Brands, Medical Use, Clinical Data
- Anticholesteremic Agents
- HMG-CoA Reductase Inhibitors
- Tablet (10 mg, 20 mg, or 40 mg)
Brands / Synonyms
Amlodipine and Atorvastatin; Atorvastatin calcium; Atorvastatin calcium salt; Atorvastatin, Calcium salt; Caduet; Cardyl; Lipitor; Sotis; Torvast; Tozalip; Xavator
For management as an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels in patients with primary hypercholesterolemia and mixed dyslipidemia.
Atorvastatin, a selective, competitive HMG-CoA reductase inhibitor, is used to lower cholesterol and triglycerides in patients with hypercholesterolemia and mixed dyslipidemia and in the treatment of homozygous familial hypercholesterolemia. Atorvastatin has a unique structure, long half-life, and hepatic selectivity, explaining its greater LDL-lowering potency compared to other HMG-CoA reductase inhibitors.
Mechanism of Action
Atorvastatin selectively and competitively inhibits the hepatic enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. As HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate, this results in a decrease in mevalonate, a precursor of cholesterol, and a subsequent decrease in hepatic cholesterol levels and increase in uptake of LDL cholesterol.
Atorvastatin is rapidly absorbed after oral administration. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%.
Rhabdomyolysis, eye hemorrhages, and liver problems.
Biotrnasformation / Drug 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.
Active liver disease or unexplained persistent elevations of serum transaminases.
Hypersensitivity to any component of this medication.
Pregnancy and Lactation
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.
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 this drug,
therapy should be discontinued and the patient apprised of the potential hazard to the fetus.
The risk of myopathy during treatment with drugs of this class is increased with concurrent administration of
cyclosporine, fibric acid derivatives, niacin (nicotinic acid), erythromycin, azole antifungals.
Antacid: When atorvastatin and MaaloxÒ TC suspension 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
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 coadministration 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.
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
Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve
vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating
doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma
area-under-the-curve (AUC, 0-24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was
seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions
have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses
up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0-24) based on the
maximum recommended human dose of 80 mg/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of
perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug
in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically
normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the
mean drug level in humans taking the highest recommended dose.