Lipitor (Atorvastatin Calcium)

LIPITOR™

Parke-Davis

Atorvastatin Calcium

Lipid Metabolism Regulator

Action And Clinical Pharmacology: Atorvastatin 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.

Atorvastatin 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).

Atorvastatin reduces LDL-cholesterol (LDL-C) and the number of LDL particles, and lowers very low density lipoprotein-cholesterol (VLDL-C) and serum triglycerides (TG), as well as the number of apolipoprotein B (apo B) containing particles.

Pharmacokinetics: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Atorvastatin tablets are 95 to 99% bioavailable compared to solutions.

Mean distribution of atorvastatin is approximately 565 L. Atorvastatin is ³98% bound to plasma proteins. Atorvastatin is extensively metabolized by cytochrome P450 3A4 to ortho-and para-hydroxylated derivatives and various beta-oxidation products. Approximately 70% of circulating inhibitory activity for HMG Co-A reductase is attributed to active metabolites.

Atorvastatin and its metabolites are eliminated by biliary excretion. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of longer-lived active metabolites.

Indications And Clinical Uses: As an adjunct to diet, at least equivalent to the American Heart Association (AHA) Step 1 diet, for the reduction of elevated total cholesterol, LDL-C, triglycerides (TG) and apolipoprotein B (apo B) in hyperlipidemic and dyslipidemic conditions, when response to diet and other nonpharmacological measures alone has been inadequate, including: primary hypercholesterolemia (Type IIa); combined (mixed) hyperlipidemia (Type IIb), including familial combined hyperlipidemia, regardless of whether cholesterol or triglycerides are the lipid abnormality of concern; heterozygous familial hypercholesterolemia.

In clinical trials, atorvastatin (10 to 80 mg/day) significantly improved lipid profiles in patients with a wide variety of hyperlipidemic and dyslipidemic conditions. In 2 dose-response studies in mildly to moderately hyperlipidemic patients (Fredrickson Types IIa and IIb), atorvastatin reduced the levels of total cholesterol (29 to 45%), LDL-C (39 to 60%), apo B (32 to 50%), TG (19 to 37%), and increased HDL-C levels (5 to 9%). Comparable responses were achieved in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, combined hyperlipidemia, including familial combined hyperlipidemia and patients with non-insulin dependent diabetes mellitus. In patients with hypertriglyceridemia TG >3.95 mmol/L (>350 mg/dL), atorvastatin lowered TG levels by 27 to 42%.

Limited data are available in homozygous familial hypercholesterolemia (FH). An open-label study with atorvastatin 80 mg/day in homozygote FH patients showed a LDL-C lowering of 30% for patients not on plasmapheresis and of 31% for patients who continued plasmapheresis. A LDL-C lowering of 35% was observed in receptor defective patients and of 19% in receptor negative patients.

Prior to initiating therapy with atorvastatin, secondary causes should be excluded for elevations in plasma lipid levels (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, and alcoholism), and a lipid profile performed to measure total cholesterol, LDL-C, HDL-C, and TG. For patients with TG
LDL-C (mmol/L)=total cholesterol -[(0.37´(TG)+HDL-C)]

LDL-C (mg/dL)=total cholesterol -[(0.2´(TG)+HDL-C)]

For patients with TG levels >4.52 mmol/L (>400 mg/dL), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation.

Contra-Indications: Hypersensitivity to any component of this medication. Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal (see Warnings).

Pregnancy and Lactation (see Precautions).

Manufacturers’ Warnings In Clinical States: Pharmacokinetic Interactions : 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 P450 enzyme system. Atorvastatin is metabolized by cytochrome P450 isoform 3A4 and as such may interact with agents that inhibit this enzyme (see Warnings, Muscle Effects and Precautions, Drug Interactions and Cytochrome P450-mediated Interactions).

Hepatic Effects: In clinical trials, persistent increases in serum transaminases greater than 3 times the upper limit of normal occurred in
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.

Atorvastatin 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 atorvastatin; if such a condition should develop during therapy, the drug should be discontinued.

Muscle Effects: Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatinine phosphokinase (CPK) values to greater than 10 times the upper limit of normal, should be considered in any patient with diffuse myalgia, 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. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, niacin (nicotinic acid), azole antifungals or nefazodone. As there is no experience to date with the use of atorvastatin given concurrently with these drugs, with the exception of a pharmacokinetic study with erythromycin, the benefits and risks of such combined therapy should be carefully considered (see Precautions, Drug Interactions).

Rhabdomyolysis has been reported in very rare cases with atorvastatin (see Precautions, Drug Interactions).

Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has also been reported with HMG-CoA reductase inhibitors. Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (such as severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

Precautions: General: The effects of atorvastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol on cardiovascular morbidity or mortality or total mortality have not been established.

Before instituting therapy with atorvastatin, 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). Patients should be advised to inform subsequent physicians of the prior use of atorvastatin or any other lipid-lowering agents.

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

Effect on Ubiquinone (CoQ10) Levels: 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.

Effect on Lipoprotein (a): 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) levels. Until further experience is obtained, it is suggested, where feasible, that measurements of serum Lp(a) be followed up in patients placed on atorvastatin therapy.

Hypersensitivity: 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, atorvastatin should be discontinued if hypersensitivity is suspected.

Pregnancy: Atorvastatin is contraindicated during pregnancy (see Contraindications).

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 may cause harm to the fetus when administered to pregnant women. There are no data on the use of atorvastatin during pregnancy. Atorvastatin 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 atorvastatin, the drug should be discontinued and the patient apprised of the potential risk to the fetus.

Lactation : 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 atorvastatin should not breast-feed (see Contraindications).

Children: Treatment experience in a pediatric population is limited to doses of atorvastatin up to 80 mg/day for 1 year in 8 patients with homozygous familial hypercholesterolemia. No clinical or biochemical abnormalities were reported in these patients.

Renal Insufficiency: Plasma concentrations and LDL-C lowering efficacy of atorvastatin 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 atorvastatin should be used in these patients. Similar precautions apply in patients with severe renal insufficiency (creatinine clearance
Refer also to Dosage.

Endocrine Function: 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.

Drug Interactions: Concomitant Therapy with Other Lipid Metabolism Regulators: Combined drug therapy should be approached with caution as information from controlled studies is limited.

Bile Acid Sequestrants: Patients With Mild to Moderate Hypercholesterolemia: LDL-C reduction was greater when atorvastatin 10 mg and colestipol 20 g were coadministered (-45%) than when either drug was administered alone (-35% for atorvastatin and -22% for colestipol).

Patients With Severe Hypercholesterolemia: LDL-C reduction was similar (-53%) when atorvastatin 40 mg and colestipol 20 g were coadministered when compared with that of atorvastatin 80 mg alone. Plasma concentration of atorvastatin was lower (approximately 26%) when atorvastatin 40 mg plus colestipol 20 g were coadministered compared with atorvastatin 40 mg alone.

However, the combination drug therapy was less effective in lowering the triglycerides than atorvastatin monotherapy in both types of hypercholesterolemic patients. When atorvastatin is used concurrently with colestipol or any other resin, an interval of at least 2 hours should be maintained between the two drugs, since the absorption of atorvastatin may be impaired by the resin.

Fibric Acid Derivatives (Gemfibrozil, Fenofibrate, Bezafibrate) and Niacin (Nicotinic Acid): Although there is no experience with the use of atorvastatin given concurrently with fibric acid derivatives and niacin, the benefits and risks of such combined therapy should be carefully considered. The risk of myopathy during treatment with other drugs in this class is increased with concurrent administration (see Warnings, Muscle Effects).

Coumarin Anticoagulants: Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy.

Digoxin: Coadministration of multiple doses of atorvastatin and digoxin increased steady-state plasma digoxin concentrations by approximately 20%. Patients taking digoxin should be monitored closely and appropriately.

Oral Contraceptives: Coadministration of atorvastatin with an oral contraceptive, containing 1 mg norethindrone and 35 µg ethinyl estradiol, increased plasma concentrations (AUC levels) of norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively. These increases should be considered when selecting an oral contraceptive.

Antacids: Administration of aluminum and magnesium based antacids, such as Maalox TC suspension, with atorvastatin decreased plasma concentrations of atorvastatin by approximately 35%. LDL-C reduction was not altered but the triglyceride-lowering effect of atorvastatin may be affected.

Cimetidine: Administration of cimetidine with atorvastatin did not alter plasma concentrations or LDL-C lowering efficacy of atorvastatin, however, the triglyceride-lowering effect of atorvastatin was reduced from 34 to 26%.

Cytochrome P450-mediated Interactions : Atorvastatin is metabolized by the cytochrome P450 isoenzyme, CYP 3A4. Erythromycin, a CYP 3A4 inhibitor, increased atorvastatin plasma levels by 40%. Coadministration of CYP 3A4 inhibitors, such as grapefruit juice, macrolide antibiotics (including erythromycin), immunosuppressants (cyclosporine), azole antifungal agents (i.e., itraconazole, ketoconazole), or some antidepressants (e.g., nefazodone), may have the potential to increase plasma concentrations of HMG CoA reductase inhibitors, including atorvastatin. Caution should thus be exercised with concomitant use of these agents (see Warnings, Pharmacokinetic Interactions, Muscle Effects; Dosage).

In a study with healthy subjects, coadministration of maximum doses of both atorvastatin (80 mg) and terfenadine (120 mg), a CYP 3A4 substrate, was shown to produce modest increases in AUC values. The QTc interval remained unchanged. However, since an interaction between these two drugs cannot be excluded in patients with predisposing factors for arrhythmia, (e.g., pre-existing prolonged QT interval, severe coronary artery disease, hypokalemia), caution should be exercised when these agents are coadministered (see Warnings, Pharmacokinetic Interactions and Dosage).

Antipyrine: Antipyrine was used as a nonspecific model for drugs metabolized by the microsomal hepatic enzyme system (cytochrome P450 system). Atorvastatin had no effect on the pharmacokinetics of antipyrine, thus interactions with other drugs metabolized via the same cytochrome isozymes are not expected.

Erythromycin: In healthy individuals, plasma concentrations of atorvastatin increased approximately 40% with coadministration of atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4 (see Warnings, Muscle Effects).

Other Concomitant Therapy: Caution should be exercised with concomitant use of immunosuppressive agents and azole antifungals (see Warnings, Muscle Effects).

In clinical studies, atorvastatin was used concomitantly with antihypertensive agents and estrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with specific agents have not been conducted.

Patients with Severe Hypercholesterolemia: Higher drug dosages (80 mg/day) required for some patients with heterozygous familial hypercholesterolemia or severe 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, Pharmacokinetic Interactions, Muscle Effects; Precautions, Drug Interactions and Dosage).

Drug/Laboratory Test Interactions : Atorvastatin may elevate serum transaminase and creatinine phosphokinase levels (from skeletal muscle). In the differential diagnosis of chest pain in a patient on therapy with atorvastatin, cardiac and noncardiac fractions of these enzymes should be determined.

Adverse Reactions: Atorvastatin is generally well-tolerated. Adverse reactions have usually been mild and transient. In controlled clinical studies (placebo-controlled and active-controlled comparative studies with other lipid lowering agents) involving 2 502 patients,
Adverse experiences occurring at an incidence ³1% in patients participating in placebo-controlled clinical studies of atorvastatin and reported to be possibly, probably or definitely drug.

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

Postmarketing Experience: Very rare reports of severe myopathy with or without rhabdomyolysis have been reported (see Warnings, Muscle Effects; Precautions, Renal Insufficiency and Drug Interactions).

Ophthalmologic Observations: see Precautions.

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

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no specific treatment for atorvastatin overdosage. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

Dosage And Administration: Patients should be placed on a standard cholesterol-lowering diet [at least equivalent to the American Heart Association (AHA) Step 1 diet] before receiving atorvastatin, and should continue on this diet during treatment. If appropriate, a program of weight control and physical exercise should be implemented.

Primary Hypercholesterolemia and Combined (Mixed): Hyperlipidemia, Including Familial Combined Hyperlipidemia: The recommended dose of atorvastatin is 10 mg once a day. The majority of patients achieve and maintain target cholesterol levels with atorvastatin 10 mg/day. A significant therapeutic response is evident within 2 weeks, and the maximum response is usually achieved within 2 to 4 weeks. The response is maintained during chronic therapy.

Doses can be given at any time of the day, with or without food, and should preferably be given in the evening. Doses should be individualized according to baseline LDL-C levels, the desired LDL-C target (such as that recommended by the U.S. National Cholesterol Education Program [NCEP] and/or the Canadian Consensus Conference Guidelines), the goal of therapy and the patient’s response. Adjustments of dosage, if necessary, should be made at intervals of 4 weeks or more. The recommended dose range for most patients is 10 to 40 mg/day. The maximum dose is 80 mg/day, which may be required in a minority of patients (see severe hypercholesterolemia). Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of atorvastatin if cholesterol falls below the targeted range such as that recommended by guidelines.

The following reductions in total cholesterol and LDL-C levels have been observed in 2 dose-response studies, and may serve as a guide to treatment of patients with mild to moderate hypercholesterolemia.

Severe Hypercholesterolemia: In patients with severe hypercholesterolemia, including heterozygous familial hypercholesterolemia, higher dosages (up to 80 mg/day) may be required (see Warnings, Muscle Effects and Precautions, Drug Interactions).

Concomitant Therapy: See Precautions, Drug Interactions.

Renal Insufficiency: See Precautions.

Availability And Storage: 10 mg: 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, candelilla wax, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, polysorbate 80 and simethicone emulsion. Bottles of 90.

20 mg: 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, candelilla wax, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, polysorbate 80 and simethicone emulsion. Bottles of 90.

40 mg: 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, candelilla wax, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, polysorbate 80 and simethicone emulsion. Bottles of 90.

Store at controlled room temperature 15 to 25°C.

LIPITOR™ Parke-Davis Atorvastatin Calcium Lipid Metabolism Regulator

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