Atorvastatin

From Pubdrug

Jump to: navigation, search

Contents
image:pdgreen.GIF This page has been completed and reviewed for accuracy.
You are reading a certified PubDrug document. This document is complete and accurate to the best of the knowledge of the author and reviewer. This document cannot be edited without being unlocked by a PubDrug admin. Edits or updates may be recommended under the Discussion tab.

Authored by: WilliamJ4 09:40, 25 January 2007 (PST)
Certified by: Khlee3 14:04, 25 February 2007 (PST)

Atorvastatin quick reference

Atorvastatin
Atorvastatin general drug information
 Pronunciation a TORE va sta tin (.wav file)
 Trade Name(s) Lipitor
 How Supplied Tablets: 10 mg, 20 mg, 40 mg, 80 mg
 Generic Availability No generics available
 Patent Expiry Date February 9, 2010
 Classification HMG-CoA reductase inhibitor
 Schedule Rx
 Pregnancy Category X
 Breast-feeding Do not breast feed.
Atorvastatin chemical information
 IUPAC Name [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole 1-heptanoic acid
 Empirical Formula (C33H34FN2O5)2Ca•3H2O
 Molecular Weight 1209.42 g/mol
pharmacokinetic information  |  pharmacogenomic information

Description

Atorvastatin belongs to a class of medications known as the statins. Statins are all inhibitors of the enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, which is the enzyme responsible for the rate-limiting step in hepatic intracellular cholesterol synthesis. Clinical and pathological studies show that high plasma levels of total cholesterol (total-C), low density lipoproteins (LDL-C), and apolipoprotein-B (Apo-B) are associated with the build up of intravascular plaques leading to atherosclerosis. High total-C, LDL-C, and Apo-B associated atherosclerosis increases the risk for the development of cardiovascular disease. Conversely, increased plasma levels of high density lipoproteins (HDL-C) are associated with a decreased risk for the development of cardiovascular disease. Atorvastatin lowers plasma cholesterol and lipoproteins, mainly at the hepatic level, by inhibiting HMG-CoA reductase, which in turn increases the number of hepatocelluar LDL receptors on the cell surface.[1][2]

Atorvastatin is used to lower cholesterol and triglycerides in patients with hypercholesterolemia and/or mixed dyslipidemia, as well as homozygous familial hypercholesterolemia. The goal of reducing circulating cholesterol (mainly LDL-C) is for the primary and/or secondary prevention of cardiovascular diseases (CVD) such as coronary artery disease (CAD), acute myocardial infarction (AMI), and ischemic cerebrovascular attacks (stroke). Atorvastatin decreases LDL-C by a mean of 39, 43, 50, and 60% for daily doses of 10, 20, 40, and 80 mg, respectively. Furthermore, atorvastatin decreases triglycerides by a mean of 29, 33, 37, 45% for daily doses of 10, 20, 40, and 80 mg, respectively. Atorvastatin increases HDL-C by a mean of 6, 9, 6, and 5% for daily doses of 10, 20, 40, and 80 mg, respectively. Atorvastatin has also shown efficacy in lowering plasma LDL-C levels in patients with homozygous familial hypercholesterolemia (FH), who typically do not respond to lipid lowering therapy.[2]

Mechanism of Action

Atorvastatin, like all statins, is a selective, competitive inhibitor of HMG-CoA reductase. HMG-CoA reductase catalyzes the rate limiting step in hepatic intracellular cholesterol synthesis. HMG-CoA reductase converts HMG-CoA to mevalonate in the cholesterol synthesis cascade[1]. Inhibition of intrahepatocellular cholesterol synthesis results in the activation of sterol regulatory element binding proteins (SREBPs). SREBPs are transcription factors and are part of a cellular signaling cascade responsible for the regulation of LDL-receptor (LDL-R) gene expression. Once activated, SREBPs are able to diffuse across the nuclear membrane where they bind to sterol response elements (SREs) resulting in up-regulation of the LDL-R gene transcription and increased expression of LDL-Rs in the hepatocellular membrane. The increased expression of LDL-Rs causes increased cellular uptake of LDL molecules effectively lowering the intravascular (blood) circulating LDL concentration.[1][2]

Time Required for Therapeutic Response

  • Initial: within 2 weeks[2]
  • Maximum: within 4 weeks[2]

Pharmacokinetics

Absorption
Atorvastatin has rapid oral absorption with an approximate time to maximum plasma concentration (Tmax) of 1-2 hours. The absolute bioavailability of atorvastatin is approximately 14%, however, the systemic availability for HMG-CoA reductase activity is approximately 30%. Atorvastatin undergoes high intestinal clearance and first-pass metabolism, which is the main cause for the low systemic availability. Food has shown to reduce the rate and extent of atorvastatin absorption. Administration of atorvastatin with food produces a 25% reduction in Cmax (rate of absorption) and a 9% reduction in AUC (extent of absorption). However, food does not affect the plasma LDL-C lowering efficacy of atorvastatin. Evening atorvastatin dose administration is known to reduce the Cmax (rate of absorption) and AUC (extent of absorption) by 30% each. However, time of administration does not affect the plasma LDL-C lowering efficacy of atorvastatin.[2]

Distribution
Atorvastatin has a mean volume of distribution of approximately 381 L. Additionally, atorvastatin is highly protein bound (≥98%) with a blood/plasma concentration ratio of 0.25 indicating a low red blood cell distribution.[2]

Metabolism
The primary proposed mechanism of atorvastatin metabolism is through cytochrome P450 3A4 hydroxylation to form active ortho- and parahydroxylated metabolites, as well as various beta-oxidation metabolites. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic HMG-CoA reductase activity. The ortho-hydroxy metabolite undergoes further metabolism via glucuronidation. As a substrate for the CYP 3A4 isozyme it has shown susceptibility to inhibitors and inducers of CYP 3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested in vitro with concurrent administration of erythromycin, a known CYP 3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin.[2] Atorvastatin is also an inhibitor of CYP 3A4.[3]

Excretion
Atorvastatin is primarily eliminated via hepatic biliary excretion with less than 2% of atorvastatin recovered in the urine. Bile elimination follows hepatic and/or extra-hepatic metabolism. There does not appear to be any entero-hepatic recirculation. Atorvastatin has an approximate elimination half-life of 14 hours. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life of 20-30 hours, which is thought to be due to the active metabolites.[2] Atorvastatin is also a substrate of the intestinal P-glycoprotein efflux transporter, which pumps the drug back into the intestinal lumen during drug absorption.[3]

Back to top

Special Population Pharmacokinetics

  • Renal insufficiency: Renal insufficiency does not affect the plasma drug concentrations or its pharmacodynamic efficacy. It is not necessary to adjust the dose for renal disease.[2]
  • Hepatic insufficiency: Plasma drug concentrations are significantly affected by concurrent liver disease. Patients with Childs-Pugh A stage liver disease show a 4-fold increase in both Cmax and AUC. Patients with Childs-Pugh B stage liver disease show an 16-fold increase in Cmax and an 11-fold increase in AUC.[2]
  • Hemodialysis: The effects of hemodynamics on the pharmacokinetics of atorvastatin have not been studied, however, it is unlikely to affect the plasma drug clearance because atorvastatin is extensively protein bound.[4]
  • Geriatric: Geriatric patients (>65 years old) show altered pharmacokinetics of atorvastatin compared to young adults. The mean AUC and Cmax values are higher (40% and 30%, respectively) for geriatric patients. Additionally, healthy elderly patients show a greater pharmacodynamic response to atorvastatin at any dose, therefore, this population may have lower effective doses.[2]
  • Pediatric: Data not available.[2]
  • Gender: The Cmax and AUC of atorvastatin differs among men and women (20% higher Cmax and 10% lower AUC for women compared to men), however, this difference in pharmacokinetics does not translate into a clinically significant change in LDL-C lowering efficacy.[2]

Indications and Dosages

FDA Approved Indications

Hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb) to reduce total cholesterol, LDL-C, apo-B, and TG levels, as well as increase HDL levels[2][5]

  • Starting Dose:
    • Typically, 10 to 20 mg once daily, or 40 mg once daily for patients who require a large (>45%) reduction in LDL-C levels.
  • Maintenance Dose: Maintenance dose is determined based on individual patient LDL-C goals according to coronary heart disease risk factors. Goals for therapy are determined by the NCEP ATP Treatment Guidelines.
  • Titration Schedule: After initiating or change in dose, lipid panel should be done within 2-4 weeks and dose adjusted accordingly.

Heterozygous familial hypercholesterolemia in pediatric patients (10-17 years old)[2]

  • Starting Dose:
    • Typically, 10 mg once daily.
  • Maintenance Dose: Maintenance dose is determined based on individual patient LDL-C goals according to the recommended goal of therapy set forth by the NCEP Blood Cholesterol Guidelines in Children and Adolescents.
  • Titration Schedule: Titration should be individualized based on treatment goals every 4 weeks or more up to a maximum daily dose of 20 mg.

Homozygous familial hypercholesterolemia[2]

  • Starting Dose:
    • Typically, 10 mg once daily. Treatment with atorvastatin in this patient population should be adjunctive to other lipid lowering treatments. May be used as monotherapy if other treatment options are not available.
  • Maintenance Dose: Maintenance dose is determined based on individual patient LDL-C goals according to coronary heart disease risk factors. Goals for therapy are determined by the NCEP ATP Treatment Guidelines.
  • Titration Schedule: Titrate up to target goal to a maximum daily dose of 80 mg.

Hypertriglyceridemia (Fredrickson Type IV)
Primary dysbetalipoproteinemia (Fredrickson Type III)
Prophylaxis for myocardial infarction, stroke, unstable angina, and revascularization prophylaxis in patients with multiple risk factors without evident CHD
Myocardial infarction and stroke prophylaxis in patients with type II diabetes

Concomitant Therapy Considerations[2]
Atorvastatin may be used in combination with bile acid resins. It is not recommended to combine statin treatment with fibrates because of the increased risk of myopathy related adverse reactions.

Non-FDA Approved Indications

None known.

Dosage Adjustment

Hepatic insufficiency: Active liver disease or unexplained persistent elevations in liver transaminase levels are contraindications to atorvastatin use. If AST or ALT progress to greater than 3 times the UNL and persist, dose reduction or drug withdrawal is recommended (see Monitoring Parameters).[2]
Hemodialysis: No adjustment likely.[2]
Geriatric: A large clinical trial[5] concluded that elderly patients have a higher LDL-C lowering response compared to young adults given the same dose.
Pediatric: No adjustment likely, however, the maximum studied dose is 20 mg once daily.[2]

Dosage Limits

  • Adults: 80 mg/day
  • Elderly: 80 mg/day
  • Adolescents and children ≥10 years: 20 mg/day PO
  • Children <10 years: Unknown; safety and efficacy has not been established in this population.


Back to top

Administration

  • Route: Oral[2]
  • Method:
    • Swallow tablet with full (8 oz) glass of water. Tablet should be taken once daily at any time during the day (time should be consistent from day to day) and may be taken without regard to meals.[2]
    • Patients should be placed on a standard low cholesterol diet before initiating statin therapy.[2]

Monitoring Parameters

  • Lipid panel: LDL-C levels should be monitored within 2-4 weeks of initiating or changing dosage (adolescents and children ≥every 4 weeks).[2]
  • Liver function tests (LFTs): Baseline LFTs and at 12 weeks post drug initiation and post dosage change. After 12 week LFTs, if no change in dosage, LFTs should be monitored every 6 months. If AST or ALT progress to greater than 3 times the UNL and persist, dose reduction or drug withdrawal is recommended.[2]
  • Creatine Phosphokinase (CPK/CK): CPK levels are recommended at baseline in patients who are at high risk of developing myopathies. CPK levels should be done if a patient complains of muscle pains, or muscle weakness.[2]

Contraindications/Precautions

Contraindications

  • Active liver disease: cholestasis, hepatic encephalopathy, hepatitis, and jaundice.[2]
  • Unexplained elevations in AST or ALT levels[2]
  • Pregnancy[2]
  • Breast-feeding[2]

Precautions

  • Rhabdomyolysis: Rare cases of rhabdomyolysis have been reported with the use of atorvastatin. Rhabdomyolysis is very serious and can lead to acute renal failure due to myoglobinuria. If rhabdomyolysis is suspected or diagnosed, atorvastatin therapy should be discontinued immediately.[2]
  • Myopathy: Muscle aches or weakness with concurrent increased creatine phosphokinase (CPK) levels greater than 10 times the UNL. Patients should be instructed to report any unexplained myalgias (muscle pain) or muscle weakness, especially if concurrent with fever and malaise. Atorvastatin should be discontinued if a patient has markedly elevated CPK levels or if a myopathy is suspected or diagnosed. The likelihood of developing a myopathy is increased by the co-administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, and azole antifungals.[2]

Pregnancy indications

Category X [2]

Atorvastatin is absolutely contraindicated in pregnancy. HMG-CoA reductase inhibitors are likely to cause harm to fetal development because of the importance of cholesterol and various products in the cholesterol biosynthesis pathway for fetal development, including steroid synthesis and cell membrane production. HMG-CoA reductase inhibitors should not be taken by pregnant women or women who are breast feeding.[2]

Breast-feeding indications

Experiments with rats indicate that atorvastatin is likely to be secreted into human milk. It is not recommended that nursing mothers take atorvastatin due to the possibility of adverse reactions in nursing infants.[2]

Back to top

Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

Adverse Reactions/Side Effects

Atorvastatin is generally well tolerated with a low discontinuation rate (<2%) in clinical trials involving 2502 patients. The most common adverse reactions experienced in clinical trials were constipation, flatulence, dyspepsia, and abdominal pain.>[2][6]

Atorvastatin Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All Headache (3-17%)
1-10% CNS Weakness (0-4%), insomnia, dizziness
Cardiovascular Chest pain, peripheral edema
Dermatologic Rash (1-4%)
GI Abdominal pain (0-4%), constipation (0-3%), diarrhea (0-4%), dyspepsia (1-3%), flatulence (1-3%), nausea
GU Urinary tract infection
Neuromuscular/skeletal Arthralgia (0-5%), myalgia (0-6%), back pain (0-4%), arthritis
Respiratory Sinusitis (0-6%), pharyngitis (0-3%), bronchitis, rhinitis
Miscellaneous Infection (2-10%), flu-like syndrome (0-3%), allergic reaction (0-3%)
<1% All Alopecia, anaphylaxis, angina, angioneurotic edema, arrhythmia, bullous rashes, cholestatic jaundice, deafness, dyspnea, erythema multiforme, esophagitis, facial paralysis, glaucoma, gout, hepatitis, hyperkinesias, impotence, migraine, myasthenia, myopathy, myositis, nephritis, pancreatitis, paresthesia, peripheral neuropathy, petechiae, photosensitivity, postural hypotension, pruritus, rectal hemorrhage, rhabdomyolysis, somnolence, Stevens-Johnson syndrome, syncope, tendinous contracture, thrombocytopenia, tinnitus, torticollis, toxic epidermal necrolysis, urticaria, vaginal hemorrhage, vomiting.

Overdosage Measures

Treatment of atorvastatin overdose is generally guided by symptoms and supportive treatment should be initiated as necessary. Hemodialysis is not expected to expedite drug clearance because atorvastatin is highly protein bound (≥98%).[2]

Back to top

Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
10 mg tablet white oval 10/PD 155
20 mg tablet white oval 20/PD 156
40 mg tablet white oval 40/PD 157
80 mg tablet white oval 80/PD 158
  • Inactive ingredients for tablets: calcium carbonate, candelilla wax, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, Opadry White YS-1-7040, (hypromellose, polyethylene glycol, talc, titanium dioxide), polysorbate 80, simethicone emulsion.

Patient Information

  • Take tablet with a full glass of water, with or without food, at the same time each day.
Back to top

References

  1. ↑ 1.0 1.1 Armstrong, E. J., P. K. Safo, et al. (2005). Pharmacology of Cholesterol and Lipoprotein Metabolism. Eds: Golan DE., et al. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. pgs: 389-69. Baltimore, Lippincott Williams & Wilkins.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 2.29 2.30 2.31 2.32 2.33 2.34 2.35 2.36 2.37 Lipitor® (atorvastatin calcium) package insert. New York, NY; Parke-Davis; 2006 Dec.
  3. ↑ 3.0 3.1 Hansten PD, Horn JR. Cytochrome P450 Enzymes and Drug Interactions, Table of Cytochrome P450 Substrates, Inhibitors, Inducers and P-glycoprotein, withFootnotes. In: The Top 100 Drug Interactions - A guide to Patient Management. 2006 Edition. Edmonds, WA: H&H Publications; 2006:160—174.
  4. ↑ Lins RL, Matthys KE, Verpooten GA, Peeters PC, Dratwa M, Stolear JC, et al. Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients. Nephrology Dialysis Transplantation 2003;18(5):967-76.
  5. ↑ 5.0 5.1 Andrews TC, Ballantyne CM, Hsia JA, Kramer JH. Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins. Am J Med 2001;111(3):185-91.
  6. ↑ Lexi-Comp (2003). Drug Information Handbook. 11th Edition., APhA.

PUBMED References

Efficacy Trial Articles

  1. Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn JL, Weiss SR, et al. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. Jama 1996;275(2):128-33.
  2. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361(9364):1149-58.Full Text Here
  3. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. Jama 2001;285(13):1711-8.
  4. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364(9435):685-96.
  5. Neil HA, DeMicco DA, Luo D, Betteridge DJ, Colhoun HM, Durrington PN, et al. Analysis of efficacy and safety in patients aged 65-75 years at randomization: Collaborative Atorvastatin Diabetes Study (CARDS). Diabetes Care 2006;29(11):2378-84.
  6. Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL, Schwartz SL, Lupien PJ, et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol 1995;15(5):678-82.Free Full Text
  7. Marais AD, Firth JC, Bateman ME, Byrnes P, Martens C, Mountney J. Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1997;17(8):1527-31.
  8. McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial. J Pediatr 2003;143(1):74-80.
  9. Ozaki K, Kubo T, Imaki R, Shinagawa H, Fukaya H, Ohtaki K, Ozaki S, Izumi T, Aizawa Y. The anti-atherosclerotic effects of lipid lowering with atorvastatin in patients with hypercholesterolemia. J Atheroscler Thromb. 2006 Aug;13(4):216-9
  10. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106(25):3143-421.Text Here
  11. Andrews TC, Ballantyne CM, Hsia JA, Kramer JH. Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins. Am J Med 2001;111(3):185-91.
Back to top

Therapeutic Class Comparison Articles

  1. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81(5):582-7.
  2. Gentile S, Turco S, Guarino G, Sasso CF, Amodio M, Magliano P, et al. Comparative efficacy study of atorvastatin vs simvastatin, pravastatin, lovastatin and placebo in type 2 diabetic patients with hypercholesterolaemia. Diabetes Obes Metab 2000;2(6):355-62.

Pharmacokinetics Articles

Back to top

Drug Interaction Articles

  1. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 2002;41(5):343-70.

Adverse Effects Articles

Back to top

Compliance Articles

Pharmacoeconomic Articles

Back to top

External Links

Clinical treatment guidelines

Patient information pages

Other resources

Back to top
Retrieved from "http://www.smbrower.com/mediawiki/index.php/Atorvastatin"
Personal tools