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Pravastatin


Pronunciation

 (PRA va stat in)


U.S. Brand Names

 Pravachol®


Synonyms

 Pravastatin Sodium


Generic Available

 No


Canadian Brand Names

 Apo-Pravastatin®; Lin-Pravastatin; Novo-Pravastatin; PMS-Pravastatin; Pravachol®; ratio-Pravastatin


Use

 Use with dietary therapy for the following:

Primary prevention of coronary events: In hypercholesterolemic patients without established coronary heart disease to reduce cardiovascular morbidity (myocardial infarction, coronary revascularization procedures) and mortality.

Secondary prevention of cardiovascular events in patients with established coronary heart disease: To slow the progression of coronary atherosclerosis; to reduce cardiovascular morbidity (myocardial infarction, coronary vascular procedures) and to reduce mortality; to reduce the risk of stroke and transient ischemic attacks

Hyperlipidemias: Reduce elevations in total cholesterol, LDL-C, apolipoprotein B, and triglycerides (elevations of 1 or more components are present in Fredrickson type IIa, IIb, III, and IV hyperlipidemias)

Heterozygous familial hypercholesterolemia (HeFH): In pediatric patients, 8-18 years of age, with HeFH having LDL-C 190 mg/dL or LDL 160 mg/dL with positive family history of premature cardiovascular disease (CVD) or 2 or more CVD risk factors in the pediatric patient


Pregnancy Risk Factor

 X


Pregnancy Implications

 Safety and efficacy have not been established for use during pregnancy (treatment should be discontinued if pregnancy is recognized). Administer to women of childbearing potential only if conception is unlikely; females should be counseled on appropriate contraceptive methods.


Lactation

 Enters breast milk/contraindicated


Contraindications

 Hypersensitivity to pravastatin or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; pregnancy; breast-feeding


Warnings/Precautions

 Secondary causes of hyperlipidemia should be ruled out prior to therapy. Liver function must be monitored by periodic laboratory assessment. Rhabdomyolysis with acute renal failure has occurred. Risk may be increased with concurrent use of other drugs which may cause rhabdomyolysis (including gemfibrozil, fibric acid derivatives, or niacin at doses 1 g/day). Temporarily discontinue in any patient experiencing an acute or serious condition predisposing to renal failure secondary to rhabdomyolysis. Use caution in patients with previous liver disease or heavy ethanol use. Treatment in patients <8 years of age is not recommended.


Adverse Reactions

 As reported in short-term trials; safety and tolerability with long-term use were similar to placebo

1% to 10%:

Cardiovascular: Chest pain (4%)

Central nervous system: Headache (2% to 6%), fatigue (4%), dizziness (1% to 3%)

Dermatologic: Rash (4%)

Gastrointestinal: Nausea/vomiting (7%), diarrhea (6%), heartburn (3%)

Hepatic: Transaminases increased (>3x normal on two occasions - 1%)

Neuromuscular & skeletal: Myalgia (2%)

Respiratory: Cough (3%)

Miscellaneous: Influenza (2%)

<1%: Allergy, alopecia, appetite decreased, dermatitis, dry skin, edema, fever, flushing, insomnia, lens opacity, libido change, memory impairment, muscle weakness, neuropathy, paresthesia, pruritus, sexual dysfunction, taste disturbance, tremor, urticaria, vertigo

Postmarketing and/or case reports: Anaphylaxis, cholestatic jaundice, cirrhosis, cranial nerve dysfunction, dermatomyositis, erythema multiforme, ESR increase, fulminant hepatic necrosis, gynecomastia, hemolytic anemia, hepatitis, hepatoma, lupus erythematosus-like syndrome, myopathy, pancreatitis, peripheral nerve palsy, polymyalgia rheumatica, positive ANA, purpura, rhabdomyolysis, Stevens-Johnson syndrome, vasculitis

Additional class-related events or case reports (not necessarily reported with pravastatin therapy): Angioedema, cataracts, depression, dyspnea, eosinophilia, erectile dysfunction, facial paresis, hypersensitivity reaction, impaired extraocular muscle movement, impotence, leukopenia, malaise, memory loss, ophthalmoplegia, paresthesia, peripheral neuropathy, photosensitivity, psychic disturbance, skin discoloration, thrombocytopenia, thyroid dysfunction, toxic epidermal necrolysis, transaminases increased, vomiting


Overdosage/Toxicology

 Treatment is symptomatic.


Drug Interactions

 Substrate of CYP3A4 (minor); Inhibits CYP2C8/9 (weak), 2D6 (weak), 3A4 (weak)

Cholestyramine: Reduces pravastatin absorption; separate administration times by at least 4 hours.

Clofibrate and fenofibrate: May increase the risk of myopathy and rhabdomyolysis.

Colestipol: Reduces pravastatin absorption; separate administration by 1 hour.

Cyclosporine: Concurrent use may increase the risk of myopathy and rhabdomyolysis.

Gemfibrozil: Increased risk of myopathy and rhabdomyolysis.

Imidazole antifungals (itraconazole, ketoconazole): May modestly increase pravastatin concentrations (AUC).

Niacin: May increase the risk of myopathy and rhabdomyolysis.

P-glycoprotein inhibitors (eg, amiodarone, cyclosporine, ketoconazole): May increase pravastatin concentrations.


Ethanol/Nutrition/Herb Interactions

Ethanol: Consumption of large amounts of ethanol may increase the risk of liver damage with HMG-CoA reductase inhibitors.

Herb/Nutraceutical: St John's wort may decrease pravastatin levels.


Stability

 Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture and light.


Mechanism of Action

 Pravastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is the rate-limiting enzyme involved in de novo cholesterol synthesis.


Pharmacodynamics/Kinetics

Onset of action: Several days

Peak effect: 4 weeks

Absorption: Rapidly absorbed; average absorption 34%

Protein binding: 50%

Metabolism: Hepatic to at least two metabolites

Bioavailability: 17%

Half-life elimination: ~2-3 hours

Time to peak, serum: 1-1.5 hours

Excretion: Feces (70%); urine ( 20%, 8% as unchanged drug)


Dosage

 Oral: Note: Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and patient response; adjustments should be made at intervals of 4 weeks or more; doses may need adjusted based on concomitant medications

Children: HeFH:

8-13 years: 20 mg/day

14-18 years: 40 mg/day

Dosage adjustment for pravastatin based on concomitant immunosuppressants (ie, cyclosporine): Refer to Adults dosing section

Adults: Hyperlipidemias, primary prevention of coronary events, secondary prevention of cardiovascular events: Initial: 40 mg once daily; titrate dosage to response; usual range: 10-80 mg; (maximum dose: 80 mg once daily)

Dosage adjustment for pravastatin based on concomitant immunosuppressants (ie, cyclosporine): Initial: 10 mg/day, titrate with caution (maximum dose: 20 mg/day)

Elderly: No specific dosage recommendations. Clearance is reduced in the elderly, resulting in an increase in AUC between 25% to 50%. However, substantial accumulation is not expected.

Dosing adjustment in renal impairment: Initial: 10 mg/day

Dosing adjustment in hepatic impairment: Initial: 10 mg/day


Administration

 May be taken without regard to meals.


Monitoring Parameters

 Obtain baseline LFTs and total cholesterol profile; creatine phosphokinase due to possibility of myopathy. Repeat LFTs prior to elevation of dose. May be measured when clinically indicated and/or periodically thereafter.


Dietary Considerations

 May be taken without regard to meals. Before initiation of therapy, patients should be placed on a standard cholesterol-lowering diet for 6 weeks and the diet should be continued during drug therapy.


Patient Education

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take at same time each day. Follow diet and exercise regimen as prescribed. Avoid excess alcohol. You will have periodic blood tests to assess effectiveness. May cause mild nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); diarrhea (buttermilk, boiled milk, or yogurt may help); or headache (see prescriber for analgesic). Report chest pain; CNS changes (memory loss, depression, personality changes); numbness, weakness, tingling, pain, or cramping in extremities or muscles; vision changes; rash; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Consult prescriber for appropriate barrier contraceptive measures to use during and for 1 month following therapy. This drug may cause severe fetal defects. Do not donate blood during or for 1 month following therapy. Do not breast-feed.


Nursing Implications

 Liver enzyme elevations may be observed during therapy with pravastatin; diet, weight reduction, and exercise should be attempted prior to therapy with pravastatin


Anesthesia and Critical Care Concerns/Other Considerations

 Myopathy: Currently-marketed HMG-CoA reductase inhibitors appear to have a similar potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The factors that increase risk include advanced age (especially >80 years), gender (occurs in women more frequently than men), small body frame, frailty, multisystem disease (eg, chronic renal insufficiency especially due to diabetes), multiple medications, perioperative periods (higher risk when continued during hospitalization for major surgery) , and drug interactions (use with caution or avoid).


Cardiovascular Considerations

 HMG-CoA reductase inhibitors are effective in primary and secondary prevention of cardiovascular events in patients with hyperlipidemia. For primary prevention, a patient's major risk factors (cigarette smoking, hypertension or currently taking antihypertensives, low HDL-C, family history, age, gender) should be evaluated. Patients with multiple risk factors ( 2) require more intensive therapy guided by the calculation of a 10-year absolute CHD risk (ie, the percent probability of having a CHD event in next 10 years). An individual's 10-year absolute CHD risk can be calculated at www.med-decisions.com/cvtool/phys/phys.html (last accessed July 3, 2003). LDL cholesterol goals, therapeutic lifestyle changes, and drug therapy are determined based upon a patient's risk factor profile.

Primary prevention trials show that cholesterol-lowering drugs reduce the risk of major coronary events, coronary death, and cerebrovascular events even in the first 6-12 months of use. The WOSCOP trial suggested a trend towards enhanced survival using pravastatin in their patients (mean LDL-cholesterol of 192 mg/dL and no history of MI). In a recent trial (ASCOT-LLA), patients with HTN and at least 3 other risk factors defined by the authors benefited in reducing nonfatal CV events with the use of statins; however, no significant difference in CV mortality or overall mortality was observed. These patients had a total cholesterol below 250 mg/dL before treatment.

Secondary prevention trials indicate that "statin" therapy reduces mortality, major coronary events, coronary artery procedures, and stroke. The Heart Protection Study proved that lowering serum cholesterol levels reduces the rate of major vascular events among high-risk individuals with documented vascular disease (CHD, cerebrovascular, peripheral vascular) or diabetes regardless of initial cholesterol concentrations.

HMG-CoA reductase inhibitors decrease levels of high-sensitivity C-reactive protein (hs-CRP). They also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects. These nonlipid effects may be beneficial when HMG-CoA reductase inhibitors are introduced early in the management of acute coronary syndromes (de Denus S, Spinler SA, 2002).

Myopathy: Currently marketed HMG-CoA reductase inhibitors appear to have a similar potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The factors that increase risk include advanced age (especially >80 years of age), women more frequently than men, small body frame, frailty, multisystem disease (eg, chronic renal insufficiency especially due to diabetes), multiple medications, perioperative periods (higher risk when continued during hospitalization for major surgery), drug interactions (use with caution or avoid). The combination of a HMG-CoA reductase inhibitor plus nicotinic acid seems to carry a lower risk of myopathy than does a HMG-CoA reductase inhibitor plus a fibrate. Other medications, when used concurrently, may enhance the risk of myopathy associated with statins; these include drugs that inhibit CYP3A4 isoenzymes (lovastatin, simvastatin, atorvastatin) or CYP2C9 isoenzymes (fluvastatin). HMG-CoA reductase inhibitors may exacerbate exercise-induced skeletal muscle injury. Many experts favor getting a baseline creatine kinase (CK) measurement before initiating therapy (asymptomatic CK elevations are common). Obtain a CK measurement if patient complains of muscle soreness, tenderness, or pain.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 May cause dizziness


Mental Health: Effects on Psychiatric Treatment

 None reported


Dosage Forms

 Tablet, as sodium: 10 mg, 20 mg, 40 mg, 80 mg


References

de Denus S and Spinler SA, "Early Statin Therapy for Acute Coronary Syndromes," Ann Pharmacother , 2002, 36(11):1749-58.

Dupuis J, Tardif JC, Cernacek P, et al, "Cholesterol Reduction Rapidly Improves Endothelial Function After Acute Coronary Syndromes. The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) Trial," Circulation , 1999, 99(25):3227-33.

"Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)," JAMA , 2001, 285(19):2486-97.

Fonarow GC, French WJ, Parsons LS, et al, "Use of Lipid-Lowering Medications at Discharge in Patients With Acute Myocardial Infarction: Data From the National Registry of Myocardial Infarction 3," Circulation , 2001, 103(1):38-44.

Koren MJ, Smith DG, Hunninghake DB, et al, "The Cost of Reaching National Cholesterol Education Program (NCEP) Goals in Hypercholesterolaemic Patients. A Comparison of Atorvastatin, Simvastatin, Lovastatin and Fluvastatin," Pharmacoeconomics , 1998, 14(1):59-70.

Lewis SJ, Moye LA, Sacks FM, et al, "Effect of Pravastatin on Cardiovascular Events in Older Patients With Myocardial Infarction and Cholesterol Levels in the Average Range. Results of the Cholesterol and Recurrent Events (CARE) Trial," Ann Intern Med , 1998, 129(9):681-9.

"MRC/BHF Heart Protection Study of Cholesterol Lowering With Simvastatin in 20,536 High-Risk Individuals: A Randomised Placebo-Controlled Trial. Heart Protection Study Collaborative Group," Lancet , 2002, 360(9326):7-22.

Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al, "ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins," Stroke , 2002, 33(9):2337-41. Available at: http://www.acc.org/clinical/alerts/statins_june02.htm. Accessed June 18, 2003.

Pearson TA, Mensah GA, Alexander RW, et al, "Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association," Circulation , 2003, 107(3):499-511.

Phillips BG, Yim JM, Brown EJ Jr, et al, "Pharmacologic Profile of Survivors of Acute Myocardial Infarction at United States Academic Hospitals," Am Heart J , 1996, 131(5):872-8.

"Prevention of Cardiovascular Events and Death With Pravastatin in Patients With Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels. The Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group," N Engl J Med , 1998, 339(19):1349-57.

Sacks FM, Pfeffer MA, Moye LA, et al, "The Effect of Pravastatin on Coronary Events After Myocardial Infarction in Patients With Average Cholesterol Levels. Cholesterol and Recurrent Events Trial Investigators," N Engl J Med , 1996, 335(14):1001-9.

Sever PS, Dahlof B, Poulter NR, et al, "Prevention of Coronary and Stroke Events With Atorvastatin in Hypertensive Patients Who Have Average or Lower-Than-Average Cholesterol Concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA): A Multicentre Randomised Controlled Trial," Lancet , 2003, 361(9364):1149-58.

Shepherd J, Cobbe SM, Ford I, et al, "Prevention of Coronary Heart Disease With Pravastatin in Men With Hypercholesterolemia. West of Scotland Coronary Prevention Study Group," N Engl J Med , 1995, 333(20):1301-7.

White HD, Simes RJ, Anderson NE, et al, "Pravastatin Therapy and the Risk of Stroke," N Engl J Med , 2000, 343(5):317-26.


International Brand Names

 Aplactin® (IT); Apo-Pravastatin® (CA); Bristacol® (ES); Cholespar® (ID); Elisor® (FR); Galastat® (YU); Lin-Pravastatin (CA); Lipemol® (ES); Lipidal® (IL); Liplat® (ES); Lipostat® (BG, CZ, GB, HU, IE, NZ, PL, RO, YU); Mevalotin® (BR, CH, DE, ID, JP, TH); Mevalotin Protect® (TH); Novales® (ID); Novo-Pravastatin (CA); PMS-Pravastatin (CA); Prareduct® (BE, ES); Prasterol® (IT); Prava Basics® (DE); Pravabeta® (DE); Pravachol® (AT, AU, CA, CN, DK, FI, ID, NO, PL, SE, SG, TR); Pravacol® (AR, BR, CL, CO, CR, EC, GT, HN, MX, PA, PT, SV); Pravagamma® (DE); PravaLich® (DE); Pravaselect® (IT); Pravasin® (DE, LU); Pravasine® (BE); Pravastatin-1A Pharma® (DE); Pravastatina Alter® (PT); Pravastatin AbZ® (DE); Pravastatin AL® (DE); Pravastatin AWD® (DE); Pravastatin "Cross Pharma"® (DK); Pravastatin-ct® (DE); Pravastatin dura® (DE); Pravastatin Hexal® (DE); Pravastatin-Isis® (DE); Pravastatin Kwizda® (DE); Pravastatin-ratiopharm® (DE); Pravastatin Sandoz® (DE); Pravastatin-Stada® (DE); Pravastatin-Teva® (IL); Pravator® (IN); Prava® (ZA); Pravyl® (CO); ratio-Pravastatin (CA); Sanaprav® (AT, IT, PT); Selectin® (IT); Selektine® (NL); Selipran® (AT, CH); Statim® (HR); Vasten® (FR)


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