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  • CLASSES

    HMG-CoA Reductase Inhibitors/Statins

    DEA CLASS

    Rx

    DESCRIPTION

    Oral HMG Co-A reductase inhibitor; hydrophilic; less potent than atorvastatin or simvastatin; used for hypercholesterolemia or hypertriglyceridemia; reduces LDL and total cholesterol, plasma triglycerides, and apolipoprotein B; increases HDL; improves mortality in CAD patients; FDA-approved for stroke prophylaxis.

    COMMON BRAND NAMES

    Pravachol

    HOW SUPPLIED

    Pravachol/Pravastatin/Pravastatin Sodium Oral Tab: 10mg, 20mg, 40mg, 80mg

    DOSAGE & INDICATIONS

    For the treatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary control.
    To reduce elevated total cholesterol, LDL-cholesterol, apolipoprotein B, and triglyceride concentrations, and to increase HDL-cholesterol in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson types IIa or type IIb); or to treat Fredrickson Type IV (hypertriglyceridemia, increased VLDL) or Fredrickson Type III (primary dysbetalipoproteinemia) hyperlipoproteinemias.
    Oral dosage
    Adults 19 years and older

    The recommended starting dose is 40 mg once daily. If this dose does not achieve the desired cholesterol reduction, adjust the dose in 4-week intervals. The dose range is 10 to 80 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Adolescents 14 years and older and Adults 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 8 to 12 years and Adolescents 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 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

    Initially, 40 mg PO once daily. If desired cholesterol reduction is not achieved, the dose may be increased to 80 mg PO once daily.[45507] Dosage adjustments should be made at four-week intervals. In the LIPID study, pravastatin 40 mg given once daily, reduced mortality from coronary heart disease, overall mortality, and cardiovascular events, in patients with a history of myocardial infarction or unstable angina.[25069] In the CARE trial, pravastatin 40 mg given once daily, provided a significant impact on coronary events in patients who had sustained a myocardial infarction. In addition to significant reductions in nonfatal myocardial infarction or death due to coronary heart disease, pravastatin also reduced the risk of stroke or transient ischemic attack. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    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

    Initially, 40 mg PO once daily. If desired cholesterol reduction is not achieved, the dose may be increased to 80 mg PO once daily.[45507] Dose adjustments should be made at four-week intervals. 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Contraindicated in patients with active liver disease or with unexplained or persistent hepatic transaminase elevations.

    Renal Impairment

    Dosage should be modified depending on clinical response and degree of renal impairment. A starting dose of 10 mg PO once daily is recommended in adult patients with significant renal dysfunction. Specific recommendations for dosage adjustment in pediatric patients with renal impairment are not available.
     
    Intermittent hemodialysis
    The dialyzability of pravastatin is unknown.

    ADMINISTRATION

     
     
    NOTE: Patients receiving pravastatin therapy should also be placed on a standard cholesterol-lowering diet, and this diet should be continued throughout therapy. Serum lipoprotein concentrations should be determined periodically and dosage adjusted according to individual response and established NCEP treatment guidelines.

    Oral Administration

    Pravastatin may be taken without regard to meals.
    Pravastatin may be taken once-daily. HMG-CoA reductase inhibitors are generally proposed to be most effective when administered at bedtime due to diurnal variation in hepatic cholesterol synthesis. However, 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.

    STORAGE

    Pravachol:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Pravastatin is contraindicated in any patient with pravastatin hypersensitivity or hypersensitive to any component of the medication.

    Alcoholism, hepatic disease, hepatic encephalopathy, hepatitis, jaundice

    Pravastatin is contraindicated in patients with active hepatic disease (e.g., hepatic encephalopathy, active hepatitis, jaundice) or unexplained persistent elevations in serum aminotransferase concentrations. Assess liver function tests (LFTs) prior to initiation of pravastatin therapy and repeat as clinically indicated. Caution should be exercised when pravastatin is administered to patients who have a recent history (less than 6 months) of liver disease, have signs that may suggest active liver disease (e.g., unexplained aminotransferase elevations), have alcoholism or are heavy users of alcohol. Patients with a history of hepatic impairment should be closely monitored and started at the lower end of the recommended dosage range; titrate the dose to the desired therapeutic effect. 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 interrupted. If an alternate etiology is not found, do not restart pravastatin.

    Electrolyte imbalance, endocrine disease, females, hypotension, hypothyroidism, infection, myopathy, organ transplant, renal disease, renal failure, renal impairment, rhabdomyolysis, seizure disorder, surgery, trauma

    Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the ULN, was rare (less than 0.1%) in pravastatin clinical trials. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of creatine phosphokinase (CPK). Patients should be advised to promptly report to their physician any unexplained and/or persistent muscle pain, tenderness, or weakness. Pravastatin therapy should be discontinued if myopathy or rhabdomyolysis is diagnosed or suspected. Pravastatin may be contraindicated or temporarily withheld in conditions that can cause decreased renal perfusion since renal failure is possible if pravastatin-induced myopathy and rhabdomyolysis occurs. Predisposing risk factors for myopathy and/or rhabdomyolysis include renal disease or renal insufficiency, females, advanced age, hypotension, acute infection, endocrine disease such as uncontrolled hypothyroidism, electrolyte imbalance, uncontrolled seizure disorder, major surgery, and trauma. The risk of developing myopathy is increased when HMG-CoA reductase inhibitors are used in combination with selected other drugs. The risk of myopathy during treatment with statins is increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or fibrates and selected other medications. Patients with organ transplant receiving cyclosporine or other immunosuppressive agents may also be at risk. Pravastatin dosage adjustment is needed in patients with severe renal impairment. The manufacturer recommends a lower starting dose (10 mg/day PO) for patients with significant renal impairment. Renal impairment does not appear to effect the pharmacokinetics of pravastatin or its 3-alpha-hydroxy isomeric metabolite; however, a small increase in the mean AUC and half-life has been documented for the inactive enzymatic ring hydroxylation metabolite.

    Diabetes mellitus

    If pravastatin is initiated in a patient with diabetes, increased monitoring of blood glucose control may be warranted. The usual recommended starting dose of pravastatin extended-release should be limited to 20 mg/day PO in patients with complicated medical conditions (renal insufficiency, diabetes); higher doses should be used only after careful consideration of the potential risks and benefits. Increased hemoglobin A1c, hyperglycemia, and worsening glycemic control have been reported during therapy with HMG-CoA reductase inhibitors. 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 mellitus 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. Although an analysis of participants from the JUPITER trial found an increased incidence of developing diabetes in patients allocated to rosuvastatin compared to placebo (270 reports of diabetes vs. 216 in the placebo group; HR 1.25, 95% CI 1.05 to 1.49, p = 0.01), the cardiovascular and mortality benefits of statin therapy exceeded the diabetes hazard even in patients at high risk for developing diabetes (i.e., patients with one or more major diabetes risk factor: metabolic syndrome, impaired fasting glucose, BMI 30 kg/m2 or more, or HbA1c more than 6%). In patients at high risk for developing diabetes, treatment with rosuvastatin was associated with a 39% reduction in the primary endpoint (composite of non-fatal myocardial infarction, non-fatal stroke, unstable angina or revascularization, and cardiovascular death) (HR 0.61, 95% CI 0.47 to 0.79, p = 0.0001), nonsignificant reductions in venous thromboembolism (VTE) (HR 0.64, CI 0.39 to 1.06, p = 0.08) and total mortality (HR 0.83, CI 0.64 to 1.07, p = 0.15), and a 28% increase in diabetes (HR 1.28, CI 1.07 to 1.54, p = 0.01). In patients with no major diabetes risk factor, treatment with rosuvastatin was associated with a 52% reduction in the primary endpoint (HR 0.48, 95% CI 0.33 to 0.68, p = 0.0001), nonsignificant reductions in VTE (HR 0.47, 0.21—1.03, p = 0.05) and total mortality (HR 0.78, CI 0.59 to 1.03, p = 0.08), and no increase in diabetes (HR 0.99, CI 0.45 to 2.21, p = 0.99). For those at high risk for developing diabetes, 134 total cardiovascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. In those without major risk factors, 86 total cardiovascular events or deaths were avoided with no excess new cases of diabetes diagnosed.

    Immune-mediated necrotizing myopathy

    Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred with HMG-CoA reductase inhibitors, such as atorvastatin. IMNM is characterized by proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Statin-induced IMNM is a rare event making it difficult to determine the true incidence of this adverse reaction; however, available literature reports a range of 1 to 3 of every 100,000 patients treated with an HMG-CoA reductase inhibitor develop IMNM. Based on the available data, patients with IMNM have myalgia with symmetrical and proximal weakness that occurs months to years after starting HMG-CoA reductase therapy and the myopathy persists or even progress following therapy discontinuation. 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.    Prior to starting the patient on another HMG-CoA reductase inhibitor, the risks of therapy should be carefully considered. Any patient started on an alternate HMG-CoA reductase inhibitor should be monitored for signs and symptoms of IMNM.

    Pregnancy

    Pravastatin is contraindicated for use during pregnancy and should be administered to females of childbearing potential only when such patients are highly unlikely to conceive because of the potential effects of HMG-CoA reductase inhibitors on cholesterol pathways and the potential for fetal harm. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Treatment should be immediately discontinued as soon as pregnancy is recognized. 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. In a prospective review of about 100 pregnancies in women exposed to simvastatin or lovastatin, the incidence of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. In 89% of the pregnancies, drug treatment was initiated prior to pregnancy and discontinued during the first trimester. 

    Contraception requirements, reproductive risk

    Discuss the reproductive risk of pravastatin with females patients of childbearing potential. Pravastatin use may cause fetal harm when administered to a pregnant woman. Contraception requirements are suggested; advise females of reproductive potential to use effective contraception during treatment with pravastatin. The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately.

    Breast-feeding

    Pravastatin is contraindicated in breast-feeding women. Limited data suggest pravastatin is present in human milk. There are no data on the effects of pravastatin on the breastfed infant or the effects 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. Advise patients that breastfeeding is not recommended during pravastatin therapy due to potential for serious adverse reactions in a breastfed infant. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should 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.

    Children, infants

    The safety and efficacy of pravastatin have not been established for infants or children less 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.

    Geriatric

    Since advanced age (65 years or more) is a predisposing factor for myopathy, pravastatin should be prescribed with caution in geriatric patients. Older adult patients 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 elderly patients, based on cumulative data from various clinical trials, including the LIPID trials. The mean exposure (AUC) for pravastatin is slightly higher (25% to 50%) in healthy elderly subjects than in healthy younger subjects, but other pharmacokinetic parameters are similar. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, HMG-CoA reductase inhibitors may impair liver function, and liver function monitoring should occur consistent with individual manufacturer recommendations (e.g., baseline, 12 weeks after initiation, after any dose increase, and periodically thereafter). HMG-CoA reductase inhibitors may cause myalgia, myopathy, and rhabdomyolysis that can precipitate kidney failure, particularly in combination with other cholesterol-lowering medications.

    Myasthenia gravis

    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.

    ADVERSE REACTIONS

    Severe

    hepatoma / Delayed / 0-1.0
    hepatic necrosis / Delayed / 0-1.0
    hepatic failure / Delayed / 0-1.0
    cirrhosis / Delayed / 0-1.0
    immune-mediated necrotizing myopathy / Delayed / 0-1.0
    rhabdomyolysis / Delayed / 0-0.1
    renal failure (unspecified) / Delayed / Incidence not known
    myoglobinuria / Delayed / Incidence not known
    renal tubular obstruction / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    myasthenia gravis / Delayed / Incidence not known

    Moderate

    angina / Early / 0.1-3.1
    chest pain (unspecified) / Early / 0.3-2.6
    constipation / Delayed / 1.2-2.4
    dyspnea / Early / 1.6-1.6
    blurred vision / Early / 1.6-1.6
    elevated hepatic enzymes / Delayed / 0-1.2
    myasthenia / Delayed / 0-1.0
    memory impairment / Delayed / 0-1.0
    depression / Delayed / 1.0-1.0
    edema / Delayed / 0-1.0
    dysuria / Early / 0.7-1.0
    cataracts / Delayed / 0-1.0
    myopathy / Delayed / 0-0.1
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    confusion / Early / Incidence not known
    eosinophilia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    interstitial lung disease / Delayed / Incidence not known

    Mild

    musculoskeletal pain / Early / 1.4-6.0
    pyrosis (heartburn) / Early / 2.0-3.5
    dyspepsia / Early / 2.0-3.5
    fatigue / Early / 1.9-3.4
    flatulence / Early / 1.2-2.7
    dizziness / Early / 1.0-2.2
    rash / Early / 1.3-2.1
    diarrhea / Early / 2.0-2.0
    abdominal pain / Early / 1.6-2.0
    nausea / Early / 1.6-2.0
    vomiting / Early / 1.6-2.0
    muscle cramps / Delayed / 2.0-2.0
    headache / Early / 1.7-1.9
    diplopia / Early / 1.6-1.6
    myalgia / Early / 0.6-1.4
    infection / Delayed / 1.3-1.3
    anorexia / Delayed / 0-1.0
    vertigo / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    insomnia / Early / 0-1.0
    anxiety / Delayed / 1.0-1.0
    tremor / Early / 0-1.0
    urticaria / Rapid / 0-1.0
    alopecia / Delayed / 0-1.0
    xerosis / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    cough / Delayed / 0.1-1.0
    nocturia / Early / 0.7-1.0
    libido increase / Delayed / 0-1.0
    libido decrease / Delayed / 0-1.0
    increased urinary frequency / Early / 0.7-1.0
    flushing / Rapid / 0-1.0
    fever / Early / 0-1.0
    rhinitis / Early / 0.1-0.1
    dysgeusia / Early / Incidence not known
    weakness / Early / Incidence not known
    drowsiness / Early / Incidence not known
    nightmares / Early / Incidence not known
    chills / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    purpura / Delayed / Incidence not known
    malaise / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    influenza / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known
    Co-Enzyme Q-10 deficiency / Delayed / Incidence not known

    DRUG INTERACTIONS

    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.
    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.
    Boceprevir: (Moderate) Pravastatin systemic exposure is increased when coadministered with boceprevir. According to the manufacturer, dose modifications are not required during concomitant use; however, close clinical monitoring for pravastatin-related adverse events is advised.
    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: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    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: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
    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%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Adult doses of pravastatin must be limited to no more than 40 mg/day when administered with paritaprevir-containing regimens. The dose should be re-adjusted after completion of the hepatitis C treatment regimen. Monitor for pravastatin related adverse events, such as myopathy or rhabdomyolysis. Use of these drugs together results in elevated pravastatin serum concentrations.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for pravastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) during coadministration of elexacaftor; tezacaftor; ivacaftor as concurrent use may increase exposure of pravastatin. Pravastatin is a substrate for the transporters OATP1B1 and OATP1B3; elexacaftor; tezacaftor; ivacaftor may inhibit uptake of OATP1B1 and OATP1B3.
    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.
    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.
    Erythromycin; Sulfisoxazole: (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: (Major) The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is generally increased with concurrent therapy with fibric acid derivatives. The use of fibrates alone may occasionally be associated with myopathy. Combination therapy with pravastatin and gemfibrozil is generally not recommended. The combined use of pravastatin and fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. Preliminary data suggest that the addition of gemfibrozil to therapy with pravastatin is not associated with greater reduction in LDL-cholesterol than that achieved with pravastatin alone. Pravastatin and gemfibrozil have been administered together in a study of 290 patients, with two patients developing asymptomatic elevations of CPK; severe myopathy was not observed, although muscle biopsies were not performed. In addition, a trial of pravastatin (40 mg/day) coadministration with gemfibrozil (1200 mg/day) has not been shown to be associated with myopathy, although 4 of 75 patients receiving the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. A trend has been reported toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared to the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. In a crossover study in 20 healthy male volunteers given concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. In addition, there was a significant increase in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906.
    Fenofibric Acid: (Major) The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is generally increased with concurrent therapy with fibric acid derivatives. The use of fibrates alone may occasionally be associated with myopathy. Combination therapy with pravastatin and gemfibrozil is generally not recommended. The combined use of pravastatin and fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. Preliminary data suggest that the addition of gemfibrozil to therapy with pravastatin is not associated with greater reduction in LDL-cholesterol than that achieved with pravastatin alone. Pravastatin and gemfibrozil have been administered together in a study of 290 patients, with two patients developing asymptomatic elevations of CPK; severe myopathy was not observed, although muscle biopsies were not performed. In addition, a trial of pravastatin (40 mg/day) coadministration with gemfibrozil (1200 mg/day) has not been shown to be associated with myopathy, although 4 of 75 patients receiving the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. A trend has been reported toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared to the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. In a crossover study in 20 healthy male volunteers given concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. In addition, there was a significant increase in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906.
    Fibric acid derivatives: (Major) The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is generally increased with concurrent therapy with fibric acid derivatives. The use of fibrates alone may occasionally be associated with myopathy. Combination therapy with pravastatin and gemfibrozil is generally not recommended. The combined use of pravastatin and fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. Preliminary data suggest that the addition of gemfibrozil to therapy with pravastatin is not associated with greater reduction in LDL-cholesterol than that achieved with pravastatin alone. Pravastatin and gemfibrozil have been administered together in a study of 290 patients, with two patients developing asymptomatic elevations of CPK; severe myopathy was not observed, although muscle biopsies were not performed. In addition, a trial of pravastatin (40 mg/day) coadministration with gemfibrozil (1200 mg/day) has not been shown to be associated with myopathy, although 4 of 75 patients receiving the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. A trend has been reported toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared to the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. In a crossover study in 20 healthy male volunteers given concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. In addition, there was a significant increase in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906.
    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) The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is generally increased with concurrent therapy with fibric acid derivatives. The use of fibrates alone may occasionally be associated with myopathy. Combination therapy with pravastatin and gemfibrozil is generally not recommended. The combined use of pravastatin and fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. Preliminary data suggest that the addition of gemfibrozil to therapy with pravastatin is not associated with greater reduction in LDL-cholesterol than that achieved with pravastatin alone. Pravastatin and gemfibrozil have been administered together in a study of 290 patients, with two patients developing asymptomatic elevations of CPK; severe myopathy was not observed, although muscle biopsies were not performed. In addition, a trial of pravastatin (40 mg/day) coadministration with gemfibrozil (1200 mg/day) has not been shown to be associated with myopathy, although 4 of 75 patients receiving the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. A trend has been reported toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared to the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. In a crossover study in 20 healthy male volunteers given concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. In addition, there was a significant increase in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906.
    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.
    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.
    Lovastatin; Niacin: (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.
    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.
    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.
    Niacin; Simvastatin: (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.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Adult doses of pravastatin must be limited to no more than 40 mg/day when administered with paritaprevir-containing regimens. The dose should be re-adjusted after completion of the hepatitis C treatment regimen. Monitor for pravastatin related adverse events, such as myopathy or rhabdomyolysis. Use of these drugs together results in elevated pravastatin serum concentrations.
    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: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
    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.
    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.
    Simeprevir: (Moderate) Although coadministration of pravastatin with simeprevir has not been studied, use of these drugs together is expected to increase pravastatin exposure. If these drugs are given together, titrate the pravastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    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.
    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.
    Telbivudine: (Moderate) The risk of myopathy may be increased if an HMG-CoA reductase inhibitor is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Telithromycin: (Major) Pravastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1. Coadministration of pravastatin with inhibitors of OATP, such as telithromycin may theoretically result in increased concentrations of pravastatin.
    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.
    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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Pravastatin is contraindicated for use during pregnancy and should be administered to females of childbearing potential only when such patients are highly unlikely to conceive because of the potential effects of HMG-CoA reductase inhibitors on cholesterol pathways and the potential for fetal harm. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Treatment should be immediately discontinued as soon as pregnancy is recognized. 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. In a prospective review of about 100 pregnancies in women exposed to simvastatin or lovastatin, the incidence of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. In 89% of the pregnancies, drug treatment was initiated prior to pregnancy and discontinued during the first trimester. 

    Pravastatin is contraindicated in breast-feeding women. Limited data suggest pravastatin is present in human milk. There are no data on the effects of pravastatin on the breastfed infant or the effects 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. Advise patients that breastfeeding is not recommended during pravastatin therapy due to potential for serious adverse reactions in a breastfed infant. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should 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.

    MECHANISM OF ACTION

    Mechanism of Action: Pravastatin is a selective, competitive 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 from the circulation. In addition, pravastatin inhibits hepatic synthesis of VLDL, the precursor for LDL. The result is a reduction of circulating total cholesterol and LDL cholesterol. Minor effects are also seen on HDL cholesterol (increase) and triglycerides (decrease). HMG-CoA reductase inhibitors are generally proposed to be most effective when administered at bedtime due to diurnal variation in hepatic cholesterol synthesis. However, 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 dosing.
     
    HMG-CoA reductase inhibitors have also been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.

    PHARMACOKINETICS

    Pravastatin is administered orally. While administration in the evening results in lower systemic bioavailability, the efficacy is slightly higher (but not 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 the diurnal variation in cholesterol synthesis. Protein binding is approximately 50%. Pravastatin undergoes extensive first-pass extraction and metabolism by the liver. Roughly 20% of a dose is eliminated in the urine and 70% in the feces. Metabolites do not possess clinical activity.
     
    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.
     

    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%. The presence of food reduces bioavailability further, but no difference in the lipid-lowering effect was detected between patients receiving pravastatin with meals compared with those receiving it 1 hour before meals. Pravastatin is relatively more hydrophilic than the other agents. Bioavailability data can be misleading with drugs like pravastatin.

    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.