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PRODUCT PROFILE Atorvastatin calcium is [R-(R*,
R*)]-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-
3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-1-heptanoic acid, calcium salt
(2:1) trihydrate.
Clinical Pharmacology
Atorvastatin
is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting
enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a
precursor of sterols, including cholesterol. Cholesterol and triglycerides
circulate in the bloodstream as part of lipoprotein complexes. With
ultracentrifugation, these complexes separate into HDL (high-density
lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density
lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides
(TG) and cholesterol in the liver are incorporated into VLDL and released into
the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is
catabolized primarily through the high-affinity LDL receptor. Clinical and
pathologic studies show that elevated plasma levels of total cholesterol
(total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B - a membrane
complex for LDL-C) promote human atherosclerosis and are risk factors for
developing cardiovascular disease, while increased levels of HDL-C are
associated with a decreased cardiovascular risk. In
animal models, 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 LDL receptors on the cell-surface to enhance
uptake and catabolism of LDL; atorvastatin also reduces LDL production and the
number of LDL particles. Atorvastatin reduces LDL-C in some patients with
homozygous familial hypercholesterolemia (FH), a population that rarely responds
to other lipid-lowering medications. A variety of clinical studies have demonstrated that elevated levels of
total-C, LDL-C, and apo B promote human atherosclerosis. Similarly, decreased
levels of HDL-C (and its transport complex, apo A) are associated with the
development of atherosclerosis. Epidemiologic investigations have established
that cardiovascular morbidity and mortality vary directly with the level of
total-C and LDL-C, and inversely with the level of HDL-C. Atorvastatin reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridermia. Atorvastatin reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia. The effect of atorvastatin on cardiovascular morbidity and mortality has not been determined. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (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. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. Atorvastatin
as well as some of its metabolites are pharmacologically active in humans. The
liver is the primary site of action and the principal site of cholesterol
synthesis and LDL clearance. Drug dosage rather than systemic drug concentration
correlates better with LDL-C reduction. Individualization of drug dosage should
be based on therapeutic response Absorption Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1-2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% 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 hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration Distribution Mean volume
of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ³98%
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 Metabolism Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozyme. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Excretion Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. 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 20-30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. Special Populations Geriatric Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ³65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults Pediatric Pharmacokinetic data in the pediatric population are not available. Gender Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women. Renal Insufficiency Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary. Hemodialysis While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins. Hepatic Insufficiency In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease Atorvastatin is indicated:
Therapy
with lipid-altering agents should be a component of multiple-risk-factor
intervention in individuals at increased risk for atherosclerotic vascular
disease due to hypercholesterolemia. Lipid-altering agents should be used in
addition to a diet restricted in saturated fat and cholesterol only when the
response to diet and other nonpharmacological measures has been inadequate. Atorvastatin is contraindicvated in active liver disease or unexplained persistent elevations of serum transaminases and in hypersensitivity to the drug. 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 fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers. HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy and any elevation of dose and periodically (e.g., semiannually) thereafter. Atorvastatin
should be used with caution in patients who consume substantial quantities of
alcohol and/or have a history of liver disease. Uncomplicated myalgia has been reported in atorvastatin-treated patients. Myopathy should be considered in any patient wlth diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of creatine phosphokinase (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 other drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, or azole antifungals. Before instituting therapy with atorvastatin, an attempt should be made
to control hypercholesterolemia with appropriate diet, exercise, and weight
reduction in obese patients, and to treat other underlying medical problems. HMG-CoA reductase inhibitors
interfere with cholesterol synthesis and theoretically might blunt adrenal
and/or gonadal steroid production. Clinical studies have shown that atorvastatin
does not reduce basal plasma cortisol concentration or impair adrenal reserve.
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. Caution should be exercised if an
HMG-CoA reductase inhibitor is administered concomitantly with drugs that may
decrease the levels or activity of endogenous steroid hormones, such as
ketoconazole, spironolactone, and cimetidine. Pregnancy Safety in pregnant women has not been established (see contraindications). If a woman becomes pregnant while taking atorvastatin, it should be discontinued. Nursing Mothers Nursing
rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that
in their mother's milk. Because of the potential for adverse reactions in
nursing infants, women taking atorvastatin should not breast-feed (see
contraindications). Pediatric Use Treatment
experience in pediatric population
is limited and hence sufficient caution should be exercised in prescribing the
drug in this population. Geriatric Use The safety
and efficacy of atorvastatin (10-80 mg) in the geriatric population (³65
years of age) was evaluated in the ACCESS study (835 patients). The mean change
in LDL-C from baseline after 6 weeks of treatment with atorvastatin 10 mg was
-38.2% in the elderly patients versus -34.6% in the non-elderly group. The
rates of discontinuation due to adverse events were similar between the two age
groups. There were no differences in
clinically relevant laboratory abnormalities between the age groups. Myopathy: The risk of myopathy during treatment with other drugs of this class
is increased with concurrent administration of cyclosporine, fibric acid
derivatives, niacin (nicotinic acid), erythromycin, azole antifungals. Antacid: When
atorvastatin and antacids were coadministered, plasma concentrations of
atorvastatin decreased approximately 35%. However, LDL-C reduction was not
altered. Antipyrine: Because atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isozymes are not expected. Colestipol: Plasma
concentrations of atorvastatin decreased approximately 25% when colestipol and
atorvastatin were coadministered. However, LDL-C reduction was greater when
atorvastatin and colestipol were coadministered than when either drug was given
alone. Cimetidine: Atorvastatin
plasma concentrations and LDL-C reduction were not altered by coadministration
of cimetidine. Digoxin: When
multiple doses of atorvastatin and digoxin were coadministered, steady-state
plasma digoxin concentrations increased by approximately 20%. Patients taking
digoxin should be monitored appropriately. Erythromycin: In
healthy individuals, plasma concentrations of atorvastatin increased
approximately 40% with coadministratlon of atorvastatin and erythromycin, a
known inhibitor of cytochrome P450 3A4. Oral
Contraceptives: Coadministration of atorvastatin and an oral
contraceptive increased AUC values for norethindrone and ethinyl estradiol by
approximately 30% and 20%. These increases should be considered when selecting
an oral contraceptive for a woman taking atorvastatin. Warfarin: Atorvastatin
had no clinically significant effect on prothrombin time when administered to
patients receiving chronic warfarin treatment. Atorvastatin is generally
well-tolerated. Adverse reactions have usually been mild and transient. In
controlled clinical studies of 2502 patients, <2% of patients were
discontinued due to adverse experiences attributable to atorvastatin. The most
frequent adverse events thought to be related to atorvastatin were constipation,
flatulence, dyspepsia, and abdominal pain. Uncomplicated myalgia not associated with elevated creatine kinase has been reported in atorvastatin- treated patients. In clinical trials <1% of patients had confirmed transaminase elevations greater than three times the upper limit of normal. Most elevations occurred within 16 weeks of starting treatment. The
ocular lens is completely avascular and depends largely on endogenous
cholesterol synthesis. Therefore, reductase inhibitors could have an adverse
effect on the human lens after long-term treatment. Historically, no correlation
between the use of reductase inhibitors and the development of lenticular
opacities has been established in humans. In a 1-year study in which
patients received 10 or 20 mg atorvastatin daily, there was no associated
increased risk of lenticular opacity developments Rhabdomyolysis with acute renal failure secondary to myoglobinuria has
been reported with other drugs in this class. 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 (e.g. severe acute
infection, hypotension, major surgery, trauma, severe metabolic, endocrine and
electrolyte disorders and uncontrolled seizures). The patient
should be placed on a standard cholesterol-lowering diet before receiving
atorvastatin and should continue on this diet during treatment with atorvastatin. Hypercholesterolemia
(Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson
Types IIa and IIb) The recommended starting dose of atorvastatin is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin is 10-80 mg once daily. Atorvastatin can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of atorvastatin should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of atorvastatin, lipid levels should be analyzed within 2-4 weeks and dosage adjusted accordingly. Homozygous Familial Hypercholesterolemia The dosage of
atorvastatin in patients with homozygous FH is 10-80 mg daily. Atorvastatin
should be used as an adjunct to other lipid-lowering treatments (e.g., LDL
apheresis) in these patients or if such treatments are unavailable. Concomitant Therapy Atorvastatin
may be used in combination with a bile acid binding resin for additive effect.
The combination of HMG-CoA reductase inhibitors and fibrates should generally be
avoided. Dosage in Patients With Renal Insufficiency Renal disease
does not affect the plasma concentrations nor LDL-C reduction of atorvastatin;
thus, dosage adjustment in patients with renal dysfunction is not necessary There is no
specific treatment for atorvastatin overdosage. In the event of an overdose, 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.
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