Lipitor (atorvastatin calcium)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Atorvastatin calcium, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin), is an antilipemic agent.
Atorvastatin calcium is a synthetic antilipemic agent. The drug is a selective, competitive inhibitor of 3-hydroxymethylglutaryl-CoA (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate (an early and rate-limiting step in cholesterol biosynthesis). Inhibition of HMG-CoA reductase results in reduction of hepatic cholesterol biosynthesis, which leads to a compensatory increase in the expression of low-density lipoprotein (LDL) receptors on hepatic cell surfaces and, subsequently, increased hepatic uptake and clearance of LDL-cholesterol from blood.
Atorvastatin reduces serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), triglyceride, very low-density lipoprotein (VLDL)-cholesterol, intermediate-density lipoprotein (IDL)-cholesterol, and non-high-density lipoprotein (HDL) cholesterol concentrations, and increases serum HDL-cholesterol and apolipoprotein A-1 (apo A-1) concentrations in patients with primary hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia, or primary dysbetalipoproteinemia. Other favorable effects of statins (pleiotropic effects) include an antiproliferative influence on smooth muscle cells, reconstruction of endothelial activity, antioxidant, antithrombotic, anticancer, and anti-inflammatory effects.
Atorvastatin is lipophilic, undergoes first-pass metabolism in the liver, and peak plasma concentration is attained in 1-2 hours. The absolute bioavailability of atorvastatin is 14%, however the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The extent of atorvastatin absorption increases in proportion to the dose.
Following the administration of atorvastatin tablets with food, the rate and extent of absorption is decreased approximately 25 and 9%, respectively, as assessed by atorvastatin peak plasma concentration and AUC. LDL-cholesterol reduction is similar whether the tablets are administered with or without food. Following the administration of atorvastatin oral suspension with a high fat meal, atorvastatin AUC and peak plasma concentration decreased approximately 30 and 63%, respectively, compared with what was observed in the fasted state.
This decreased exposure can be clinically significant, and therefore atorvastatin oral suspension should be administered on an empty stomach (1 hour before or 2 hours after a meal). Atorvastatin peak plasma concentrations and AUC are approximately 30% lower following evening drug administration compared with morning; LDL-cholesterol reduction is the same regardless of the time of day of drug administration. Atorvastatin is >=98% bound to plasma proteins.
Atorvastatin is distributed mainly to the liver, the primary site of action and principal site of cholesterol synthesis and LDL-cholesterol clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-cholesterol reduction; therefore, individualization of drug dosage should be based on therapeutic response. Therapeutic response is observed within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during long-term therapy.
Atorvastatin is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 to active metabolites (i.e., o- and p-hydroxylated derivatives, various beta-oxidation products). In vitro inhibition of HMG-CoA reductase by the activeo- and p-hydroxylated metabolites is similar to that by atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
In animals, theo-hydroxy metabolite undergoes further glucuronidation. Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. The 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 an orally administered dose of atorvastatin is recovered in urine. Atorvastatin peak plasma concentrations and AUC are approximately 20% higher and 10% lower, respectively, in females compared to males; however, there is no clinically significant difference in LDL-cholesterol reduction.
USES: Atorvastatin is used along with a proper diet to help lower "bad" cholesterol and fats (such as LDL, triglycerides) and raise "good" cholesterol (HDL) in the blood. It belongs to a group of drugs known as "statins." It works by reducing the amount of cholesterol made by the liver. Lowering "bad" cholesterol and triglycerides and raising "good" cholesterol decreases the risk of heart disease and helps prevent strokes and heart attacks.
In addition to eating a proper diet (such as a low-cholesterol/low-fat diet), other lifestyle changes that may help this medication work better include exercising, losing weight if overweight, and stopping smoking. Consult your doctor for more details.
Generic name: atorvastatin calcium
Pronunciation: (a-TOR-va-STAT-in)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
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Indications
The following indications are listed for Lipitor:
- Atherosclerotic Cardiovascular Disease
- Cardiovascular Event Risk Reduction In Type 2 Diabetes Mellitus
- Heterozygous Familial Hypercholesterolemia
- Homozygous Familial Hypercholesterolemia
- Hypercholesterolemia
- Hyperlipidemia
- Hypertriglyceridemia
- Mixed Hyperlipidemia
- Myocardial Infarction Prevention
- Prevention Of Cerebrovascular Accident
- Primary Dysbetalipoproteinemia
- Treatment To Slow Progression Of Coronary Artery Disease
Also known as: Abnormally Increased Triglycerides In The Blood, Acute Mi Prophylaxis, Acute Myocardial Infarction Prophylaxis, Ami Prophylaxis, Atherosclerosis, Atherosclerotic Vascular Disease, Cardiac Infarct Prophylaxis, Cardiac Infarction Prophylaxis, Cardiovascular Disease Related To Atherosclerosis, Combined Hypercholesterolemia And Hypertriglyceridemia, Cva Prophylaxis, Elevated Blood Cholesterol Level, Elevated Triglyceride Level, Familial Heterozygous Hypercholesterolemia, Familial Homozygous Hypercholesterolemia, Familial Type 3 Hyperlipoproteinemia, Fredrickson Type Iii Hyperlipoproteinemia, Heterozygous Familial Elevated Blood Cholesterol, Hyperlipoidemia, Increased Triglyceride Levels, Lipemia, Lipidemia, Lipoidemia, Mi Prophylaxis, Mixed Dyslipidemia, Myocardial Infarct Prophylaxis, Myocardial Infarction Prophylaxis, Stroke Prophylaxis, Treatment To Slow Progression Of Cad, Type Iii Hyperlipoproteinemia.
Dosing
Dosage of atorvastatin calcium is expressed in terms of atorvastatin.
Dosage adjustment based on LDL-cholesterol levels may occur as early as 4 weeks after atorvastatin initiation and/or titration.
Antiviral drugs: In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, atorvastatin dosage should not exceed 20 mg once daily. In patients taking nelfinavir, atorvastatin dosage should not exceed 40 mg once daily.
Clarithromycin: In patients taking clarithromycin, atorvastatin dosage should not exceed 20 mg once daily.
Itraconazole: In patients taking itraconazole, atorvastatin dosage should not exceed 20 mg once daily.
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Drug interactions
Atorvastatin is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.
Atorvastatin is a substrate of P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), and organic anion transporter protein (OATP) 1B1/1B3.
When atorvastatin is used in fixed combination with amlodipine, interactions associated with amlodipine should be considered. No formal drug interaction studies have been performed to date with the fixed-combination preparation containing atorvastatin and amlodipine.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Acute liver failure or decompensated cirrhosis.
*Known hypersensitivity to atorvastatin or any component in the formulation. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported.
*Atorvastatin and amlodipine fixed-combination tablets: Pregnancy, lactation, active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in >=5% of patients receiving atorvastatin include nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Safety and efficacy of atorvastatin have not been evaluated in children younger than 10 years of age with heterozygous- (HeFH) or homozygous familial hypercholesterolemia (HoFH), or in pediatric patients with other types of hyperlipidemia. Safety and effectiveness of atorvastatin as an adjuct to diet to reduce LDL-cholesterol in pediatric patients >=10 years of age with HeFH have been established in a limited (N=187), randomized, double-blind, placebo-controlled study. There were no substantial adverse effects on growth or sexual maturation in adolescent males or on duration of menstrual cycle in females.
In an open-label, 8-week study that included pediatric HeFH patients (10-17 years of age), the apparent oral clearance of atorvastatin appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in the atorvastatin population pharmacokinetic model.
Safety and effectiveness of atorvastatin as an adjunct to other LDL-cholesterol-lowering therapies to reduce LDL-cholesterol in pediatric patients >=10 years of age with HoFH have been established based on an uncontrolled study in 8 pediatric patients (10 years of age or older).
Safety and efficacy of atorvastatin in fixed combination with amlodipine (Caduet(R)and generic equivalents) have not been established in pediatric patients. The effect of the amlodipine component, of the atorvastatin/amlodipine (Caduet(R) and generic equivalents) fixed preparation, on blood pressure in patients less than 6 years of age is not known.
All statins were previously contraindicated in pregnant females because the fetal risk with these drugs was thought to outweigh any possible benefit. This determination was based on several factors including safety signals from animal data. Increased post-implantation loss occurred in rats and rabbits at maternally toxic doses of 300- and 50- or 100 mg/kg per day, respectively; decreased fetal body weight was observed at 300- and 100 mg/kg per day, respectively. Decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups, decreased pup body weight through postnatal day 21 and 91, and pup developmental delays were observed when pregnant and lactating rats received 100- or 225 mg/kg per day (a maternally toxic dose), doses corresponding to 6- and 22-times the human exposure at the maximum recommended human dose, based on AUC. In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant females who were exposed to a lipophilic statin during the first trimester.
Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm. More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use. The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects. While an increased risk of miscarriage has been reported in pregnant females exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors.
FDA conducted a comprehensive review of all available clinical and nonclinical data of statin use in pregnant women and concluded that the totality of evidence suggests limited potential for statins to cause malformations and other adverse embryofetal effects. Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins. While FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with homozygous familial hypercholesterolemia or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits. Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.
Atorvastatin is distributed into milk in rats. It is not known whether atorvastatin is distributed into human milk; however, the drug is probably distributed into human milk because a small amount of another statin is distributed into human milk. Because of the potential for serious adverse reactions from atorvastatin in nursing infants, the drug is not recommended in nursing females. Females who require atorvastatin therapy should not breast-feed their infants. Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula.
There are no specific dosage recommendations for geriatric patients. Dose selection in geriatric patients (>=65 years of age) should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients for the increased risk of myopathy.
Of the total number of patients receiving atorvastatin in clinical studies, 40% were 65 years of age or older, and 7% were 75 years of age or older. No overall differences in efficacy or safety were observed between geriatric and younger patients. Data from a pharmacokinetic study indicate that peak plasma concentration and AUC of atorvastatin were 40 or 30% higher, respectively, in geriatric individuals (65 years of age or older) compared with younger adults.
Because advanced age (65 years and older) is a predisposing factor for myopathy, including rhabdomyolysis, atorvastatin should be used with caution in geriatric patients. The manufacturer recommends cautious dosage selection of atorvastatin in geriatric patients, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving atorvastatin for the increased risk of myopathy.
Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects of statin therapy should be considered before initiating statin therapy in this population.
Safety and efficacy of atorvastatin in fixed combination with amlodipine (Caduet(R)) have not been established in geriatric patients.
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Last reviewed · Source: First Databank (FDB) drug data
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