Pravastatin is an oral antilipemic agent which inhibits HMG-CoA reductase and is indicated for the treatment of primary hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia, and primary dysbetalipoporteinemia, as well as for primary and secondary prevention of coronary heart disease and stroke prophylaxis in adults. Pravastatin is also indicated for the treatment of heterozygous familial hypercholesterolemia in children and adolescents 8 years and older. Pravastatin 40 mg to 80 mg once daily is considered to be a moderate-intensity statin (expected to lower low-density lipoprotein cholesterol (LDL-C) by 30% to 49%), while pravastatin 10 mg to 20 mg once daily is considered low-intensity (expected to lower LDL-C by less than 30%). Choice of moderate-or high-intensity statin therapy dependent on patient age, baseline LDL-C, ASCVD risk factors, and concomitant diseases. High-intensity therapy provides greatest LDL-C reductions and is associated with a significantly greater reduction in ASCVD events versus moderate-intensity therapy. Pravastatin is not metabolized via the cytochrome P450 (CYP) system; thus, it has a lower propensity for metabolic-driven drug interactions versus other "statins" with significant CYP metabolism. Hepatotoxicity, myopathy, rhabdomyolysis, and immune-mediated necrotizing myopathy (IMNM) have been reported with any statin therapy. Individuals 65 years or older, taking concomitant medications that may cause myopathy (e.g., niacin, fibrates, or colchicine), taking high pravastatin dosages, or those with uncontrolled hypothyroidism or renal impairment are at increased risk of myopathy. Discontinue pravastatin is markedly elevate creatine phosphokinase (CK) levels occur, myopathy is suspected or diagnosed, IMNM is suspected, or hepatic injury witch clinical symptoms, hyperbilirubinemia, or jaundice occurs. Guidelines recommend assessment of liver function at baseline and if signs or symptoms of hepatic injury occur. Monitor lipid concentrations at 4 to 12 weeks after initiation or dose adjustment and then every 3 to 12 months as necessary.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-May be administered without regard to meals.
-Pravastatin may be taken once-daily. The product labeling states that pravastatin may be taken anytime of day, but guidelines suggest administration in the evening. Pravastatin has been shown to be similarly effective (slightly less effective, but not significantly different) in lowering cholesterol when administered in the morning versus evening.
Thyroid function abnormalities have been reported with post marketing experience of pravastatin.
Amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease) has been reported to the FDA in a higher than expected number of patients taking statins. ALS is a progressive motor neuron disorder with symptoms such as difficulty walking or standing, difficulty with fine motor skills, atrophy of tongue and hand muscles, dysphagia, dysarthria, and muscle paralysis. Due to the seriousness of ALS and the extensive use of statins, FDA further examined data from 41 long-term controlled clinical trials. The results of the review showed no increased incidence of ALS in patients treated with a statin compared with placebo. Specifically, 9 of approximately 64,000 patients treated with a statin (4.2 cases per 100,000 patient-years) and 10 of approximately 56,000 patients treated with placebo (5 case per 100,000 patient-years) were diagnosed with ALS. FDA is examining the feasibility of performing additional epidemiologic studies to further examine the incidence and clinical course of ALS in patients taking statins.
Pravastatin has been well tolerated in controlled clinical trials. In three large, placebo-controlled trials (WOS, CARE, and LIPID) involving a total of 19,768 patients treated with pravastatin or placebo, the safety and tolerability profile in the pravastatin group was comparable to that of the placebo group over the median 4.8 to 5.9 years of follow-up. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. GI adverse reactions were reported during pravastatin clinical trials, but the incidence of these effects was generally similar to placebo. These reactions include nausea/vomiting (1.6-2% vs. 1.6-1.9%), diarrhea (2% vs. 2.9%), abdominal pain (1.6-2% vs. 1.6-3.9%), constipation (1.2-2.4% vs. 1.3-5.1%), flatulence (1.2-2.7% vs. 0.7-1.1-3.4%), and dyspepsia or pyrosis (heartburn) (2-3.5%-0.7-3.7%). Anorexia was reported in <1% of patients treated with pravastatin in long-term trials. Dysgeusia has been reported in post marketing experience with pravastatin.
During short- and long-term placebo-controlled clinical trials of pravastatin, fatigue was reported in 1.9-3.4% of patients (vs. 1-3.3% placebo). Moderate doses of pravastatin (40 mg/day PO) were associated with tiredness and exertional fatigue in a study that randomized 1016 patients with LDL concentrations of 115-190 mg/dL and no cardiovascular disease or diabetes to simvastatin 20 mg/day PO, pravastatin 40 mg/day PO or placebo for 6 months. Patients rated their change in energy and fatigue with exertion on a five-point scale from "much less" (-2) to "much more" (+2) on 6 month follow-up compared to baseline. Results showed a statistically significant adverse effect on energy and exertional fatigue associated with statin use compared to placebo (-0.21 vs. -0.06, respectively; p = 0.005). The effects appeared to be stronger with simvastatin (-0.25) than pravastatin (-0.17) and were more common in women than men. The authors recommend clinicians consider the impact of these adverse effects on quality of life when prescribing statins particularly in primary prevention patients where a mortality benefit has not been established (e.g., non-smokers and those without raised CRP).
HMG-CoA reductase inhibitors have been associated with toxicity to skeletal muscles. During controlled short- and long-term clinical trials, localized musculoskeletal pain (1.4% to 6% vs. 1.5% to 5.8%), myasthenia (less than 1%), muscle cramps (2% vs. 1.8%) or myalgia (0.6% to 1.4% vs. 0 to 1.4%) did not occur significantly more frequently with pravastatin compared to placebo. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal, has been rarely reported (less than 0.1%) during pravastatin clinical trials. Tendon disorders and polymyositis have been reported with the post-marketing use of pravastatin. Because of the seriousness of this reaction, patients receiving pravastatin should be closely monitored for clinical signs of myopathy. Statin-induced myopathy is generally dose-related. In general, the risk of developing myopathy is increased when HMG-CoA reductase inhibitors are used in combination with certain interacting drugs. Rhabdomyolysis and acute renal failure (unspecified) (secondary to renal tubular obstruction, myoglobinuria) have been reported with pravastatin and other HMG-CoA reductase inhibitors. In general, rhabdomyolysis is a rare (less than 1/100,000 prescriptions) complication of HMG-CoA reductase inhibitor ('statin') therapy. Rhabdomyolysis may occur anytime during drug treatment and the risk may be increased by a number of confounding factors including age, concomitant drug therapy, renal dysfunction, and concomitant disease states. Many cases result in hospitalization and a need for dialysis for treatment. Vigilant clinical monitoring during prescribing can help limit serious adverse events. Patients should be monitored for symptoms of myopathy or rhabdomyolysis (unexplained lethargy/drowsiness, myalgia, muscle cramps, muscle weakness, muscle tenderness, weakness/asthenia, myasthenia, fatigue, and/or fever) and elevated creatine phosphokinase (CPK) serum concentrations. Pravastatin should be discontinued immediately in any patient who develops myopathy or elevations in CPK.
Although rare, severe hepatotoxicity may occur during HMG-CoA reductase inhibitor therapy. Hepatitis, fatty changes of the liver, cholestasis with jaundice, pancreatitis, and rarely, cirrhosis, fulminant hepatic necrosis, hepatic failure, and hepatoma have been reported during therapy with HMG-CoA reductase inhibitors. Pravastatin therapy has been associated with elevated hepatic enzymes. Liver function tests (LFTs) should be performed prior to initiation of therapy with pravastatin and then repeated as clinically indicated. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with pravastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart pravastatin. Marked elevations of ALT or AST have been reported in <= 1.2% of patients receiving either placebo or pravastatin during long-term clinical trials (WOS, LIPID, CARE). Overall, clinical trial experience showed that liver function test abnormalities observed during pravastatin therapy were usually asymptomatic, not associated with cholestasis, and did not appear to be related to treatment duration.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) with HMG-CoA reductase inhibitors, such as pravastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed.
During clinical trials for pravastatin, the most common central nervous system adverse effects include dizziness (1-2.2% vs. 0.5-2.1%), headache (1.7-1.9% vs. 0.2-1.8%), depression (1% vs. 1%), anxiety/nervousness (1% vs. 1.2%), and sleep disturbances (1% vs. 0.9%). Rare cases of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) have been associated with the use of statins. A review of available data by the FDA did not find an association between the event and a specific statin, statin dose, concomitant medication, or age of the patient. In general, post-marketing reports described patients over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon statin discontinuation. The cases did not appear to be associated with progressive or fixed dementia. The time to symptom onset (1 day to years) and resolution (median 3 weeks) is variable. Vertigo, insomnia, paresthesias, and tremor and memory impairment occurs in < 1% of patients. Nightmares, impairment of extraocular movement, facial paresis, and peripheral nerve palsy have been reported through post marketing experience of pravastatin. In a 2-year controlled study of children and adolescents aged 8-18 years with heterozygous familial hypercholesterolemia, the safety and tolerability profile of pravastatin was generally similar to placebo, with headache common in both treatment groups. The PROSPER trial demonstrated that pravastatin reduced risk of cardiovascular events in high-risk elderly patients without adverse effects on cognitive function relative to placebo.
Anemia, thrombocytopenia, and leukopenia have been reported with HMG-CoA reductase inhibitors. Transient, asymptomatic eosinophilia has been reported with pravastatin; eosinophil counts generally return to normal with continued therapy.
Dermatological or hypersensitivity reactions during pravastatin therapy may include rash (unspecified) (1.3-2.1% vs. 0.9-2.2%) or less frequent reactions (< 1%, frequency similar to placebo) such as alopecia, dermatitis, dry skin (xerosis), urticaria, edema (face/neck), or pruritus. Angioedema has been reported rarely during post-marketing experience with pravastatin. A variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails) has been reported during post-marketing experience of pravastatin. An apparent hypersensitivity syndrome has been reported rarely with HMG-CoA reductase inhibitors which has included one or more of the following features or anaphylactoid reactions: anaphylaxis, angioedema, lupus-like symptoms, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson syndrome.
An association between HMG-CoA reductase inhibitors (statins), including pravastatin, and peripheral neuropathy has been reported in the literature (case series, case-control studies, cohort studies). In a nested case-control study of a Danish population, the odds ratio for idiopathic peripheral neuropathy in 166 patients that ever or were currently taking a statin, was 3.7 (95% CI 1.8-7.6); similar results have been found in other population based studies, although the number of patients studied was significantly smaller. Case reports and series indicate that the onset of neuropathy is typically > 1 year after drug initiation and is reversible with drug discontinuation. However, cases describing irreversible neuropathy are also reported. The adverse effect appears to be a class effect because in all cases, when a patient is either rechallenged or treated with a different statin, the symptoms of neuropathy return. While the data appear to support an association between HMG-CoA reductase inhibitors and peripheral neuropathy, the incidence is rare and estimated to be approximately 1 per 14,000 person-years. Furthermore, a causal relationship cannot be definitively established based on the observational nature of the available data. The benefits of statin therapy far outweigh any risk of peripheral neuropathy; however, until more information is available, health care providers should be aware of this adverse effect.
Increased hemoglobin A1c and fasting serum glucose (hyperglycemia) have been reported during therapy with HMG-CoA reductase inhibitors. A meta-analysis of 13 statin trials with 91,140 participants showed a 9% increase in the likelihood of the development of diabetes mellitus (OR 1.09; 95% CI 1.02-1.17). The incidence of diabetes was higher in high-risk patients (i.e., age 70-82 years with or at high risk of cardiovascular disease, myocardial infarction within the last 6 months, or heart failure) compared to patients with low diabetes risk (i.e., low BMI). Additionally, an analysis of the data from the Women's Health Initiative (WHI) trial found that statin use in postmenopausal women is associated with an increased risk of new-onset diabetes mellitus (multivariate-adjusted HR 1.48; 95% CI 1.38-1.59). No difference in the risk for diabetes between statins was detected in either analysis. Because the use of statins has been associated with significant benefit for cardiovascular risk reduction and all-cause mortality at comparable rates in diabetic and non-diabetic patients , no changes to clinical practice guidelines have been recommended in either population. However, the increased risk of diabetes should be considered when initiating pravastatin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established.
Respiratory adverse reactions reported during short- and long-term placebo-controlled clinical trials of pravastatin include dyspnea (1.6% vs. 1.6%), cough (0.1% to 1% vs. 0 to 1%), upper respiratory infection (1.3% vs. 1.3%), and rhinitis (0.1% vs. 0%). In a 2-year controlled study of children and adolescents aged 8 to 18 years with heterozygous familial hypercholesterolemia, the safety and tolerability profile of pravastatin was generally similar to placebo, with influenza common in both treatment groups. During postmarketing use of pravastatin, interstitial lung disease has been reported.
Dysuria, nocturia, and increased urinary frequency were reported in 0.7-1% of patients (vs. 0.8-1.2% placebo) in short- and long-term clinical trials of pravastatin. Sexual dysfunction and libido decrease or libido increase (reported as libido change) were reported in <1% of patients in long-term trials of pravastatin, and gynecomastia has been reported through post marketing surveillance.
During short- and long-term placebo-controlled clinical trials of pravastatin, angina pectoris was reported in 0.1-3.1% of patients (vs. 0-3.4% placebo) and chest pain (unspecified) was reported in 0.3-2.6% (vs. 0.2-2.6% placebo) of patients.
Blurred vision and diplopia was reported in 1.6% of patients during long-term clinical trials of pravastatin (vs. 1.3% placebo), and cataracts (reported as lens opacity) was reported in <1% of patients.
Fever and flushing were reported in < 1% of patients during long-term pravastatin trials.
HMG-CoA reductase inhibitors (statins), such as pravastatin, inhibit the synthesis of mevalonate and decrease Co-Enzyme Q-10 concentrations, which may lead to Co-Enzyme Q-10 deficiency. Supplementation with vitamin Co-Enzyme Q-10 may limit potential adverse reactions.
Exacerbation and induction of myasthenia gravis has been reported during treatment with statins, including pravastatin. In a review of adult patients enrolled at a neuromuscular disease clinic over a 4-year time period, 6 of 54 myasthenia gravis patients (11%) receiving statin therapy experienced worsening myasthenia gravis. In a disproportionality analysis of the World Health Organization's VigiBase pharmacovigilance database, 169 of 3,967 (4.2%) of adverse reactions with the term 'myasthenia gravis and related conditions' were related to statin therapy. The reporting odds ratio (ROR) of myasthenia gravis relative to all other adverse reactions was 2.66 [95% CI: 2.28, 3.1] for statin therapy. In addition, the ROR was greater than 1 and statistically significant for all individual statins except lovastatin. The onset of symptoms following initiation of statin therapy has ranged from 1 week to 4 months for exacerbation and 6 months to 6 years for induction of myasthenia gravis. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents. Though this appears to be a rare adverse reaction, clinicians should closely monitor patients with myasthenia gravis for disease exacerbation and encourage them to report any muscle-related symptoms.
Pravastatin is contraindicated in any patient with pravastatin hypersensitivity or hypersensitive to any component of the medication.
Pravastatin is contraindicated in patients with certain types of liver disease, specifically acute hepatic failure and decompensated cirrhosis (hepatic decompensation). Elevations in serum transaminases have been reported with pravastatin therapy, including persistent increases to more than 3 times the upper limit of normal (ULN). In most cases, the serum transaminase elevations occurred soon after therapy initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or following brief interruption in therapy. Although rare, there have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin. Patients who consume large amounts of alcohol or have a history of hepatic disease, including cholestasis, hepatic encephalopathy, hepatitis, or jaundice, are at an increased risk for hepatic injury. Patients should minimize ethanol ingestion while receiving pravastatin therapy and pravastatin should be avoided in patients with alcoholism. Consider assessing liver enzymes prior to initiation of pravastatin therapy and repeat as clinically indicated. Previous recommendations included a specific schedule for monitoring liver enzymes; however, after extensive data review, the FDA concluded that the risk of serious liver injury is very low and routine periodic monitoring of liver enzymes has not been effective in detection or prevention of serious hepatic injury. Instruct patients to promptly report any symptoms of hepatic injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice). If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with pravastatin, therapy should be promptly discontinued.
Pravastatin may cause myopathy and rhabdomyolysis. Acute renal failure secondary to myoglobinuria and rare fatalities have been reported due to rhabdomyolysis in patients treated with statin therapy, including pravastatin. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CK) values to greater than 10 times the ULN, was rare (less than 0.1%) in pravastatin clinical trials. Patients should be advised to promptly report to their physician any unexplained and/or persistent muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Discontinue pravastatin in any patient who develops markedly elevated CK levels or if myopathy is diagnosed or suspected. Predisposing risk factors for myopathy and/or rhabdomyolysis include advanced age (65 years or older), uncontrolled hypothyroidism, females, renal disease, renal insufficiency or renal failure, liver disease, diabetes, uncontrolled seizure disorder, pre-existing muscle disease, Chinese ancestry, major surgery, and trauma. Temporarily discontinue pravastatin in patients experiencing an acute or serious condition that places them at high risk of developing renal failure due to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic disorder, endocrine disease, or electrolyte imbalance; or uncontrolled epilepsy). The risk of developing myopathy is increased when pravastatin is used concomitantly with selected other drugs, such as gemfibrozil, erythromycin, cyclosporine, niacin, fibrates, colchicine, and OATP1B1 inhibitors. Although renal impairment does not appear to alter the pharmacokinetics of pravastatin, a lower initial dose and careful dosage titration is recommended in patients with severe renal impairment since renal insufficiency is a risk factor for myopathy.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) with HMG-CoA reductase inhibitors, such as pravastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed.
Increased glycosylated hemoglobin A1c (A1C), hyperglycemia, and worsening glycemic control have been reported during therapy with HMG-CoA reductase inhibitors. Although statin therapy has been associated with a risk hyperglycemia and new-onset diabetes mellitus, this is not deemed to be of clinical importance as the beneficial effects of statins on cardiovascular event reduction outweigh potential risk. Inform patients of the potential risk and the importance of optimizing lifestyle measures, including regular exercise, maintaining a healthy bodyweight, and making healthy food choices.
Pravastatin therapy should be discontinued once pregnancy is identified in most patients. Alternatively, consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events during pregnancy, such as those with homozygous familial hypercholesterolemia or with established cardiovascular disease. Based on the mechanism of action, pravastatin may cause fetal harm when administered to pregnant patients due to decreases in the synthesis of cholesterol and possibly other biologically active substances derived from cholesterol. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. The U.S. Food and Drug Administration (FDA) completed a review of data from case series, prospective and retrospective observational cohort studies over decades of statin use in pregnant patients and concluded that these studies have not identified a drug-associated risk of major congenital malformations associated with statin use during pregnancy. In a Medicaid cohort linkage study of 1,152 statin-exposed pregnant women, no significant teratogenic effects were observed following maternal statin use during the first trimester of pregnancy after adjusting for potential confounders (i.e., maternal age, diabetes mellitus, hypertension, obesity, alcohol use, and tobacco use); the relative risk (RR) of congenital malformations was 1.07 (95% confidence interval (CI), 0.85 to 1.37). In addition, after accounting for confounders, there were no statistically significant increases in organ-specific malformations. In the study, statin treatment was started prior to pregnancy and was discontinued within the first trimester after pregnancy was detected in a majority of patients. In another cohort study of 469 patients who were dispensed statins during pregnancy, it was determined that there was no increase in congenital anomalies after adjustment for maternal age and comorbidities; however, statin use was associated with an increased risk of preterm labor (RR, 1.99 [95% CI, 1.46 to 2.71]) and low birth weight (RR, 1.51 [95% CI, 1.05 to 2.16]). In a published, retrospective cohort study of 281 statin-exposed pregnant women, patients on statin therapy had a miscarriage rate of 25% compared to 21% for pregnant women not on statin therapy (n = 2,643); adjusted hazard ratio was 1.64 (95% CI, 1.1 to 2.46). The FDA also re-reviewed non-clinical, animal data statin development programs and concluded that statins have a limited potential to cause malformations or embryofetal lethality, and limited potential to affect nervous system development during embryofetal development during the pre- and post-natal period. In animal reproduction studies, fetal skeletal abnormalities, offspring mortality, and developmental delays did occur when pregnant rats were administered 10 to 12 times the maximum recommended human dose during organogenesis to parturition. Overall, available data have not identified a drug-associated risk of major congenital malformations, but published data are insufficient to determine if there is a drug-associated risk of miscarriage. Temporary discontinuation of lipid-lowering therapy, such as pravastatin, should have minimal impact on the long-term therapy of primary hyperlipidemia, as atherosclerosis is a chronic process. Advise pregnant patients and patients of child-bearing potential of the potential risk of statin therapy to the fetus and the importance of informing their health care provider of known or suspected pregnancy.
Pravastatin is not recommended for use during breast-feeding. There is no information about the presence of pravastatin in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for infant growth and development, including synthesis of steroids and cell membranes. HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway. The importance of continued pravastatin therapy to the mother should be considered in making the decision whether to discontinue breast-feeding or to discontinue the medication. If pharmacotherapy for hypercholesterolemia is necessary in the nursing mother, an alternative agent such as a nonabsorbable resin(cholestyramine, colesevelam, or colestipol) may be considered. These agents do not enter the bloodstream and thusly will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant.
Safety and efficacy of pravastatin have not been established in infants and children younger than 8 years of age. Because cholesterol plays a crucial role in growth and development, the clinical implications of using pharmacologic therapy to alter the normal production of cholesterol in young children is not clear. Because of these potential safety concerns and lack of safety data, most experts generally recommend delaying cholesterol-lowering medications until the child is at least 8 to 10 years old. In some cases of severe familial hypercholesterolemia, however, HMG-CoA reductase inhibitors have been used in younger children with careful monitoring of growth and development.
Since advanced age (65 years or more) is a predisposing factor for myopathy, pravastatin should be prescribed with caution in geriatric adults. Older adults are more sensitive to the effects of the usual adult dosage of HMG CoA-reductase inhibitors. However, the manufacturer does not recommend dosage reduction for older adults based on cumulative data from various clinical trials, including the LIPID trials.
Exacerbation and induction of myasthenia gravis have been reported during treatment with statins, including pravastatin. The onset of symptoms following initiation of statin therapy has ranged from 1 week to 4 months for exacerbation and 6 months to 6 years for induction of myasthenia gravis. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents. Though this appears to be a rare adverse reaction, clinicians should closely monitor patients with myasthenia gravis for disease exacerbation and encourage them to report any muscle-related symptoms.
-Pravastatin 40 mg to 80 mg once daily is considered to be a moderate-intensity statin (expected to lower low-density lipoprotein cholesterol (LDL-C) by 30% to 49%), while pravastatin 10 mg to 20 mg once daily is considered low-intensity (expected to lower LDL-C by less than 30%).
-Choice of moderate- or low-intensity statin therapy is dependent on patient age, baseline LDL-C, ASCVD risk factors, and concomitant diseases. High-intensity therapy provides greatest LDL-C reductions and is associated with a significantly greater reduction in ASCVD events vs. moderate- or low-intensity therapy.
-Guidelines recommend assessment of liver function at baseline and if signs or symptoms of hepatic injury occur.
-Monitor lipid concentrations at 4 to 12 weeks after initiation or dose adjustment, and then every 3 to 12 months as necessary.
For general dosing information in persons requiring moderate-intensity statin therapy:
Oral dosage:
Adults: 40 or 80 mg PO once daily.
For general dosing information in persons requiring low-intensity statin therapy:
Oral dosage:
Adults: 10 or 20 mg PO once daily.
For the treatment of hypercholesterolemia, including heterozygous familial hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary control:
Oral dosage:
Adults 19 years and older: 40 to 80 mg PO once daily. Max: 80 mg/day. Assess LDL-C 4 to 12 weeks after pravastatin initiation or dose adjustment and adjust dosage as necessary. Lipid panels should be repeated every 3 to 12 months as needed. For patients unable to achieve LDL-C goal level on pravastatin therapy, consider switching to a high-intensity statin (if tolerated) or adding another lipid-lowering agent. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents and young Adults 14 to 18 years: 40 mg PO once daily is the FDA-approved dosage. Alternatively, 10 mg PO once daily initially, then titrated up in 10 mg increments every 2 months (Max: 60 mg/day) was studied in a small observational study of 30 patients with familial hypercholesterolemia (ages 4.1 to 18.5 years). Pravastatin was started at 10 mg in all patients regardless of age or size; the dosage was increased gradually if the target total cholesterol concentration of 194 mg/dL or less was not achieved. At 2 years, doses of pravastatin in patients available for follow-up were as follows: 10 mg, n = 1; 20 mg, n = 4; 40 mg, n = 2; 50 mg, n = 4; 60 mg, n = 3. Decreases in mean serum total cholesterol, LDL, and triglyceride concentrations reported in observational and placebo-controlled studies were 18% to 26%, 24% to 32%, and 6% to 34%, respectively, after 2 years of treatment. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 8 to 13 years: 20 mg PO once daily is the FDA-approved dosage. Alternatively, 10 mg PO once daily initially, then titrated up in 10 mg increments every 2 months (Max: 60 mg/day) was studied in a small observational study of 30 patients with familial hypercholesterolemia (ages 4.1 to 18.5 years). Pravastatin was started at 10 mg in all patients regardless of age or size; the dosage was increased gradually if the target total cholesterol concentration of 194 mg/dL or less was not achieved. At 2 years, doses of pravastatin in patients available for follow-up were as follows: 10 mg, n = 1; 20 mg, n = 4; 40 mg, n = 2; 50 mg, n = 4; 60 mg, n = 3. Decreases in mean serum total cholesterol, LDL, and triglyceride concentrations reported in observational and placebo-controlled studies were 18% to 26%, 24% to 32%, and 6% to 34%, respectively, after 2 years of treatment. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 4 to 7 years*: Pharmacologic therapy is not generally recommended for young children; however, 10 mg PO once daily initially, then titrated up in 10 mg increments every 2 months (Max: 60 mg/day) was studied in a small observational study of 30 patients with familial hypercholesterolemia (ages 4.1 to 18.5 years). Pravastatin was started at 10 mg in all patients regardless of age or size; the dosage was increased gradually if the target total cholesterol concentration of 194 mg/dL or less was not achieved. At 2 years, doses of pravastatin in patients available for follow-up were as follows: 10 mg, n = 1; 20 mg, n = 4; 40 mg, n = 2; 50 mg, n = 4; 60 mg, n = 3. Mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 26%, 32%, and 34%, respectively, after 2 years of treatment. Although pharmacologic therapy is not routinely recommended for patients younger than 10 years of age, it may be considered in patients with severe primary hyperlipidemia or high level risk factors (e.g. diabetes, organ transplant, obesity, hypertension, chronic renal disease, strong family history of premature cardiovascular disease). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For myocardial infarction prophylaxis or stroke prophylaxis:
-for primary prevention in patients with hypercholesterolemia but without coronary artery disease to reduce the risk of MI, reduce the need for myocardial revascularization, and/or to reduce the risk of cardiovascular mortality:
Oral dosage:
Adults: 40 to 80 mg PO once daily. Max: 80 mg/day. Assess LDL-C 4 to 12 weeks after pravastatin initiation or dose adjustment and adjust dosage as necessary. Lipid panels should be repeated every 3 to 12 months as needed. For patients unable to achieve LDL-C goal level on pravastatin therapy, consider switching to a high-intensity statin (if tolerated) or adding another lipid-lowering agent. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for secondary prevention of and reduction of cardiovascular mortality and acute coronary events, stroke, TIA, coronary revascularization procedures, and atherosclerosis progression in patients with coronary artery disease:
Oral dosage:
Adults: 40 to 80 mg PO once daily. Max: 80 mg/day. Assess LDL-C 4 to 12 weeks after pravastatin initiation or dose adjustment and adjust dosage as necessary. Lipid panels should be repeated every 3 to 12 months as needed. For patients unable to achieve LDL-C goal level on pravastatin therapy, consider switching to a high-intensity statin (if tolerated) or adding another lipid-lowering agent. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For cerebral vasospasm prophylaxis* after aneurysmal subarachnoid hemorrhage:
Oral dosage:
Adults: Dosage not established. 40 mg PO once daily for 14 days has been used. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Maximum Dosage Limits:
-Adults
80 mg/day PO.
-Geriatric
80 mg/day PO.
-Adolescents
14 to 18 years: 40 mg/day PO is the FDA-approved maximum dose; however, higher doses were reported in a small study (exact maximum dosage for this age group was not defined, overall maximum for the study was 60 mg/day).
13 years: 20 mg/day PO is the FDA-approved maximum dose; however, higher doses were reported in a small study (exact maximum dosage for this age was not defined, overall maximum for the study was 60 mg/day).
-Children
8 to 12 years: 20 mg/day PO is the FDA-approved maximum dose; however, higher doses were reported in a small study (exact maximum dosage for this age group was not defined, overall maximum for the study was 60 mg/day).
4 to 7 years: Safety and efficacy have not been established; however, doses of 10 mg/day PO or more were reported in a small study (exact maximum dosage for this age group was not defined, overall maximum for the study was 60 mg/day).
1 to 3 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Contraindicated in patients with acute hepatic failure and decompensated cirrhosis (hepatic decompensation, e.g., Child-Pugh class C).
Patients with Renal Impairment Dosing
Adults:
Mild to moderate renal impairment: Dosage adjustments are not needed; the dosage is the same as for adults with normal renal function.
Severe renal impairment (estimated CrCl less than 30 mL/minute): 10 mg PO once daily initially; monitor closely. May adjust based on clinical response/tolerance. Max: 40 mg PO once daily.
Pediatric patients 8 to 17 years:
Specific recommendations for dosage adjustment in pediatric patients with renal impairment are not available.
*non-FDA-approved indication
Amoxicillin; Clarithromycin; Omeprazole: (Major) Do not exceed 40 mg per day of pravastatin if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Coadministration of clarithromycin increased the AUC and Cmax of pravastatin by 110% and 128%, respectively.
Asciminib: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with asciminib is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; asciminib is an OATP1B1/3 inhibitor.
Atazanavir: (Moderate) Concurrent use of atazanavir with pravastatin may result in elevated pravasatin serum concentrations. Pravastatin is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an inhibitor of OATP1B1. Monitor for increased toxicities if these drugs are given together, such as myopathy.
Atazanavir; Cobicistat: (Major) The plasma concentrations of pravastatin may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as rhabdomyolysis or GI effects, is recommended during coadministration. Cobicistat is a organic anion transporting polypeptide (OATP) inhibitor, while pravastatin is a OATP1B1 substrate. (Moderate) Concurrent use of atazanavir with pravastatin may result in elevated pravasatin serum concentrations. Pravastatin is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an inhibitor of OATP1B1. Monitor for increased toxicities if these drugs are given together, such as myopathy.
Azithromycin: (Moderate) Azithromycin has the potential to increase pravastatin exposure when used concomitantly. Coadminister pravastatin and azithromycin cautiously due to a potential increased risk of myopathies.
Bempedoic Acid: (Major) Do not exceed a pravastatin dose of 40 mg/day in patients taking bempedoic acid due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving pravastatin 60 mg/day or greater who need to be started on bempedoic acid, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of bempedoic acid and pravastatin against the potential risks. Bempedoic acid increases the pravastatin AUC and Cmax by 2-fold.
Bempedoic Acid; Ezetimibe: (Major) Do not exceed a pravastatin dose of 40 mg/day in patients taking bempedoic acid due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving pravastatin 60 mg/day or greater who need to be started on bempedoic acid, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of bempedoic acid and pravastatin against the potential risks. Bempedoic acid increases the pravastatin AUC and Cmax by 2-fold.
Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like HMG-CoA reductase inhibitors; the risk of peripheral neuropathy may be additive.
Cholestyramine: (Moderate) Administer pravastatin 1 hour before or 4 hours after a dose of cholestyramine if both agents are used together. Bile acid-sequestering agents, such as cholestyramine, have been shown to significantly reduce serum concentrations of pravastatin. Coadministration with cholestyramine decreases the AUC of pravastatin by about 40-50%.
Cimetidine: (Moderate) Use HMG-CoA reductase inhibitors with caution with concomitant drugs that may decrease the levels or activity of endogenous steroids, such as cimetidine. Evaluate patients with signs and symptoms of endocrine dysfunction appropriately. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production.
Clarithromycin: (Major) Do not exceed 40 mg per day of pravastatin if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Coadministration of clarithromycin increased the AUC and Cmax of pravastatin by 110% and 128%, respectively.
Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OAT1 and OAT3, and pravastatin, a substrate of OAT protein (OATP), may result in altered clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g., hand and foot syndrome, rash, pruritus) in patients also receiving OATP substrates.
Cobicistat: (Major) The plasma concentrations of pravastatin may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as rhabdomyolysis or GI effects, is recommended during coadministration. Cobicistat is a organic anion transporting polypeptide (OATP) inhibitor, while pravastatin is a OATP1B1 substrate.
Colchicine: (Moderate) Concomitant use of colchicine and HMG-CoA reductase inhibitors (statins) may increase the risk for myopathy and rhabdomyolysis. If concomitant use is necessary, monitor for signs and symptoms of muscle pain, tenderness, or weakness especially following therapy initiation and upward dose titration. The use of low dose colchicine may further reduce the risk for myopathy.
Colestipol: (Major) Bile acid-sequestering agents, such as colestipol, have been shown to significantly reduce serum concentrations of pravastatin. Coadministration of the bile acid-sequestering agent cholestyramine decreases the AUC of pravastatin by about 40-50%. Administering pravastatin 1 hour before or 4 hours after a dose of cholestyramine is advised if both agents are used together.
Cyclosporine: (Major) FDA-approved labeling recommends limiting the dose of pravastatin to 20 mg/day if coadministered with cyclosporine. However, guidelines recommend limiting the pravastatin dose to 40 mg/day in patients receiving cyclosporine. Concomitant administration increases the risk of myopathy and rhabdomyolysis. During pharmacokinetic trials, a single dose of cyclosporine increased the AUC and Cmax of pravastatin by 282% and 327%, respectively. However, neither myopathy nor significant increases in CPK levels have been observed in 3 reports involving 100 post-transplant (cardiac or renal) patients treated for up to 2 years with pravastatin (10 to 40 mg) and cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies.
Daclatasvir: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
Daptomycin: (Major) Temporarily suspend HMG-CoA reductase inhibitors in patients taking daptomycin as cases of rhabdomyolysis have been reported with concomitant use. Both agents can cause myopathy and rhabdomyolysis when given alone and the risk may be increased when given together.
Darolutamide: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; darolutamide is an OATP1B1/3 inhibitor.
Darunavir: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with pravastatin. If treatment with darunavir is required, consider using an alternate HMG-CoA reductase inhibitor (such as pitavastatin or fluvastatin). When concurrent administration is unavoidable, initiate pravastatin at the lowest possible dose with gradual dose increases based on clinical response. Carefully monitor for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. When pravastatin is coadministered with darunavir (in the FDA approved dosage regimen), its AUC is increased by 81% and its Cmax is increased by 63%.
Darunavir; Cobicistat: (Major) The plasma concentrations of pravastatin may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as rhabdomyolysis or GI effects, is recommended during coadministration. Cobicistat is a organic anion transporting polypeptide (OATP) inhibitor, while pravastatin is a OATP1B1 substrate. (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with pravastatin. If treatment with darunavir is required, consider using an alternate HMG-CoA reductase inhibitor (such as pitavastatin or fluvastatin). When concurrent administration is unavoidable, initiate pravastatin at the lowest possible dose with gradual dose increases based on clinical response. Carefully monitor for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. When pravastatin is coadministered with darunavir (in the FDA approved dosage regimen), its AUC is increased by 81% and its Cmax is increased by 63%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) The plasma concentrations of pravastatin may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as rhabdomyolysis or GI effects, is recommended during coadministration. Cobicistat is a organic anion transporting polypeptide (OATP) inhibitor, while pravastatin is a OATP1B1 substrate. (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with pravastatin. If treatment with darunavir is required, consider using an alternate HMG-CoA reductase inhibitor (such as pitavastatin or fluvastatin). When concurrent administration is unavoidable, initiate pravastatin at the lowest possible dose with gradual dose increases based on clinical response. Carefully monitor for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. When pravastatin is coadministered with darunavir (in the FDA approved dosage regimen), its AUC is increased by 81% and its Cmax is increased by 63%.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with elexacaftor is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; elexacaftor is an OATP1B1/3 inhibitor.
Eltrombopag: (Moderate) Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as pravastatin, may exhibit an increase in systemic exposure if coadministered with eltrombopag; monitor patients for adverse reactions if these drugs are coadministered.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) The plasma concentrations of pravastatin may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as rhabdomyolysis or GI effects, is recommended during coadministration. Cobicistat is a organic anion transporting polypeptide (OATP) inhibitor, while pravastatin is a OATP1B1 substrate.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The plasma concentrations of pravastatin may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as rhabdomyolysis or GI effects, is recommended during coadministration. Cobicistat is a organic anion transporting polypeptide (OATP) inhibitor, while pravastatin is a OATP1B1 substrate.
Enasidenib: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; enasidenib is an OATP1B1/3 inhibitor.
Encorafenib: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; encorafenib is an OATP1B1/3 inhibitor.
Erythromycin: (Moderate) Monitor for evidence of myopathy during coadministration of pravastatin and erythromycin. With concurrent therapy of erythromycin, the risk of myopathy increases. The pravastatin labeling recommends caution during concurrent use.
Etravirine: (Moderate) Concomitant use of etravirine and pravastatin has no effect on the serum concentration of pravastatin; however, the risk of myopathy, including rhabdomyolysis, may be increased when antiretrovirals are given in combination with HMG-CoA reductase inhibitors.
Everolimus: (Moderate) Carefully weigh the benefits of combined use of everolimus and pravastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Although FDA-approved labeling for everolimus state that dosage adjustments are not necessary, guidelines recommend limiting the dose of pravastatin to 40 mg/day if combined with everolimus. In a drug interaction study in healthy subjects, the pharmacokinetics of pravastatin were not significantly altered by single dose administration of everolimus.
Fenofibrate: (Moderate) Monitor for an increase in pravastatin-related adverse reactions if coadministration with fenofibrate is necessary. Concomitant use increases the risk for rhabdomyolysis and has been shown to increase the overall exposure of pravastatin by 13%.
Fenofibric Acid: (Moderate) Monitor for an increase in pravastatin-related adverse reactions if coadministration with fenofibric acid is necessary. Concomitant use increases the risk for rhabdomyolysis and has been shown to increase the overall exposure of pravastatin by 13%.
Fostemsavir: (Moderate) Monitor for pravastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) during concomitant use of fostemsavir as concurrent use may increase exposure of pravastatin. Pravastatin is a substrate for the transporters OATP1B1/3 and fostemsavir is an inhibitor of OATP1B1/3.
Gemfibrozil: (Major) Avoid concomitant use of pravastatin and gemfibrozil due to increased risk for rhabdomyolysis. The benefit of combined therapy with gemfibrozil and HMG-CoA reductase inhibitors does not outweigh the risks for most patients. If combination therapy with gemfibrozil and an HMG-CoA reductase inhibitor is necessary, consider an alternative statin. Coadministration has also been shown to increase the overall exposure of pravastatin by 2-fold; pravastatin is an OATP1B1 substrate and gemfibrozil is an OATP1B1 inhibitor.
Glecaprevir; Pibrentasvir: (Major) Reduce pravastatin dose by 50% when coadministered with glecaprevir due to an increased risk of myopathy, including rhabdomyolysis. Pravastatin is a substrate of the drug transporters OATP1B1 and OATP1B3; glecaprevir is an inhibitor of these transporters. Coadministration may increase the plasma concentrations of pravastatin. In drug interaction studies, coadministration of pravastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of pravastatin. (Major) Reduce pravastatin dose by 50% when coadministered with pibrentasvir due to an increased risk of myopathy, including rhabdomyolysis. Coadministration may increase the plasma concentrations of pravastatin. Pravastatin is a substrate of the drug transporters OATP1B1 and OATP1B3; pibrentasvir is an inhibitor of these transporters. In drug interaction studies, coadministration of pravastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of pravastatin.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with pravastatin, a CYP3A substrate, as pravastatin toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of atorvastatin, simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
Isoniazid, INH; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of atorvastatin, simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Do not exceed 40 mg per day of pravastatin if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Coadministration of clarithromycin increased the AUC and Cmax of pravastatin by 110% and 128%, respectively.
Lanthanum Carbonate: (Major) To limit absorption problems, HMG-CoA reductase inhibitors ("statins") should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like statin cholesterol treatments, may also be bound by lanthanum carbonate. Separate the times of administration appropriately. Monitor the patient's lipid profile to ensure the appropriate response to statin therapy is obtained.
Leflunomide: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Leniolisib: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with leniolisib is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; leniolisib is an OATP1B1/3 inhibitor.
Letermovir: (Moderate) Closely monitor for pravastatin-related adverse events (myopathy, rhabdomyolysis) and consider a pravastatin dose reduction if administered with letermovir. Do not exceed a pravastatin dose of 20 mg daily if the patient is also receiving cyclosporine. The magnitude of this interaction may be increased if letermovir is given with cyclosporine. Concurrent administration of letermovir, an organic anion-transporting polypeptide (OATP1B1/3) inhibitor, with pravastatin, an OATP1B1/3 substrate, may result in a clinically relevant increase in pravastatin plasma concentration.
Maralixibat: (Minor) Maralixibat may reduce the oral absorption of HMG-CoA reductase inhibitors, also known as statins, which may reduce their efficacy. This risk is greatest with maralixibat doses greater than 4.75 mg. Monitor statin therapy and adjust the dose as needed based on clinical response. Maralixibat is a OATP2B1 inhibitor and statins are OATP2B1 substrates.
Midostaurin: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; midostaurin is an OATP1B1 inhibitor.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Carefully weigh the benefits of combined use of sirolimus and pravastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of pravastatin to 40 mg/day if combined with sirolimus.
Niacin, Niacinamide: (Major) There is no clear indication for routine use of niacin in combination with pravastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with pravastatin. If coadministered, consider lower starting and maintenance does of pravastatin. Monitor patients closely for myopathy or rhabdomyolysis, particularly in the early months of treatment or after upward dose titration of either drug. Consider monitoring serum creatinine phosphokinase (CPK) and potassium periodically in such situations. Discontinue pravastatin immediately if myopathy is diagnosed or suspected.
Nitisinone: (Moderate) Monitor for increased pravastatin-related adverse effects if coadministered with nitisinone. Increased pravastatin exposure is possible. Nitisinone inhibits OAT3. Pravastatin is an OAT3 substrate.
Omeprazole; Amoxicillin; Rifabutin: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
Orlistat: (Moderate) Serum concentrations of pravastatin increased by approximately 30% when administered with orlistat in a parallel study of 24 normal-weight, mildly hypercholesterolemic subjects. Orlistat produced additive lipid-lowering effects when used concomittantly with pravastatin. However, another study failed to show any changes in pravastatin pharmacokinetics when coadministered with orlistat. Use caution and monitor patients carefully if using these drugs together.
Probenecid; Colchicine: (Moderate) Concomitant use of colchicine and HMG-CoA reductase inhibitors (statins) may increase the risk for myopathy and rhabdomyolysis. If concomitant use is necessary, monitor for signs and symptoms of muscle pain, tenderness, or weakness especially following therapy initiation and upward dose titration. The use of low dose colchicine may further reduce the risk for myopathy.
Raltegravir: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Red Yeast Rice: (Contraindicated) Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with HMG-CoA reductase inhibitors. The administration of more than one HMG-CoA reductase inhibitor at one time would be duplicative therapy and perhaps increase the risk of drug-related toxicity including myopathy and rhabdomyolysis.
Resmetirom: (Major) Limit the dose of pravastatin to 40 mg once daily during concomitant use with resmetirom. Concomitant use was observed to increase pravastatin overall exposure by 1.4-fold which may increase the risk for pravastatin-related adverse effects.
Rifabutin: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of atorvastatin, simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
Sirolimus: (Moderate) Carefully weigh the benefits of combined use of sirolimus and pravastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of pravastatin to 40 mg/day if combined with sirolimus.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of pravastatin have been shown to increase when pravastatin is administered concurrently with voxilaprevir. To prevent adverse effects, i.e., myopathy or rhabdomyolysis, the pravastatin dose should not exceed 40 mg when given with voxilaprevir. Pravastatin is a substrate of the Organic Anion Transporting Polypeptides 1B1/1B3 (OATP1B1/1B3). Voxilaprevir is an OATP1B1/1B3 inhibitor.
Sulfacetamide; Sulfur: (Moderate) HMG-CoA reductase inhibitors have been administered safely with niacin (nicotinic acid) in some patients; however the risk of potential myopathy should be considered. Rare cases of rhabdomyolysis have been reported in patients taking niacin (nicotinic acid) in lipid-altering doses (i.e., >=1 g/day) and HMG-CoA reductase inhibitors (Statins) concurrently. The serious risk of myopathy or rhabdomyolysis should be carefully weighed against the potential risks. Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy.
Tacrolimus: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and pravastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of pravastatin40 mg/day is recommended.
Teriflunomide: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Trofinetide: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; trofinetide is an OATP1B1/3 inhibitor.
Vitamin B Complex Supplements: (Major) There is no clear indication for routine use of niacin in combination with pravastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with pravastatin. If coadministered, consider lower starting and maintenance does of pravastatin. Monitor patients closely for myopathy or rhabdomyolysis, particularly in the early months of treatment or after upward dose titration of either drug. Consider monitoring serum creatinine phosphokinase (CPK) and potassium periodically in such situations. Discontinue pravastatin immediately if myopathy is diagnosed or suspected.
Voclosporin: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with voclosporin is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; voclosporin is an OATP1B1/3 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Do not exceed 40 mg per day of pravastatin if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Coadministration of clarithromycin increased the AUC and Cmax of pravastatin by 110% and 128%, respectively.
Warfarin: (Moderate) Coadministration of pravastatin (40 mg) has been reported to have no clinically significant effect on prothrombin time in normal elderly subjects previously stabilized on warfarin. However, per prescribing information for warfarin sodium (Coumadin), all HMG-CoA reductase inhibitors (statins), including pravastatin, have been associated with potentiation of warfarin's clinical effect. However, it appears that pravastatin may be less likely to significantly interact with warfarin based on drug interaction studies. In general, it is prudent to monitor INR at baseline, at initiation of pravastatin, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
Pravastatin is a reversible inhibitor of hydroxymethylglutaryl-Coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting hepatic enzyme responsible for converting HMG-CoA to mevalonate, a precursor of sterols including cholesterol. Inhibition of HMG-CoA reductase lowers the amount of mevalonate and subsequently reduces cholesterol levels in hepatic cells. This, in turn, results in upregulation of LDL-receptors and increased hepatic uptake of LDL-cholesterol (LDL-C) from the blood. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins (VLDL), the precursor for LDL. The result is a reduction of circulating total cholesterol and LDL-C. Minor effects are also seen on HDL cholesterol (increase) and triglycerides (decrease).
HMG-CoA reductase inhibitors have also been reported to decrease endogenous coeznzyme Q10 (CoQ10) serum concentrations; the clinical significance of these effects is unknown.
Pravastatin is administered orally. It is approximately 50% protein bound and undergoes extensive first-pass extraction by the liver (extraction ratio 0.66). The major metabolic pathways for pravastatin are: (a) isomerization of 6-epi pravastatin and the 3-alpha-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to the metabolite SQ 31,945. Metabolites do not possess significant clinical activity. After oral administration, roughly 20% of an oral dose is eliminated in the urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation). The elimination half-life of pravastatin in approximately 1.6 to 1.8 hours in humans and the elimination half-life for total radioactivity (pravastatin plus metabolites) is 77 hours.
Affected cytochrome P450 isoenzymes and drug transporters: OATP1B1, OATP1B3, OAT3, and MRP2
Pravastatin is a substrate for the drug transporters OATP1B1, OATP1B3, OAT3, and MRP2. In vitro and in vivo data with known CYP3A4 inhibitors suggest that pravastatin is not a clinically significant CYP3A4 substrate, in contrast to 'statins' which are primarily metabolized by the CYP3A4 isoenzyme (e.g., atorvastatin, lovastatin, simvastatin). For example, diltiazem (CYP3A4 inhibitor and substrate) has no effect on the pharmacokinetics of pravastatin. Pravastatin may be considered an alternative HMG-CoA reductase inhibitor for patients requiring therapy with potent CYP3A4 inhibitors.
-Route-Specific Pharmacokinetics
Oral Route
Pravastatin is rapidly absorbed from the GI tract. Unlike lovastatin or simvastatin, pravastatin does not require hydrolysis for activation. Peak plasma concentrations are achieved in 1 to 1.5 hours. The average absorption is 34%, but due to significant first-pass elimination (extraction ratio 0.66), bioavailability is 17%. While the presence of food reduces AUC by 31% and Cmax by 49%, the lipid-lowering effect was similar whether pravastatin was taken with or 1 hour prior to meals. Systemic bioavailability of pravastatin following a bedtime dose was 60% lower than the bioavailability following morning administration. Despite this difference in bioavailability, the efficacy of pravastatin is slightly higher (but not statistically significantly different) with evening dosing relative to morning dosing. This may be explained by more extensive uptake of the drug by hepatocytes, the site of action, and/or diurnal variation in cholesterol synthesis.
Intravenous Route
After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance occurs via renal excretion. Non-renal clearance (e.g., biliary, metabolic biotransformation) accounts for about 53% of total body clearance.
-Special Populations
Hepatic Impairment
Pravastatin undergoes extensive first-pass extraction and metabolism by the liver. Although data are limited, it appears that patients with cirrhosis display significantly altered pharmacokinetics; the effect of less severe hepatic disease is not clear. In a study comparing the pharmacokinetics of pravastatin in patients with cirrhosis (n = 7) to individuals with normal hepatic function (n = 7), pravastatin demonstrated large inter-subject pharmacokinetic variability in patients with liver cirrhosis. The mean AUC varied by 18-fold and the Cmax by 47-fold in patients with cirrhosis compared to 5-fold and 6-fold, respectively, in healthy patients. Pravastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis.
Renal Impairment
Renal impairment does not appear to affect the pharmacokinetics of pravastatin or its 3-alpha-hydroxy isomeric metabolite. However, compared to healthy individuals with normal renal function, an increase in the mean AUC and Cmax of 69% and 37%, respectively, and decrease in the half-life of the inactive enzymatic ring hydroxylation metabolite has been documented.
Pediatrics
Children and Adolescents
The pharmacokinetics of pravastatin in patients with heterozygous familial hypercholesterolemia (n = 20, age 4.9 to 15.6 years) after a single oral dose of 10 mg were similar to those of adults. The mean Cmax, AUC, and elimination half-life were 15.7 ng/mL (SD, 14.4), 26.6 ng x hour/mL (SD, 17), and 1.6 hours (SD, 0.7), respectively, compared to 11.6 ng/mL, 31.3 ng x hour/mL, and 1.8 hours in adults. There was a significant negative correlation between Cmax and age and weight, indicating that plasma concentrations of pravastatin are higher in younger and smaller patients. In another study of pravastatin 20 mg PO once daily for 2 weeks in pediatric patients 8 to 17 years of age, Cmax and AUC were 42.4 ng/mL and 80.7 ng x hour/mL, respectively, in children aged 8 to 11 years and 18.6 ng/mL and 44.8 ng x hour/mL, respectively, in adolescents aged 12 to 16 years.
Geriatric
In a single dose study using pravastatin 20 mg, the mean AUC was approximately 27% and the mean cumulative urinary excretion (CUE) approximately 19% lower in older adult men (65 to 75 years of age) compared to younger adult men (19 to 31 years of age). In a similar study conducted in women, the mean AUC was 46% higher and the mean CUE about 18% lower in older adult women (aged 65 to 78 years) compared to younger adult women (aged 18 to 38 years). However, in both studies, the mean Cmax, Tmax, and half-life were similar between older and younger adult patients; substantial accumulation of pravastatin would not be expected in adult individuals based on age.