Therapy with lipid-altering agents should be considered a component of multiple risk factor intervention in those individuals at increased risk for atherosclerotic vascular disease due to dyslipidemia. PRAVACHOL (pravastatin sodium) should be used in addition to a diet restricted in saturated fat and cholesterol when the response to diet and other non-pharmacological measures alone has been inadequate (see National Cholesterol Education Program (NCEP) Guidelines in Table 1).

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:

LDL-C (mmol/L)=Total Cholesterol−[(0.37×triglycerides)+HDL-C] LDL-C (mg/dL)=Total Cholesterol−[(0.16×triglycerides)+HDL-C]

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.

The National Cholesterol Education Program's (NCEP) Treatment Guidelines are summarized in Table 1.

Table 1: PRAVACHOL

NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories

Risk Category	LDL Goal mmol/L	LDL Level at Which to Initiate Therapeutic Lifestyle Changes mmol/L	LDL Level at Which to Consider Drug Therapy mmol/L
CHDa or CHD risk equivalents (10-year risk >20%)	<2.6	≥2.6	≥3.4 (2.6–3.4 drug optional)b
2+Risk factors (10-year risk ≤20%)	<3.4	≥3.4	10-year risk 10–20%: ≥3.4 10-year risk <10%: ≥4.1
0–1 Risk factorc	<4.1	≥4.1	≥4.9 (4.1–4.9 LDL-lowering drug optional)

^a. CHD, coronary heart disease.
^b. Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <2.6 mmol/L cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that pimarily 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.

After the LDL-C goal has been achieved, if the TG is still ≥5.2 mmol/L, non-HDL-C (total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 0.78 mmol/L 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 ≥3.6 mmol/L (see NCEP Guidelines in Table 1).

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, 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).

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.

  
  

 

In the West of Scotland Study (WOS), the effect of PRAVACHOL treatment on fatal and nonfatal coronary heart disease (CHD) was assessed in 6 595 patients (aged 45 to 64 years) without a previous myocardial infarction, but with elevated LDL-C levels between 4-6.7 mmol/L (156-254 mg/dL). The patients were followed for a median of 4.8 years.

PRAVACHOL significantly reduced the rate of first coronary events (either CHD death or nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, non-fatal MI=204] vs 174 events in the PRAVACHOL group [CHD death=31, non-fatal MI=143], p=0.0001). The effect of these cumulative cardiovascular event rates was evident after 6 months of treatment. The risk reduction with PRAVACHOL was similar and significant throughout the entire range of baseline LDL cholesterol levels. This reduction was also similar and significant across the age range studied with a 40% risk reduction for patients younger than 55 years and a 27% risk reduction for patients 55 years and older.

PRAVACHOL also significantly decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft surgery by 37% [80 vs 51 patients, p=0.009] and coronary angiography by 31% [128 vs 90, p=0.007]). Cardiovascular deaths were decreased by 32% (73 vs 50, p=0.03), and there was no increase in deaths from non-cardiovascular causes.

The West of Scotland Study excluded female patients, elderly subjects and most patients with familial hypercholesterolemia (FH). Consequently it has not been established to what extent the findings of the WOS study can be extrapolated to these subpopulations of hypercholesterolemic patients.

• In patients with heterozygous FH, optimal reduction in total and LDL cholesterol necessitates a combination drug therapy in the majority of patients. (For homozygous FH see Warnings and Precautions, Homozygous Familial Hypercholesterolemia.)

  
  

• Because information on familial combined hyperlipidemic (FCH) patients is not available from the WOS study, the effect of PRAVACHOL in this subgroup of high risk dyslipidemic patients could not be assessed.

  
  

 

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

  
  

 

In the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study, the effect of PRAVACHOL 40 mg daily was assessed in 9014 men and women with normal to elevated serum cholesterol levels (baseline Total-C=155-271 mg/dL [4.0-7.0 mmol/L]; median Total- C=218 mg/dL [5.66 mmol/L]; median LDL-C=150 mg/dL [3.88 mmol/L]), and who had experienced either a myocardial infarction or had been hospitalized for unstable angina pectoris in the preceding 3-36 months.

Treatment with PRAVACHOL significantly reduced the risk for CHD death by 24% (p=0.0004). The risk for coronary events (either CHD death or nonfatal MI) was significantly reduced by 24% (p<0.0001) in the PRAVACHOL treated patients. The risk for fatal or nonfatal myocardial infarction was reduced by 29% (p<0.0001). PRAVACHOL reduced both the risk for total mortality by 23% (p<0.0001) and cardiovascular mortality by 25% (p<0.0001). The risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) was significantly reduced by 20% (p<0.0001) in the PRAVACHOL treated patients. PRAVACHOL also significantly reduced the risk for stroke by 19% (p=0.0477). Treatment with PRAVACHOL significantly reduced the number of days of hospitalization per 100 person-years of follow-up by 15% (p<0.001). The effect of PRAVACHOL on reducing CHD events was consistent regardless of age, gender, or diabetic status.

In the Cholesterol and Recurrent Events (CARE) study the effect of PRAVACHOL 40 mg daily on coronary heart disease death and nonfatal MI was assessed in 4159 men and women with normal serum cholesterol levels (baseline mean Total-C=209 mg/dL [5.4 mmol/L]), and who had experienced a myocardial infarction in the preceding 3-20 months. Treatment with PRAVACHOL significantly reduced the rate of a recurrent coronary event (either CHD death or nonfatal MI) by 24% (274 patients with events [13.3%] in the placebo group vs. 212 patients [10.4%] in the PRAVACHOL group, p=0.003). The reduction in risk for this combined endpoint was significant for both men and women; in women, the reduction in risk was 43% (p=0.033). The risk of undergoing revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) was significantly reduced by 27% (p<0.001) in the PRAVACHOL treated patients (391 [19.6%] vs 294 [14.2%] patients). PRAVACHOL also significantly reduced the risk for stroke by 32% (p=0.032), and stroke or transient ischemic attack (TIA) combined by 26% (124 [6.3%] vs 93 [4.7%] patients, p=0.025).

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 target 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.

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.

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.

Patients who are hypersensitive to this drug or to any ingredient in the formulation.

Active liver disease or unexplained persistent elevations of serum transaminases (see Warnings and Precautions).

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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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).

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).

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 2 and Table 3).

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.

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

Table 2: PRAVACHOL

Adverse Events in >2 Percent of Patients Treated with Pravastatin 10–40 mg in Short-term Placebo-controlled Trials

^a. Statistically significantly different from placebo.

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.

In seven randomized double blind placebo-controlled trials involving over 21 500 patients treated with pravastatin (N=10 784) or placebo (N=10 719), the safety and tolerability in the pravastatin group was comparable to that of the placebo group. Over 19 000 patients were followed for a median of 4.8-5.9 years, while the remaining patients were followed for two years or more.

Clinical adverse events probably or possibly related, or of uncertain relationship to therapy, occurring in at least 0.5% of patients treated with pravastatin or placebo in these long-term morbidity/mortality trials are shown in Table 3.

Table 3: PRAVACHOL

Clinical Adverse Events Reported in Placebo-controlled Studies

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

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

angioedema.

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

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.

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

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.

allergy.

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.

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

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).