Crestor 5/10/20/40 5mg. 10mg. 20mg. 40mg FC Tablets

To reduce the risk 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, CRESTOR is indicated to reduce the risk of non-fatal stroke, non-fatal MI, and the need for arterial revascularisation.

In adult patients with hypercholesterolaemia:

• CRESTOR is indicated for patients with primary hypercholesterolaemia, mixed dyslipidaemia and isolated hypertriglyceridaemia (including Fredrickson Type IIa, IIb and IV; and heterozygous familial and non-familial hypercholesterolaemia) as an adjunct to diet when response to diet and exercise is inadequate.
• CRESTOR is indicated to treat patients with primary dysbetalipoproteinaemia (Fredrickson Type III hyperlipoproteinaemia).
• CRESTOR is also indicated to reduce Total Cholesterol and LDL-C in patients with homozygous familial hypercholesterolaemia, either alone or as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis).

CRESTOR 40 mg should only be considered in patients with severe hypercholesterolaemia and high cardiovascular risk who do not achieve their treatment goal on 20 mg of CRESTOR or alternative therapy and in whom routine follow-up will be performed (see section 4.4). Specialist supervision is recommended when the 40 mg dose is initiated (see section 4.4).

Children and adolescents 10-17 years of age: CRESTOR is indicated to reduce the Total Cholesterol, LDL-C and Apo B in patients with heterozygous familial hypercholesterolaemia (HeFH).

Posology Before treatment initiation, the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment.

Treatment of hypercholesterolaemia: The recommended start dose is 5 mg orally once daily in both statin nau00efve or patients switched from another HMG CoA reductase inhibitor. The choice of start dose should take into account the individual patient's cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions (see below). A dose adjustment to the next dose level can be made after 4 weeks, if necessary (see section 5.1). In light of the increased reporting rate of adverse reactions with the 40 mg dose compared to lower doses (see section 4.8), a final titration to the maximum dose of 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 (see section 4.4). Specialist supervision is recommended when the 40 mg dose is initiated.

The dosage of CRESTOR should be individualised according to the goal of therapy and patient response. The majority of patients are controlled at the 10 mg dose. However, if necessary, dose adjustment can be made at 4 week intervals (see section 5.1).

Adults: Primary hypercholesterolaemia (including heterozygous familial hypercholesterolaemia), mixed dyslipidaemia, dysbetalipoproteinaemia (Fredrickson Type III hyperlipoproteinaemia), and isolated hypertriglyceridaemia: The recommended start dose is 5 mg once a day. For patients with severe hypercholesterolaemia (including heterozygous familial hypercholesterolaemia), a start dose of 20 mg may be considered. Homozygous familial hypercholesterolaemia: For patients with homozygous familial hypercholesterolaemia a start dose of 20 mg once a day is recommended.

Special populations Use in the elderly: The usual dose range applies. Dosage in patients with renal insufficiency: No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended start dose is 5 mg in patients with moderate renal impairment (creatinine clearance <60 ml/min). The 40 mg dose is contraindicated in patients with moderate renal impairment. The use of CRESTOR in patients with severe renal impairment is contraindicated for all doses (see sections 4.3 and 5.2). 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. The usual starting dose applies in patients with mild to moderate hepatic impairment. However, increased systemic exposure has been observed in subjects with Child-Pugh scores of 8 and 9 (see section 5.2). In these patients an assessment of renal function should be considered (see section 4.4). There is no experience in subjects with Child-Pugh scores above 9. Patients with severe hepatic impairment should start therapy with CRESTOR 5 mg. Increased systemic exposure to rosuvastatin has been observed in these patients, therefore the use of doses above CRESTOR 10 mg should be carefully considered (see section 5.2). CRESTOR is contraindicated in patients with active liver disease (see section 4.3). Race: A 5 mg starting dose of CRESTOR should be considered for Asian patients. Increased plasma concentration of rosuvastatin has been seen in Asian subjects (see section 4.4 and 5.2). The increased systemic exposure should be taken into consideration when treating Asian patients whose hypercholesterolaemia is not adequately controlled at doses up to 20 mg daily. The 40 mg dose is contraindicated in these patients. Genotypes of SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA have been shown to be associated with an increase in rosuvastatin exposure (AUC) compared to SLCO1B1 c.521TT and ABCG2 c.421CC. For patients known to have the c.521CC or c.421AA genotype, a maximum once daily dose of 20 mg of CRESTOR should not be exceeded (see section 4.4, 4.5 and 5.2).

Concomitant therapy: Rosuvastatin is a substrate of various transporter proteins (e.g. OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when CRESTOR is administered concomitantly with certain medicinal products that may increase the plasma concentration of rosuvastatin due to interactions with these transporter proteins (e.g. ciclosporin and certain protease inhibitors including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir (see section 4.4 & 4.5). It is recommended that prescribers consult the relevant product information when considering administration of such products together with CRESTOR. Whenever possible, alternative medications should be considered, and if necessary, consider temporarily discontinuing CRESTOR therapy. In situations where co-administration of these medicinal products with CRESTOR is unavoidable, the benefit and the risk of concurrent treatment and CRESTOR dosing adjustments should be carefully considered (see section 4.4).

Paediatric population Children and adolescents 10-17 years of age: In children and adolescents with heterozygous familial hypercholesterolaemia the usual dose range is 5-20 mg orally once daily. The dose should be appropriately titrated to achieve treatment goal. Safety and efficacy of doses greater than 20 mg have not been studied in this population. In children and adolescents with homozygous familial hypercholesterolaemia experience is limited to a small number of patients (aged 8 years and above).

Method of administration CRESTOR may be given at any time of the day, with or without food.

CRESTOR is contraindicated in:

• patients with hypersensitivity to the active substance or to any of the excipients of CRESTOR.
• 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).
• patients with severe renal impairment (creatinine clearance <30 ml/min).
• patients with myopathy
• concomitant use with ciclosporin (see section 4.5)
• 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/rhabdomyolisis. 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 sections 4.4, 4.5 and 5.2)

Liver Effects: CRESTOR 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 enzyme tests be performed before the initiation of CRESTOR, 3 months following, the initiation of treatment and if signs or symptoms of liver injury occur. The reporting rate for serious hepatic events (consisting mainly of increased hepatic transaminases) in post-marketing use is higher at the 40 mg dose. There have been rare post marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including CRESTOR. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with CRESTOR, promptly interrupt therapy. If an alternate aetiology is not found, do not restart CRESTOR.

Renal effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of CRESTOR, 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 section 4.8). The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40 mg.

Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, myopathy and rhabdomyolysis have been reported in patients treated with CRESTOR. The reporting rate for rhabdomyolysis in post-marketing use is higher at the highest marketed dose. Patients who develop any signs or symptoms suggestive of myopathy should have their Creatine kinase (CK) levels measured. CRESTOR therapy should be discontinued if myopathy is diagnosed or suspected.

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 u2013 7 days. If the repeat test confirms a baseline CK >5xULN, treatment should not be started.

Before Treatment: CRESTOR 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 sections 4.2, 4.5 and 5.2)
• 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 u22645xULN). If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing Crestor 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 reports of an immune-mediated necrotizing myopathy clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase during treatment or following discontinuation of statins, including CRESTOR. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required.

An increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with ciclosporin, fibric acid derivatives, including gemfibrozil, nicotinic acid, azole antifungals and macrolide antibiotics. CRESTOR 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 section 4.5). 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 coadministration of Crestor and fusidic acid should only be considered on a case by case basis and under close medical supervision.

CRESTOR should be prescribed with caution in patients with pre-disposing factors for myopathy, such as renal impairment, advanced age and hypothyroidism or situations where an increase in plasma levels may occur (see section 4.5 and section 5.2). CRESTOR 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).

Diabetes Mellitus: Increases in HbA1c and serum glucose levels have been observed in patients treated with CRESTOR and in some instances these increases may exceed the threshlod for the diagnosis of diabetes mellitus. This was observed primarily in patients already at high risk for developing diabetes (see section 4.8). Patients at risk (fasting glucose 5.6 to 6.9 mmol/l, BMI >30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

In the JUPITER study, the reported overall frequency of diabetes mellitus was 2.8 % in rosuvastatin and 2.3 % in placebo, mostly in patients with fasting glucose 5.6 to 6.9 mmol/l (100-124 md/dL).

Race: Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians (see section 4.2 and section 5.3).

Children and adolescents 10-17 years of age: The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in paediatric patients taking rosuvastatin is limited to a 1 year period (see section 5.1)

Protease inhibitors: CRESTOR should be used with caution in patients taking various protease inhibitors in combination with ritonavir as pharmacokinetic studies have shown an increase in the AUC and Cmax of rosuvastatin (see section 4.2 and section 4.4).

Lactose: CRESTOR contains lactose. Patients with rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency or glucose-galactose malabsorption should not take CRESTOR.

Interstitial Lung Disease: Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy (see section 4.8). 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.

Effect of co-administered medicines 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 CRESTOR with medicines that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy (see sections 4.2, 4.4 and 4.5 Table 1).

Ciclosporin: During concomitant treatment with CRESTOR and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). CRESTOR is contraindicated in patients receiving concomitant ciclosporin (see section 4.3). 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 (see Table 1). For instance, in a pharmacokinetic study, co-administration of 10 mg rosuvastatin and a combination product of two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with an approximately three-fold and sevenfold increase in rosuvastatin AUC and Cmax, respectively. The concomitant use of CRESTOR and some protease inhibitor combinations may be considered after careful consideration of CRESTOR dose adjustments based on the expected increase in rosuvastatin exposure (see sections4.2, 4.4 and 4.5 Table 1).

Gemfibrozil and other lipid-lowering products: Concomitant use of CRESTOR and gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and AUC (see section 4.4).

CRESTOR is contraindicated in pregnancy and lactation. The safety of CRESTOR during pregnancy and whilst breastfeeding has not been established. 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. Animal studies provide limited evidence of reproductive toxicity (see section 5.3). If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.

Studies to determine the effect of CRESTOR on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, CRESTOR is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

a. Summary of the safety profile In controlled clinical trials less than 4 % of CRESTOR treated patients were withdrawn due to adverse events. The incidence of adverse reactions tends to increase with increasing dose.

b. Tabulated summary of adverse reactions The frequencies of adverse events are ranked according to the following: Common (u22651/100, < 1/10); uncommon (u2265 1/1 000, < 1/100); rare (u2265 1/10 000, < 1/1 000); very rare (<1/10 000), not known (cannot be estimated from the available data).

Table 2. Adverse reactions based on data from clinical studies and post-marketing experience

System organ class Frequency Adverse Event Blood and lymphatic system disorders Rare Thrombocytopenia Endocrine disorders Common Diabetes mellitus 1 Psychiatric disorder Not known Depression Nervous system disorders Common Headache, dizziness Very Rare Polyneuropathy Memory loss Not known Peripheral neuropathy Sleep disturbances (including insomnia and nightmares) Respiratory, thoracic and mediastinal disorders Not known Cough Dyspnoea Gastrointestinal disorders Common Constipation, nausea, abdominal pain Rare Pancreatitis Hepatobiliary disorders Rare Increased hepatic transaminases Very rare Jaundice Hepatitis Not known Fatal and non-fatal hepatic failure Skin and subcutaneous tissue disorders Uncommon Pruritus, rash, urticaria Rare Hypersensitivity reactions including angio-oedema Not known Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders Common Myalgia Rare Myopathy including (myositis), rhabdomyolysis Lupus-like syndrome Muscle rupture Arthralgia Not known Tendon disorders, sometimes complicated by rupture Immune-mediated necrotising myopathy Renal and urinary disorders Very Rare Haematuria Reproductive system and breast disorders Not known Gynaecomastia General disorders and administration site conditions Common Asthenia 1 Frequency will depend on the presence or absence of risk factors (fasting blood glucose u2265 5.6 mmol/L, BMI >30 kg/m2, raised triglycerides, history of hypertension). There have been post-marketing reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally non-serious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

c. Description of selected adverse reactions Skeletal muscle effects: Rhabdomyolysis, which may occasionally be associated with impairment of renal function, has been reported with rosuvastatin CRESTOR. Renal effects: Proteinuria (see: u201cLaboratory effectsu201d). Laboratory effects: A dose-related increase in liver transaminases and Creatine kinase (CK) has been observed in patients taking CRESTOR. Increases in HbA1c have also been observed in patients treated with CRESTOR (see section 4.4). Abnormal urinalysis testing (dipstick-positive proteinuria with haematuria) has been seen in patients taking CRESTOR. The protein detected was mostly tubular in origin. In most cases, proteinuria decreases or disappears spontaneously on continued therapy and is not predictive of acute or progressive renal disease. Other effects In a long-term controlled clinical trial CRESTOR was shown to have no harmful effects on the ocular lens. In CRESTOR treated patients, there was no impairment of adrenocortical function. The reporting rate for rhabdomyolysis in post-marketing use is higher at the highest marketed dose.

d. Paediatric population Children and adolescents 10-17 years of age: The safety profile of CRESTOR is similar in children or adolescent patients and adults although CK elevations > 10 x ULN and muscle symptoms following exercise or increased physical activity, which resolved with continued treatment, were observed more frequently in clinical trials of children and adolescents. However, the same warnings and special precautions for use in adults also apply to children and adolescents (see section 4.4)

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.