Rosetta

Rosuvastatin.

Rosetta 10: Round, convex, pink film-coated tablets with "BERLIN" and "10" on one side and score on the other side (Functional scoring).
Each film-coated tablet contains rosuvastatin 10 mg (as rosuvastatin calcium).
Rosetta 20: Round, convex, pink film-coated tablets with "BERLIN" and "20" on one side and plain on the other side.
Each film-coated tablet contains rosuvastatin 20 mg (as rosuvastatin calcium).

Pharmacotherapeutic group: HMG-CoA reductase inhibitors. ATC code: C10AA07.
Rosuvastatin is a hydrophilic statin.
Pharmacology: Pharmacodynamics: Mechanism of Action: Rosuvastatin is a selective and competitive inhibitor of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate. This conversion is an early and rate-limiting step in cholesterol biosynthesis.
By inhibiting this enzyme, rosuvastatin reduces plasma concentrations of total cholesterol and low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (Apo B), non-high-density lipoprotein-cholesterol (non-HDL-C) and triglyceride (TG), and increases high-density lipoprotein-cholesterol (HDL-C) concentrations in patients with primary hyperlipidemia or mixed dyslipidemia. Rosuvastatin also reduces TG concentrations in patients with primary hypertriglyceridemia.
The mechanism of the LDL-lowering effect may involve both reduction of very low-density lipoprotein (VLDL) synthesis and induction of the LDL receptors on hepatocyte membranes, leading to reduced production and/or increased uptake and catabolism of LDL.
A marked response was seen within 1 to 2 weeks, and the maximum therapeutic response occurred within 4 to 6 weeks. The response was maintained during therapy. Reductions in LDL are dose dependent and log linear. Therefore, LDL levels decreased by 6% with each doubling of the administered dose. In patients with TG levels higher than 200 mg/dL, TGs decrease in direct proportion to LDL decreases. In patients with very high TG levels, the LDL decreases are less than observed in patients with low TG levels.
Pharmacokinetics: Absorption: Rosuvastatin, the active moiety, is rapidly absorbed. Maximum rosuvastatin plasma concentrations are achieved approximately 3 to 5 hours after oral administration. The absolute bioavailability is approximately 20%.
Distribution: Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.
Metabolism: Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-based metabolism. CYP2C9 was the principal isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a lesser extent. The main metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin whereas the lactone form is considered clinically inactive. Rosuvastatin accounts for greater than 90% of the circulating HMG-CoA reductase inhibitor activity.
Excretion: Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces (consist of absorbed and non-absorbed active substance) and the remaining part is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not increase at higher doses.
Special populations and conditions: Race: Pharmacokinetic studies show an approximate 2-fold elevation in median exposure to rosuvastatin (AUC and C_max) in Asian patients compared with Caucasian patients. Dosage of rosuvastatin should be adjusted in Asian patients.
Genetic polymorphisms: Disposition of statins, including rosuvastatin, involves the uptake transporter OATP1B1 and efflux transporter BCRP located in the liver, the major site of rosuvastatin action. In patients with SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) genetic polymorphisms there is a risk of increased rosuvastatin exposure.
Since rosuvastatin is the substrate of OATP1B1 and BCRP, attention should be paid to the OATP1B1 or BCRP-mediated drug-drug interaction of rosuvastatin in coadministration with other drugs that may inhibit the function of OATP1B1 or BCRP.
Hepatic impairment: Plasma concentrations of rosuvastatin are modestly increased in patients with chronic alcoholic liver disease. Peak plasma concentrations and AUC of rosuvastatin are increased by 60% and 5%, respectively, in patients with Child-Pugh class A disease and by 100% and 21%, respectively, in patients with Child-Pugh class B disease compared with individuals with normal liver function.
Rosuvastatin should be used with caution in patients with a history of liver disease (e.g., chronic alcoholic liver disease) and/or in patients who consume substantial amounts of alcohol.
Renal impairment: Exposure to rosuvastatin (i.e., plasma concentrations) does not appear to be influenced by mild or moderate renal impairment (creatinine clearance [CrCl] of 30 mL/min/1.73 m² or greater). However, plasma concentrations of rosuvastatin were increased to a clinically important extent (about 3-fold) in patients with severe renal impairment (CrCl less than 30 mL/min/1.73 m²) not undergoing hemodialysis compared with healthy individuals (CrCl greater than 80 mL/min/1.73 m²). Steady-state plasma concentrations of rosuvastatin in patients undergoing chronic hemodialysis were approximately 50% greater than those in healthy individuals with normal renal function.

Prevention of Cardiovascular Events: In adult patients with an increased risk of atherosclerotic cardiovascular disease based on the presence of cardiovascular disease risk markers such as an elevated high sensitivity C-reactive protein (hsCRP) level, age, hypertension, low HDL-C, smoking or a family history of premature coronary heart disease, Rosuvastatin is indicated to reduce total mortality and the risk of major cardiovascular events (cardiovascular death, stroke, myocardial infraction, unstable angina, or arterial revascularization).
In adult patients with hypercholesterolaemia: Primary hypercholesterolaemia (type IIa including heterozygous familial hypercholesterolaemia) or mixed dyslipidaemia (type IIb) as an adjunct to diet when response to diet and other nonpharmacological treatments (e.g. exercise, weight reduction) is inadequate.
Homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.
Slow or delay the progression of atherosclerosis.
Children and adolescents 6 to 17 years of age: Rosuvastatin is indicated to reduce the Total Cholesterol, LDL-C and Apo B in patients with heterozygous familial hypercholesterolaemia (HeFH).

Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment. The dose should be individualised according to the goal of therapy and patient response, using current consensus guidelines.
The recommended start dose is 5 or 10 mg once daily in both statin naïve patients or patients switched from another HMG CoA reductase inhibitor. The choice of starting dose should take into account the individual patient's cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions. A dose adjustment to 20 mg can be made after 2 to 4 weeks. A doubling of the dose to 40 mg should only be considered in patients with severe hypercholesterolaemia at high cardiovascular risk (in particular those with familial hypercholesterolaemia), who do not achieve their treatment goal on 20 mg, and in whom routine follow-up will be performed.
Rosuvastatin may be given at any time of day, with or without food.
Children and adolescents 6 to 17 years of age: In children 6 to 9 years of age with heterozygous familial hypercholesterolaemia, the usual dose range is 5-10 mg orally once daily. Safety and efficacy of doses greater than 10 mg have not been studied in this population.
In children 10 to 17 years of age with heterozygous familial hypercholesterolaemia, the usual dose range is 5-20 mg orally once daily. Safety and efficacy of doses greater than 20 mg have not been studied in this population.
The dose should be appropriately titrated to achieve treatment goal. In children and adolescents with homozygous familial hypercholesterolaemia experience is limited to a small number of patients (aged 8 years and above).
Mode of Administration: Rosuvastatin is administered orally as a single dose, with or without food, at any time of the day.

Overdose and Treatment: Limited information is available on the acute toxicity of statins. Supportive and symptomatic treatment should be initiated and the patient observed closely. Specific recommendations for the management of rosuvastatin overdosage currently are not available.

Rosuvastatin is contraindicated in patients: with hypersensitivity to rosuvastatin or to any component of the formulation; with active liver disease including unexplained persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3x the upper limit of normal (ULN); with concomitantly administered cyclosporine; during pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures; severe renal impairment (CrCl less than 30 mL/min/1.73 m²). Use of 40 mg dose in Asian patients is contraindicated.

Warning (according to Thailand's Notification of Ministry of Public Health): Contraindicated in pregnant and lactating women.
Contraindicated in patients with liver disease.
After taking this medication, if pain or ache (myalgia) developed on the calf, back or body muscles, discontinue the medication and consult the doctor.
Should have liver function tests (LFTs) performed before treatment and 6 and 12 weeks after the initiation of the treatment. Patients regularly receiving this medication should have LFTs done every 6 months or as advised by a doctor. If transaminase level is higher than 3x upper normal limit, discontinue the medication and consult a doctor.
Use with caution when co-administered with digoxin and warfarin, because blood levels of these drugs may be increased to harmful levels.
Risk of myopathy and rhabdomyolysis will be increased when statins are concomitantly used with the following medications: azole antifungals (e.g., ketoconazole, itraconazole); macrolides (e.g., erythromycin, clarithromycin); HIV protease inhibitors (e.g., indinavir, ritonavir, nelfinavir, saquinavir); verapamil; diltiazem; gemfibrozil; nicotinic acid; cyclosporine; amiodarone.
Risk of rhabdomyolysis is increased in the following conditions: using high dosage, elderly, hepatic/renal impairment, chronic alcoholism, hypothyroidism etc.
Use with caution when co-administered with colchicine especially in the elderly or in patients with impaired renal function because of the risk of myopathy or rhabdomyolysis.
This medicine may increase the risk of having increased blood sugar levels.

Musculoskeletal Effects: Myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported in patients receiving rosuvastatin. These adverse effects can occur at any dosage, but the risk is increased with the highest dosage of rosuvastatin (40 mg daily).
Creatine Kinase Measurement: Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase which may confound interpretation of the result. If CK levels are significantly elevated at baseline (>5 x ULN) a confirmatory test should be carried out within 5-7 days. If the repeat test confirms a baseline CK >5 x ULN, treatment should not be started.
Before Treatment: Rosuvastatin, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include: renal impairment, hypothyroidism, personal or family history of hereditary muscular disorders, previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate, alcohol abuse, age >70 years, situations where an increase in plasma levels may occur, concomitant use of fibrates.
In such patients the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If Creatine Kinase (CK) levels are significantly elevated at baseline (>5 x ULN) treatment should not be started.
Whilst on Treatment: Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5 x ULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are less than or equal to 5 x ULN). If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing rosuvastatin or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring. Routine monitoring of CK levels in asymptomatic patients is not warranted. There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with statins, including rosuvastatin, IMNM is clinically characterized by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.
In clinical trials there was no evidence of increased skeletal muscle effects in the small number of patients dosed with rosuvastatin and concomitant therapy. However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors. Therefore, the combination of rosuvastatin and gemfibrozil is not recommended. 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 such combinations.
Rosuvastatin should not be used 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).
Hepatic Effects: In patients with secondary hypercholesterolemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with rosuvastatin. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy. If an alternative etiology is not identified, do not restart rosuvastatin.
Used with caution in patients who consume large amounts of alcohol or have a history of liver disease.
Increases in serum aminotransferase (i.e., AST [SGOT], ALT [SGPT]) concentrations have been reported in patients receiving rosuvastatin. These increases usually were transient and resolved or improved with continued therapy or after temporary interruption of therapy.
It is recommended that liver function tests should be carried out prior to initiation and 12 weeks following initiation of therapy or any increase in dosage and as clinically indicated.
Renal Effects: Transient dipstick-positive proteinuria and microscopic hematuria have been reported in patients receiving rosuvastatin, more frequently in patients receiving doses of 40 mg daily compared with lower doses of rosuvastatin or comparator statins, but typically transient and not associated with a decrease in renal function. Consider dosage reduction if unexplained proteinuria and/or hematuria persists.
Race: Pharmacokinetic studies shows an approximate 2-fold elevation in median exposure to rosuvastatin (AUC and Cmax) in Asian patients compared with Caucasian patients. Dosage of rosuvastatin should be adjusted in Asian patients.
Endocrine effect: Increases in glycosylated hemoglobin (HbA_1C) and fasting serum glucose concentrations have been reported in patients receiving rosuvastatin. Treatment with statins including rosuvastatin may increase the risk of developing diabetes mellitus.

Rosuvastatin is contraindicated in pregnancy and lactation.
Pregnancy: There are no adequate and well controlled studies using statins in pregnant women and there is no known clinical benefit for continued use during pregnancy. Because statins including rosuvastatin may cause fetal harm when administered to pregnant women. Therefore, rosuvastatin is contraindicated in women who are or may become pregnant. If the patient becomes pregnant while receiving the drug, it should be discontinued immediately and the patient informed of the potential fetal hazard and the lack of known clinical benefit with continued use during pregnancy.
Lactation: Rosuvastatin is excreted into milk in rats. It is not known whether rosuvastatin is distributed into human milk. However, the drug is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants. Women who require rosuvastatin therapy should not breast-feed their infants.

Central nervous system: Dizziness, headache.
Endocrine & metabolic: Diabetes mellitus (new onset).
Gastrointestinal: Constipation, nausea.
Genitourinary: Cystitis (interstitial).
Hepatic: Increased serum ALT (>3 x ULN).
Neuromuscular & skeletal: Arthralgia, increased creatine phosphokinase, myalgia, weakness.
Rare but important or life-threatening: Abnormal thyroid function test, cognitive dysfunction (reversible; including amnesia, confusion, memory impairment), depression, elevated glycosylated hemoglobin (HbA_1c), gynecomastia, hematuria (microscopic), hepatic failure, hepatitis, hypersensitivity reaction (including angioedema, pruritus, rash, urticaria), immune-mediated necrotizing myopathy, increased gamma-glutamyltransferase, increased serum alkaline phosphatase, increased serum bilirubin, increased serum glucose, increased serum transaminases, interstitial pulmonary disease, jaundice, myoglobinuria, myopathy, myositis, pancreatitis, peripheral neuropathy, proteinuria (dose related), renal failure, rhabdomyolysis, sleep disorder (including insomnia and nightmares), thrombocytopenia.

Rosuvastatin is minimally (approximately 10%) metabolized by cytochrome P 450 (CYP) isoenzyme 2C9. Clearance of rosuvastatin is not dependent on metabolism by CYP 3A4 to a clinically important extent.
Antacid: The simultaneous dosing of rosuvastatin (40 mg as a single dose) with an antacid suspension containing aluminium hydroxide and magnesium hydroxide resulted in a decrease in rosuvastatin C_max and AUC by 50 and 54%, respectively. This effect was mitigated when the antacid was dosed 2 hours after rosuvastatin. Therefore, if rosuvastatin and aluminium- magnesium hydroxide antacid are used concomitantly, the antacid should be administered at least 2 hours after rosuvastatin.
Cyclosporine: Concomitant use of rosuvastatin and cyclosporine may increase the risk of myopathy. Following concomitant treatment with rosuvastatin and cyclosporine, rosuvastatin C_max and AUC values were increased by 11- and 7.1- fold, respectively. Side effects were considered clinically important and concomitant use is contraindicated.
Digoxin: Concomitant use of rosuvastatin and digoxin increased both C_max and AUC of digoxin by 4%. Based on data from specific interaction studies, no clinically relevant interactions are expected.
Erythromycin: Concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in AUC and a 30% decrease in C_max of rosuvastatin.
Fibric acid derivatives: Fenofibrate: Concomitant use of rosuvastatin and fenofibrate may increase the risk of myopathy. Caution is advised if rosuvastatin is used concomitantly with fenofibrate.
Gemfibrozil: Concomitant use of rosuvastatin and gemfibrozil may increase the risk of myopathy and should be avoided. Concomitant use resulted in a 2-fold increase in rosuvastatin C_max and AUC. If used concomitantly with gemfibrozil, dosage of rosuvastatin should not be exceed 10 mg once daily.
HIV Protease inhibitors: Strongly increase rosuvastatin exposure. Caution is advised if these drugs are used concomitantly.
Niacin: Concomitant use of rosuvastatin and antilipemic dosages (1 g daily or higher) of niacin may increase the risk of myopathy. Caution is advised if rosuvastatin is used concomitantly with antilipemic dosages of niacin.
Oral contraceptive: Concomitant use of rosuvastatin and an oral contraceptive (ethinyl estradiol and norgestrel) resulted in an increase in ethinyl estradiol and norgestrel AUC of 26% and 34%, respectively.
Warfarin: Rosuvastatin potentiate the effects of coumarin-derivative anticoagulants in prolonging prothrombin time (PT)/international normalized ratio (INR); the drug has been shown to substantially increase INR in patients receiving coumarin anticoagulants. Caution should be exercised when rosuvastatin is used concomitantly with anticoagulants. INR should be stable prior to initiating rosuvastatin and should be monitored frequently enough during early therapy or following rosuvastatin dosage adjustment.

Store below 30°C.

Dyslipidaemic Agents

C10AA07 - rosuvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.

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