Each film coated tablet contains:
Rosuvastatin (as calcium) 5 mg
Rosuvastatin (as calcium) 10 mg
Rosuvastatin (as calcium) 20 mg
Rosuvastatin Calcium is a synthetic lipid-lowering agent. It 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. Rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt. The empirical formula for Rosuvastatin calcium is (C22H27FN3O6S)2 Ca.
INDICATIONS AND USAGE
Rosuvastatin is indicated :
as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, non-HDL-C, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (excluding heterozygous familial and non-familial hypercholesterolemia) and mixed dyslipidemia (Fredrickson Type IIa and IIb)
as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV)
to reduce LDL-C, total-C and ApoB in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable
Rosuvastatin is contraindicated in patients with a known hypersensitivity to Rosuvastatin or to any component of this product. It is contraindicated in patients with active liver disease or with unexplained persistent elevations of serum transaminases.
Mechanism of Action
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. Studies have shown Rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. 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, it inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles. Rosuvastatin reduces total cholesterol (total-C), LDL-C, ApoB, and non-HDL-C (total cholesterol minus HDL-C). Rosuvastatin also reduces TG and produces increases in HDL-C. Rosuvastatin reduces total-C, LDL-C, VLDL-cholesterol (VLDL-C), ApoB, non-HDL-C and TG, and increases HDL-C in patients with isolated hypertriglyceridemia.
In clinical pharmacology studies in man, peak plasma concentrations of Rosuvastatin were reached 3 to 5 hours following oral dosing. Both peak concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in approximate proportion to Rosuvastatin dose. The absolute bioavailability of Rosuvastatin is approximately 20%. Administration of Rosuvastatin with food decreased the rate of drug absorption by 20% as assessed by Cmax, but there was no effect on the extent of absorption as assessed by AUC. Plasma concentrations of Rosuvastatin do not differ following evening or morning drug administration. Significant LDL-C reductions are seen when Rosuvastatin is given with or without food, and regardless of the time of day of drug administration.
Mean volume of distribution at steady state of Rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.
Rosuvastatin is not extensively metabolized; approximately 10% of a radio labeled dose is recovered as metabolite. The major metabolite is N-desmethyl Rosuvastatin, which is formed principally by cytochrome P450 2C9, and in vitro studies have demonstrated that N-desmethyl Rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of Rosuvastatin. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by Rosuvastatin.
Following oral administration, Rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t1/2) of Rosuvastatin is approximately 19 hours.
Plasma concentrations of Rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (ClCr < 30 mL/min/1.73m2) compared with healthy subjects (ClCr > 80 mLlmin/1.73m2).
Steady-state plasma concentrations of Rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.
In patients with chronic alcohol liver disease, plasma concentrations of Rosuvastatin were modestly increased. In patients with Child-Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.
PREGNANCY AND LACTATION
HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers. Rosuvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus.
HMG CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. It is recommended that liver function tests be performed before and at 12 weeks following both the initiation of 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 (upper limit of normal) persist, reduction of dose or withdrawal of Rosuvastatin is recommended. Rosuvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Patients with active liver disease or unexplained persistent transaminase elevations are contraindications to the use of Rosuvastatin.
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with Rosuvastatin and with other drugs in this class. Uncomplicated myalgia has been reported in Rosuvastatin treated patients. 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 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. Rosuvastatin therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with 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 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 Rosuvastatin may be increased in circumstances which increase Rosuvastatin drug levels. 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).
In the Rosuvastatin clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among Rosuvastatin treated patients, predominantly in patients dosed above the recommended dose range (i.e., 80 mg). A dose reduction should be considered for patients on Rosuvastatin 40mg therapy with unexplained persistent proteinuria during routine urinalysis testing.
Cytochrome P450 3A4: In vitro and in vivo data indicate that Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. This has been confirmed in studies with known cytochrome P450 3A4 inhibitors (ketoconazole, erythromycin, itraconazole).
Cyclosporine: Coadministration of cyclosporine with Rosuvastatin resulted in no significant changes in cyclosporine plasma concentrations. However, Cmax and AUC of Rosuvastatin increased 11- and 7-fold, respectively, compared with historical data in healthy subjects. These increases are considered to be clinically significant.
Warfarin: Coadministration of Rosuvastatin to patients on stable warfarin therapy resulted in clinically significant rises in INR (>4, baseline 2-3). In patients taking coumarin anticoagulants and Rosuvastatin concomitantly, INR should be determined before starting 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. Rosuvastatin therapy has not been associated with bleeding or with changes in INR in patients not taking anticoagulants.
Gemfibrozil: Coadministration of gemfibrozil (600 mg twice daily for 7 days) with Rosuvastatin (80 mg) resulted in a 90% and 120% increase for AUC and Cmax of Rosuvastatin, respectively. This increase is considered to be clinically significant.
Antacid: Coadministration of an antacid (aluminum and magnesium hydroxide combination) with Rosuvastatin (40 mg) resulted in a decrease in plasma concentrations of Rosuvastatin by 54%. However, when the antacid was given 2 hours after Rosuvastatin, there were no clinically significant changes in plasma concentrations of Rosuvastatin.
Oral contraceptives: Coadministration of oral contraceptives (ethinyl estradiol and norgestrel) with Rosuvastatin resulted in an increase in plasma concentrations of ethinyl estradiol and norgestrel by 26% and 34%, respectively.
Endocrine Function: Although clinical studies have shown that Rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if any HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.
Rosuvastatin is generally well tolerated. Adverse reactions have usually been mild and transient. The most frequent adverse events thought to be related to Rosuvastatin were myalgia, constipation, asthenia, abdominal pain, and nausea.
The patient should be placed on a standard cholesterol-lowering diet before receiving Rosuvastatin and should continue on this diet during treatment. Rosuvastatin can be administered as a single dose at any time of day, with or without food.
Hypercholesterolemia (excluding Heterozygous familial and non-familial hypercholesterolemia) and Mixed Dyslipidemia (Fredrickson Type IIa and IIb)
The dose range for Rosuvastatin is 5 to 20 mg once daily. Therapy with Rosuvastatin should be individualized according to goal of therapy and response. The usual recommended starting dose of Rosuvastatin is 10 mg once daily. Initiation of 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 dose may be considered. The 40-mg dose of Rosuvastatin should be reserved for those patients who have not achieved goal LDL-C at 20 mg. After initiation and/or upon titration of Rosuvastatin, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.
Homozygous Familial Hypercholesterolemia
The recommended starting dose of Rosuvastatin is 20 mg once daily in patients with homozygous FH. The maximum recommended daily dose is 40 mg. 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 therapy should be estimated from pre-apheresis LDL-C levels.
Dosage in Patients Taking Cyclosporine
In patients taking cyclosporine, therapy should be limited to Rosuvastatin 5 mg once daily.
Concomitant Lipid-Lowering Therapy
The effect of Rosuvastatin on LDL-C and total-C may be enhanced when used in combination with a bile acid binding resin. If Rosuvastatin is used in combination with gemfibrozil, the dose of Rosuvastatin should be limited to 10 mg once daily.
Dosage in Patients with Renal Insufficiency
No modification of dosage is necessary for patients with mild to moderate renal insufficiency. For patients with severe renal impairment (Clcr <30 mL/min/1.73 m2) not on hemodialysis, dosing of Rosuvastatin should be started at 5 mg once daily and not to exceed 10 mg once daily. Or as prescribed by the physician.
Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.
STORE AT TEMPERATURES NOT EXCEEDING 300C. Protect from light.
ROSUCOL® is a registered trademark of Ajanta Pharma Philippines, Inc.
Rosuvastatin (Rosucol®) 5mg Tablet X 30 tablets / box / strip foil
Rosuvastatin (Rosucol®) 10mg Tablet X 30 tablets / box / strip foil
Rosuvastatin (Rosucol®) 20mg Tablet X 30 tablets / box / strip foil