Atorvastatin (Lipitor): Drug Whys


Generic name: Atorvastatin (no generic available, U.S. patent expires in 2010)
Common U.S. brand name: Lipitor® (Parke-Davis)
Popularity: Second most commonly prescribed drug between 2002-2007 (U.S.)
Class: Lipid lowering agent (antihyperlipidemic)

Treatment Uses – For primary prevention of MI or stroke in high risk cardiovascular disease (CVD) patients (includes patients with type 2 diabetes or two or more risk factors) without evidence of cardiovascular disease. Used for secondary prevention against risk of stroke, MI, angina, and need for revascularization procedures in patients with evidence of CVD. In heart failure patients, reduces risk of hospitalization and lowers mortality from all causes. Atorvastatin lowers cholesterol and/or lipid levels in a variety of conditions including patients with (or at risk for) CVD, inherited high cholesterol or lipid disorders, generalized atherosclerosis, and cholesterol elevations resulting from immunosuppressive drugs to prevent rejection of solid organ transplants or lipid level elevations caused by antiretroviral drugs used to treat HIV.

Decreases rates of diabetic retinopathy. Prevention of atherosclerosis following coronary artery bypass surgery and restenosis after percutaneous coronary interventions (PCI). Reduces the incidence of atrial fibrillation in chronic CVD and following cardiac surgery. Used with some success to prevent dementia and reduce cognitive impairment, especially in older women. May be beneficial in decreasing progression of chronic kidney disease as well as decreasing osteoporosis fracture risk in older women (up to 60 percent). Possibly decreases risk of clots in patients with prior deep vein thromboses (DVTs). May help decrease age related macular degeneration, mitigate degeneration of prosthetic aortic valve replacements, and provide modest clinical benefit in rheumatoid arthritis (RA). It is estimated that some 36 million Americans should be taking a statin (ATP III Guidelines) for prevention of CVD events (such as heart attack, stroke, and sudden death), yet only 11 million are currently. Nonetheless, statins comprise a $13.5 billion annual U.S. market and atorvastatin (Lipitor®) held a $6.1 billion share of this in 2007.

Always remember the first line of therapy for treating hypercholesterolemia is diet, exercise, weight reduction, and treatment of underlying medical problems.

Dosing and Administration – The recommended starting dose of atorvastatin for adults is 10 mg orally each day. Adjustments are made at four week intervals based on therapeutic goals which, for most patients, will be cholesterol lowering tied to blood levels of Low Density Lipoprotein – Cholesterol (LDL-C). The goal is an LDL-C of less than 100 milligrams per deciliter (mg/dl). Most recent studies support an LDL-C of less than 70 mg/dl in very high risk patients, and encourage treatment even if baseline LDL-C is less than 100 mg/dl. These data also confirm that older patients benefit from therapeutic lowering of LDL-C regardless of risk factors. Patients requiring large reductions in cholesterol may be started at 40 mg daily. Pediatric data are sparse, but in the 10 –17 year old age group, 10 mg is the recommended daily starting dose. Maximum daily doses above 20 mg have not been extensively studied in children. For adults, the maximum daily dose is 80 mg, and data from the PROVE-IT study found a dramatic decrease in major cardiovascular events (heart attacks, strokes, etc.) in patients who took the 80 mg dose following hospitalization for heart attack or unstable angina in contrast to a standard dose of pravastatin (Pravachol®), the leading competitor to atorvastatin. The irony in the PROVE-IT trial was its design by Bristol-Myers Squibb (makers of pravastatin) intending to demonstrate similar benefits between the competing drugs, which instead showed superiority of their competitor's atorvastatin.

Taking atorvastatin with food decreases the rate of absorption by 25 percent and total absorption by 9 percent although this does not appear to influence drug effects. Earlier data suggested that best response to statins was achieved when taken in a single daily dose during evening hours. More recent studies show no clinical effects when taken at other times during the day. Eating oat bran with atorvastatin significantly decreases drug absorption. Note that red yeast rice contains an estimated 2.4 milligrams of atorvastatin in every 600 milligrams of rice.

Dosage adjustments are not necessary in patients with kidney disease. Atorvastatin is not dialyzable and dose adjustments are unnecessary in hemodialysis patients. The drug should be used with caution and at the lower end of the dosing range in patients with liver disease, or who consume substantial quantities of alcohol as the liver is the primary site of atorvastatin’s action. When given to patients also taking cyclosporine, do not exceed 10 milligrams once daily. Up to 3 percent of the population is allergic to atorvastatin or hypersensitive to its components.

Older patients tend to develop higher plasma levels with corresponding greater LDL lowering effects than younger (< 65 year-old) patients taking atorvastatin. Lower doses may achieve desired effects.

At least one study suggests the possibility of tachyphylaxis with long-term use of atorvastatin. Tachyphylaxis is the need for increasingly higher doses of a medication in order to achieve desired effects, without any change in toxic thresholds. In this study, maximal reductions in LDL-C were seen between six and eight weeks, followed by an increase in LDL-C, with a plateau effect seen at 220 days from the point where lowest LDL-C levels were seen. If nothing else, these data highlight the need for continued monitoring of LDL levels.

There is no specific treatment for atorvastatin overdoses except supportive care. Hemodialysis does not enhance atorvastatin clearance.

Pharmacology/Pharmacokinetics/Stability – Following oral administration, atorvastatin is absorbed rapidly from the gut, reaching peak plasma drug levels in one to two hours. There is considerable individual variation in atorvastatin elimination speed. The average half-life (time needed for half the active drug to be eliminated from the body) is 14 hours, but can range from 11 to 19 hours. Significant reductions in cholesterol levels are seen within 24 to 72 hours of starting treatment. Peak response in cholesterol reduction is seen two weeks after starting atorvastatin. ignificant increases in LDL-C are seen within 48 to 72 hours following discontinuation of the drug.

Atorvastatin is metabolized primarily in the liver and near completely excreted in bile; kidneys eliminate 2 percent. It is unknown whether human breast milk contains excreted atorvastatin although it has been detected in the breast milk of lactating rats. Since cholesterol is essential to fetal development, statins should not be given to women of childbearing age likely to become pregnant or women who are breastfeeding. Likewise, women taking statins should not breastfeed. Studies have demonstrated fetal abnormalities in animals and humans. The risk to pregnant women clearly outweighs any benefit. Furthermore, since atherosclerosis is a gradual process, discontinuation of lipid-lowering agents during pregnancy is unlikely to affect overall cholesterol lowering outcomes.

Atorvastatin is a synthetic lipid-lowering agent that inhibits HMG-CoA reductase and cholesterol synthesis in the liver. It increases the number of LDL receptors in the liver to enhance absorption and breakdown of LDL which, in turn, lowers blood cholesterol levels. There is also increasing evidence that statins affect blood vessel walls through a complex series of actions that ultimately stabilize plaque, prevent rupture, and possibly act to prevent blood clotting.

Atorvastatin tablets are white, elliptical shaped, film coated, and come in 10, 20, 40, and 80 mg strengths, and should be stored at room temperature (68-77 F).

Cautions and Warnings – Liver function tests (LFTs) should be performed prior to, and 12 weeks after starting atorvastatin. They are also recommended with dose increases and at least semiannually thereafter. Significantly elevated liver function tests have been reported with atorvastatin, and usually occur within the first three months of therapy (if at all). While highly publicized, the actual incidence LFT elevations in patients taking atorvastatin is only 0.2 to 2.3 percent and is dose related. Liver function tests (ALT or AST) exceeding three times the upper normal limits require dose adjustment or discontinuation of atorvastatin. The lowest possible doses should be used to prevent adverse effects. Severe muscle damage that if untreated can lead to kidney failure (myopathy leading to rhabdomyolysis), has also occurred in patients treated with statins. Patients should be instructed to report unexplained muscle pains or tenderness, especially if accompanied by a fever. Although rare, both liver and muscle damage are extremely serious adverse effects that can be fatal if not recognized and treated. A blood test for creatinine phosphokinase (CPK) is advised when myopathy is suspected.

Curiously, while used to prevent stroke in at-risk patients, there is a significantly greater risk of hemorrhagic stroke in patients taking high dose (80 milligrams per day) atorvastatin in the six months following a stroke or TIA (transient ischemic attack).

Important Side Effects and Interactions – Gastrointestinal side effects are the most commonly reported by patients taking atorvastatin. These include abdominal pain (up to 3.85 percent), constipation (2.5 percent), excessive gas (flatulence – 1.1 to 2.8 percent), and indigestion (1.3 to 2.8 percent). Headache is also listed in some studies as a commonly reported side effect (range 2.5 to 16.7 percent).

Currently, there are 29 drugs reported to interact with atorvastatin. Of these, none are significant to prehospital and emergency medicine providers. It might be helpful to know that certain drugs increase risks of myopathy in patients taking statins. These include clarithromycin, erythromycin, protease inhibitors, diltiazem, and proton pump inhibitors (PPIs). Patients who drink large quantities of grapefruit juice (greater than 1 quart or 1.2 liters per day) have markedly greater risks of severe muscle damage (orange juice may be substituted).

Average Costs – U.S.
10 mg tablet/ 20 mg tablet (brand name Lipitor)
Patient cost: $2.20 each/ $3.15 each ($66.00/ $94.50 for 30 tabs)
Large Hospital cost: $2.07 each/ $3.01 each ($62.10/ $90.30 for 30 tabs)
*(Wal Mart® and Target don’t include this med in their $4/month programs)


References:
1. MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed April, 2008).
2. Albany Medical Center Pharmacy, Albany, New York.
3. National Cholesterol Education Program. ATP III Update 2004: Implications of Recent Clinical Trials for the ATP III Guidelines (Adult Treatment Panel III). National Institutes of Health, 2004. [on-line] available: www.nhlbi.nih.gov/chd/

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