Lipitor

Coadministration of grapefruit juice has the potential to increase plasma concentrations of HMG-CoA reductase inhibitors including LIPITOR. The equivalent of 1.2 litres per day resulted in a 2.5 fold increase in AUC of atorvastatin.

Atorvastatin is metabolized by the cytochrome P-450 isoenzyme, CYP 3A4. Erythromycin, a CYP 3A4 inhibitor, increased atorvastatin plasma levels by 40%. Coadministration of CYP 3A4 inhibitors, such as grapefruit juice, some macrolide antibiotics (i.e. erythromycin, clarithromycin), immunosuppressants (cyclosporine), azole antifungal agents (i.e. itraconazole, ketoconazole), protease inhibitors, or the antidepressant, nefazodone, may have the potential to increase plasma concentrations of HMG-CoA reductase inhibitors, including LIPITOR. Caution should thus be exercised with concomitant use of these agents and lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs (see Warnings and Precautions, Pharmacokinetic Interactions, Muscle Effects, Renal Insufficiency and Endocrine Function; Dosage and Administration).

LIPITOR may elevate serum transaminase and creatine kinase levels (from skeletal muscle). In the differential diagnosis of chest pain in a patient on therapy with LIPITOR, cardiac and noncardiac fractions of these enzymes should be determined.

Interactions with herbal products have not been established.

Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g. cyclosporine) can increase the bioavailability of atorvastatin.

Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (eg efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous coadministration of atorvastatin with rifampin resulted in a mean increase in C_max and AUC of atorvastatin of 12 and 190%, respectively. In contrast, a delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction (approximately 80%) in atorvastatin plasma concentrations.

Based on post-marketing surveillance, gemfibrozil, fenofibrate, other fibrates, and lipid-modifying 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; lower starting and maintenance doses of atorvastatin should be considered.

Pharmacokinetic interaction studies conducted with drugs in healthy subjects may not detect the possibility of a potential drug interaction in some patients due to differences in underlying diseases and use of concomitant medications (see also Warnings and Precautions, Renal Insufficiency, Patients with Severe Hypercholesterolemia; Special Populations, Geriatrics).

Clinical trials conducted that evaluated atorvastatin in the primary prevention of myocardial infarction used a dose of 10 mg atorvastatin once daily.

For secondary prevention of myocardial infarction, optimal dosing may range from 10 mg to 80 mg atorvastatin once daily, to be given at the discretion of the prescriber, taking into account the expected benefit and safety considerations relevant to the patient to be treated.

In patients with severe dyslipidemias, including homozygous and heterozygous familial hypercholesterolemia and dysbetalipoproteinemia (Type III), higher dosages (up to 80 mg/day) may be required (see Warnings and Precautions, Pharmacokinetic Interactions, Muscle Effects; Drug Interactions).

See Warnings and Precautions.

In this population, the recommended starting dose of LIPITOR is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg/day have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy (see Indications and Clinical Use). Adjustments should be made at intervals of 4 weeks or more.

The recommended starting dose of LIPITOR is 10 or 20 mg once daily, depending on patient's LDL-C reduction required. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of LIPITOR is 10 to 80 mg once daily. Doses can be given at any time of the day with or without food, and should preferably be given in the evening. A significant therapeutic response is evident within 2 weeks, and the maximum response is usually achieved within 2-4 weeks. The response is maintained during chronic therapy. Adjustments of dosage, if necessary, should be made at intervals of 2 to 4 weeks. The maximum dose is 80 mg/day.

The dosage of LIPITOR should be individualized according the baseline LDL-C, total-C/HDL-C ratio and/or TG levels to achieve the recommended desired lipid values at the lowest dose needed to achieve LDL-C desired level. Lipid levels should be monitored periodically and, if necessary, the dose of LIPITOR adjusted based on desired lipid levels recommended by guidelines.

See Drug Interactions.

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

Very Rare Reports: severe myopathy with or without rhabdomyolysis (see Warnings and Precautions, Muscle Effects, Renal Insufficiency and Drug Interactions).

Isolated Reports: Gynecomastia, thrombocytopenia, arthralgia and allergic reactions (including urticaria, angioneurotic edema, anaphylaxis and bullous rashes [including erytheme multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis]), fatigue, back pain, chest pain, malaise, dizziness, amnesia, peripheral edema, weight gain, abdominal pain, insomnia, hypoesthesia, tinnitus, tendon rupture and dysgeusia.

These may have no causal relationship to atorvastatin.

Ophthalmologic Observations: See Warnings and Precautions.

Laboratory Tests: Increases in serum transaminase levels have been noted in clinical trials (see Warnings and Precautions).

The following additional adverse events were reported in clinical trials; not all events listed below have been associated with a causal relationship to LIPITOR therapy: muscle cramps, myositis, myopathy, paresthesia, peripheral neuropathy, pancreatitis, hepatitis, cholestatic jaundice, anorexia, vomiting, alopecia, pruritus, rash, impotence, hyperglycemia, and hypoglycemia.

The criteria for clinically significant laboratory changes were >3× the upper limit of normal (ULN) for liver enzymes, and >5×ULN for creatine kinase. A total of 8 unique subjects met one or more of these criteria during the double-blind phase. Hence, the incidence of patients who experienced abnormally high enzymatic levels (AST/ALT and creatine kinase) was >4% (8/187).

Five atorvastatin and one placebo subjects had increases in CK >5×ULN during the double-blind phase; two of the five atorvastatin treated subjects had increases in CK >10×ULN.

There were 2 subjects who had clinically significant increases in ALT.

In a 26-week controlled study in boys and postmenarchal girls (n=187, where 140 patients received LIPITOR), the safety and tolerability profile of LIPITOR 10 to 20 mg daily was similar to that of placebo. The adverse events reported in ≥1% of patients were as follows: abdominal pain, depression and headache (see Warnings and Precautions, Pediatrics).

LIPITOR is indicated to reduce the risk of myocardial infarction in adult hypertensive patients without clinically evident coronary heart disease, but with at least three additional risk factors for coronary heart disease such as age ≥55 years, male sex, smoking, type 2 diabetes, left ventricular hypertrophy, other specified abnormalities on ECG, microalbuminuria or proteinuria, ratio of plasma total cholesterol to HDL-cholesterol ≥6, or premature family history of coronary heart disease.

LIPITOR is also indicated to reduce the risk of myocardial infarction and stroke in adult patients with type 2 diabetes mellitus and hypertension without clinically evident coronary heart disease, but with other risk factors such as age ≥55 years, retinopathy, albuminuria or smoking.

LIPITOR is indicated to reduce the risk of myocardial infarction in patients with clinically evident coronary heart disease.

Each white, elliptical, film-coated tablet, coded “80” on one side and “PD 158” on the other, contains: atorvastatin calcium 80 mg. Nonmedicinal ingredients: calcium carbonate, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, simethicone emulsion, talc and titanium dioxide. Blisters of 30 (3 strips×10).

Each white, elliptical, film-coated tablet, coded “40” on one side and “PD 157” on the other, contains: atorvastatin calcium 40 mg. Nonmedicinal ingredients: calcium carbonate, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, simethicone emulsion, talc, and titanium dioxide. Bottles of 90.

Each white, elliptical, film-coated tablet, coded “20” on one side and “PD 156” on the other, contains: atorvastatin calcium 20 mg. Nonmedicinal ingredients: calcium carbonate, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, simethicone emulsion, talc and titanium dioxide. Bottles of 90.

Each white, elliptical, film-coated tablet, coded “10” on one side and “PD 155” on the other, contains: atorvastatin calcium 10 mg. Nonmedicinal ingredients: calcium carbonate, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, simethicone emulsion, talc and titanium dioxide. Bottles of 90.

LIPITOR, 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; situations where an increase in plasma levels of active ingredient may occur.

The risk of myopathy and rhabdomyolysis during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporin, fibric acid derivatives, erythromycin, clarithromycin, niacin (nicotinic acid), azole antifungals or nefazodone. Therefore, lower starting and maintenance doses of atorvastatin should also be considered when taken concomitantly with the aforementioned drugs. In cases where coadministration of LIPITOR with cyclosporine is necessary, the dose of LIPITOR should not exceed 10 mg (see Drug Interactions, Overview, Drug-Drug Interactions).

LIPITOR therapy should be temporarily withheld or discontinued in any patient with an acute serious condition suggestive of myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (such as sepsis, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

LIPITOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Clinical studies with atorvastatin and other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma cortisol concentration or impair adrenal reserve and do not reduce basal plasma testosterone concentration. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with atorvastatin 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.

In clinical trials, persistent increases in serum transaminases greater than three times the upper limit of normal occurred in <1% of patients who received LIPITOR. When the dosage of LIPITOR was reduced, or when drug treatment was interrupted or discontinued, serum transaminase levels returned to pretreatment levels. The increases were generally not associated with jaundice or other clinical signs or symptoms. Most patients continued treatment with a reduced dose of LIPITOR without clinical sequelae.

Liver function tests should be performed before the initiation of treatment, and periodically thereafter. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients measurements should be repeated promptly and then performed more frequently.

If increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) show evidence of progression, particularly if they rise to greater than 3 times the upper limit of normal and are persistent, the dosage should be reduced or the drug discontinued.

LIPITOR, 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 transaminase elevations are contraindications to the use of LIPITOR; if such a condition should develop during therapy, the drug should be discontinued.

In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in Lp(a) lipoprotein concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease. It is thus desirable to maintain and reinforce lifestyle changes in high risk patients placed on atorvastatin therapy.

Safety and effectiveness of LIPITOR in patients 10-17 years of age (N=140) with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months duration in adolescent boys and postmenarchal girls. Patients treated with LIPITOR had a safety and tolerability profile generally similar to that of placebo. Doses greater than 20 mg have not been studied in this patient population.

Safety and effectiveness of LIPITOR in pediatric patients has not been determined in the prevention of myocardial infarction.

LIPITOR had no effect on growth or sexual maturation in boys and in girls. The effects on menstrual cycle were not assessed [see Adverse Reactions, Pediatrics Patients and Dosage and Administration for Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 years of age)].

Adolescent females should be counselled on appropriate contraceptive methods while on LIPITOR therapy (see Contraindications and Warnings and Precautions, Pregnant Women). LIPITOR has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age.

Doses of LIPITOR up to 80 mg/day for 1 year have been evaluated in 8 pediatric patients with homozygous familial hypercholesterolemia.

LIPITOR is contraindicated during pregnancy (see Contraindications).

There are no data on the use of LIPITOR during pregnancy. LIPITOR 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 LIPITOR, the drug should be discontinued and the patient apprised of the potential risk to the fetus.

Treatment experience in adults 70 years or older (N=221) with doses of LIPITOR up to 80 mg/day has demonstrated that the safety and effectiveness of atorvastatin in this population was similar to that of patients <70 years of age. Pharmacokinetic evaluation of atorvastatin in subjects over the age of 65 years indicates an increased AUC. 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).

Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not 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.

An apparent hypersensitivity syndrome has been reported with other HMG-CoA reductase inhibitors which has included 1 or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Although to date hypersensitivity syndrome has not been described as such, LIPITOR should be discontinued if hypersensitivity is suspected.

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

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

Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine kinase (CK) values to greater than ten times the upper limit of normal, should be considered in any patient with diffuse myalgia, 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 accompanied by malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. LIPITOR therapy should be discontinued if markedly elevated CK levels are measured or myopathy is diagnosed or suspected.

Before instituting therapy with LIPITOR (atorvastatin calcium), an attempt should be made to control elevated serum lipoprotein levels with appropriate diet, exercise, and weight reduction in overweight patients, and to treat other underlying medical problems (see Indications and Clinical Use). Patients should be advised to inform subsequent physicians of the prior use of LIPITOR or any other lipid-lowering agents.

The use of HMG-CoA reductase inhibitors has been associated with severe myopathy, including rhabdomyolysis, which may be more frequent when they are coadministered with drugs that inhibit the cytochrome P-450 enzyme system. Atorvastatin is metabolized by cytochrome P-450 isoform 3A4 and as such may interact with agents that inhibit this enzyme. (See Warnings and Precautions, Muscle Effects and Drug Interactions.)

Current long-term data from clinical trials do not indicate an adverse effect of atorvastatin on the human lens.

Plasma concentrations and LDL-C lowering efficacy of LIPITOR was shown to be similar in patients with moderate renal insufficiency compared with patients with normal renal function. However, since several cases of rhabdomyolysis have been reported in patients with a history of renal insufficiency of unknown severity, as a precautionary measure and pending further experience in renal disease, the lowest dose (10 mg/day) of LIPITOR should be used in these patients. Similar precautions apply in patients with severe renal insufficiency [creatinine clearance <30 mL/min (<0.5 mL/sec)]; the lowest dosage should be used and implemented cautiously (see Warnings and Precautions, Muscle Effects; Drug Interactions). Refer also to Dosage and Administration.

Higher drug dosages (80 mg/day) required for some patients with severe hypercholesterolemia (including familial hypercholesterolemia) are associated with increased plasma levels of atorvastatin. Caution should be exercised in such patients who are also severely renally impaired, elderly, or are concomitantly being administered digoxin or CYP 3A4 inhibitors (see Warnings and Precautions, Pharmacokinetic Interactions, Muscle Effects; Drug Interactions; Dosage and Administration).

In rats, milk concentrations of atorvastatin are similar to those in plasma. It is not known whether this drug is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking LIPITOR should not breast-feed (see Contraindications).

Plasma concentrations of atorvastatin are markedly increased (approximately 16-fold in C_max and 11-fold in AUC) in patients with chronic alcoholic liver disease (Childs-Pugh B).

Plasma concentrations of atorvastatin are higher (approximately 40% for C_max and 30% for AUC) in healthy elderly subjects (age 65 years or older) compared with younger individuals. LDL-C reduction, however, is comparable to that seen in younger patient populations.

Mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk.

Atorvastatin is rapidly absorbed after oral administration; maximal plasma concentrations occur within 1 to 2 hours. Extent of absorption and plasma atorvastatin concentrations increase in proportion to atorvastatin dose. Atorvastatin tablets are 95-99% bioavailable compared to solutions. The absolute bioavailability (parent drug) of atorvastatin is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or first-pass metabolism in the liver. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, as assessed by C_max and AUC respectively, LDL-C reduction and HDL-C elevation are similar when atorvastatin is given with and without food. Plasma atorvastatin concentrations are lower (approximately 30% for C_max and AUC) following drug administration in the evening compared with morning dosing. However, LDL-C reduction and HDL-C elevation are the same regardless of the time of drug administration.

LIPITOR (atorvastatin calcium) is a synthetic lipid-lowering agent. It is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.

LIPITOR lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic Low Density Lipoprotein (LDL) receptors on the cell surface for enhanced uptake and catabolism of Low Density Lipoprotein (LDL).

LIPITOR reduces LDL-Cholesterol (LDL-C) and the number of LDL particles. Lipitor also reduces Very Low Density Lipoprotein-Cholesterol (VLDL-C), serum triglycerides (TG) and Intermediate Density Lipoproteins (IDL), as well as the number of apolipoprotein B (apo B) containing particles, but increases High Density Lipoprotein-Cholesterol (HDL-C). Elevated serum cholesterol due to elevated LDL-C is a major risk factor for the development of cardiovascular disease. Low serum concentration of HDL-C is also an independent risk factor. Elevated plasma TG is also a risk factor for cardiovascular disease, particularly if due to increased IDL, or associated with decreased HDL-C or increased LDL-C.

Epidemiologic, clinical and experimental studies have established that high LDL-C, low HDL-C and high plasma TG promote human atherosclerosis and are risk factors for developing cardiovascular disease. Some studies have also shown that the total (TC):HDL-C ratio (TC:HDL-C) is the best predictor of coronary artery disease. In contrast, increased levels of HDL-C are associated with decreased cardiovascular risk. Drug therapies that reduce levels of LDL-C or decrease TG while simultaneously increasing HDL-C have demonstrated reductions in rates of cardiovascular mortality and morbidity.

Plasma concentrations of atorvastatin are similar in black and white subjects.

Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, the drug does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life for inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of longer-lived active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.

Plasma concentrations and LDL-C lowering efficacy of LIPITOR are similar in patients with moderate renal insufficiency compared with patients with normal renal function. However, since several cases of rhabdomyolysis have been reported in patients with a history of renal insufficiency of unknown severity, as a precautionary measure and pending further experience in renal disease, the lowest dose (10 mg/day) of LIPITOR should be used in these patients. Similar precautions apply in patients with severe renal insufficiency [creatinine clearance <30 mL/min (<0.5 mL/sec)]; the lowest dosage should be used and implemented cautiously (see Warnings and Precautions, Muscle Effects; Drug Interactions; Dosage and Administration).

Plasma concentrations of atorvastatin in women differ (approximately 20% higher for C_max and 10% lower for AUC) from those in men; however, there is no clinically significant difference in LDL-C reduction between men and women.

Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives by cytochrome P-450 3A4 (CYP 3A4) and to various beta-oxidation products. In vitro, inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Atorvastatin and its metabolites are eliminated by biliary excretion.

The lowering of total cholesterol, LDL-C and ApoB have been shown to reduce the risk of cardiovascular events and mortality.

LIPITOR (atorvastatin calcium) is a selective, competitive inhibitor of HMG-CoA reductase. In both subjects and in patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia, and dysbetalipoproteinemia, LIPITOR has been shown to reduce levels of total cholesterol (total-C), LDL-C, apo B and total TG, and raises HDL-C levels.

Epidemiologic and clinical studies 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. Like LDL, cholesterol-enriched lipoproteins, including VLDL, IDL and remnants can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (metabolic syndrome). Clinical studies have also shown that serum triglycerides can be an independent risk factor for CAD. CAD risk is especially increased if the hypertriglyceridemia is due to increased intermediate density lipoproteins (IDL) or associated with decreased HDL or increased LDL-C. In addition, high TG levels are associated with an increased risk of pancreatitis. Although epidemiological and preliminary clinical evidence link low HDL-C levels and high triglyceride levels with coronary artery disease and atherosclerosis, the independent effect of raising HDL or lowering TG on the risk of coronary and cerebrovascular morbidity and mortality has not been demonstrated in prospective, well-controlled outcome studies. 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. Regardless of the intervention used (lowfat/low-cholesterol diet, partial ileal bypass surgery or pharmacologic therapy), effective treatment of hypercholesterolemia/dyslipidemia has consistently been shown to reduce the risk of CAD.

LIPITOR reduces LDL-C and the number of LDL particles, lowers Very Low Density Lipoprotein-Cholesterol (VLDL-C) and serum triglyceride, reduces the number of apo B containing particles, and also increases HDL-C. LIPITOR is effective in reducing LDL-C in patients with homozygous familial hypercholesterolemia, a condition that rarely responds to any other lipid-lowering medication. In addition to the above effects, LIPITOR reduces IDL-C and apolipoprotein E (apo E) in patients with dysbetalipoproteinemia (Type III).

In patients with type II hyperlipidemia, atorvastatin improved endothelial dysfunction. Atorvastatin significantly improved flow-mediated endothelium-dependent dilatation induced by reactive hyperemia, as assessed by brachial ultrasound (p<0.01).

Assessment of pharmacokinetic parameters such as C_max, AUC and bioavailability of LIPITOR in pediatric patients (>10-<17 years old, postmenarche) was not performed during the 6-month, placebo-controlled trial referred to earlier (see Warnings and Precautions, Pediatrics).

Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). LIPITOR 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 LIPITOR, 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 long-term therapy of primary hypercholesterolemia (see Warnings and Precautions, Pregnant Women, Nursing Women).