Rosuvor

Rosuvastatin calcium.

Each film coated tablet contains: Rosuvastatin Calcium 10.4mg (eq. Rosuvastatin 10mg).
Rosuvastatin Calcium 20.8 mg (eq. Rosuvastatin 20mg).
10mg: The tablet is not intended to be cut into half.
20mg: The tablet is intended to be cut into half.

Pharmacotherapeutic group: HMG-CoA reductase inhibitors.
Pharmacology: Pharmacodynamics: 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 for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering.
Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.
Pharmacokinetics: Absorption: Maximum rosuvastatin plasma concentrations are achieved approximately 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 L. 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 (consisting 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. The geometric mean plasma clearance is approximately 50 litres/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important in the hepatic elimination of rosuvastatin.
Linearity: Systemic exposure of rosuvastatin increases in proportion to dose. There are no changes in pharmacokinetic parameters following multiple daily doses.
Special populations: Age and sex: There was no clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin in adults. The exposure in children and adolescents with heterozygous familial hypercholesterolemia appears to be similar to or lower than that in adult patients with dyslipidaemia.
Race: A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics between Caucasian and Black groups.
Renal insufficiency: Varying degrees of renal impairment, mild to moderate renal disease had no influence on plasma concentration of rosuvastatin or the N-desmethyl metabolite. Those with severe impairment (CrCl <30 ml/min) had a 3-fold increase in plasma concentration and a 9-fold increase in the N-desmethyl metabolite concentration compared to healthy person. Steady-state plasma concentrations of rosuvastatin in patient undergoing haemodialysis were approximately 50% greater compared to healthy person.
Hepatic Insufficiency: There was no evidence of increased exposure to rosuvastatin in person with Child-Pugh scores of 7 or below besides varying degrees of hepatic impairment.
Genetic polymorphisms: Disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves OATP1B1 and BCRP transporter proteins. Individual polymorphisms of SLCO1B1 c.521CC and ABCG2 c.421AA are associated with a higher rosuvastatin exposure (AUC) compared to the SLCO181 c.521TT or ABCG2 c.421CC genotypes. This specific genotyping is not established in clinical practice, but for patients who are known to have these types of polymorphisms, a lower daily dose of Rosuvor is recommended.
Paediatric population: Rosuvastatin exposure was predictable with respect to dose and time over a 2-year period.

Rosuvor Tablet (rosuvastatin calcium) is indicated as an adjunct to diet, at least equivalent to the Adult Treatment Panel III (ATP III TLC diet), for the reduction of elevated total cholesterol, LDL-cholesterol, ApoB, the total cholesterol: HDL-cholesterol ratio and triglycerides and for increasing HDL-C, in hyperlipidemic and dyslipidemic conditions, when response to diet and exercise alone has been inadequate including: 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 hsCRP level, age, hypertension, low HDL-C, smoking or a family history of premature coronary heart disease, Rosuvor Tablet is indicated to reduce total mortality and the risk of major cardiovascular events (cardiovascular death, stroke, Ml, unstable angina, or arterial revascularization).
Rosuvor Tablet is indicated as an adjunct to diet for the treatment of patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).
Combined (mixed) dyslipidemia (Type IIb).
Homozygous familial hypercholesterolaemia where Rosuvor Tablet is used either alone or as an adjunct to diet and other lipid lowering treatment such as apheresis.
Rosuvor Tablet is indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C to target levels.

Patients should be placed on a standard cholesterol-lowering diet (at least equivalent to the Adult Treatment Panel III (ATP III TLC diet)) before receiving Rosuvastatin and should continue on this diet during treatment with Rosuvastatin. If appropriate, a program of weight control and physical exercise should be implemented.
Prior to initiating therapy with Rosuvastatin, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed. After initiation or upon titration of Rosuvastatin, lipid levels should be analyzed within 2-4 weeks and the dosage adjusted accordingly.
The usual recommended starting dose of Rosuvastatin is 10 mg once daily. However, initiation of therapy with 5 mg once daily should be considered for special patient populations or patients requiring less aggressive LDL-C reductions. The choice of starting dose should take into account the individual patients' cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions. Rosuvastatin may be taken in the morning or evening, with or without food. The majority of patients are controlled at the 10mg dose. However, if necessary, dose adjustments to the next dose level can be made after 4-week intervals. The maximum response is usually achieved within 2-4 weeks and is maintained during chronic therapy. Increasing the dose to 40 mg should be reserved for 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 should only be initiated under specialist supervision (see Precautions). The physician who elects to use Rosuvastatin at a dose higher than 20 mg should periodically re-evaluate the long term risk/benefit of Rosuvastatin for the individual patient. Rosuvastatin should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis (see Precautions). The dosage of Rosuvastatin should be individualised according to baseline LDL-C, total-C/HDL-C ratio and/or TG levels, the recommended target lipid values and the patient response.
Lipid levels should be monitored periodically and, if necessary, the dose of Rosuvastatin adjusted based on target lipid levels recommended by guidelines.
Dosage in patients with renal insufficiency: The usual dose range applies in patients with mild to moderate renal impairment.
The use of Rosuvastatin Calcium in patients with severe renal impairment is contraindicated.
Dosage in patients with hepatic insufficiency: There was no increase in systemic exposure to rosuvastatin in subjects with Child-Pugh scores of 7 or below. However, increased systemic exposure has been observed in subjects with Child-Pugh scores of 8 and 9. In these patients an assessment of renal function should be considered. There is no experience in subjects with Child-Pugh scores above 9. Rosuvastatin Calcium is contraindicated in patients with active liver disease.
Use in the elderly: The overall frequency of adverse events and types of adverse events were similar in patients above and below 65 years of age. The efficacy of rosuvastatin in the geriatric population (≥65 years of age) was comparable to the efficacy observed in the non-elderly.
Use in children below 10 years: The safety and effectiveness in children have not been established. In children and adolescents with homozygous familial hypercholaesterolemia experience is limited to eight patients (aged 8 years and above).
Dosage on Asian patients: Initiation of Rosuvastatin Calcium therapy with 5 mg once daily should be considered for Asian patients. The potential for increased systemic exposures relative to Caucasians is relevant when considering escalation of dose in cases where hypercholesterolaemia is not adequately controlled at doses of 5, 10 or 20 mg once daily (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Genetic polymorphisms: Specific types of genetic polymorphisms are known that can lead to increased rosuvastatin exposure (see Pharmacology: Pharmacokinetics under Actions). For patients who are known to have such specific types of polymorphisms, a lower daily dose of Rosuvor is recommended.
Dosage in patients with pre-disposing factors to myopathy: The recommended start dose is 5 mg in patients with pre-disposing factors to myopathy.
Concomitant therapy: Rosuvastatin is a substrate of various transporter proteins (e.g. OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when rosuvastatin is administered concomitantly with certain medicinal products that may increase the plasma concentration of rosuvastatin due to interactions with these transporter proteins (e.g. certain protease inhibitors including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir).
Whenever possible, alternative medications should be considered, and if necessary, consider temporarily discontinuing Rosuvor therapy. In situations where co-administration of these medicinal products with rosuvastatin is unavoidable, the benefit and the risk of concurrent treatment and rosuvastatin dosing adjustments should be carefully considered.
Route of Administration: Oral administration.

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. Haemodialysis is unlikely to be of benefit.

Rosuvor is contraindicated: in patients receiving concomitant cyclosporin; in patients with hypersensitivity to rosuvastatin or to any of the excipients; in patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 times the upper limit of normal (ULN); in patients with severe renal impairment (creatinine clearance <30 ml/min); in patients with myopathy; during pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.
The 40 mg dose is contraindicated in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include: moderate renal impairment (creatinine clearance < 60 ml/min); hypothyroidism; personal or family history of hereditary muscular disorders; previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate; alcohol abuse; situations where an increase in plasma levels may occur; asian patients; concomitant use of fibrates.
(See Precautions, Interactions and Pharmacology: Pharmacokinetics under Actions).

Renal Effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in individuals treated with higher doses of Rosuvor, in particular 40 mg, where it was transient or intermittent in most cases.
Proteinuria has not been shown to be predictive of acute or progressive renal disease (see Precautions). An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40 mg.
Skeletal Muscle Effects: 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 risk of such combinations.
A pharmacodynamic interaction cannot be excluded (see Interactions) and caution should be exercised with their combined use. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with Rosuvor in post-marketing use is higher at the 40 mg dose.
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 (>5xULN) a confirmatory test should be carried out within 5 - 7 days. If the repeat test confirms a baseline CK >5xULN, treatment should not be started.
Before Treatment: Rosuvor, 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 (See Dosage & Administration, Interactions, Pharmacology: Pharmacokinetics under Actions), 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 CK levels are significantly elevated at baseline (>5xULN) 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 (>5xULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are ≤5xULN). If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing Rosuvor 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 necrotising myopathy (IMNM) during or after treatment with statins, including rosuvastatin. IMNM is clinically characterised by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.
Rosuvor must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see Interactions). Patients should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for co-administration of Rosuvor and fusidic acid should only be considered on a case by case basis and under close medical supervision.
Rosuvor 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).
Liver Effects: As with other HMG-CoA reductase inhibitors, Rosuvor should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease.
It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. Rosuvor should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal. The reporting rate for serious hepatic events (consisting mainly of increased hepatic transaminases) in post-marketing use is higher at the 40 mg dose. In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with Rosuvor.
Protease Inhibitors: Increased systemic exposure to rosuvastatin has been observed in patients receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of Rosuvor in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating Rosuvor doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of Rosuvor is adjusted (see Dosage & Administration and Interactions).
Lactose Intolerance: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Interstitial Lung Disease: Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term, therapy (see Adverse Reactions). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.
Diabetes Mellitus: Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/l, BMI >30kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.
Use in Children: Data shows no effect on growth, weight, BMI or sexual maturation was detected.

Rosuvor is contraindicated in pregnancy and lactation.
Women of child bearing potential should use appropriate contraceptive measures.
Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the foetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.
There are no data with respect to excretion in milk in humans (see Contraindications).

The adverse reactions seen with Rosuvor are generally mild and transient.
Tabulated list of adverse reactions: Adverse reactions listed as follows are classified according to frequency and system organ class (SOC). (See table.)

Click on icon to see table/diagram/image

As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.
Renal effects: In most cases, proteinuria decreases or disappears spontaneously on continued therapy.
Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported in Rosuvor-treated patients with all doses and in particular with doses > 20 mg. If CK levels are elevated (>5xULN), treatment should be discontinued (see Precautions).
Liver effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient.
The following adverse events have been reported with some statins: Sexual dysfunction.
Exceptional cases of interstitial lung disease, especially with long term therapy (see Precautions).
The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Effect of co-administered medicinal products on rosuvastatin: Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of Rosuvor with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy (see Dosage & Administration, Precautions and Interactions).
Ciclosporin: Concomitant treatment of Rosuvor and ciclosporin results in increased rosuvastatin AUC. Rosuvor is contraindicated in patients receiving concomitant ciclosporin. Concomitant administration did not affect plasma concentrations of ciclosporin.
Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure. The concomitant use of Rosuvor and some protease inhibitor combinations may be considered after careful consideration of Rosuvor dose adjustments based on the expected increase in rosuvastatin exposure.
Gemfibrozil and other lipid-lowering products: Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin C_max and AUC. Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated with concomitant use of a fibrate. These patients should also start with the 5 mg dose.
Ezetimibe: Concomitant use of 10 mg Rosuvor and 10 mg ezetimibe resulted in a 1.2-fold increase in AUC of rosuvastatin. A pharmacodynamic interaction, in terms of adverse effects, between Rosuvor and ezetimibe cannot be ruled out.
Antacid: The simultaneous dosing of Rosuvor with an antacid suspension containing aluminium and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration of approximately 50%. This effect was mitigated when the antacid was dosed 2 hours after Rosuvor.
Erythromycin: Concomitant use of Rosuvor and erythromycin resulted in a 20% decrease in AUC and a 30% decrease in C_max of rosuvastatin.The concomitant use of rosuvastatin and erythromycin may increase gut motility.
Cytochrome P450 enzymes: Drug interactions resulting from cytochrome P450-mediated metabolism are not expected. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
Effect of rosuvastatin on co-administered medicinal products: Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of Rosuvor in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of Rosuvor may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.
Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of Rosuvor and an oral contraceptive resulted in an increase in ethinyl estradiol and norgestrel AUC. These increased plasma levels should be considered when selecting oral contraceptive doses.
Other medicinal products: Digoxin: No clinically relevant interaction with digoxin is expected.
Fusidic Acid: The risk of myopathy, including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with systemic fusidic acid is necessary, Rosuvor treatment should be discontinued throughout the duration of the fusidic acid treatment (see Precautions).

Store at temperature below 30°C. Protect it from light and moisture.
Shelf-Life: 3 years.

Dyslipidaemic Agents

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

B