Pravachol

On the average, antacids (one hour prior to PRAVACHOL) reduce and cimetidine increases the bioavailability of pravastatin. These changes were not statistically significant. The clinical significance of these interactions is not known but is probably minimal as judged from the interaction with food (see Action and Clinical Pharmacology, Human Pharmacology).

No information is available regarding interactions with erythromycin (see Warnings and Precautions, Muscle Effects).

Although specific interaction studies were not performed during clinical trials, no noticeable drug interactions were reported when PRAVACHOL was added to diuretics, antihypertensives, angiotensin converting-enzyme (ACE) inhibitors, calcium channel blockers, or nitroglycerin.

In a multicentre study, the AUC values of pravastatin were shown to be five-fold higher in the presence of cyclosporine. There was no accumulation of pravastatin after multiple doses (see Dosage and Administration).

Co-administration of propranolol and pravastatin reduced the AUC values by 23% and 16% respectively.

Pravastatin had no clinically significant effect on prothrombin time when administered in a study to normal elderly subjects who were stabilized on warfarin.

Antipyrine was used as a model for drugs metabolized by the microsomal hepatic enzyme system (cytochrome P450 system). Pravastatin had no effect on the pharmacokinetics of antipyrine.

Pravastatin may elevate creatine phosphokinase and transaminase levels. This should be considered in the differential diagnosis of chest pain in a patient on therapy with pravastatin.

Gemfibrozil and nicotinic acid do not statistically significantly affect the bioavailability of pravastatin. However, in a limited size clinical trial, a trend toward CK elevations and musculoskeletal symptoms was seen in patients treated concurrently with pravastatin and gemfibrozil.

Myopathy, including rhabdomyolysis, has occurred in patients who were receiving coadministration of HMG-CoA reductase inhibitors with fibric acid derivatives and niacin, particularly in subjects with pre-existing renal insufficiency (see Warnings and Precautions, Muscle Effects).

Preliminary evidence suggests that the cholesterol-lowering effects of PRAVACHOL and the bile acid sequestrants, cholestyramine/colestipol are additive.

When pravastatin was administered one hour before or four hours after cholestyramine or one hour before colestipol and a standard meal, there was no clinically significant decrease in bioavailability or therapeutic effect. Concomitant administration resulted in an approximately 40 to 50% decrease in the mean AUC of pravastatin (see Dosage and Administration, Concomitant Therapy).

The use of HMG-CoA reductase inhibitors has been associated with severe myopathy, including rhabdomyolysis, which may be more frequent when they are administered with drugs that inhibit the cytochrome P450 enzyme system. 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.

Based on post-marketing surveillance, gemfibrozil, fenofibrate, other fibrates and lipid lowering doses of niacin (nicotinic acid) may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone (see Warnings and Precautions, Muscle Effects). Therefore, combined drug therapy should be approached with caution.

Coadministration of digoxin and other HMG-CoA reductase inhibitors has been shown to increase the steady state digoxin concentrations. The potential effects of coadministration of digoxin and PRAVACHOL are not known. As a precautionary measure, patients taking digoxin should be closely monitored.

The recommended starting dose is 20 mg once daily at bed time. Patients who require a large dose reduction in LDL-C may be started at 40 mg once daily. The dose of 80 mg once daily should be reserved for patients who do not achieve their treatment goal with lower doses. PRAVACHOL may be taken without regard to meals (see Action and Clinical Pharmacology).

In patients with a history of significant renal or hepatic dysfunction, a starting dose of 10 mg daily is recommended.

Patients should be placed on a standard cholesterol-lowering diet (at least equivalent to the Adult Treatment Panel III [ATP III TLC diet]) before receiving PRAVACHOL, and should continue on this diet during treatment with PRAVACHOL. If appropriate, a program of weight control and physical exercise should be implemented.

Prior to initiating therapy with PRAVACHOL, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed.

Some patients may require combination therapy with one or more lipid- lowering agents. Pharmacokinetic interaction with pravastatin administered concurrently with nicotinic acid, or gemfibrozil did not statistically significantly affect the bioavailability of pravastatin. The combined use of pravastatin and fibrates should however generally be avoided (see Warnings and Precautions, Muscle Effects).

The lipid-lowering effects of PRAVACHOL on Total and Low Density Lipoprotein Cholesterol are additive when combined with a bile acid- binding resin. However, when administering a bile acid-binding resin (e.g. cholestyramine, colestipol) and pravastatin, PRAVACHOL should not be administered concomitantly, but should be given either one hour or more before or at least four hours following the resin (see Drug Interactions, Concomitant Therapy with Other Lipid Metabolism Regulators).

In patients taking cyclosporine, with or without other immunosuppressive drugs, concomitantly with pravastatin, therapy should be initiated with 10 mg per day and titration to higher doses should be performed with caution. Most patients treated with this combination received a maximum pravastatin dose of 20 mg/day (see Warnings and Precautions and Drug Interactions, Other Concomitant Therapy, Cyclosporine).

The dosage of PRAVACHOL should be individualized according to baseline LDL-C, total- C/HDL-C ratio and/or TG levels to achieve the desired lipid values at the lowest possible dose.

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

Current data from clinical trials do not indicate an adverse effect of pravastatin on the human lens.

pancreatitis, hepatitis and fulminant hepatic necrosis, jaundice (including cholestatic), fatty change in liver, cirrhosis, thrombocytopenia, hepatoma, abnormal stool and appetite change. Liver Function Test (LFT) abnormalities have also been reported.

The following adverse events have also been rarely reported during post-marketing experience with PRAVACHOL, regardless of causality assessment:

Increases in serum transaminases and in creatine phosphokinase (CK) in patients treated with PRAVACHOL have been discussed (see Warnings and Precautions).

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

eye symptoms (including soreness, dryness or itching), tinnitus, taste disturbance.

The following have also been reported with other statins: hepatitis, cholestatic jaundice, anorexia, psychic disturbances including anxiety, hypospermia and hypersensitivity (see Warnings and Precautions).

allergy.

gynecomastia, impotence (see Warnings and Precautions, Endocrine and Metabolism), urticaria, sexual dysfunction, libido change.

anaphylaxis, 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.

myopathy, rhabdomyolysis.

dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), peripheral nerve palsy, paresthesia equilibrium disturbance, vertigo, memory impairment, tremor, mood change.

chest pain (non cardiovascular), weakness, excess sweating hot flashes and fever.

Pravastatin is generally well tolerated. Adverse events have been usually mild to moderate and transient. Adverse events observed or reported in short- and long-term trials are as follows (see Table 1 and Table 2).

a variety of skin changes (pruritis, scalp hair abnormalities, skin dryness and dermatitis).

angioedema.

In hypercholesterolemic patients without clinically evident coronary heart disease, PRAVACHOL is indicated to:

• Reduce the risk of myocardial infarction;

  
  

• Reduce the risk for undergoing myocardial revascularization procedures;

  
  

• Reduce the risk of total mortality by reducing cardiovascular deaths.

Pharmacokinetic evaluation of pravastatin in patients over the age of 65 years indicates an increased AUC. As a precautionary measure, the lowest dose should be administered initially in these patients.

PRAVACHOL is indicated as an adjunct to diet (at least an equivalent of the Adult Treatment Panel III [ATP III TLC diet]) for the reduction of elevated Total and Low Density Lipoprotein Cholesterol (LDL-C) levels in patients with primary hypercholesterolemia (Types IIa and IIb), when the response to diet and other non-pharmacologic measures alone has been inadequate.

Prior to initiating therapy with PRAVACHOL, secondary causes for hypercholesterolemia, such as obesity, poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy or alcoholism, should be excluded and it should be determined that patients for whom treatment with PRAVACHOL is being considered have an elevated LDL-C level as the cause for an elevated total serum cholesterol. A lipid profile should be performed to measure Total Cholesterol, High Density Lipoprotein Cholesterol (HDL-C) and Triglycerides (TG).

For patients with total triglycerides less than 4.52 mmol/L (400 mg/dL), LDL-C can be estimated using the following equation:

When total triglyceride levels exceed 4.52 mmol/L (400 mg/dL), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation.

As with other lipid-lowering therapy, PRAVACHOL is not indicated when hypercholesterolemia is due to hyperalphalipoproteinemia (elevated HDL-C). The efficacy of pravastatin has not been evaluated in conditions where the major abnormality is elevation of chylomicrons, VLDL or LDL (i.e. hyperlipoproteinemia or dyslipoproteinemia types I, III, IV or V).

There is no experience to date with the use of PRAVACHOL in such patients. Treatment in these patients is not recommended at this time.

In patients with total cholesterol in the normal to moderately elevated range who have clinically evident coronary heart disease, PRAVACHOL is indicated to:

• Reduce the risk of total mortality

  
  

• Reduce the risk of death due to coronary heart disease

  
  

• Reduce the risk of myocardial infarction

  
  

• Reduce the risk of undergoing myocardial revascularization procedures

  
  

• Reduce the risk of stroke and transient ischemic attack (TIA)

  
  

• Reduce total hospitalization

  
  

PRAVACHOL was also found to reduce the rate of progression of atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower Total and LDL-cholesterol to desired levels. In two trials including this type of patients{*Pravastatin Limitation of Atherosclerosis in the Coronary/Carotid Arteries (PLAC I and II)} (i.e. in a secondary prevention intervention), PRAVACHOL monotherapy was shown to reduce the rate of progression of atherosclerosis as evaluated by quantitative angiography and B-mode ultrasound. This effect may be associated with an improvement in the coronary endpoints (fatal or non fatal myocardial infarction). In these trials, however, no effect was observed in all cause mortality.

Each yellow, rounded, rectangular-shaped, biconvex tablet, with a P embossed on one side and PRAVACHOL 20 engraved on the other, contains: pravastatin sodium 20 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose, magnesium oxide, magnesium stearate, microcrystalline cellulose, povidone and yellow ferric oxide. Bottles of 90.

Each green, rounded, rectangular-shaped, biconvex tablet, with a P embossed on one side and PRAVACHOL 40 engraved on the other, contains: pravastatin sodium 40 mg. Nonmedicinal ingredients: croscarmellose sodium, D&C yellow no. 10, FD&C blue no. 1, lactose, magnesium oxide, magnesium stearate, microcrystalline cellulose and povidone. Bottles of 90.

Each pink to peach, rounded, rectangular-shaped, biconvex tablet, with a P embossed on one side and PRAVACHOL 10 engraved on the other, contains: pravastatin sodium 10 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose, magnesium oxide, magnesium stearate, microcrystalline cellulose, povidone and red ferric oxide. Bottles of 90.

A 21-month oral study in mice, with doses of 10 to 100 mg/kg daily of pravastatin did not demonstrate any carcinogenic potential. In a 2-year oral study in rats, a statistically significant increase in the incidence of hepatocellular carcinoma was observed in male rats given 100 mg/kg daily (60 times the maximum human dose) of pravastatin. This change was not seen in male rats given 40 mg/kg daily (25 times the recommended human dose) or less, or in female rats at any dose level.

Pravastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. Most HMG-CoA reductase inhibitors are less or not effective in this subgroup of hypercholesterolemic patients.

A significant short-term decrease in plasma CoQ10 levels in patients treated with PRAVACHOL has been observed. Longer clinical trials have also shown reduced serum ubiquinone levels during treatment with pravastatin and other HMG-CoA reductase inhibitors. The clinical significance of a potential long-term statin-induced deficiency of CoQ10 has not yet been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.

In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lipoprotein (a)[Lp(a)] level. Further research is ongoing to elucidate the significance of Lp(a) variations. Therefore, until further experience is obtained, where feasible, it is suggested that measurements of serum Lp(a) be followed up in patients placed on pravastatin therapy.

Pharmacokinetic evaluation of pravastatin in patients over the age of 65 years indicates an increased AUC. There were no reported increases in the incidence of adverse effects in these or other studies involving patients in that age group. As a precautionary measure, the lowest dose should be administered initially.

Elderly patients may be more susceptible to myopathy (see Warnings and Precautions, Muscle Effects, Pre-disposing Factors for Myopathy/Rhabdomyolysis).

PRAVACHOL is contraindicated during pregnancy (see Contraindications).

Safety in pregnant women has not been established. Although pravastatin was not teratogenic in rats at doses as high as 1000 mg/kg daily nor in rabbits at doses of up to 50 mg/kg daily, PRAVACHOL should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of potential hazards. If a woman becomes pregnant while taking PRAVACHOL, PRAVACHOL should be discontinued and the patient advised again as to the potential hazards to the fetus.

Only limited experience with the use of statins in children is available. There is no experience to date with the use of PRAVACHOL in such patients. Treatment in these patients is not recommended at this time.

HMG-CoA reductase inhibitors have been associated with biochemical abnormalities of liver function. As with other lipid-lowering agents, including non-absorbable bile acid-binding resins, increases in liver enzymes to less than three times the upper limit of normal have occurred during therapy with pravastatin. The significance of these changes, which usually appear during the first few months of treatment initiation, is not known. In the majority of patients treated with pravastatin, in clinical trials, these increased values declined to pretreatment levels despite continuation of therapy at the same dose.

Marked persistent increases (greater than three times the upper limit of normal) in serum transaminases were seen in 6 out of 1142 (0.5%) patients treated with pravastatin in clinical trials (see Adverse Reactions). The increases usually appeared 3 to 12 months after the start of therapy with PRAVACHOL (pravastatin sodium). These elevations were not associated with clinical signs and symptoms of liver disease and usually declined to pretreatment levels upon discontinuation of therapy. Patients rarely had persistent marked abnormalities possibly attributable to therapy. In the largest long-term placebo-controlled trial with pravastatin (Pravastatin Primary Prevention Study/WOSCOPS), no patient with normal liver function after 12 weeks of treatment (N=2875 pravastatin-treated patients) had subsequent ALT elevations greater than three times the upper limit of normal on two consecutive measurements. Two of these 2875 patients treated with pravastatin (0.07%) and one of 2919 placebo patients (0.03%) had elevations of AST greater than three times the upper limit of normal on two consecutive measurements during the 4.8 years (median treatment) of the study.

Liver function tests should be performed at baseline and at 12 weeks following initiation of therapy or the elevation of dose. Special attention should be given to patients who develop increased transaminase levels. Liver function tests should be repeated to confirm an elevation and subsequently monitored at more frequent intervals. If increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equal or exceed three times the upper limit of normal and persist, therapy should be discontinued.

PRAVACHOL, as well as other HMG-CoA reductase inhibitors should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained serum transaminase elevations are contraindications to the use of PRAVACHOL; if such condition develops during therapy, the drug should be discontinued.

With lovastatin an apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus-like syndrome, polymyalgia rheumatica, thrombocytopenia, leukopenia, hemolytic anemia, positive antinuclear antibody (ANA), erythrocytes sedimentation rate (ESR) increase, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever and malaise.

Although to date hypersensitivity syndrome has not been described as such, in few instances eosinophilia and skin eruptions appear to be associated with PRAVACHOL treatment. If hypersensitivity is suspected PRAVACHOL should be discontinued. Patients should be advised to report promptly any signs of hypersensitivity such as angioedema, urticaria, photosensitivity, polyarthralgia, fever, malaise.

Elevations of creatinine phosphokinase levels (CK [MM fraction]), have been reported with the use of HMG-CoA reductase inhibitors, including PRAVACHOL.

Effects on skeletal muscle such as myalgia, myopathy and, rarely, rhabdomyolysis have been reported in patients treated with PRAVACHOL.

Muscle weakness and rhabdomyolysis have been reported in patients receiving other HMG-CoA reductase inhibitors concomitantly with itraconozole and cyclosporine.

The benefits and risks of using HMG-CoA reductase inhibitors concomitantly with immunosuppressive drugs, fibrates, erythromycin, systemic azole derivative antifungal agents or lipid-lowering doses of niacin should be carefully considered.

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria, have been reported with PRAVACHOL and with other HMG-CoA reductase inhibitors.

Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine phosphokinase (CK) values to greater than ten times the upper limit of normal, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. PRAVACHOL therapy should be discontinued if markedly elevated CK levels are measured or myopathy is diagnosed or suspected.

As with other statins, the risk of myopathy including rhabdomyolysis may be substantially increased by concomitant immunosuppressive therapy including cyclosporines, and by concomitant therapy with gemfibrozil, erythromycin or niacin (see Warnings and Precautions).

Myopathy has not been observed in clinical trials involving small numbers of patients who were treated with PRAVACHOL together with immunosupressants, fibric acid derivatives or niacin.

The use of fibrates alone is occasionally associated with myopathy. In a limited size clinical trial of combined therapy with pravastatin (40 mg/day) and gemfibrozil (1200 mg/day), myopathy was not reported, although a trend towards CK elevations and musculoskeletal symptoms was seen. The combined use of pravastatin and fibrates should generally be avoided.

No information is available on the combined therapy of pravastatin with erythromycin.

Pre-disposing Factors for Myopathy/Rhabdomyolysis: PRAVACHOL, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include: personal or family history of hereditary muscular disorders; previous history of muscle toxicity with another HMG-CoA reductase inhibitor; concomitant use of a fibrate or niacin; hypothyroidism; alcohol abuse; excessive physical exercise; age >70 years; renal impairment; hepatic impairment; diabetes with hepatic fatty change; surgery and trauma; frailty; situation where an increase in plasma levels of active ingredient may occur.

PRAVACHOL therapy should be temporarily withheld or discontinued in any patient with an acute serious condition suggestive of myopathy or predisposing to the development of rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic endocrine and electrolyte disorders, or uncontrolled seizures).

Before instituting therapy with PRAVACHOL (pravastatin sodium), an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in overweight and obese patients, and to treat other underlying medical problems (see Indications and Clinical Use). The patient should be advised to inform subsequent physicians of the prior use of PRAVACHOL.

Pravastatin may elevate creatine phosphokinase and transaminase levels. This should be considered in the differential diagnosis of chest pain in a patient on therapy with pravastatin.

Current data from clinical trials do not indicate an adverse effect of pravastatin on the human lens.

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such could theoretically blunt adrenal and/or gonadal steroid production.

In one long-term study investigating the endocrine function in hypercholesterolemic patients, PRAVACHOL exhibited no effect upon basal and stimulated cortisol levels, as well as on aldosterone secretion. Although no change was reported in the testicular function, conflicting results were observed in the analysis of sperm motility after administration of PRAVACHOL. A case of reversible impotence has been reported in a 57-year old man administered pravastatin 20 mg/day and metoprolol. A causal relationship to therapy with PRAVACHOL has not been established. Further studies are needed to clarify the effects of HMG-CoA reductase inhibitors on male fertility. Furthermore, the effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with PRAVACHOL who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone, or cimetidine) that may decrease the levels of endogenous steroid hormones.

There have been no studies on the use of pravastatin in patients with renal insufficiency. As a precautionary measure, the lowest dose should be used in these patients (see Warnings and Precautions, Muscle Effects).

Higher doses (≥40 mg/day) required for some patients with severe hypercholesterolemia are associated with increased plasma levels of pravastatin. Caution should be exercised in such patients who are also significantly renally impaired or elderly (see Warnings and Precautions, Muscle Effects).

A negligible amount of pravastatin is excreted in human breast milk. Because of the potential for adverse reactions in nursing infants, if the mother is being treated with PRAVACHOL, nursing should be discontinued or treatment with PRAVACHOL stopped.

Studies of PRAVACHOL administered as a single dose to healthy elderly male and female subjects (age 65 to 78 years) indicated a 30-50% increase in plasma levels.

Pravastatin undergoes extensive first pass extraction in the liver (estimated hepatic extraction ratio, 66%), its primary site of action, and is excreted in the bile. Therefore, plasma levels of the drug are probably of limited value in predicting therapeutic effectiveness. Nevertheless, measurement of plasma pravastatin concentrations by gas chromatography and massspectrometry showed dose proportionality for area under the concentration-time curve (AUC) and maximum and steady-state plasma levels. Steady-state areas under the plasma concentrationtime- curves and maximum (C_max) or minimum (C_min) plasma concentrations showed no accumulation following once or twice-daily administration of PRAVACHOL tablets.

PRAVACHOL (pravastatin sodium) is one of a new class of lipid-lowering compounds known as HMG-CoA reductase inhibitors (statins) that reduce cholesterol biosynthesis. These agents are competitive inhibitors of 3-hydroxy- 3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate. Pravastatin is isolated from a strain of Penicillium citrinum. The active drug substance is the hydroxyacid form.

PRAVACHOL produces its lipid-lowering effect in two ways. First, as a consequence of its reversible inhibition of HMG-CoA reductase activity, it effects modest reductions in intracellular pools of cholesterol. This results in an increase in the number of Low Density Lipoproteins (LDL)-receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of circulating LDL. Second, pravastatin inhibits LDL production by inhibiting hepatic synthesis of Very Low Density Lipoproteins (VLDL), the LDL precursor.

Epidemiologic and clinical investigations have associated the risk of coronary artery disease (CAD) with elevated levels of Total-C, LDL-C and decreased levels of HDL-C. These abnormalities of lipoprotein metabolism are considered as major contributors to the development of the disease. Other factors, e.g. interactions between lipids/ lipoproteins and endothelium, platelets and macrophages, have also been incriminated in the development of human atherosclerosis and of its complications.

In long-term, prospective clinical trials effective treatment of hypercholesterolemia/ dyslipidemia has consistently been associated with a reduction in the risk of CAD.

Treatment with PRAVACHOL has been shown to reduce circulating Total-C, LDL-C, and apolipoprotein B, modestly reduce VLDL-C and triglycerides (TG) while producing increases of variable magnitude in HDL-C and apolipoprotein A. Clinical trials suggest that PRAVACHOL's effect on reducing clinical events appears to incorporate both cholesterol modification and some ancillary mechanism.

Pravastatin has complex pharmacokinetic characteristics.

Protein binding of pravastatin is approximately 50%. The plasma elimination half-life of pravastatin is between 1.5 and 2 hours (2.5-3 hours in hypercholesterolemic subjects). Approximately 20% of a radiolabelled oral dose is excreted in the urine and 70% in the feces.

After intravenous administration to healthy subjects, approximately 47% of the total drug clearance occurs via renal excretion of intact pravastatin, and about 53% is cleared by non-renal routes, i.e. biliary excretion and biotransformation.

No studies have been carried out in patients with renal insufficiency.

In both normal volunteers and patients with hypercholesterolemia, treatment with PRAVACHOL (pravastatin sodium) reduced total-C, LDL-C, apolipoprotein B, VLDL-C and TG while increasing HDL-C and apolipoprotein A. The mechanism of action of PRAVACHOL (pravastatin sodium) is complex. Inhibition of hepatic VLDL synthesis and/or secretion occurs, leading to a decrease in LDL precursor formation. The reduction in hepatic cellular pools of cholesterol, resulting from the specific and reversible inhibition of HMG-CoA reductase activity, leads to an increase in the fractional catabolic rate of IDL and LDL via increased expression of LDL receptors on the surface of hepatic cells. Through a combination of these and possibly other unknown metabolic effects, a decline in the serum level of cholesterol results.

Pravastatin is extensively metabolized. The major metabolite is the 3 α-hydroxy isomer, which has one-tenth to one-fortieth of the inhibitory activity of the parent compound on HMG-CoA reductase.

Only limited experience with the use of statins in children is available. There is no experience to date with the use of PRAVACHOL in such patients. Treatment in these patients is not recommended at this time.

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 such as PRAVACHOL (pravastatin sodium) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women. PRAVACHOL should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the possible harm. If the patient becomes pregnant while taking PRAVACHOL, the drug should be discontinued immediately and the patient apprised of the potential harm to the fetus. Atherosclerosis being a chronic process, discontinuation of lipid metabolism regulating drugs during pregnancy should have little impact on the outcome of longterm therapy of primary hypercholesterolemia (see Warnings and Precautions, Pregnant Women, Nursing Women).