risks of total mortality and nonfatal coronary events.^[1] In the Cholesterol and Recurrent Events (CARE) study, therapy with pravastatin sodium (40 mg daily) in patients with prior MI and average cholesterol concentrations (baseline total, LDL-, and high-density lipoprotein [HDL]-cholesterol concentrations averaging 209, 139, and 39 mg/dL, respectively), was associated with a 24% reduction in fatal or nonfatal coronary events (i.e., CHD death, nonfatal MI) compared with placebo after an average follow-up period of approximately 5 years.^[1][17] Therapy with pravastatin also reduced the risk of undergoing myocardial revascularization procedures (e.g., coronary artery bypass grafting, percutaneous transluminal coronary angioplasty) by 27% and the risk of stroke or TIA by 26% (risk reduction of 31% for stroke alone).^[1][17][54] The reduction in the incidence of combined coronary events (coronary death, nonfatal MI, revascularization procedures, stroke or TIA) reported in the CARE trial also was observed in women, in geriatric patients (65 years of age and older), in patients with diabetes mellitus, and in those who had undergone coronary revascularization.^[49][50][52] Treatment with pravastatin also was associated with a reduction in overall mortality when compared with placebo.^[1][48][65] In the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, therapy with pravastatin sodium (40 mg daily) in patients with a history of MI or hospitalization for unstable angina and normal or elevated total cholesterol concentrations resulted in reductions in overall mortality (22%), CHD mortality (24%), MI (29%), stroke (19%), and coronary revascularization procedures (20%) compared with placebo after an average follow-up period of 6.1 years.^[29][48][65]

Clinical findings indicate that intensive antilipemic therapy may be more effective than moderate antilipemic therapy in reducing the risk of cardiovascular events in patients with acute coronary syndrome.^[69] In a randomized, double-blind, active-control study (Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE-IT]) in over 4000 patients hospitalized for an acute coronary syndrome within the preceding 10 days, treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or moderate antilipemic therapy (pravastatin sodium 40 mg daily) for 2 years reduced LDL-cholesterol concentrations to a median of 62 or 95 mg/dL, respectively.^[69] Compared with the moderate regimen, treatment with the intensive regimen resulted in a 16% reduction in the composite risk of primary endpoints, including a 14% reduction in the need for revascularization procedures and a 29% reduction in the risk of recurrent unstable angina requiring hospitalization.^[69] Atorvastatin therapy also was associated with reductions in the endpoints of death from any cause (28%) and of death or MI (18%) compared with pravastatin therapy, but these differences were not statistically significant.^[69] Results of this study suggest that among patients who have recently had an acute coronary syndrome, an intensive antilipemic regimen provides greater protection against death or major cardiovascular events than does a standard regimen, and patients benefit from early and continued lowering of LDL-cholesterol to levels substantially below currently recommended target levels.^[69]

Pravastatin has been shown to slow the progression and/or induce regression of atherosclerosis in both coronary and carotid arteries by reducing intimal-medial wall thickness.^{[14][15][16][26][57]} Indouble-blind, placebo-controlled studies (i.e., the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries [PLAC I] and the Regression Growth Evaluation Statin Study [REGRESS] in men and women with clinical evidence of CHD and/or angina pectoris and normal to moderately elevated lipoprotein concentrations), progression of atherosclerosis at 2-3 years (measured as the mean per-patient changes from baseline in mean and minimal coronary artery lumen diameters, percent diameter stenosis, and formation of new lesions) was reduced in patients who received pravastatin sodium (40 mg daily) compared with that in those receiving placebo.^[1][14][16]

Treatment with pravastatin also has been shown to reduce the rate of progression of atherosclerosis in the carotid arteries.^{[15][26][27][57]} Inrandomized, placebo-controlled studies (the Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries [PLAC II], the Kuopio Atherosclerosis Prevention Study [KAPS], the REGRESS subgroup study), hypercholesterolemic patients with or without CHD who received pravastatin sodium (20-40 mg daily) for a median of 2-3 years had less progression of atherosclerosis (as determined by B-mode ultrasound quantification of carotid artery intimal-medial thickness [IMT]) compared with those receiving placebo.^[15][26][27] Limited data indicate that pravastatin also may slow progression of atherosclerosis in patients with clinical evidence of CHD who have normal cholesterol concentrations.^[57][60]

Clinical findings indicate that intensive antilipemic therapy may be more effective than moderate antilipemic therapy in slowing the progression of coronary atherosclerosis in patients with CHD.^[70] In a randomized, double-blind, active-control study (Reversal of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL]) in 654 patients with CHD, treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or moderate antilipemic therapy (pravastatin sodium 40 mg daily) for 18 months reduced LDL-cholesterol concentrations to a mean of 79 or 110 mg/dL, respectively; concentrations of C-reactive protein were reduced by 36.4% in atorvastatin-treated patients and by 5.2% in pravastatin-treated patients.^[70] Treatment with the intensive regimen was associated with a substantially lower progression rate (measured by percent change in atheroma volume) compared with treatment with the moderate regimen.^[70] Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden, whereas patients treated with pravastatin showed progression of coronary atherosclerosis.^[70] It has been suggested that the differences in atherosclerosis progression between atorvastatin and pravastatin may be related to the greater reduction in atherogenic lipoproteins and C-reactive protein concentrations in patients treated with atorvastatin.^[70]

Pooled data from several atherosclerosis regression trials in patients with documented CHD, including atherosclerosis and angina pectoris, and mild to moderate hypercholesterolemia indicate that treatment with pravastatin is associated with a reduction in the incidence of clinical events (i.e., death, MI, revascularization procedures) compared with that in patients receiving placebo.^{[13][14][15][16][26]}

Clinical Perspective

The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) cholesterol management guideline emphasizes lifestyle modification as the foundation of atherosclerotic cardiovascular disease (ASCVD) risk reduction.^[400] If pharmacologic therapy is needed, hydroxymethyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin) therapy is recommended.^[400] Statins are considered the first-line drugs of choice for reducing LDL-cholesterol, the lipoprotein fraction found to be a major cause of clinical ASCVD.^{[400][401][402]} There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for secondary or primary prevention in high-risk patients.^{[336][337][338][400][401][402]} Because the relative risk reduction is correlated with the degree of LDL lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits.^{[400][401][402]}

When considering whether to initiate statin therapy for primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.^[400] The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels >=190 mg/dL, adults 40-75 years of age with diabetes mellitus, adults 40-75 years of age without diabetes mellitus but with LDL-cholesterol levels >=70 mg/dL and an estimated 10-year ASCVD risk >=7.5%, and adults 40-75 years of age with chronic kidney disease (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70-189 mg/dL who have a 10-year ASCVD risk >=7.5%.^[400][401]

The guideline states that patients with clinical ASCVD (defined as those with acute coronary syndromes [ACS], history of MI, stable or unstable angina or coronary or other arterial revascularization, stroke, TIA, or peripheral artery disease [PAD], including those with aortic aneurysm) should be treated with a statin in conjunction with lifestyle modification to reduce LDL-cholesterol concentrations.^[400] Because patients >75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.^[400] The maximum tolerated intensity of a statin should be used to achieve optimum ASCVD benefits.^[400] AHA/ACC recommends the use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by at least 50%).^[400] If high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) may be used.^[400]

Intensity of Statin Therapy

The appropriate intensity of a statin should be used to reduce the risk of ASCVD.^[400] Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the AHA/ACC guideline panel, pravastatin 40-80 mg daily is considered to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30-49%).^[400]

Combination Antilipemic Therapy

Theaddition of a nonstatin drug (e.g., ezetimibe, PCSK9 inhibitor) to statin therapy may be useful in certain high-risk patients who experience an inadequate reduction in LDL-cholesterol concentrations despite maximally tolerated statin therapy (e.g., <50% reduction in LDL-cholesterol or LDL-cholesterol concentration >=55 mg/dL or non-HDL-cholesterol >=85 mg/dL).^[400][403] If combination therapy is necessary, selection of the nonstatin drug should be based on the risk and benefit profile (i.e., reduction in ASCVD risk outweighs the drug's potential for adverse effects and drug interactions) and patient preferences.^[400][403]

A 2022 consensus decision pathway published by the ACC addresses the use of nonstatin therapies for primary or secondary prevention of ASCVD.^[403] In patients with primary hypercholesterolemia without ASCVD who require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 monoclonal antibody (mAb) inhibitor are considered preferred initial nonstatin therapies due to demonstrated benefits in cardiovascular outcomes.^[403] If therapeutic goals are not achieved, other nonstatin therapies (e.g., inclisiran, bempedoic acid, evinacumab, lomitapide) may be considered.^[403]

In patients receiving statin therapy as secondary prevention who are at very high risk of ASCVD and require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 inhibitor are considered preferred initial nonstatin therapies.^[403] In patients receiving statin therapy as secondary prevention who are not at very high risk of ASCVD, ezetimibe is considered the preferred initial nonstatin therapy, followed by addition or replacement with a PCSK9 inhibitor if additional LDL-lowering therapy is needed.^[403] If therapeutic goals are not achieved in the secondary prevention setting, inclisiran (in place of a PCSK9 inhibitor) or bempedoic acid may be considered.^[403]

A 2022 scientific statement published by the National Lipid Association (NLA) addresses the use of nonstatin therapies for ASCVD risk reduction in patients with statin intolerance.^[406] Nonstatin LDL-lowering therapy may be considered in patients with complete or partial statin intolerance, including during the course of attempting to identify a tolerable alternate statin regimen in patients with high or very high ASCVD risk.^[406] When nonstatin therapies are used, agents that have demonstrated cardiovascular outcome benefit in randomized trials are preferred.^[406]

Dyslipidemias

Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) to decrease elevatedLDL-cholesterol concentrations in the treatment of adults withprimary hyperlipidemia, primary dysbetalipoproteinemia, and/or hypertriglyceridemia.^[1]

Primary Hyperlipidemia

Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in adults for the treatment of primary hyperlipidemia.^{[1][2][3][5][17]}

Mean reductions in total cholesterol concentrations of 13-27%, LDL-cholesterol concentrations of 21-37%, and triglyceride concentrations of 9-24% have been reported in controlled and uncontrolled studies in patients with primary hypercholesterolemia who received 5-80 mg of pravastatin daily for at least 6 weeks.^{[1][17][23][25][28][33][34][44][47][56]} Modest and variable increases in HDL-cholesterol concentrations (2-12%) also were observed in these patients.^{[1][12][17][23][47]} In long-term controlled and uncontrolled studies (at least 36 weeks), mean total and LDL-cholesterol reductions of 20-29 and 26-34%, respectively, were observed with 40 mg of pravastatin daily.^[12][17][56] In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of 277 patients with primary hyperlipidemia, treatment with pravastatin 80 mg administered once daily significantly decreased total-cholesterol, LDL-cholesterol, and triglyceride levels by 27, 37, and 19%, respectively.^[1]

Reductions in total and LDL-cholesterol concentrations produced by usual dosages of pravastatin sodium appear to be similar to or less than those produced by monotherapy with most other statins (e.g., atorvastatin, lovastatin, rosuvastatin, simvastatin).^{[47][32][33][34][375]} In a randomized, multicenter, parallel-group study comparing the efficacy of various statins, patients with hypercholesterolemia who received pravastatin sodium 10-40 mg daily experienced similar or smaller reductions in plasma total and LDL-cholesterol concentrations (13-24 and 19-34%, respectively) than those who received atorvastatin 10-80 mg daily (28-42and 38-54%, respectively), lovastatin 20-80 mg daily (21-36 and 29-48%, respectively), and simvastatin 10-40 mg daily (21-30 and 28-41%, respectively).^[32] However, patients receiving pravastatin sodium dosages of 10-40 mg daily had greater reductions in plasma total and LDL-cholesterol concentrations (13-24 and 19-34%, respectively) than those who received fluvastatin 20-40 mg daily (13-19 and 17-23%, respectively).^[32]

Limited data from comparative studies suggest that reductions in total and LDL-cholesterol concentrations produced by pravastatin may be similar to or greater than those of other antilipemic agents (i.e., bile acid sequestrants, niacin, fibric acid derivatives).^{[35][36][37][45][46][38]} In 2 placebo-controlled studies comparing 12-24 weeks of pravastatin sodium therapy (40-80 mg daily) with that of cholestyramine (24 g daily in 2 divided doses) in patients with primary hypercholesterolemia, total and LDL-cholesterol reductions with pravastatin (24-30 and 30-39%, respectively) were similar to those with cholestyramine (18-23 and 28-32%, respectively); effects on increasing HDL-cholesterol concentrations also were similar (5-8% for pravastatin versus 5% for cholestyramine).^[35][38] However, pravastatin was more effective than cholestyramine in improving triglyceride concentrations, as evidenced by 13-19% decreases in pravastatin-treated patients and 12-21% increases in cholestyramine-treated patients.^[35][38] Pravastatin appears to be more effective than niacin or gemfibrozil in reducing total and LDL-cholesterol concentrations but less effective than these agents in reducing triglycerides and increasing HDL-cholesterol concentrations.^{[36][37][46][45]} In several randomized, comparative studies in patients with primary types IIa and IIb hyperlipoproteinemia, therapy with pravastatin sodium 40 mg daily produced greater reductions in total and LDL-cholesterol concentrations (23-26 and 30-34%, respectively) than niacin 1-4 g daily in 2 or 3 divided doses (11 and 16%, respectively) or gemfibrozil 600 mg twice daily (14-15 and 16-17%, respectively); however, reductions in triglyceride (4-14%) and increases in HDL-cholesterol concentrations (3-6%) associated with pravastatin therapy were less pronounced than those reported with niacin (32% reduction and 27% increase) or gemfibrozil (37-42% reduction and 13-15% increase).^{[36][37][46][45]}

The combination of pravastatin and other antilipemic agents (e.g., bile acid sequestrants, niacin, fibric acid derivatives) generally results in additive antilipemic effects; however, the risk of myopathy and rhabdomyolysis may be increased.^{[1][35][41][42][45][46]} The addition of a bile acid sequestrant to pravastatin therapy further reduced LDL-cholesterol by 14-20%, resulting in overall LDL-cholesterol reductions of 45-51% in patients receiving pravastatin 40 mg daily and cholestyramine 24 g daily.^[35] Combining niacin (1-3 g daily in 2 or 3 divided doses) with pravastatin sodium (20-40 mg daily) for 8-18 weeks in hypercholesterolemic patients with or without documented CHD further reduced total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations by 9, 9-11, 11, and 20-27%, respectively, and increased HDL-cholesterol and apolipoprotein A (apo A) concentrations by 3-29 and 11%, respectively.^[41][46] Similar effects also were observed in diabetic patients with hyperlipidemia who received low-dose pravastatin sodium (20 mg daily) and niacin (500 mg 3 times daily) therapy for 4 weeks.^[42] Pravastatin (40 mg daily) in combination with gemfibrozil (600 mg twice daily) in patients with primary hypercholesterolemia further reduced triglyceride concentrations by 28% and increased HDL-cholesterol concentrations by 11%.^[45] The increased risk of adverse skeletal muscle effects should be considered when pravastatin is used in combination with some antilipemic agents (i.e., fibric acid derivatives, niacin at lipid-modifying dosages [at least 1 g daily]).^[1]

Primary Dysbetalipoproteinemia

Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) for the treatment of adults withprimary dysbetalipoproteinemia.^[1]

Treatment with pravastatin has resulted in substantial reductions in total and LDL-cholesterol, very low-density lipoprotein (VLDL)-cholesterol, triglyceride, and non-HDL-cholesterol concentrations.^[1] In 2 small, double-blind, crossover studies in 46 patients with primary dysbetalipoproteinemia (genotype E2/E2)who received pravastatin, total cholesterol, LDL-cholesterol, VLDL-cholesterol, triglyceride, and non-HDL-cholesterol concentrations decreased by 31-33, 30-41, 36-44, 12-24, and 36-37%, respectively.^[1]

Hypertriglyceridemia

Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in the treatment of adults with hypertriglyceridemia.^[1]

The response to pravastatin in patients with hypertriglyceridemia (baseline triglyceride level >200 mg/dL and LDL-cholesterol level <160 mg/dL) was evaluated in a subgroup analysis of a double-blind, placebo-controlled study in patients with hypertriglyceridemia who received 40 mg of pravastatin daily for a median of 4.9 years.^[1] The median baseline triglyceride level was 246 mg/dL in pravastatin-treated subjects.^[1] Mean reductions in total cholesterol concentrations of 22%, LDL-cholesterol concentrations of 32%, triglyceride concentrations of 21%, and non-HDL-cholesterol concentrations of 27% were reported.^[1] Modest increases in HDL-cholesterol concentrations (7%) also were observed in these patients.^[1]

Adolescent Patients with Heterozygous Familial Hypercholesterolemia

Pravastatin also is used as an adjunct to dietary therapy to reduce LDL-cholesterol in children 8 years of age and older with heterozygous familial hypercholesterolemia.^[1]

Efficacy and safety of pravastatin for this use were established in a 2 year, double-blind, placebo-controlled study.^[1] In this study, 214 pediatric patients (8-18 years of age) with heterozygous familial hypercholesterolemia were randomized to receive pravastatin 20 mg (8-13 years of age), 40 mg (14-18 years of age), or placebo once daily.^[1] Patients were required to have an LDL-cholesterol level >95^th percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercholesterolemia.^[1] Mean baseline LDL-cholesterol was 239 and 237 mg/dL in the pravastatin and placebo groups, respectively.^[1] Pravastatin significantly decreased plasma LDL-cholesterol, total cholesterol, and apo B levels by24, 18, and 21%, respectively, in the combined pravastatin patient group.^[1] The effect of pravastatin treatment in the 2 age groups was similar.^[1] The mean achieved LDL-cholesterol was 186 mg/dL in the pravastatin group compared to 236 mg/dL in the placebo group.^[1]

Clinical Perspective

Elevated serum cholesterol, especially the LDL-cholesterol fraction, is a major cause of clinical ASCVD; other major risk factors include cigarette smoking, hypertension, diabetes, age, heterozygous familial hypercholesterolemia, chronic kidney disease (eGFR 15-59 mL/minute per 1.73m²), history of heart failure, and other lipoprotein abnormalities.^[400][403] Therefore, the goal of antilipemic therapy in patients with hyperlipidemia is to reduce the risk of ASCVD.^[400] Clinical studies have demonstrated that pravastatin 40-80 mg daily is considered to be amoderate-intensity statin producing approximate LDL-cholesterol reductions of 30-49% when used alone.^[400]

The 2018 AHA/ACC cholesterol management guideline emphasizes lifestyle modification as the foundationofASCVD risk reduction.^[400] If pharmacologic therapy is needed, statin therapy is considered the first-line drug of choice.^{[1] [400]}

When considering whether to initiate statin therapy for dyslipidemia in the setting of primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.^[400] The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels >=190 mg/dL, adults 40-75 years of age with diabetes mellitus, adults 40-75 years of age without diabetes mellitus but with LDL-cholesterol levels >=70 mg/dL and an estimated 10-year ASCVD risk >=7.5%, and adults 40-75 years of age with chronic kidney disease (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70-189 mg/dL who have a 10-year ASCVD risk of 7.5% or higher.^[400][401]

There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for such patients.^{[336][337][338][400][401][402][403]} Because the relative risk reduction is correlated with the degree of LDL lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits.^{[400][401][402]}

Combination Antilipemic Therapy

An ACC expert committee update on nonstatin drug therapies recommends that adults without clinical ASCVD with baseline LDL-cholesterol concentrations >190 mg/dL not due to secondary causes may be considered for ezetimibe and/or a PCSK9 mAb inhibitor if they have not met certain thresholds of LDL-cholesterol reduction on maximally tolerated statin therapy for primary prevention (e.g., at least 50% reduction in LDL-cholesterol with an LDL-cholesterol <100 mg/dL or a non-HDL-cholesterol concentration <130 mg/dL).^[403] Individuals with LDL-cholesterol concentrations >190 mg/dL are more likely to have genetic disorders associated with hypercholesterolemia, such as heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia.^[403] Current treatments for patients with heterozygous familial hypercholesterolemia include lifestyle modifications (e.g., low-fat diet, maintenance of a healthy body weight, smoking cessation), first-line treatment with statins, and, if necessary, combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe, PCSK9 inhibitors, bempedoic acid, inclisiran).^[403]

Hypertriglyceridemia

Patients with moderate or severe hypertriglyceridemia (fasting or non-fasting triglyceride levels 175-499 mg/dL or fasting levels >=500 mg/dL, respectively)generally are at increased risk of ASCVD and pancreatitis (especially in patients with fasting levels >=500 mg/dL).^[400][403] The AHA/ACC cholesterol management guideline recommends assessment and modification of lifestyle (obesity and metabolic syndrome), secondary disorders (e.g., diabetes mellitus, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that increase triglycerides.^[400] Initiation or intensification of statin therapy may be considered in adults 40-75 years of age with moderate or severe hypertriglyceridemia and ASCVD risk of >=7.5%.^[400] Experts state statins alone cannot prevent increasing levels of triglycerides in the face of secondary causes from triggering acute hypertriglyceridemic pancreatitis.^[400]

Pediatric Patients

In addition to early identification of children with familial hypercholesterolemia, dietary (e.g., caloric restriction, Mediterranean-style diet) and lifestyle modification (e.g., physical activity) are prioritized for the management of hypercholesterolemia in children and adolescents.^[400][404] Evidence from randomized controlled trials coupled with the increasedrisk of cardiovascular disease in untreated severe hypercholesterolemia, support the use of statins in children and adolescents at ages >=10 years who have familialy hypercholesterolemia.^[400]

In children and adolescents >=10 years of age with an LDL-cholesterol level persistently >=190 mg/dL or >=160 mg/dL with a clinical presentation consistent with familial hypercholesterolemia and who do not respondadequately with 3-6 months of lifestyle therapy, experts state it is reasonable to initiate statintherapy.^[400] Experts state that statins may be considered as early as 8 years of age in the presence of concerning family history, extremely elevated LDL-cholesterol level, or elevated lipoprotein (a) and in the context of informed shared decision-making and counseling with the patient and family.^[400][404] Treatment intensity should be based on the severity of the hypercholesterolemia and should incorporate patient/family preference; some experts recommend initiation at the lowest recommended dose and up-titration according to the LDL-cholesterol lowering response and tolerability.^[400][404] These experts recommend a target LDL-cholesterol level <130 mg/dL or >=50% reduction from pre-treatment levels, particularly in those with high-risk conditions or other major risk factors; combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe) may be required.^[404]

General

Pretreatment Screening

Obtain baseline liver enzyme tests (e.g., AST, ALT).^[1]Obtain baseline hepatic panel in appropriate patients with chronic stable liver disease (including non-alcoholic fatty liver disease).^[400]Obtain baseline lipid panel.^[400]

Patient Monitoring

Perform fasting lipid panel periodically 4-12 weeks after statin initiation or dose adjustment; monitoring should continue every 3-12 months thereafter as clinically indicated.^[1][400]Periodically reinforce adherence to lifestyle modifications.^[400] Antilipemic therapy is an adjunct to, not a substitute for, lifestyle modification therapies that reduce the risk of ASCVD.^[400]Perform repeat liver function tests (e.g., AST, ALT, total bilirubin, alkaline phosphatase) when clinically indicated (i.e., symptoms suggesting hepatotoxicity); routine monitoring in the absence of symptoms is not recommended.^[1][400]Monitor hepatic panel in appropriate patients with chronic stable liver disease (including non-alcoholic fatty liver disease).^[400]Obtain creatine kinase (CK) levels in patients with severe statin-associated muscle weakness; routine monitoring in the absence of symptoms is not recommended.^[400]

Administration

Pravastatin sodium is administered orally.^[1][2][3][5] The drug may be taken without regard to meals or time of day.^[1]

Pravastatin sodium tablets should be stored in well-closed, light-resistant containers at 20-25°C; the tablets should be protected from moisture.^[1]

Dosage

Adults

Reduction in Risk of Cardiovascular Events

For the reduction of risk of cardiovascular events, primary or secondary prevention, the recommended initial dosage of pravastatin sodium in adults is 40-80 mg once daily.^[1] For patients that require a high-intensity statin or are unable to achieve their LDL-cholesterol goal receiving pravastatin sodium tablets 80 mg daily, the manufacturer states an alternative LDL-cholesterol lowering treatment should be prescribed.^[1]

The AHA/ACC cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce ASCVD risk.^[400] The guideline recommends use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by >=50%); if high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) should be used.^[400] The AHA/ACC guideline panel considers pravastatin 40-80 mg daily to be a moderate-intensity statin.^[400]

Dyslipidemias

The recommended initial dosage of pravastatin sodium in adults is 40-80 mg once daily as an adjunct to diet to reduce LDL-cholesterol in patients with primary hyperlipidemia and as an adjunct to diet in those with primary dysbetalipoproteinemia or hypertriglyceridemia.^[1] Dosage should be increased at intervals of no less than 4 weeks.^[1] For patients that require a high-intensity statin or are unable to achieve their LDL-cholesterol goal receiving pravastatin sodiumtablets 80 mg daily, the manufacturer states an alternative LDL-cholesterol lowering treatment should be prescribed.^[1]

Pediatric Patients

Dyslipidemias

The recommended initial dosage of pravastatin sodium in children 8-13 or 14-18 years of age is 20 or 40 mg once daily, respectively, as an adjunct to diet to reduce LDL-cholesterol in patients with heterozygous familial hypercholesterolemia.^[1] Safety and efficacy of dosages exceeding 40 mg daily in children >=8 years of age have not been evaluated.^[1]

Dosage Modifications for Concomitant Therapy

Patients receiving cyclosporine concomitantly with pravastatin should receive an initial pravastatin sodium dosage of 10 mg once daily;. the manufacturer states the pravastatin sodium dosage should not exceed 20 mg once daily.^[1]

In patients receiving concomitant clarithromycin or erythromycin, the maximum recommended dosage of pravastatin sodium is 40 mg once daily.^[1]

Special Populations

Hepatic Impairment

The manufacturers make no specific dosage recommendations for patients with hepatic impairment.^[1]

Renal Impairment

Patients with severe renal impairment should receive an initial pravastatin sodium dosage of 10 mg once daily; the maximum recommended dosagein such patients is 40 mg once daily.^[1] Dosage of pravastatin sodium for patients with mild or moderate renal impairment is the same as for patients with normal renal function.^[1]

Geriatric Patients

The manufacturers make no specific dosage recommendations for geriatric patients.^[1] Dose selection in geriatric patients (>=65 years of age) should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy.^[1]

Pharmacogenomic Considerations

Patients with solute carrier organic anion transporter (SLCO) 1B1 decreased or possible decreased function phenotypes will have increased pravastatin exposure compared to those with normal function which may translate to an increased risk of statin-associated musculoskeletal symptoms if dosage exceeds 40 mg per day.^[500] In such patients, based on pharmacokinetic data, initiate and adjust pravastatin dosage based on disease-specific guidelines; there is a risk of musculoskeletal symptoms, especially with dosages >40 mg per day.^[500]

Patients with SLCO1B1 poor function phenotypes will have increased pravastatin exposure compared to those with normal and decreased function, which may translate to an increased risk of statin-associated musculoskeletal symptoms if dosage exceeds 40 mg per day.^[500] In such patients, based on pharmacokinetic data, initiate pravastatin at <=40 mg per day and adjust dosage based on disease-specific guidelines.^[500] If the patient is tolerating 40 mg per day, but a higher potency is needed, consider a higher dosage (>40 mg), an alternative statin, or combination therapy (i.e., pravastatin plus a nonstatin guideline directed medical therapy); there is a risk of musculoskeletal symptoms, especially with dosages >40 mg per day.^[500]

Contraindications

Hypersensitivity to pravastatin or any component of the formulation.^[1]Acute liver failure or decompensated cirrhosis.^[1]

Warnings/Precautions

Musculoskeletal Effects

Myopathy manifested as muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK) and rhabdomyolysis with acute renal injury secondary to myoglobinuria have been reported in patients receiving statins, including pravastatin; rare fatalities have occurred.^[1] Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CK values to greater than 10 times the upper limit of normal (ULN), occurred in <0.1% of pravastatin-treated patients in clinical trials.^[1]

Predisposing factors for myopathy include advanced age (>=65 years of age), concomitant use of statins with certain other drugs (including other lipid-lowering drugs), and those with renal impairment, uncontrolled hypothyroidism, and higher pravastatin dosage.^[1] Pravastatin is not recommended in patients taking gemfibrozil.^[1] Pravastatin dosage reduction is necessary when used concomitantly with cyclosporine, erythromycin, or clarithromycin.^[1] When used concomitantly with pravastatin, niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis.^[1]

AHA/ACC cholesterol management guideline recommends measurement of CK levels in patients with severe statin-associated muscle symptoms; however, routine monitoring is not useful.^[400]

Pravastatin should be discontinued if CK concentrations become markedly elevated or if myopathy is diagnosed or suspected.^[1] Pravastatin therapy should be temporarily withheld in any patient experiencing an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled seizures).^[1]

Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.^[1]

Immune-Mediated Necrotizing Myopathy

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has been reported rarely in patients receiving statins, including reports of recurrence when the same or a different statin was administered.^[1] The condition is characterized by proximal muscle weakness and elevated CK concentrations that persist despite discontinuance of statin therapy, positive anti-HMG CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement following therapy with immunosuppressive agents.^[1] Additional neuromuscular and serologic testing may be necessary.^[1]

Discontinue pravastatin if IMNM is suspected.^[1]

Hepatic Effects

Increases in serum aminotransferase (i.e., AST, ALT) concentrations have been reported in patients receiving statins, including pravastatin.^[1] In most cases, the elevations appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy.^[1] Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 1% of patients receiving pravastatin or placebo in clinical trials.^[1] Marked persistent increases of hepatic transaminases have also occurred with pravastatin.^[1]

Consider liver enzyme tests prior to pravastatin initiation and repeat as clinically indicated.^[1] Serious statin-related liver injury is rare and unpredictable in individual patients, and routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious statin-related liver injury.^[200] The AHA/ACC cholesterol management guideline states that, during statin therapy, it is reasonable to obtain liver function tests in adults experiencing symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of the skin or sclera); however, routine monitoring is not recommended.^[200][400]

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin.^[1] If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, pravastatin therapy should be promptly discontinued.^[1]

Patients who consume substantial amounts of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.^[1] Pravastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis.^[1]

Hyperglycemic Effects

Increases in glycosylated hemoglobin (hemoglobin A1c [HbA1c]) and fasting serum glucose concentrations have been reported in patients receiving statins, including pravastatin.^[1][200]

Data from meta-analyses and clinical trials with other statins indicate that statin therapy may increase the risk of developing diabetes mellitus.^[200] AHA/ACC cholesterol management guideline states that patients receiving statin therapy should be evaluated for new-onset diabetes mellitus but because the benefits of statin therapy outweigh the risks of new-onset diabetes, the possibility of this adverse effect should not be a contraindication to statin therapy or a reason for discontinuance of therapy.^[400]

Specific Populations

Pregnancy

All statins were previously contraindicated in pregnant women because the fetal risk with these drugs was thought to outweigh any possible benefit.^[405] This determination was based on several factors including safety signals from animal data.^[405] No evidence of fetal malformations was seen in pregnant rats or rabbits orally administered pravastatin during the period of organogenesis at doses that resulted in 10 and 120 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg/day, based on body surface area (mg/m²).^[1] An imbalance in some fetal skeletal variations, increased offspring mortality, and developmental delays occurred when pregnant rats were exposed to 10-12 times the MRHD during organogenesis to parturition.^[1]

In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant women who were exposed to a lipophilic statin (pravastatin is a hydrophilic statin) during the first trimester.^[400] Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there was also a concern that these drugs could potentially cause fetal harm.^[405] More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use.^[405] The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects.^[405] While an increased risk of miscarriage has been reported in pregnant women exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors.^[400][405]

FDA conducted a comprehensive review of all available clinical and nonclinical data related to statin use in pregnant women and concluded that the totality of evidence suggests that there is limited potential for statins to cause malformations and other adverse embryofetal effects.^[405] Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins.^[405] While FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with homozygous familial hypercholesterolemia or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits.^{[400][402][405]} Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.^[405]

Lactation

Pravastatin is distributed into human milk.^[1] Effects of the drug on breast-fed infants or milk production are not known.^[1] Because of the potential for serious adverse reactions from pravastatin in nursing infants, the drug is not recommended in nursing women; women who require pravastatin therapy should not breast-feed their infants.^[1] Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula.^{[400][402][405]}

Females and Males of Reproductive Potential

In rats receiving pravastatin sodium in dosages up to 500 mg/kg daily, no adverse effects on fertility or general reproductive performance were observed.^[1]

AHA/ACC cholesterol management guideline recommends women (including adolescents) of childbearing age who are sexually active should be counseled to use a reliable form of contraception.^[400]

Pediatric Use

Safety and effectiveness of pravastatin as an adjunct to diet to reduce LDL-cholesterol in pediatric patients 8 years of age and older with heterozygous familial hypercholesterolemia (HeFH) have been established in a double-blind, placebo-controlled study.^[1] Dosages greater than 40 mg daily have not been studied in this population.^[1]

Safety and efficacy of pravastatin have not been evaluated inpediatric patients with other types of hyperlipidemia.^[1]

Geriatric Use

In clinical studies, 4,797 (36.4%) pravastatin-treated patients were >=65 years of age, and 110 (0.8%) were >=75 years of age.^[1] No overall differences in efficacy or safety were observed between geriatric and younger patients.^[1] Data from a pharmacokinetic study indicate that mean AUC of pravastatin is 25-50% higher in geriatric individuals compared with younger adults.^[1] However, because mean peak plasma concentration, time to peak plasma concentration, and half-life are similar between geriatric and younger individuals, substantial accumulation of pravastatin would not be expected in geriatric patients.^[1]

Because patients >75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.^[400]

Hepatic Impairment

Pravastatin shows a large inter-subject variability in patients with liver cirrhosis.^[1] The mean AUC and peak concentrations varied 18- and 47-fold, respectively, in patients with biopsy-confirmed cirrhosis compared to 5- and 6-fold, respectively, in healthy subjects.^[1]

Patients who consume substantial amounts of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.^[1]

Pravastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis.^[1]

Renal Impairment

In patients with severe renal impairment, the mean AUC and peak plasma concentrations were 69 and 37% higher, respectively, compared to healthy subjects with normal renal function.^[1] No pharmacokinetic differences were observed among other patients with varying degrees of renal impairment.^[1]

Renal impairment is a risk factor for myopathy and rhabdomyolysis.^[1] Patients with severe renal impairment should receive an initial pravastatin sodium dosage of 10 mg daily and maximum recommended dosage in such patients is 40 mg once daily.^[1]

Monitor all patients with renal impairment for the development of myopathy.^[1]

Pharmacogenomic Considerations

Genetic variation in the solute carrier organic anion transporter (SLCO) family member (SLCO1B1), ABCG2 (also known as breast cancer resistance protein [BCRP]), and cytochrome P-450 (CYP) 2C9 genes alter systemic exposure to statins (i.e., lovastatin, simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin), which can increase the risk for statin-associated musculoskeletal symptoms.^[500] SLCO1B1 encodes a transporter (SLCO1B1; alternative names include organic ion transporter protein [OATP] 1B1 or OATP-C) that facilitates the hepatic uptake of all statins.^[500] ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin and atorvastatin; CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins (e.g., fluvastatin).^[500]

In patients with phenotypes that result in increased statin exposure, the potential for other patient-specific issues that may increase statin exposure (e.g., renal and hepatic function, drug-drug interactions) must also be considered.^[500] Experts state that given the balance of statin-associated musculoskeletal symptoms risk versus known cardiovascular disease benefit, for patients who are candidates for new statin therapy, pharmacogenetic test results may provide additional useful information.^[500]

Pharmacogenetic test results may be used as the basis for changing to another statin type or dose for patients currently prescribed statin therapy, depending on how long the patient has been tolerating the statin.^[500] Experts state statin therapy should neither be discontinued nor avoided based on SLCO1B1, ABCG2, or CYP2C9 genotype results for patients with an indication for statin therapy, especially if the statin therapy is based on the shared decision making between patient and provider.^[500]

Patients with SLCO1B1 decreased, possible decreased, or poor function phenotypes will have increased pravastatin exposure, which may translate to an increased risk of statin-associated musculoskeletal symptoms if the dosage exceeds 40 mg per day.^[500]

Common Adverse Effects

Adverse effects reported in >=2% of patients, and greater than placebo, receiving pravastatin include musculoskeletal pain, nausea/vomiting, upper respiratory infection, diarrhea, and headache.^[1]

Pravastatin does not undergo cytochrome P450 isoenzyme metabolism.^[1][339] Pravastatin is a substrate of organic anion transporter protein (OATP) 1B1, 1B3, and 2B1.^{[339][501][502]}

Drugs Affecting or Affected by Transport Systems

Pravastatin is a substrate of organic anion transporter protein (OATP) 1B1, 1B3, and 2B1.^{[339][501][502]} Concomitant administration of pravastatin with drugs inhibiting OATP1B1, 1B3, or 2B1 may increase drug exposure and increase the risk of statin-induced toxicity (e.g., myopathy).^{[1][501][502]}

Other Lipid-Lowering Drugs

Concomitant administration of pravastatin with other lipid-lowering drugs (e.g., gemfibrozil, other fibrates, niacin) may increase the risk of myopathy and/or rhabdomyolysis.^[1][339]

Concomitant administration of a single dose of pravastatin 20 mg once with a single dose of niacin 1 g resulted in a 3.6 and 8.2% decrease in pravastatin AUC and peak plasma concentration, respectively.^[1]

Concomitant administration of a single dose of pravastatin 20 mg once with a single dose of gemfibrozil 600 mg resulted in a 7 and 20% decrease in pravastatin AUC and peak plasma concentration, respectively.^[1]

Avoid the combined use of gemfibrozil and pravastatin.^[1] Experts state it is safer to use fenofibrate than gemfibrozil because of a lower risk of severe myopathy.^[400] The benefit of further alterations in lipid levels by the combined use of pravastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations.^[1] If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration.^[1]

Bile Acid Sequestrants

Variable effects on pravastatin pharmacokinetics are observed when administered with bile acid sequestrants (i.e., cholestyramine, colestipol).^[1]

Concomitant administration of a single dose of pravastatin 20 mg administered 4 hours after a single dose of cholestyramine 4 g resulted in a 12 and 6.8% decrease in pravastatin AUC and peak plasma concentration, respectively.^[1]

Concomitant administration of a single dose of pravastatin 20 mg administered 1 hour prior to a single dose of cholestyramine 4 g resulted in a 12 and 30% increase in pravastatin AUC and peak plasma concentration, respectively.^[1]

Concomitant administration of a single dose of pravastatin 20 mg administered simultaneously with a single dose of cholestyramine 4 g resulted in a 40 and 39% decrease in pravastatin AUC and peak plasma concentration, respectively.^[1]

Concomitant administration of a single dose of pravastatin 20 mg administered with a single dose of colestipol 10 g resulted in a 47 and 53% decrease in pravastatin AUC and peak plasma concentration, respectively.^[1]

Concomitant administration of pravastatin 5, 10, or 20 mg administered twice daily for 8 weeks with cholestyramine 24 g daily for 4 weeks resulted in variable pravastatin AUC (decreased 38, 18, and 51%, respectively) and peak plasma concentration (increase 23%, decrease 33%, increase 4.9%, respectively) changes.^[1]

In patients taking a bile acid sequestrant, administer pravastatin at least 1 hour before or at least 4 hours after the bile acid sequestrant.^[1]

Drugs Affecting Gastric Acidity

Concomitant administration of a single dose of pravastatin 20 mg with 15 mL antacid four times a day for 3 days resulted in a 28 and 24% decrease in pravastatin AUC and peak plasma concentration, respectively.^[1]

Concomitant administration of a single dose of pravastatin 20 mg with cimetidine 300 mg four times a day for 3 days resulted in a 30 and 9.8% increase in pravastatin AUC and peak plasma concentration, respectively.^[1]

Antifungals, Azole

Concomitant administration of a single dose of pravastatin (20 mg oral plus 10 mg IV) and fluconazole 200 mg IV for 6 days resulted in a 34 and 33% decrease in pravastatin AUC and peak plasma concentration, respectively.^[1]

Concomitant administration of a single dose of pravastatin (20 mg oral plus 10 mg IV) and fluconazole (oral) 200 mg for 6 days resulted in a 16 and 16% decrease in pravastatin AUC and peak plasma concentration, respectively.^[1]

Concomitant administration of pravastatin 40 mg daily for 30 days with oral itraconazole 200 mg daily for30 days resulted in an 11 and 17% increase in pravastatin AUC and peak plasma concentration on day 30 compared to day 1, respectively.^[1]

Aspirin

Concomitant administration of a single dose of pravastatin 20 mg with aspirin 324 mg resulted in a 4.7 and 8.9% increase in pravastatin AUC and peak plasma concentration, respectively.^[1]

Calcium-channel Blocking Agents

Concomitant administration of a single dose of pravastatin 20 mg with diltiazem resulted in a 2.7 and 30% increase in pravastatin AUC and peak plasma concentration, respectively.^[1]

Concomitant administration of a single dose of pravastatin 40 mg with verapamil 120 mg immediate-release for 1 day followed by verapamil 480 mg extended-release for 3 days resulted in a 31 and 42% increase in pravastatin AUC and peak plasma concentration, respectively.^[1]

Some experts state a non-CYP3A4-metabolized statin (i.e., pravastatin) is preferred in combination with diltiazem or verapamil.^[339]

Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported when pravastatin was used concomitantly with colchicine.^[1] Some experts state the combination is reasonable when clinically indicated and while closely monitoring patients for signs and symptoms of myopathy.^[339][502]

The benefit of the combined use of pravastatin with colchicine should be carefully weighed against the increased risk of myopathy and rhabdomyolysis.^[1] If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration.^[1]

Cyclosporine

Concomitant use of pravastatin and cyclosporine can increase pravastatin exposure and risk of myopathy and rhabdomyolysis.^[1][339]

Concomitant administration of a single dose of pravastatin 40 mg with a single dose of cyclosporine 5 mg/kg resulted in a 282 and 327% increase in pravastatin AUC and peak plasma concentration, respectively.^[1]

Patients receiving immunosuppressive drugs such as cyclosporine concomitantly with pravastatin should receive an initial pravastatin sodium dosage of 10 mg once daily.^[1] The manufacturer states that in patients receiving cyclosporine, the dosage of pravastatin sodium should not exceed 20 mg once daily.^[1]

Digoxin

Concomitant administration of pravastatin 20 mg with digoxin 0.2 mg daily for 9 days resulted in a 23 and 26% increase in pravastatin AUC and peak plasma concentration, respectively; digoxin AUC and peak plasma concentration increased 4.6 and 5.3%, respectively.^[1]

Grapefruit Juice

Concomitant administration of a single dose of pravastatin 40 mg with grapefruit juice resulted in 1.8% decreased pravastatin AUC and 3.7% increased peak plasma concentration, respectively.^[1]

HIV Protease Inhibitors

Concomitant administration of a single dose of pravastatin 40 mg with darunavir 600 mg plus ritonavir 100 mg twice daily for 7 days resulted in an 81 and 63% increase in pravastatin AUC and peak plasma concentration, respectively.^[1]

Concomitant administration of pravastatin 20 mg once daily for 4 days with lopinavir 400 mg plus ritonavir 100 mg twice daily for 14 days resulted in a 33 and 26% increase in pravastatin AUC and peak plasma concentration, respectively; the AUC and peak plasma concentration of lopinavir and ritonavir were unchanged.^[1]

Experts recommend clinicians follow the dosing recommendation to administer the lowest effective pravastatin dose while monitoring for adverse events provided by the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV.^[502][503]

Macrolide Antibiotics

Concomitant administration of pravastatin with erythromycin or clarithromycin may increase the risk of myopathy and rhabdomyolysis.^[1][502] The manufacturer states other macrolides (e.g., azithromycin) have the potential to increase pravastatin exposures and increase the risk of myopathy and rhabdomyolysis when used concomitantly, but some experts state azithromycin may be acceptable.^[1][502]

Concomitant administration of pravastatin 40 mg once daily for 8 days with clarithromycin 500 mg twice daily for 9 days resulted in a 110 and 128% increase in pravastatin AUC and peak plasma concentration, respectively.^[1]

The manufacturer states that in patients receiving erythromycin or clarithromycin, the dosage of pravastatin sodium should not exceed 40 mg once daily.^[1]

Warfarin

There are postmarketing reports of clinically evident bleeding and/or increased prothrombin time (PT) and international normalized ratio (INR) in patients taking concomitant statins and warfarin.^[339]

Concomitant administration of pravastatin 20 mg twice daily with warfarin 5 mg daily for 6 days resulted in 13% decreased pravastatin AUC and 6.7% increased peak plasma concentration, respectively; mean PT increased 0.4 seconds and warfarin AUC and peak plasma concentration increased 17 and 15%, respectively.^[1]

PT/INR should be monitored when pravastatin is initiated or dosage is adjusted in patients receiving warfarin.^[339]

Pravastatin is a competitive and reversible inhibitor of 3-hydroxymethylglutaryl-CoA (HMG-CoA) reductase (i.e., statin), an enzyme that catalyzes the conversion of HMG-CoA to mevalonate (an early and rate-limiting step in cholesterol biosynthesis).^[1][501] Pravastatin is pharmacologically related to other statins (e.g., atorvastatin, lovastatin, fluvastatin, simvastatin, pitavastatin, rosuvastatin).^{[2][3][4][5][6][502]} Pravastatin is structurally related to lovastatin and simvastatin but differs from these agents by the substitution of a hydroxyl group for the methyl group on the hexahydronaphthalene ring.^[6] This structural modification increases the hydrophilicity of pravastatin, making it approximately 100-fold more soluble in water than lovastatin or simvastatin.^[6] Unlike the lactone prodrugs lovastatin and simvastatin, pravastatin exists as an active hydroxy acid and does not require hydrolysis in vivo.^[6] Pravastatin is similar structurally to HMG-CoA and competes with this compound for interaction with HMG-CoA reductase.^[22][501]

Pravastatin reduces elevated low-density lipotrotein (LDL)-cholesterol concentrations.^[1] The mechanism of the LDL-lowering effect of pravastatin may involve both reduction of very low-density lipoprotein (VLDL) concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-cholesterol.^[1][501] Triglyceride and apolipoprotein B may decrease and high-density lipoptotein (HDL)-cholesterol concentration may increase during treatment with pravastatin.^[1][501] Other favorable effects of statins (pleitropic effects) include an antiproliferative influence on smooth muscle cells, reconstruction of endothelial activity, antioxidant, antithrombotic, anticancer, and anti-inflammatory effects.^[501]

Pravastatin is hydrophilic, average oral absorption is 34%, and absolute bioavailability is 17%.^[1][501] Bioavailability is reduced 60% when administered at bedtime compared to morning administration, however the drug is marginally more effective (not statistically significant) when administered at bedtime.^[1] Peak plasma pravastatin concentrations occur within 1-1.5 hours following oral administration.^[1] Administration with food will reduce the AUC and peak plasma concentration 31 and 49%, respectively, however the lipid-lowering effects are similar whether taken with or 1 hour prior to meals.^[1] Pravastatin plasma concentrations, AUC and time to steady state are directly proportional to administered dose.^[1] Therapeutic response, maximum LDL-cholesterol reduction, is expected within 4 weeks.^[1] Pravastatin is 50% bound to plasma proteins and present in breast milk.^[1]

Pravastatin undergoes extensive first-pass extraction in the liver and is metabolized via isomerization and hydroxylation.^[1] One isomeric metabolite has 1/10th-1/40th the HMG-CoA reductase inhibitory activity of the parent compound.^[1] Pravastatin does not undergo cytochrome P450 isoenzyme metabolism.^[1] Pravastatin is excreted in the feces and urine approximately 70 and 20%, respectively.^[1] Following single dose oral administration of radiolabeled pravastatin, the radioactive elimination half-life for pravastatin is 1.8 hours and the elimination half-life for total radioactivity (pravastatin plus metabolites) is 77 hours.^[1]

In patients with severe renal impairment, the mean AUC and peak plasma concentrations were 69 and 37% higher, respectively, compared to healthy subjects with normal renal function.^[1] No pharmacokinetic differences were observed among other patients with varying degrees of renal impairment.^[1] The mean AUC and peak concentrations varied 18- and 47-fold, respectively, in patients with biopsy-confirmed cirrhosis compared to 5- and 6-fold, respectively, in healthy subjects.^[1] Data from a pharmacokinetic study indicate that meanAUC of pravastatin is 25-50% higher in geriatric individuals compared with younger adults.^[1] However, because mean peak plasma concentration, time to peak plasma concentration, and half-life are similar between geriatric and younger individuals, substantial accumulation of pravastatin would not be expected in geriatric patients.^[1] Patients with certain solute carrier organic anion transporter (SLCO) 1B1 phenotypes (i.e., decreased, possible decreased, or poor function) will have increased pravastatin exposure compared to those with normal function.^[500]

Advise patients of the importance of adhering to nondrug therapies and measures, including adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight.^[1][400]Advise patients of the risk of myopathy and/or rhabdomyolysis; risk is increased with higher dosages or when used concomitantly with certain drugs.^[1] Stressimportance of patients promptly reporting muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, or if manifestations persist after discontinuance of therapy.^[1]Advise patients of the risk of adverse hepatic effects and the importance of promptly reporting any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).^[1]Advise patients of the risk of increased glucose concentrations and development of type 2 diabetes.^[200] Advise patients that pravastatin tablets may be administered as a single dose at any time of day, with or without food.^[1]Advise females of reproductive potential (including adolescents) of the risk to a fetus and to use effective contraception during treatment.^[400] Advise women to notify their clinician if they become pregnant or suspect pregnancy during therapy.^[405]Advise women not to breastfeed during therapy.^[1]Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^[1]Inform patients of other important precautionary information.^[1]

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