Rosuvastatin: Drug Whys
By Mike McEvoy
Generic Name: Rosuvastatin (no generic available in U.S. – patent expires in 2016)
Common Brand Name: Crestor (AstraZeneca – U.S.)
Popularity: 30th most commonly prescribed drug in U.S.
Class: lipid lowering agent (antihyperlipidemic, HMG-COA Reductase Inhibitor, statin)
Treatment Uses: For primary prevention of MI or stroke in high-risk cardiovascular disease (CVD) patients. It’s 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, it reduces risk of hospitalization and lowers mortality from all causes.
Rosuvastatin 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.
It decreases rates of diabetic retinopathy, and is used in the prevention of atherosclerosis following coronary artery bypass surgery and restenosis after percutaneous coronary interventions (PCI). It reduces the incidence of atrial fibrillation in chronic CVD and following cardiac surgery.
It has been used with some success to prevent dementia and reduce cognitive impairment, especially in older women, and may be beneficial in decreasing progression of chronic kidney disease as well as decreasing osteoporosis fracture risk in older women (up to 60 percent). It possibly decreases risk of clots in patients with prior deep vein thromboses (DVTs), and may help decrease age related macular degeneration, mitigate degeneration of prosthetic aortic valve replacements, and provide modest clinical benefit in rheumatoid arthritis (RA).
The ATP III Guidelines (Adult Treatment Panel) for management of cholesterol levels, (last updated in 2004) were replaced in 2013 by a significantly different set of guidelines issued by the American Heart Association and the American College of Cardiology.
In the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, a risk assessment tool replaced the blood cholesterol levels previously used to target treatment of patients with statins. These new guidelines led to a storm of criticisms in the media fed by the medical community that seem now to have largely resulted in failure to read the new guidelines in their entirety. The four major groups targeted for prevention of cardiovascular events include:
Patients with clinical atherosclerotic cardiovascular disease.
Patients with LDL-cholesterol levels >190 mg/dL (i.e., those with familial hypercholesterolemia).
Patients aged 40 to 75 years-old with diabetes and LDL-cholesterol levels between 70 and 189 mg/dL without evidence of atherosclerotic cardiovascular disease.
Patients without evidence of cardiovascular disease or diabetes but who have LDL-cholesterol levels between 70 and 189 mg/dL and a 10-year risk of atherosclerotic cardiovascular disease >7.5% (using the risk assessment tool).
Unchanged from previous recommendations: the first line of therapy for treating hypercholesterolemia and risk of cardiovascular events is diet, exercise, weight reduction, and treatment of underlying medical problems.
Dosing and Administration: The recommended starting dose of rosuvastatin for most indications in adults is 10 to 20 mg orally, once daily. Maintenance doses range from 5 to 40 mg, once daily. The 40-mg dose should be reserved for patients who require high-intensity therapy (based on risk assessment).
Adjustments are made at four-week intervals based on recommended therapeutic goals and percentage decrease from baseline Low Density Lipoprotein – Cholesterol (LDL-C) levels. The percentage reduction in LDL-C goal depends on what risk grouping the patient falls into.
Patients requiring large reductions in cholesterol may be started at 40 mg daily (referred to in the new guidelines as high-intensity statin therapy). Maximum daily dosing for adults is 40 mg. Pediatric data are sparse, but in the 10- to 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.
Lipid panel (total cholesterol, HDL, LDL, triglycerides) should be measured at baseline, four to 12 weeks after starting or adjusting rosuvastatin and when clinically indicated thereafter (usually every three months to one year). If more than two consecutive LDL levels are < 40 mg/dL, consider decreasing the rosuvastatin dose.
Taking rosuvastatin 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 rosuvastatin significantly decreases drug absorption. Patients should not take antacids for two hours after taking rosuvastatin (antacids interfere with absorption).
As a side note, red yeast rice contains about 2.4 mg of atorvastatin (another statin in the same class as rosuvastatin) per 600 mg of rice. Patients who consume regular or significant quantities of red yeast rice may need statin dose reductions.
In patients with severe renal impairment (creatinine clearance < 30 mL/minute), starting dose should be reduced to 5 milligrams with a maximum dose of 10 milligrams daily. Rosuvastatin is not dialyzable but dose adjustments may be needed in hemodialysis patients as studies suggest plasma levels are 50 percent greater than in healthy subjects with normal kidney function.
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 since the liver is the primary site of rosuvastatin’s action. Starting doses of 5 milligrams daily should also be used in the Asian population that has a two-fold more efficient processing of rosuvastatin.
When given to patients also taking cyclosporine, do not exceed 5 mg once daily. A small percentage of the population (0.1 percent) is allergic to HMG-CoA Reductase Inhibitors (statins). Onset seem unpredictable; skin rashes can be seen within days while more serious hypersensitivity reactions have been reported between six months and six years of starting therapy.
Older patients tend to develop higher plasma levels with corresponding greater LDL-lowering effects than patients younger than 65 taking statins. Lower doses may achieve desired effects. There have also been rare reports of cognitive impairment including confusion, memory loss, forgetfulness, and amnesia in patients taking statins.
These tend not to be serious but are reversible with discontinuation of the statin. The onset has ranged from one day to many years and usually resolves within three weeks of discontinuation of the statin.
There is no specific treatment for rosuvastatin overdoses beyond supportive care. Significant toxicity has not been reported after overdoses of statins. Vomiting and diarrhea have occurred and may necessitate correction of fluid volume deficits. Hemodialysis does not enhance rosuvastatin clearance. When significant signs and symptoms occur, consider coingestion of other drugs.
Pharmacology/Pharmacokinetics/Stability: Following oral administration, rosuvastatin is absorbed rapidly from the gut, reaching peak plasma drug levels in three to five hours. The average half-life (time needed for half the active drug to be eliminated from the body) is 19 hours.
Significant reductions in cholesterol levels are seen within one week of starting treatment. Peak response in cholesterol reduction is seen four weeks after starting a statin. Significant increases in LDL-C are seen within 48 to 72 hours following discontinuation of most statins.
Rosuvastatin is metabolized primarily in the liver and near completely excreted in feces when taken orally (90 percent). The kidneys eliminate the remainder.
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 exposed to statins in utero. The risk to the fetus clearly outweighs any benefit to the pregnant mother. Furthermore, since atherosclerosis is a gradual process, discontinuation of lipid-lowering agents during pregnancy is unlikely to affect overall cholesterol lowering outcomes.
Rosuvastatin is a synthetic lipid-lowering agent that selectively 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 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.
Rosuvastatin is the only statin without a generic in the United States. Tablets come in 5, 10, 20, and 40-mg strengths. All are biconvex, coated tablets debossed with “CRESTOR” on one side and the numerical value of their dose on the opposite side. The 5-mg tablet is yellow and round; the 10- and 20-mg tablets both pink and round; and the 40-mg tablet pink and oval. Tablets should be stored at room temperature (68-77°F) and protected from moisture.
Cautions and Warnings: Liver function tests (LFTs) should be performed prior to, and when clinically indicated after starting rosuvastatin as well as with dose increases. Patients most at risk for liver injury from rosuvastatin are those with chronic liver disease and patients who consume large quantities of alcohol.
Significantly elevated liver function tests have been reported with statins, and usually occur within the first three months of therapy (if at all). While highly publicized, the actual incidence significant LFT elevations in patients taking rosuvastatin is only 1.1 percent and is dose related. Liver function tests (ALT or AST) exceeding three times the upper normal limits require dose adjustment or discontinuation of rosuvastatin. 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 when 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. There is no rationale for routine CPK measurements.
Statins may increase the rate of functional decline when given to patients with ALS (Amyotrophic Lateral Sclerosis). Increased serum glucose levels and elevated HbA1c have been observed in patients taking statins; these increases are very small (mean 0.1 percent).
Important Side Effects and Interactions: Gastrointestinal side effects are the most commonly reported by patients taking rosuvastatin. These include nausea (2.4 to 6.3 percent) and abdominal pain (2.4 percent). Joint pain (3.8 to 10.1 percent) and muscle pain (1.9 to 12.7 percent) are also commonly reported. Headache is listed in some studies as a commonly reported side effect (range 3.1 to 8.5 percent).
Currently, there are 30 drugs reported to interact with rosuvastatin. Of these, several are worth noting for prehospital and emergency medicine providers.
- Patients taking warfarin who are started on rosuvastatin may have increased INR, requiring warfarin dose adjustments.
- Concurrent use of St. John’s Wort decreases the effectiveness of rosuvastatin.
- Niacin, sometimes used as an adjunct to lower cholesterol, increases risk of myopathy in patients taking rosuvastatin.
It also might be helpful to know that other drugs increase risks of myopathy in patients taking statins. These include:
- protease inhibitors
- 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.
5-, 10-, 2-0, and 40-mg tablet (brand name Crestor)
Patient cost: $6.55 each (available on some discount plans for $0.72 each)
Large hospital cost: $4.08 each
*(Wal Mart and Target don’t include this med in their $4 per month programs)