Crestor

Crestor Information

Crestor (rosuvastatin calcium) is a synthetic lipid-lowering agent. Rosuvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.

How Does Crestor Work?

Crestor (rosuvastatin) is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown Crestor (rosuvastatin) to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, Crestor (rosuvastatin) inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

Crestor (rosuvastatin) reduces total cholesterol (total-C), LDL-C, ApoB, and nonHDL-C (total cholesterol minus HDL-C) in patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Rosuvastatin also reduces TG and produces increases in HDL-C. Crestor (rosuvastatin) reduces total-C, LDL-C, VLDL-cholesterol (VLDL-C), ApoB, nonHDL-C and TG, and increases HDL-C in patients with isolated hypertriglyceridemia. The effect of Crestor (rosuvastatin) on cardiovascular morbidity and mortality has not been determined.

Crestor Ingredients and Composition

How To Take Crestor and Crestor Dosage and Administration

The patient should be placed on a standard cholesterol-lowering diet before receiving Crestor (rosuvastatin) and should continue on this diet during treatment. Crestor (rosuvastatin) can be administered as a single dose at any time of day, with or without food.

Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Type IIa and IIb)

The dose range for Crestor (rosuvastatin) is 5 to 40 mg once daily. Therapy with Crestor (rosuvastatin) should be individualized according to goal of therapy and response. The usual recommended starting dose of Crestor (rosuvastatin) is 10 mg once daily. Initiation of Crestor (rosuvastatin) therapy with 5 mg once daily may be considered for patients requiring less aggressive LDL-C reductions or who have predisposing factors for myopathy. For patients with marked hypercholesterolemia (LDL-C > 190 mg/dL) and aggressive lipid targets, a 20-mg starting Crestor (rosuvastatin) dose may be considered. The 40-mg dose of Crestor (rosuvastatin) should be reserved for those patients who have not achieved goal LDL-C at 20 mg. After initiation and/or upon titration of Crestor (rosuvastatin), lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.

Homozygous Familial Hypercholesterolemia

The recommended starting dose of Crestor (rosuvastatin) is 20 mg once daily in patients with homozygous FH. The maximum recommended daily dose is 40 mg. Crestor (rosuvastatin) should be used in these patients as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable. Response to Crestor (rosuvastatin) therapy should be estimated from pre-apheresis LDL-C levels.

If you suspect a Crestor Overdose

There is no specific treatment in the event of Crestor (rosuvastatin) overdose. In the event of Crestor overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.

Crestor Side Effects

Crestor Precautions and Contraindications

You should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

When taking Crestor (rosuvastatin) with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin administration.

Crestor (rosuvastatin) is contraindicated in patients with active liver disease or with unexplained persistent elevations of serum transaminases.

HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. The incidence of persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more consecutive occasions) in serum transaminases in fixed dose studies was 0.4, 0, 0, and 0.1% in patients who received rosuvastatin 5, 10, 20, and 40 mg, respectively. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.

It is recommended that liver function tests be performed before and at 12 weeks following both the initiation of Crestor (rosuvastatin) therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with rosuvastatin. Patients who develop increased transaminase levels should be monitored until the abnormalities have resolved. Should an increase in ALT or AST of >3 times ULN persist, reduction of dose or withdrawal of rosuvastatin is recommended.

Crestor (rosuvastatin) should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of Crestor (rosuvastatin).

Myopathy/Rhabdomyolysis

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with Crestor (rosuvastatin) and with other drugs in this class.

Uncomplicated myalgia has been reported in rosuvastatin-treated patients. Creatine-kinase (CK) elevations (>10 times upper limit of normal) occurred in 0.2% to 0.4% of patients taking Crestor (rosuvastatin) at doses up to 40 mg in clinical studies. Treatment-related myopathy, defined as muscle aches or muscle weakness in conjunction with increases in CK values >10 times upper limit of normal, was reported in up to 0.1% of patients taking rosuvastatin doses of up to 40 mg in clinical studies. Rare cases of rhabdomyolysis were seen with higher than recommended Crestor (rosuvastatin) doses (80 mg) in clinical trials. Factors that may predispose patients to myopathy with HMG-CoA reductase inhibitors include advanced age (>65 years), hypothyroidism, and renal insufficiency. The incidence of myopathy increased at doses of Crestor (rosuvastatin) above the recommended dosage range.

Consequently:

Rosuvastatin should be prescribed with caution in patients with predisposing factors for myopathy, such as, renal impairment, advanced age, and hypothyroidism.

Patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Crestor (rosuvastatin) therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with Crestor (rosuvastatin) may be increased with concurrent administration of other lipid-lowering therapies or cyclosporine. The benefit of further alterations in lipid levels by the combined use of Crestor (rosuvastatin) with fibrates or niacin should be carefully weighed against the potential risks of this combination. Combination therapy with rosuvastatin and gemfibrozil should generally be avoided.
The risk of myopathy during treatment with Crestor (rosuvastatin) may be increased in circumstances which increase rosuvastatin drug levels.
Crestor (rosuvastatin) therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

Crestor Drug Interactions

Crestor (rosuvastatin) drug interactions include the following:

Cyclosporine:

When Crestor (rosuvastatin) 10 mg was co-administered with cyclosporine in cardiac transplant patients, rosuvastatin mean Cmax and mean AUC were increased 11-fold and 7-fold, respectively, compared with healthy volunteers. These increases are considered to be clinically significant and require special consideration in the dosing of Crestor (rosuvastatin) to patients taking concomitant cyclosporine.

Warfarin:

Coadministration of Crestor (rosuvastatin) to patients on stable warfarin therapy resulted in clinically significant rises in INR (>4, baseline 2-3). In patients taking coumarin anticoagulants and Crestor (rosuvastatin) concomitantly, INR should be determined before starting Crestor (rosuvastatin) and frequently enough during early therapy to ensure that no significant alteration of INR occurs. Once a stable INR time has been documented, INR can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of rosuvastatin is changed, the same procedure should be repeated. Crestor (rosuvastatin) therapy has not been associated with bleeding or with changes in INR in patients not taking anticoagulants.

Gemfibrozil:

Coadministration of a single Crestor (rosuvastatin) dose to healthy volunteers on gemfibrozil (600 mg twice daily) resulted in 2.2- and 1.9-fold, respectively, increase in mean Cmax and mean AUC of rosuvastatin.

Crestor Clinical Trials and Studies

Taking Crestor during Pregnancy or Breast-feeding

Crestor (rosuvastatin) may cause fetal harm when administered to a pregnant woman. Crestor (rosuvastatin) is contraindicated in women who are or may become pregnant. Safety in pregnant women has not been established. There are no adequate and well-controlled studies of Crestor (rosuvastatin) in pregnant women. Crestor (rosuvastatin) crosses the placenta and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18. If this drug is administered to a woman with reproductive potential, the patient should be apprised of the potential hazard to a fetus.

In female rats given oral gavage doses of 5, 15, 50 mg/kg/day Crestor (rosuvastatin) before mating and continuing through day 7 postcoitus results in decreased fetal body weight (female pups) and delayed ossification at the high dose (systemic exposures 10 times human exposure at 40 mg/day based on AUC comparisons).

In pregnant rats given oral gavage doses of 2, 20, 50 mg/kg/day from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred in groups given 50 mg/kg/day, systemic exposures >12 times human exposure at 40 mg/day based on body surface area comparisons.

In pregnant rabbits given oral gavage doses of 0.3, 1, 3 mg/kg/day from gestation day 6 to lactation day 18 (weaning), exposures equivalent to human exposure at 40 mg/day based on body surface area comparisons, decreased fetal viability and maternal mortality was observed.

Crestor (rosuvastatin) was not teratogenic in rats at ≤25 mg/kg/day or in rabbits ≤3 mg/kg/day (systemic exposures equivalent to human exposure at 40 mg/day based on AUC or body surface comparison, respectively).

Nursing Mothers

It is not known whether Crestor (rosuvastatin) is excreted in human milk. Studies in lactating rats have demonstrated that Crestor (rosuvastatin)is secreted into breast milk at levels 3 times higher than that obtained in the plasma following oral gavage dosing. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Crestor (rosuvastatin) a decision should be made whether to discontinue nursing or administration of Crestor (rosuvastatin) taking into account the importance of the drug to the lactating woman.

Storing Crestor

Store Crestor (rosuvastatin) at controlled room temperature, 20-25°C (68-77°F). Protect from moisture.