Each film-coated tablet contains:
Rosuvastatin (as calcium) 10 mg
Rosuvastatin (as calcium) 20 mg
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.
Fenofibrate is a lipid regulating agent. Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total-C, LDL-C, apo B, total triglycerides and VLDL in treated patients. In addition, treatment with fenofibrate results in increases in HDL-C and apoproteins apoAI and apoAII. The effects of fenofibric acid seen in clinical practice have been explained by the activation of peroxisome proliferator activated receptor (alpha) [PPAR (alpha)]. Through this mechanism, Fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPAR (alpha) also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol. Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.
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.
The absolute bioavailability of Fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, Fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled Fenofibrate appeared in urine, primarily as Fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration. The bioavailability of Fenofibrate is optimized when taken with meals.
Upon multiple dosing of Fenofibrate, fenofibric acid steady state is achieved within 9 days. Plasma concentrations of fenofibric acid at steady state are approximately double those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.
Fenofibrate is a minor substrate of CYP3A4 isoenzymes and weakly inhibits CYP1A6, CYP2C9 and CYP2C19 activity. Following oral administration, Fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.
After absorption, Fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled Fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily administration in a clinical setting.
In elderly volunteers 77 – 87 years of age, the oral clearance of fenofibric acid following a single oral dose of Fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites.
Fenofibrate has not been investigated in adequate and well-controlled trials in children.
The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCl] ≤ 30 mL/min) showed 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (CrCl 30-80 mL/min) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of Fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment.
No pharmacokinetic studies have been conducted in patients having hepatic insufficiency.
Rosuvastatin and Fenofibrate combination is indicated as an adjunct to diet to reduce elevated total-C, LDL-C, apo B and TG levels and to increase HDL-C in these patients.
Lipid altering agents should be used in addition to diet restricted in saturated fat and cholesterol only when the response to diet and other non-pharmacological measures has been inadequate.
Rosuvastatin plus Fenofibrate tablet is contraindicated in patients with: known hypersensitivity to either component of the product; hepatic or severe renal dysfunction, including primary biliary cirrhosis, and patients with unexplained persistent liver function abnormality; unexplained persistent elevations of serum transaminases exceeding three times the upper limit of normal; pre-existing gall bladder disease; pregnancy and lactation.
The recommended dosage of Rosuvastatin and Fenofibrate combination is one tablet once daily orally administered after dinner. Or as prescribed by the physician.
WARNINGS AND PRECAUTION
Liver function: Rosuvastatin and Fenofibrate combination should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.
Skeletal muscle: The use of Rosuvastatin and Fenofibrate combination may occasionally be associated with myopathy since two drugs, individually, have been shown to cause myopathy in a small percentage of patients. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness and/or marked elevations of CPK levels. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. The CPK levels should be assessed in patients reporting these symptoms and Rosuvastatin and Fenofibrate combination therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed.
Cholelithiasis: Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gall bladder studies are indicated. Rosuvastatin and Fenofibrate combination therapy should be discontinued if gallstones are found.
Pancreatitis: Pancreatitis has been reported in patients taking fenofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.
Renal impairment: Fenofibric acid is known to be substantially excreted by the kidney and the risk of adverse reactions may be greater in patients with renal function. Rosuvastatin and Fenofibrate combination is not recommended for use in patients with severe renal impairment.
Laboratory Tests: 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: Co-administration 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: Co-administration 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: Co-administration 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: Co-administration 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: Co-administration 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.
In vitro studies using human liver microsomes indicate that Fenofibrate and fenofibric acid is not an inhibitor of cytochrome (CYP) P450 isoforms; CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.
Oral Anti-coagulants: Potentiation of coumarin-type anticoagulants has been observed with prolongation of the prothrombin time/INR. The dosage of the anticoagulant should be reduced to maintain the prothrombin time/INR at the desired level to prevent bleeding complications. Frequent prothrombin time/INR determinations are advisable until it has been definitely determined that the prothrombin time/INR has stabilized.
Bile acid sequestrants: Bile acid sequestrants have been shown to bind to other drugs given concurrently. Therefore, fenofibrate should be taken at least 1 hour before, or 4-6 hours after, a bile acid binding resin to avoid impeding its absorption.
Glimepiride: Concomitant administration of Fenofibrate once daily for 10 days with glimepiride (1 mg tablet) single dose simultaneously with the last dose of Fenofibrate resulted in a 35% increase in mean AUC of glimepiride in healthy subjects. Glimepiride Cmax was not significantly affected by Fenofibrate co-administration. There was no statistically significant effect of multiple doses of Fenofibrate on glucose nadir or AUC with the baseline glucose concentration as the covariate after glimepiride administration in healthy volunteers. However, glucose concentrations at 24 hours remained statistically significantly lower after pretreatment with Fenofibrate than with glimepiride alone. Glimepiride had no significant effect on the pharmacokinetics of fenofibric acid.
Ezetimibe: Concomitant administration of Fenofibrate with ezetimibe (10 mg) once daily for 10 days in 18 healthy adults resulted in increases in total ezetimibe AUC, Cmax and Cmin of approximately 43%, 33% and 56%, respectively, and increases in ezetimibe glucuronide AUC, Cmax and Cmin of approximately 49%, 34% and 62%, respectively. The pharmacokinetics of fenofibric acid was not significantly affected by ezetimibe and the multiple-dose pharmacokinetics of free (unconjugated) ezetimibe was not significantly affected by Fenofibrate.
PREGNANCY AND LACTATION
Pregnancy: Since statins decreased cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to the pregnant woman. Rosuvastatin and Fenofibrate combination is therefore contraindicated during pregnancy. Rosuvastatin and Fenofibrate combination 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 and the patient apprised of the potential hazard to the fetus.
Lactation: Rosuvastatin and Fenofibrate combination is contraindicated in nursing mothers. Because of the potential for adverse reactions in nursing infants, women taking Rosuvastatin and Fenofibrate combination should not breast-feed.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINE
Studies determine the effect of Rosuvastatin and Fenofibrate combination on the ability to drive and use machines have not been conducted. However, when driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.
The most common adverse effects with Rosuvastatin and Fenofibrate combination are abdominal pain, rash, fatigue, numbness and itching. Other side effects with the combination may include nausea, headache, constipation, dyspepsia, flatulence, diarrhea, dizziness, insomnia, hepatitis, cholelithiasis, cholecystitis, hepatomegaly, photosensitivity, myopathy, rhabdomyolysis, eczema, myalgia, asthenia, flu syndrome, and rhinitis.
Rosuvastatin: There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be of benefit.
Fenofibrate: No case of overdosage has been reported. No specific antidote is known. If an overdose is suspected, treat symptomatically and institute appropriate supportive measures as required. Fenofibrate cannot be eliminated by hemodialysis.
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Rosuvastatin + Fenofibrate (Rosufen) 10mg/160mg Alu-alu blister pack of 10’s; box of 30 film-coated tablets
Rosuvastatin + Fenofibrate (Rosufen) 20mg/160mg Alu-alu blister pack of 10’s; box of 30 film-coated tablets