pravastatin sodium 80 mg tab generic pravachol

Uses

Prevention of Cardiovascular Events

The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults. There is extensive evidence demonstrating that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients). Because the relative reduction in ASCVD risk is correlated with the degree of low-density lipoprotein (LDL)-cholesterol lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits. According to the ACC/AHA guidelines, pravastatin may be used for primary or secondary prevention in adults when moderate-intensity statin therapy is indicated.(See Prevention of Cardiovascular Events under Dosage and Administration: Dosage.) Nonstatin therapies do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. For additional details on prevention of ASCVD, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).

Primary Prevention

Pravastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients with hypercholesterolemia 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 (with no increase in death from noncardiovascular causes).

The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for primary prevention in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in LDL-cholesterol concentration (190 mg/dL or greater); patients 40-75 years of age with type 1 or 2 diabetes mellitus; and patients 40-75 years of age with LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. Before initiating statin therapy for primary prevention in patients without clinical ASCVD or diabetes mellitus, it is reasonable for clinicians and patients to discuss the potential for ASCVD risk reduction benefits, adverse effects, and drug interactions, as well as patient preferences for treatment.

In a randomized, placebo-controlled study (West of Scotland Coronary Prevention Study [WOSCOPS]) in men with moderate hypercholesterolemia and no history of MI, therapy with pravastatin sodium (40 mg daily) for a median of 4.9 years lowered plasma total and LDL-cholesterol by 20 and 26%, respectively, and reduced the incidence of MI and death from cardiovascular causes by approximately 31%; the risk of undergoing myocardial revascularization procedures also was reduced by 37%. Unlike some prior studies of cholesterol-lowering therapy, an increased risk of death from noncardiovascular causes was not observed in patients receiving pravastatin therapy in this study.

Despite favorable findings from the WOSCOPS study, 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). In this study (ALLHAT-LLT) in patients 55 years of age or older with well-controlled hypertension and moderately elevated LDL-cholesterol concentrations, 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. 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. This modest difference may have resulted from poor adherence to initially prescribed therapy; 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). 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. 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.

Secondary Prevention

Pravastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients with clinical evidence of CHD to reduce the risk of total mortality by reducing coronary death, to reduce the risk of MI, to reduce the risk of undergoing myocardial revascularization procedures, and to reduce the risk of stroke or transient ischemic attack (TIA).

The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for secondary prevention in patients 21-75 years of age who have clinical ASCVD (i.e., acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, peripheral arterial disease presumed to be of atherosclerotic origin) unless contraindicated.

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. 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. 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). 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. Treatment with pravastatin also was associated with a reduction in overall mortality when compared with placebo. 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.

Recent 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. 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. 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. 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. 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.

Reducing Progression of Coronary Atherosclerosis

Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in patients with clinical evidence of CHD to slow the progression of coronary atherosclerosis.

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. In several double-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.

Treatment with pravastatin also has been shown to reduce the rate of progression of atherosclerosis in the carotid arteries. In several randomized, 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. Limited data indicate that pravastatin also may slow progression of atherosclerosis in patients with clinical evidence of CHD who have normal cholesterol concentrations.

Recent 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. 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. 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. Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden, whereas patients treated with pravastatin showed progression of coronary atherosclerosis. 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.

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.

Intensity of Statin Therapy

The ACC/AHA cholesterol management guideline states that the appropriate intensity of a statin should be used to reduce the risk of ASCVD in patients most likely to benefit. Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the guideline expert panel, ACC/AHA considers pravastatin 10-20 mg daily to be a low-intensity statin (producing approximate LDL-cholesterol reductions of less than 30%) and pravastatin 40-80 mg daily to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30% to less than 50%). Individual patient response may vary in clinical practice.

Combination Antilipemic Therapy

The ACC/AHA cholesterol management guideline states that nonstatin drugs may be useful adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, LDL-cholesterol concentrations of at least 190 mg/dL, or diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy, particularly if there is evidence from randomized controlled studies suggesting that the addition of the nonstatin drug further reduces ASCVD events. 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.

Dyslipidemias

Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum total and LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia and mixed dyslipidemia, primary dysbetalipoproteinemia, and/or hypertriglyceridemia. Patients with homozygous familial hypercholesterolemia usually respond poorly to combined dietary management and drug therapy, including regimens containing a statin, in part because these patients have poorly functioning, few, or no LDL receptors. The manufacturer states that efficacy of pravastatin remains to be established in patients with elevated chylomicrons as their primary lipid abnormality.

Nondrug therapies and measures specific for the type of dyslipidemia (therapeutic lifestyle changes) are the initial treatments of choice, including dietary management (e.g., restriction of total and saturated fat and cholesterol intake, addition of plant stanols/sterols and viscous fiber to diet), weight control, an appropriate program of physical activity, and management of potentially contributory disease. Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated.

Primary Hypercholesterolemia or Mixed Dyslipidemia

Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in adults to decrease elevated serum total and LDL-cholesterol, apo B, and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia or mixed dyslipidemia (Fredrickson type IIa or IIb). Pravastatin also is used as an adjunct to dietary therapy and therapeutic lifestyle changes in the management of heterozygous familial hypercholesterolemia in children 8 years of age and older who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration of 190 mg/dL or greater or a serum LDL-cholesterol concentration of 160 mg/dL or greater and either a family history of premature cardiovascular disease or 2 or more other cardiovascular risk factors. Statins such as pravastatin also are used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are receiving optimal statin therapy; however, no additional benefit on cardiovascular morbidity and mortality has been demonstrated with such combination therapy beyond that already established with statin monotherapy.

Reductions in total and LDL-cholesterol produced by usual dosages of pravastatin sodium substantially exceed those of placebo and appear to be similar to or less than those produced by monotherapy with usual dosages of some other antilipemic agents. 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. Modest and variable increases in HDL-cholesterol concentrations (2-12%) also were observed in these patients. 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.

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). 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 (28-4% and 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). 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).

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). 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). 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. 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. 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).

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.(See Combination Antilipemic Therapy under Uses: Prevention of Cardiovascular Events.) 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. 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, apo B, and triglyceride concentrations by 9, 9-11, 11, and 20-27%, respectively, and increased HDL-cholesterol and apo A concentrations by 3-29 and 11%, respectively. 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. 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%. 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]).

Primary Dysbetalipoproteinemia

Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) for the treatment of primary dysbetalipoproteinemia (Fredrickson type III) in patients who do not respond adequately to diet.

Treatment with pravastatin has resulted in substantial reductions in total and LDL-cholesterol, VLDL-cholesterol, triglyceride, and non-HDL-cholesterol concentrations. In several small double-blind, crossover studies in a limited number of patients with primary dysbetalipoproteinemia who received pravastatin 40 mg daily, 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.

Hypertriglyceridemia

Pravastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in the treatment of elevated serum triglyceride concentrations (Fredrickson type IV). AHA states that although statins have consistently shown benefit in subgroups with or without high triglyceride concentrations, fibric acid derivatives have more commonly been shown to provide greater benefit in subgroups with increased triglyceride concentrations.

Mean reductions in total cholesterol concentrations of 22%, LDL-cholesterol concentrations of 32%, triglyceride concentrations of 21%, and non-HDL-cholesterol concentrations of 27% have been reported 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. Modest increases in HDL-cholesterol concentrations (7%) also were observed in these patients.

Other Uses

Pravastatin has been shown to slow the progression and/or induce regression of atherosclerosis in a few patients without clinical evidence of CHD who had mild to moderate elevations of LDL-cholesterol.The drug also has reduced transient myocardial ischemia in male patients with clinical evidence of CHD or unstable angina pectoris.

While some statins have been shown to reduce the rate of restenosis following coronary stent implantation, pravastatin has not been shown to reduce the incidence of restenosis in patients undergoing coronary balloon angioplasty.

Pravastatin has reduced total and LDL-cholesterol concentrations in patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia), cardiac or liver transplantation, or nephrotic syndrome (nephrotic hyperlipidemia).

For additional information on the role of pravastatin or other statins in the treatment of lipoprotein disorders, prevention of cardiovascular events, or other uses, see General Principles of Antilipemic Therapy and see Uses in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.

Dosage and Administration

Administration

Pravastatin sodium is administered orally. The drug may be taken without regard to meals or time of day.

Patients should be placed on a standard cholesterol-lowering diet before initiation of pravastatin therapy and should remain on this diet during treatment with the drug. For recommendations on dietary and other nondrug therapies (i.e., lifestyle modifications), consult the most recent American Heart Association (AHA)/American College of Cardiology (ACC) Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).

Adherence to lifestyle modifications and to statin therapy are required for atherosclerotic cardiovascular disease (ASCVD) risk reduction and, thus, should be reinforced periodically.

Dosage

Dosage of pravastatin sodium must be carefully adjusted according to individual requirements and response. Dosage should be increased at intervals of no less than 4 weeks until the desired effect on lipoprotein concentrations is observed. Serum lipoprotein concentrations should be determined periodically during pravastatin therapy. The ACC/AHA cholesterol management guideline states that lipoprotein concentrations should be determined within 4-12 weeks following initiation of statin therapy (to determine the patient's response to therapy and adherence) and monitored every 3-12 months thereafter as clinically indicated.

Prevention of Cardiovascular Events

The ACC/AHA cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce ASCVD risk in patients most likely to benefit. Giving a maximally tolerated statin intensity should be emphasized over giving lower statin dosages and adding nonstatin drugs to address low HDL-cholesterol or high triglyceride concentrations, a strategy that has not yet been shown to reduce ASCVD risk. It should be noted that although 80 mg once daily is an FDA-labeled dosage of pravastatin, this dosage was not evaluated in randomized controlled studies reviewed by the ACC/AHA expert panel.

Primary Prevention

For primary prevention of cardiovascular disease in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in low-density lipoprotein (LDL)-cholesterol concentration (190 mg/dL or greater), the ACC/AHA cholesterol management guideline recommends that high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) be initiated unless contraindicated. ( or .)

For primary prevention of cardiovascular disease in patients 40-75 years of age with type 1 or 2 diabetes mellitus and LDL-cholesterol concentrations of 70-189 mg/dL, the ACC/AHA cholesterol management guideline recommends that moderate-intensity statin therapy (e.g., pravastatin 40-80 mg once daily) be initiated or continued. In those with an estimated 10-year ASCVD risk of 7.5% or higher, it is reasonable to consider high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) unless contraindicated. In patients with diabetes mellitus who are younger than 40 or older than 75 years of age, it is reasonable to evaluate the potential benefits, adverse effects, drug interactions, and patient preferences when deciding to initiate, continue, or intensify statin therapy.

For primary prevention of cardiovascular disease in patients 40-75 years of age without clinical ASCVD or diabetes mellitus who have LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher, the ACC/AHA cholesterol management guideline recommends that moderate- (e.g., pravastatin 40-80 mg once daily) to high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) be initiated or continued. ( or .) In those with an estimated 10-year ASCVD risk of 5 to less than 7.5%, it is reasonable to offer treatment with moderate-intensity statin therapy. Before initiating statin therapy for primary prevention of ASCVD in patients 40-75 years of age without clinical ASCVD or diabetes mellitus who have LDL-cholesterol concentrations of 70-189 mg/dL, it is reasonable for clinicians and patients to discuss the potential benefits, adverse effects, drug interactions, and patient preferences for such therapy.

Secondary Prevention

For secondary prevention of cardiovascular disease in patients 21-75 years of age with clinical ASCVD, the ACC/AHA cholesterol management guideline recommends that high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) be initiated or continued unless contraindicated. In patients 21-75 years of age with clinical ASCVD who are at increased risk for developing statin-associated adverse effects or in whom high-intensity statin therapy is inappropriate or contraindicated, moderate-intensity statin therapy (e.g., pravastatin 40-80 mg once daily) should be given if tolerated. In patients older than 75 years of age with clinical ASCVD, use of statin therapy should be individualized based on the potential benefits, adverse effects, drug interactions, and patient preferences; it is reasonable to consider initiating or continuing moderate-intensity statin therapy in such patients if tolerated.

Dyslipidemias

The recommended initial dosage of pravastatin sodium in adults is 40 mg daily. If antilipemic response is inadequate with the initial dosage, the manufacturer states that dosage may be increased to 80 mg daily.

The recommended dosage of pravastatin sodium in children 8-13 or 14-18 years of age is 20 or 40 mg once daily, respectively. Safety and efficacy of dosages exceeding 20 or 40 mg daily in children 8-13 or 14-18 years of age, respectively, have not been evaluated. The manufacturer states that children and adolescents treated with pravastatin should be reevaluated in adulthood, and antilipemic therapy should then be modified appropriately.

The cholesterol-lowering effects of pravastatin sodium and bile acid sequestrants (e.g., cholestyramine) are additive or synergistic. However, since bile acid sequestrants may bind and delay absorption of pravastatin sodium, the manufacturer recommends that pravastatin sodium be administered 1 hour or more before and at least 4 hours after the bile acid sequestrant when these drugs are used concomitantly.

Because of an increased risk of myopathy during concomitant therapy, patients receiving immunosuppressive drugs such as cyclosporine concomitantly with pravastatin should receive an initial pravastatin sodium dosage of 10 mg daily at bedtime; titration to higher dosages should be done with caution. Most patients treated with this drug combination received a maximum pravastatin sodium dosage of 20 mg daily. The manufacturer states that in patients receiving cyclosporine, dosage of pravastatin sodium should not exceed 20 mg daily.

In patients receiving clarithromycin, dosage of pravastatin sodium should not exceed 40 mg daily.

Dosage Modification

The ACC/AHA cholesterol management guideline states that decreasing the statin dosage in adults may be considered when LDL-cholesterol concentrations are less than 40 mg/dL on 2 consecutive measurements; however, there are no data to suggest that LDL-cholesterol concentrations below 40 mg/dL would increase the risk of adverse effects.

Dosage in Renal and Hepatic Impairment

Patients with severe renal impairment should receive an initial pravastatin sodium dosage of 10 mg daily.

Pravastatin should be used with caution in patients who consume substantial amounts of alcohol, in patients who have a recent (less than 6 months) history of liver disease, and in those with manifestations of liver disease (e.g., unexplained increases in aminotransferase concentrations, jaundice). Pravastatin is contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.

Cautions

Pravastatin shares the toxic potentials of other statins, and the usual cautions, precautions, and contraindications associated with these drugs should be observed. Patients should be fully advised about the risks, especially rhabdomyolysis, associated with statin therapy alone or combined with other drugs. and also .)

Data from controlled studies indicate that safety and tolerability of pravastatin at a dosage of 80 mg daily is similar to those at lower dosages. However, single instances of elevated serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations exceeding 10 times the upper limit of normal occurred more frequently in patients receiving 80 mg daily (4 of 464 patients) than in those receiving 40 mg daily (none of 115 patients).

Pediatric Precautions

In several randomized, double-blind, placebo-controlled studies in children 8 years of age and older, the adverse effect profile of pravastatin sodium (20-40 mg daily for 2 years) generally was similar to that of placebo; dosages exceeding 20 or 40 mg daily in children 8-13 or 14-18 years of age, respectively, have not been evaluated. There were no detectable differences in height, weight, testicular volume, or Tanner score in pravastatin-treated children compared with those who received placebo. There also were no detectable differences in endocrine parameters (i.e., corticotropin [ACTH], cortisol, dehydroepiandrosterone sulfate [DHEA-S], follicle stimulating hormone [FSH], luteinizing hormone [LH], thyrotropin [TSH], estradiol [in girls], testosterone [in boys]) relative to placebo. If therapy with pravastatin is considered, the manufacturer states that female children and adolescents of childbearing potential should be advised to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy. (See Cautions: Pregnancy, Fertility, and Lactation.) Safety and efficacy of pravastatin have not been evaluated in children younger than 8 years of age.

For additional information on the use of statins in pediatric patients,

Geriatric Precautions

Of the 6593 patients receiving pravastatin in 2 secondary prevention studies, 36.1% were 65 years of age or older, and 0.8% were 75 years of age or older. No overall differences in efficacy (i.e., reduction in cardiovascular events, modification of lipoprotein profiles) or safety were observed between geriatric and younger patients, and other clinical experience has not revealed age-related differences in response. Data from a pharmacokinetic study indicate that mean area under the plasma concentration-time curve (AUC) of pravastatin is 25-50% higher in geriatric individuals compared with younger adults. 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.

Because advanced age (65 years of age or older) is a predisposing factor for myopathy, pravastatin should be used with caution in geriatric patients. The ACC/AHA cholesterol management guideline states that initiation of statin therapy for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients older than 75 years of age requires consideration of additional factors, including increasing comorbidities, safety considerations, and priorities of care. Therefore, the potential for an ASCVD risk reduction benefit, adverse effects, and drug interactions, along with patient preferences, must be considered before initiating statin therapy in patients older than 75 years of age.

Mutagenicity and Carcinogenicity

Pravastatin did not exhibit mutagenic potential in vitro with or without metabolic activation in 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. The drug also did not exhibit mutagenic potential in vivo in a dominant lethal test in mice or a micronucleus test in mice.

In rats receiving oral pravastatin sodium dosages of 10, 30, or 100 mg/kg daily for 2 years, there was an increased incidence of hepatocellular carcinomas in males receiving the highest dosage. These effects in rats were observed at approximately 12 or 4 times the maximum human dosage (80 mg daily), based on body surface area (mg/m or AUC, respectively.

In mice receiving oral pravastatin sodium dosages of 250 and 500 mg/kg for 2 years, there was an increased incidence of hepatocellular carcinomas in males and females receiving both dosages. There also was an increased incidence of lung adenomas in females receiving these dosages. Serum drug levels were 15 times (250 mg/kg daily) and 23 times (500 mg/kg daily) those observed in humans given 80 mg of pravastatin daily, based on AUC. In another study in mice receiving oral pravastatin sodium dosages up to 100 mg/kg daily (approximately 2 times the maximum human dosage of 80 mg daily based on AUC) for 2 years, no drug-induced tumors were reported.

Pregnancy, Fertility, and Lactation

Pregnancy

Safety of pravastatin has not been established in pregnant women; there are no known benefits of continued use of the drug during pregnancy. Limited published data are insufficient to determine whether pravastatin is associated with a risk of major congenital malformations or miscarriage. Since atherosclerosis is a chronic process, discontinuance of antilipemic agents during pregnancy generally should not have a substantial effect on the outcome of long-term therapy for primary hypercholesterolemia.

Pravastatin was not teratogenic in rats receiving dosages up to 1000 mg/kg daily (120 times the usual human exposure based on body surface area in mg/m) or in rabbits receiving dosages up to 50 mg/kg daily (10 times the usual human exposure based on body surface area in mg/m). However, another statin has produced skeletal malformations in rats and mice.

Cholesterol and other products of the cholesterol biosynthetic pathway are essential for fetal development, including synthesis of steroids and cell membranes. Because of the ability of statins such as pravastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, pravastatin may cause fetal harm when administered to pregnant women. Rarely, congenital anomalies have been reported following intrauterine exposure to other statins. Therefore, pravastatin is contraindicated in women who are or may become pregnant. The drug should be discontinued immediately if pregnancy is known or suspected. Women of childbearing potential should use effective contraception while receiving the drug. Pravastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while receiving pravastatin, the drug should be discontinued immediately and the patient informed of the potential hazard to the fetus.

Fertility

Effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. In rats receiving pravastatin sodium in dosages up to 500 mg/kg daily, no adverse effects on fertility or general reproductive performance were observed. However, decreased fertility (20%) with sperm abnormalities were observed in juvenile male rats receiving pravastatin sodium at a dosage producing an AUC of 90 times that achieved with a 40-mg dose in humans.

Lactation

Pravastatin is distributed into human milk. Effects of the drug on breast-fed infants or milk production are not known. Because of the potential for serious adverse reactions from pravastatin in nursing infants, the drug is contraindicated in nursing women; women who require pravastatin therapy should not breast-feed their infants.