PRAVASTATIN SODIUM tablet

Drug Labeling and Warnings

Drug Details [pdf]

Secondary Prevention of Cardiovascular Events

In patients with clinically evident coronary heart disease, Pravastatin Sodium Tablets are indicated to:

  • - Reduce the risk of total mortality by reducing coronary death
  • - Reduce the risk of myocardial infarction
  • - Reduce the risk of undergoing myocardial revascularization procedures
  • - Reduce the risk of stroke and stroke/transient ischemic attack (TIA)
  • - Slow the progression of coronary atherosclerosis.

    • Hyperlipidemia

    Pravastatin Sodium Tablets are indicated as an adjunct to diet to reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb).8

    Pravastatin Sodium Tablets are indicated as adjunctive therapy to diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson Type IV).

    Pravastatin Sodium Tablets are indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.

    Pravastatin Sodium Tablets are indicated as an adjunct to diet and lifestyle modification for treatment of HeFH in children and adolescent patients ages 8 years and older if after an adequate trial of diet the following findings are present:

    1. LDL-C remains ≥190 mg/dL or
    2. LDL-C remains ≥160 mg/dL and:
      • there is a positive family history of premature cardiovascular disease or
      • two or more other CVD risk factors are present in the patient.

    Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when the response to diet and other nonpharmacological measures alone has been inadequate (see NCEP Guidelines below).

    Prior to initiating therapy with pravastatin, secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure Total-C, HDL-C, and TG. For patients with triglycerides (TG) <400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation:

    LDL-C = Total-C - HDL-C - 1/5 TG

    For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In many hypertri­glyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such cases, HMG-CoA reductase inhibitors are not indicated.

    Lipid determinations should be performed at intervals of no less than four weeks and dosage adjusted according to the patient’s response to therapy.

    The National Cholesterol Education Program’s Treatment Guidelines are summarized below:

    Table 7: NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories
    Risk CategoryLDL Goal (mg/dL)LDL Level at Which to Initiate Therapeutic Lifestyle Changes
    (mg/dL)    		LDL Level at Which to Consider Drug Therapy
    (mg/dL)
    a  CHD, coronary heart disease.
    b  Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgement also may call for deferring drug therapy in this subcategory.
    c  Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.
    CHDa or CHD risk
    equivalents
    (10-year risk >20%)    		<100≥100≥130
    (100-129: drug optional)b
    2+ Risk factors
    (10-year risk ≤20 %)    		<130≥13010-year risk 10%-20%:≥130
    10-year risk <10%: ≥160
    0-1 Risk factorc<160≥160≥190
    (160-189: LDL-lowering
    drug optional)

    After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (Total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.

    At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines, above).

    Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the Total-C be used to monitor therapy.

    As with other lipid-lowering therapy, Pravastatin Sodium Tablets are not indicated when hypercholesterolemia is due to hyperalphalipoproteinemia (elevated HDL-C).

    The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below:

    CategoryTotal-C (mg/dL)LDL-C (mg/dL)
    Acceptable
    Borderline
    High    		<170
    170-199
    ≥200    		<110
    110-129
    ≥130
  • CONTRAINDICATIONS

    Hypersensitivity to any component of this medication.

    Active liver disease or unexplained, persistent elevations of serum transaminases (see WARNINGS).

    Pregnancy and Lactation. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they are contraindicated during pregnancy and in nursing mothers. Pravastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus (see PRECAUTIONS: Pregnancy).

  • WARNINGS

    Liver Enzymes

    HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. In three long-term (4.8-5.9 years), placebo-controlled clinical trials (WOS, LIPID, CARE; see CLINICAL PHARMACOLOGY: Clinical Studies), 19,592 subjects (19,768 randomized), were exposed to pravastatin or placebo. In an analysis of serum transaminase values (ALT, AST), incidences of marked abnormalities were compared between the pravastatin and placebo treatment groups; a marked abnormality was defined as a post-treatment test value greater than three times the upper limit of normal for subjects with pretreatment values less than or equal to the upper limit of normal, or four times the pretreatment value for subjects with pretreatment values greater than the upper limit of normal but less than 1.5 times the upper limit of normal. Marked abnormalities of ALT or AST occurred with similar low frequency (≤1.2%) in both treatment groups. 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. In a 320-patient placebo-controlled clinical trial, subjects with chronic (>6 months) stable liver disease, due primarily to hepatitis C or non-alcoholic fatty liver disease, were treated with 80 mg pravastatin or placebo for up to 9 months. The primary safety endpoint was the proportion of subjects with at least one ALT ≥2 times the upper limit of normal for those with normal ALT (≤ the upper limit of normal) at baseline or a doubling of the baseline ALT for those with elevated ALT (> the upper limit of normal) at baseline. By Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the prespecified safety ALT endpoint compared to 20 out of 160 (12.5%) subjects receiving placebo. Conclusions regarding liver safety are limited since the study was not large enough to establish similarity between groups (with 95% confidence) in the rates of ALT elevation.

    It is recommended that liver function tests be performed prior to the initiation of therapy and when clinically indicated.

    Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of pravastatin (see CONTRAINDICATIONS). Caution should be exercised when pravastatin is administered to patients who have a recent (<6 months) history of liver disease, have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol (see CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism). Such patients should be closely monitored, started at the lower end of the recommended dosing range (see DOSAGE AND ADMINISTRATION: Adult Patients), and titrated to the desired therapeutic effect.

    Patients who develop increased transaminase levels or signs and symptoms of active liver disease while taking pravastatin should be evaluated with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of pravastatin therapy is recommended.

    Skeletal Muscle

    Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and other drugs in this class. Uncomplicated myalgia has also been reported in pravastatin-treated patients (see ADVERSE REACTIONS). 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, was rare (<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 CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Pravastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Pravastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

    The risk of myopathy during treatment with another HMG-CoA reductase inhibitor is increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or fibrates. However, neither myopathy nor significant increases in CPK levels have been observed in three reports involving a total of 100 post-transplant patients (24 renal and 76 cardiac) treated for up to two years concurrently with pravastatin 10-40 mg and cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies. Further, in clinical trials involving small numbers of patients who were treated concurrently with pravastatin and niacin, there were no reports of myopathy. Also, myopathy was not reported in a trial of combination pravastatin (40 mg/day) and gemfibrozil (1200 mg/day), although 4 of 75 patients on the combination showed marked CPK elevations versus one of 73 patients receiving placebo. There was a trend toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared with the groups receiving placebo, gemfibrozil, or pravastatin monotherapy (see PRECAUTIONS: Drug Interactions). The use of fibrates alone may occasionally be associated with myopathy. 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.

  • PRECAUTIONS

    General

    Pravastatin Sodium Tablets may elevate creatine phosphokinase and transaminase levels (see ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with pravastatin.

    Homozygous Familial Hypercholesterolemia. Pravastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. In this group of patients, it has been reported that HMG-CoA reductase inhibitors are less effective because the patients lack functional LDL receptors.

    Renal Insufficiency. A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). A small increase was seen in mean AUC values and half-life (t½) for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945). Given this small sample size, the dosage administered, and the degree of individual variability, patients with renal impairment who are receiving pravastatin should be closely monitored.

    Information for Patients

    Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever (see WARNINGS: Skeletal Muscle).

    Drug Interactions

    Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin: See WARNINGS: Skeletal Muscle.

    Cytochrome P450 3A4 Inhibitors: In vitro and in vivo data indicate that pravastatin is not metabolized by cytochrome P450 3A4 to a clinically significant extent. This has been shown in studies with known cytochrome P450 3A4 inhibitors (see Diltiazem and Itraconazole below). Other examples of cytochrome P450 3A4 inhibitors include ketoconazole, mibefradil, and erythromycin.

    Diltiazem: Steady-state levels of diltiazem (a known, weak inhibitor of P450 3A4) had no effect on the pharmacokinetics of pravastatin. In this study, the AUC and Cmax of another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome P450 3A4 increased by factors of 3.6 and 4.3, respectively.

    Itraconazole: The mean AUC and Cmax for pravastatin were increased by factors of 1.7 and 2.5, respectively, when given with itraconazole (a potent P450 3A4 inhibitor which also inhibits p-glycoprotein transport) as compared to placebo. The mean t½ was not affected by itraconazole, suggesting that the relatively small increases in Cmax and AUC were due solely to increased bioavailability rather than a decrease in clearance, consistent with inhibition of p-glycoprotein transport by itraconazole. This drug transport system is thought to affect bioavailability and excretion of HMG-CoA reductase inhibitors, including pravastatin. The AUC and Cmax of another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome P450 3A4 increased by factors of 19 and 17, respectively, when given with itraconazole.

    Antipyrine: Since concomitant administration of pravastatin had no effect on the clearance of antipyrine, interactions with other drugs metabolized via the same hepatic cytochrome isozymes are not expected.

    Cholestyramine/Colestipol: Concomitant administration resulted in an approximately 40 to 50% decrease in the mean AUC of pravastatin. However, when pravastatin was administered 1 hour before or 4 hours after cholestyramine or 1 hour before colestipol and a standard meal, there was no clinically significant decrease in bioavailability or therapeutic effect. (See DOSAGE AND ADMINISTRATION: Concomitant Therapy.)

    Warfarin: Concomitant administration of 40 mg pravastatin had no clinically significant effect on prothrombin time when administered in a study to normal elderly subjects who were stabilized on warfarin.

    Cimetidine: The AUC0-12 hr for pravastatin when given with cimetidine was not significantly different from the AUC for pravastatin when given alone. A significant difference was observed between the AUC’s for pravastatin when given with cimetidine compared to when administered with antacid.

    Digoxin: In a crossover trial involving 18 healthy male subjects given 20 mg pravastatin and 0.2 mg digoxin concurrently for 9 days, the bioavailability parameters of digoxin were not affected. The AUC of pravastatin tended to increase, but the overall bioavailability of pravastatin plus its metabolites SQ 31,906 and SQ 31,945 was not altered.

    Cyclosporine: Some investigators have measured cyclosporine levels in patients on pravastatin (up to 20 mg), and to date, these results indicate no clinically meaningful elevations in cyclosporine levels. In one single-dose study, pravastatin levels were found to be increased in cardiac transplant patients receiving cyclosporine.

    Gemfibrozil: 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. Combination therapy with pravastatin and gemfibrozil is generally not recommended. (See WARNINGS: Skeletal Muscle.)

    In interaction studies with aspirin, antacids (1 hour prior to Pravastatin Sodium Tablets), cimetidine, nicotinic acid, or probucol, no statistically significant differences in bioavailability were seen when Pravastatin Sodium Tablets were administered.

    Endocrine Function

    HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials with pravastatin in males and post-menopausal females were inconsistent with regard to possible effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone response to human chorionic gonadotropin was significantly reduced (p<0.004) after 16 weeks of treatment with 40 mg of pravastatin. However, the percentage of patients showing a ≥50% rise in plasma testosterone after human chorionic gonadotropin stimulation did not change significantly after therapy in these patients. The effects of HMG-CoA reductase inhibitors 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. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may diminish the levels or activity of steroid hormones.

    In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were treated with pravastatin (20 mg in the children aged 8-13 years and 40 mg in the adolescents aged 14-18 years) for two years, there were no detectable differences seen in any of the endocrine parameters [ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol (girls) or testosterone (boys)] relative to placebo. There were no detectable differences seen in height and weight changes, testicular volume changes, or Tanner score relative to placebo.

    CNS Toxicity

    CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at approximately 59 times the human dose of 80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other drugs in this class.

    A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

    Carcinogenesis, Mutagenesis, Impairment of Fertility

    In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area mg/m2 and at approximately 4 times the human dose, based on AUC.

    In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the human dose of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the human dose of 80 mg, based on AUC), there were no drug-induced tumors.

    No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/- mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.

    In a study in rats, with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. However, in a study with another HMG-CoA reductase inhibitor, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. Although not seen with pravastatin, two similar drugs in this class caused drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration, and giant cell formation in dogs. The clinical significance of these findings is unclear.

    Pregnancy

    Pregnancy Category X.

    See CONTRAINDICATIONS.

    Safety in pregnant women has not been established. Pravastatin was not teratogenic in rats at doses up to 1000 mg/kg daily or in rabbits at doses of up to 50 mg/kg daily. These doses resulted in 10X (rabbit) or 120X (rat) the human exposure based on surface area (mg/meter2). Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review9 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a three- to four-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with Pravastatin Sodium Tablets during pregnancy (see CONTRAINDICATIONS), treatment should be immediately discontinued as soon as pregnancy is recognized. Pravastatin Sodium Tablets should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards.

    Nursing Mothers

    A small amount of pravastatin is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants, women taking Pravastatin Sodium Tablets should not nurse (see CONTRAINDICATIONS).

    Pediatric Use

    The safety and effectiveness of Pravastatin Sodium Tablets in children and adolescents from 8-18 years of age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that of patients treated with placebo with influenza and headache commonly reported in both treatment groups. (See ADVERSE REACTIONS: Pediatric Patients.) Doses greater than 40 mg have not been studied in this population. Children and adolescent females of childbearing potential should be counseled on appropriate contraceptive methods while on pravastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS: Pregnancy). For dosing information see DOSAGE AND ADMINISTRATION: Adult Patients and Pediatric Patients.

    Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted.

    Geriatric Use

    Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these two studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the elderly was similar to that in the overall population. Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients.

    Mean pravastatin AUCs are slightly (25-50%) higher in elderly subjects than in healthy young subjects, but mean Cmax, Tmax and t½ values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly (see CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism).

  • ADVERSE REACTIONS

    Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient. In 4-month-long placebo-controlled trials, 1.7% of pravastatin-treated patients and 1.2% of placebo-treated patients were discontinued from treatment because of adverse experiences attributed to study drug therapy; this difference was not statistically significant. (See also PRECAUTIONS: Geriatric Use.)

    Adverse Clinical Events

    Short-Term Controlled Trials

    All adverse clinical events (regardless of attribution) reported in more than 2% of pravastatin-treated patients in placebo-controlled trials of up to four months duration are identified in Table 8; also shown are the percentages of patients in whom these medical events were believed to be related or possibly related to the drug:

    Table 8: Adverse Events in >2 Percent of Patients Treated with Pravastatin 10-40 mg in Short-Term Placebo-Controlled Trials
     All EventsEvents Attributed
    to Study Drug
    Body System/EventPravastatin
    (N=900)
    % of patients    		Placebo
    (N=411)
    % of patients    		Pravastatin
    (N=900)
    % of patients    		Placebo
    (N=411)
    % of patients
    *Statistically significantly different from placebo.
    Cardiovascular
        Cardiac Chest Pain    		4.03.40.10.0
    Dermatologic
        Rash    		4.0*1.11.30.9
    Gastrointestinal
        Nausea/Vomiting
        Diarrhea
        Abdominal Pain
        Constipation
        Flatulence
        Heartburn
    7.3
    6.2
    5.4
    4.0
    3.3
    2.9
    7.1
    5.6
    6.9
    7.1
    3.6
    1.9
    2.9
    2.0
    2.0
    2.4
    2.7
    2.0
    3.4
    1.9
    3.9
    5.1
    3.4
    0.7
    General
        Fatigue
        Chest Pain
        Influenza    		3.8
    3.7
    2.4*    		3.4
    1.9
    0.7    		1.9
    0.3
    0.0    		1.0
    0.2
    0.0
    Musculoskeletal
        Localized Pain
        Myalgia    		10.0
    2.7    		9.0
    1.0    		1.4
    0.6    		1.5
    0.0
    Nervous System
        Headache
        Dizziness    		6.2
    3.3    		3.9
    3.2    		1.7*
    1.0    		0.2
    0.5
    Renal/Genitourinary
        Urinary Abnormality    		2.42.90.71.2
    Respiratory
        Common Cold
        Rhinitis
        Cough    		7.0
    4.0
    2.6    		6.3
    4.1
    1.7    		0.0
    0.1
    0.1    		0.0
    0.0
    0.0

    The safety and tolerability of Pravastatin Sodium Tablets at a dose of 80 mg in two controlled trials with a mean exposure of 8.6 months was similar to that of Pravastatin Sodium Tablets at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10X ULN compared to 0 out of 115 patients taking 40 mg of pravastatin.

    Long-Term Controlled Morbidity and Mortality Trials

    Adverse event data were pooled from seven double-blind, placebo-controlled trials (West of Scotland Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin group was comparable to that of the placebo group. Patients were exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these seven trials represent 47,613 patient-years of exposure to pravastatin. Events believed to be of probable, possible, or uncertain relationship to study drug, occurring in at least 1% of patients treated with pravastatin in these studies are identified in Table 9.

    Table 9: Adverse Events in ≥1 Percent of Patients Treated with Pravastatin 40 mg in Long-Term Placebo-Controlled Trials
    Body System/EventPravastatin
    (N=10,764)
    % of patients    		Placebo
    (N=10,719)
    % of patients
    Cardiovascular
        Angina Pectoris    		3.13.4
    Dermatologic
        Rash    		2.12.2
    Gastrointestinal
        Dyspepsia/Heartburn
        Abdominal Pain
        Nausea/Vomiting
        Flatulence
        Constipation
    3.5
    2.4
    1.6
    1.2
    1.2
    3.7
    2.5
    1.6
    1.1
    1.3
    General
        Fatigue
        Chest Pain    		3.4
    2.6    		3.3
    2.6
    Musculoskeletal
        Musculoskeletal Pain (includes arthralgia)
        Muscle Cramp
        Myalgia    		6.0
    2.0
    1.4    		5.8
    1.8
    1.4
    Nervous System
        Dizziness
        Headache
        Sleep Disturbance
        Depression
        Anxiety/Nervousness    		2.2
    1.9
    1.0
    1.0
    1.0    		2.1
    1.8
    0.9
    1.0
    1.2
    Renal/Genitourinary
        Urinary Abnormality (includes dysuria, frequency, nocturia)    		1.00.8
    Respiratory
        Dyspnea
        Upper Respiratory Infection
        Cough
    1.6
    1.3
    1.0
    1.6
    1.3
    1.0
    Special Senses
        Vision Disturbance (includes blurred vision, diplopia)    		1.61.3

    Events of probable, possible, or uncertain relationship to study drug that occurred in <1.0% of pravastatin-treated patients in the long-term trials included the following; frequencies were similar in placebo-treated patients:

    Dermatologic: pruritus, dermatitis, dryness skin, scalp hair abnormality (including alopecia), urticaria.

    Endocrine/Metabolic: sexual dysfunction, libido change.

    Gastrointestinal: decreased appetite.

    General: fever, flushing.

    Immunologic: allergy, edema head/neck.

    Musculoskeletal: muscle weakness.

    Nervous System: paresthesia, vertigo, insomnia, memory impairment, tremor, neuropathy (including peripheral neuropathy).

    Special Senses: lens opacity, taste disturbance.

    Postmarketing Experience

    In addition to the events reported above, as with other drugs in this class, the following events have been reported rarely during postmarketing experience with Pravastatin Sodium Tablets, regardless of causality assessment:

    Musculoskeletal: myopathy, rhabdomyolysis.

    Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy.

    Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

    Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma.

    Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails).

    Reproductive: gynecomastia.

    Laboratory Abnormalities: Liver Function Test abnormalities, thyroid function abnormalities.

    Laboratory Test Abnormalities

    Increases in serum transaminase (ALT, AST) values and CPK have been observed (see WARNINGS).

    Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with HMG-CoA reductase inhibitors.

    Concomitant Therapy

    Pravastatin has been administered concurrently with cholestyramine, colestipol, nicotinic acid, probucol and gemfibrozil. Preliminary data suggest that the addition of either probucol or gemfibrozil to therapy with lovastatin or pravastatin is not associated with greater reduction in LDL-cholesterol than that achieved with lovastatin or pravastatin alone. No adverse reactions unique to the combination or in addition to those previously reported for each drug alone have been reported. Myopathy and rhabdomyolysis (with or without acute renal failure) have been reported when another HMG-CoA reductase inhibitor was used in combination with immunosuppressive drugs, gemfibrozil, erythromycin, or lipid-lowering doses of nicotinic acid. Concomitant therapy with HMG-CoA reductase inhibitors and these agents is generally not recommended. (See WARNINGS: Skeletal Muscle and PRECAUTIONS: Drug Interactions.)

    Pediatric Patients

    In a two-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH, the safety and tolerability profile of pravastatin was generally similar to that of placebo. (See CLINICAL PHARMACOLOGY: Pediatric Clinical Study and PRECAUTIONS: Pediatric Use.)

  • OVERDOSAGE

    To date, there has been limited experience with overdosage of pravastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required. (See WARNINGS.)

  • DOSAGE AND ADMINISTRATION

    The patient should be placed on a standard cholesterol-lowering diet before receiving Pravastatin Sodium Tablets and should continue on this diet during treatment with Pravastatin Sodium Tablets (see NCEP Treatment Guidelines for details on dietary therapy).

    Pravastatin Sodium Tablets can be administered orally as a single dose at any time of the day, with or without food. Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines.

    Adult Patients

    The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended. In patients with a history of significant renal or hepatic dysfunction, a starting dose of 10 mg daily is recommended.

    Pediatric Patients

    Children (Ages 8 to 13 Years, Inclusive)

    The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population.

    Adolescents (Ages 14 to 18 Years)

    The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population.

    Children and adolescents treated with pravastatin should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C (see INDICATIONS AND USAGE: Hyperlipidemia: Table 7: NCEP Treatment Guidelines).

    In patients taking immunosuppressive drugs such as cyclosporine (see WARNINGS: Skeletal Muscle) concomitantly with pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and titration to higher doses should be done with caution. Most patients treated with this combination received a maximum pravastatin sodium dose of 20 mg/day.

    Concomitant Therapy

    The lipid-lowering effects of Pravastatin Sodium Tablets on Total- and LDL-cholesterol are enhanced when combined with a bile-acid-binding resin. When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol) and pravastatin, Pravastatin Sodium Tablets should be given either 1 hour or more before or at least 4 hours following the resin. (See also ADVERSE REACTIONS: Concomitant Therapy.)

  • HOW SUPPLIED

    Pravastatin Sodium Tablets are supplied as:

    10 mg tablets: Pink to peach, rounded, rectangular-shaped, biconvex with a "10" embossed on one side and "0013" engraved on the opposite side. They are supplied in bottles of 90 (NDC: 0591-0013-19). Bottles contain a desiccant canister.

    20 mg tablets: Yellow, rounded, rectangular-shaped, biconvex with a "20" embossed on one side and "0014" engraved on the opposite side. They are supplied in bottles of 90 (NDC: 0591-0014-19). Bottles contain a desiccant canister.

    40 mg tablets: Green, rounded, rectangular-shaped, biconvex with a "40" embossed on one side and "0016" engraved on the opposite side. They are supplied in bottles of 90 (NDC: 0591-0016-19). Bottles contain a desiccant canister.

    80 mg tablets: Yellow, oval-shaped tablet with "80" on one side and "0019" on the other side. They are supplied in bottles of 90 (NDC: 0591-0019-19) and bottles of 500 (NDC: 0591-0019-05). Bottles contain a desiccant canister.

    Storage

    Store at 25° C (77° F); excursions permitted to 15°-30° C (59°-86° F) [see USP Controlled Room Temperature]. Keep tightly closed (protect from moisture). Protect from light.

  • REFERENCES

    1. Shepherd J, et al. Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia (WOS). N Engl J Med 1995;333:1301-7.  
    2. The Long-term Intervention with Pravastatin in Ischemic Disease Group. Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels (LIPID). N Engl J Med 1998;339:1349-1357.
    3. Sacks FM, et al. The Effect of Pravastatin on Coronary Events After Myocardial Infarction in Patients with Average Cholesterol Levels (CARE). N Engl J Med 1996;335:1001-9.
    4. Pitt B, et al. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I): Reduction in Atherosclerosis Progression and Clinical Events. J Am Coll Cardiol 1995;26:1133-9.
    5. Jukema JW, et al. Effects of Lipid Lowering by Pravastatin on Progression and Regression of Coronary Artery Disease in Symptomatic Man With Normal to Moderately Elevated Serum Cholesterol Levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995;91:2528-2540.
    6. Crouse JR, et al. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries: Design Features of a Clinical Trial with Carotid Atherosclerosis Outcome (PLAC II). Controlled Clinical Trials 1992;13:495.
    7. Salonen R, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A Population-based Primary Preventive Trial of the Effect of LDL Lowering on Atherosclerotic Progression in Carotid and Femoral Arteries. Research Institute of Public Health, University of Kuopio, Finland. Circulation 1995;92:1758.
    8. Fredrickson DS, et al. Fat Transport in Lipoproteins-An Integrated Approach to Mechanisms and Disorders. N Engl J Med 1967;276:34-42, 94-102, 148-156, 215-224, 273-281.
    9. Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive Toxicology 1996;10(6):439-446.
  • SPL UNCLASSIFIED SECTION

    Manufactured for:
    Watson Laboratories, Inc.
    Corona, CA 92880 USA

    Manufactured by:
    Bristol-Myers Squibb Company
    Princeton, NJ 08543 USA

    1200044A1
    Revised: June 2007

  • INGREDIENTS AND APPEARANCE
    PRAVASTATIN SODIUM 
    pravastatin sodium tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0591-0013
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    pravastatin sodium (UNII: 3M8608UQ61) (pravastatin - UNII:KXO2KT9N0G) 10 mg
    Inactive Ingredients
    Ingredient NameStrength
    croscramellose sodium ()  
    lactose (UNII: J2B2A4N98G)  
    magnesium oxide (UNII: 3A3U0GI71G)  
    magnesium stearate (UNII: 70097M6I30)  
    microcrystalline cellulose (UNII: OP1R32D61U)  
    povidone (UNII: FZ989GH94E)  
    Red Ferric Oxide (UNII: 1K09F3G675)  
    Product Characteristics
    ColorpinkScoreno score
    ShapeRECTANGLESize6mm
    FlavorImprint Code 10;0013
    Contains    
    CoatingfalseSymbolfalse
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0591-0013-1990 in 1 BOTTLE
    PRAVASTATIN SODIUM 
    pravastatin sodium tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0591-0014
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    pravastatin sodium (UNII: 3M8608UQ61) (pravastatin - UNII:KXO2KT9N0G) 20 mg
    Inactive Ingredients
    Ingredient NameStrength
    croscramellose sodium ()  
    lactose (UNII: J2B2A4N98G)  
    magnesium oxide (UNII: 3A3U0GI71G)  
    magnesium stearate (UNII: 70097M6I30)  
    microcrystalline cellulose (UNII: OP1R32D61U)  
    povidone (UNII: FZ989GH94E)  
    Yellow Ferric Oxide (UNII: EX438O2MRT)  
    Product Characteristics
    ColoryellowScoreno score
    ShapeRECTANGLESize8mm
    FlavorImprint Code 20;0014
    Contains    
    CoatingfalseSymbolfalse
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0591-0014-1990 in 1 BOTTLE
    PRAVASTATIN SODIUM 
    pravastatin sodium tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0591-0016
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    pravastatin sodium (UNII: 3M8608UQ61) (pravastatin - UNII:KXO2KT9N0G) 40 mg
    Inactive Ingredients
    Ingredient NameStrength
    croscramellose sodium ()  
    lactose (UNII: J2B2A4N98G)  
    magnesium oxide (UNII: 3A3U0GI71G)  
    magnesium stearate (UNII: 70097M6I30)  
    microcrystalline cellulose (UNII: OP1R32D61U)  
    povidone (UNII: FZ989GH94E)  
    Green Lake Blend (mixture of D&C Yellow No. 10-Aluminum Lake and FD&C Blue No. 1-Aluminum Lake) ()  
    Product Characteristics
    ColorgreenScoreno score
    ShapeRECTANGLESize14mm
    FlavorImprint Code 40;0016
    Contains    
    CoatingfalseSymbolfalse
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0591-0016-1990 in 1 BOTTLE
    PRAVASTATIN SODIUM 
    pravastatin sodium tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0591-0019
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    pravastatin sodium (UNII: 3M8608UQ61) (pravastatin - UNII:KXO2KT9N0G) 80 mg
    Inactive Ingredients
    Ingredient NameStrength
    croscramellose sodium ()  
    lactose (UNII: J2B2A4N98G)  
    magnesium oxide (UNII: 3A3U0GI71G)  
    magnesium stearate (UNII: 70097M6I30)  
    microcrystalline cellulose (UNII: OP1R32D61U)  
    povidone (UNII: FZ989GH94E)  
    Yellow Ferric Oxide (UNII: EX438O2MRT)  
    Product Characteristics
    ColoryellowScoreno score
    ShapeOVALSize17mm
    FlavorImprint Code 80;0019
    Contains    
    CoatingfalseSymbolfalse
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0591-0019-1990 in 1 BOTTLE
    2NDC: 0591-0019-05500 in 1 BOTTLE
    Labeler - Watson Laboratories, Inc.
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