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  • Crestor
    / Astra Zeneca


    Active Ingredient
    Rosuvastatin (as Calcium) 5, 10, 20, 40 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Film Coated Tablets

    28 x 10 mg

    partial basket chart 60449 3754

    Film Coated Tablets

    28 x 20 mg

    partial basket chart 60450 3755

    Film Coated Tablets

    28 x 40 mg

    partial basket chart 60451 3756

    Related information


    Dosage

    The recommended start dose is 5 mg or 10 mg orally once daily in both statin naïve 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. A dose adjustment to the next dose level can be made after 4 weeks, if necessary 2 . In light of the increased reporting rate of adverse reactions with the 40 mg dose compared to lower doses, 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. Specialist supervision is recommended when the 40 mg dose is initiated. Crestor may be given at any time of day, with or without food. Paediatric use Safety and efficacy have not been established in children. Paediatric experience is limited to a small number of children (aged 8 years or above) with homozygous familial hypercholesterolaemia. Therefore, Crestor is not recommended for paediatric use at this time. Use in the elderly A start dose of 5 mg is recommended in patients >70 years. No other dose adjustment is necessary in relation to age. 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 of <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. Dosage in patients with hepatic impairment 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. Crestor is contraindicated in patients with active liver disease.
    For full details see prescribing information.


    Indications

    Primary hypercholesterolemia (type IIa including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb) as an adjunct to diet when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.Homozygous familial hypercholesterolemia as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.


    Contra-Indications

    Therapy is contraindicated 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 x the upper limit of normal (ULN); in patients with severe renal impairment (creatinine clearance <30ml/min); in patients with myopathy; in patients receiving concomitant cyclosporin; during pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.


    Special Precautions

    Renal EffectsProteinuria, 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 mostcases. Proteinuria has not been shown to be predictive of acute or progressive renal disease  The reporting rate for serious renal events in post-marketing use is higher at the 40mg 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 rarely, rhabdomyolysis, have been reported in Crestor-treated patients with all doses and in particular with doses > 20mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded and caution should be exercised with their combined use. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with Crestor in post-marketing use is higher at the 40 mg dose. There have been very rare 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 rosuvastatin. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required
    Creatine Kinase MeasurementCreatine 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: Crestor, 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 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 ≤ 5x ULN). 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 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. In clinical trials there was no evidence of increased skeletal muscle effects in the small number of patients dosed with Crestor 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, ciclosporin, 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 Crestor and gemfibrozil is not recommended If used, do not exceed CRESTOR 10 mg once daily. The benefit of further alterations in lipid levels by the combined use of Crestor with fibrates or niacin should be carefully weighed against the potential risks of such combinations. The 40 mg dose is contraindicated with concomitant use of a fibrate. 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).
    For full details see prescribing information.


    Side Effects

    The adverse events seen with Crestor are generally mild and transient. In controlled clinical trials, less than 4% of Crestor-treated patients were withdrawn due to adverse events.
    The frequencies of adverse events are ranked according to the following: Common (>1/100, <1/10); Uncommon (>1/1000, <1/100 ), Rare (>1/10,000, <1/1000); Very rare (>1/10,000). Immune system disorders
    Rare: hypersensitivity reactions including angioedema
    Endocrine disorders :Common: diabetes mellitus
    Nervous system disorders :Common: headache, dizziness
    Gastrointestinal disorders : Common: constipation, nausea, abdominal pain Rare: pancreatitis
    Skin and subcutaneous tissue disorders : Uncommon: pruritus, rash and urticaria Musculoskeletal, connective tissue and bone disorders :Common: myalgia Rare: myopathy (including myositis) and rhabdomyolysis.
    General disorders :  Common: asthenia
    For full details see prescribing information.


    Drug interactions

    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 medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy.
    Ciclosporin: During concomitant treatment with Crestor and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers Crestor is contraindicated in patients receiving concomitant ciclosporin Concomitant administration did not affect plasma concentrations of ciclosporin.
    Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of Crestor 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 Crestor may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.
    Ezetimibe: Concomitant use of 10 mg Crestor and 10 mg ezetimibe resulted in a 1.2 fold increase in AUC of rosuvastatin in hypercholesterolaemic subjects (Table 1). A pharmacodynamic interaction, in terms of adverse effects, between Crestor and ezetimibe cannot be ruled out Gemfibrozil and other lipid-lowering products: Concomitant use of Crestor and gemfibrozil resulted in a 2-fold increase in rosuvastatin C max and AUC Based on data from specific interaction studies, no pharmacokinetic relevant interaction with fenofibrate is expected, however a pharmacodynamic interaction may occur.
    Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses (> or equal to 1g/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.
    Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure. In a pharmacokinetic study, co-administration of 20 mg rosuvastatin and a combination product of two protease inhibitors (400 mg lopinavir / 100 mg ritonavir) in healthy volunteers was associated with an approximately two-fold and five-fold increase in rosuvastatin steady-state AUC(0-24) and Cmax respectively. Therefore, concomitant use of rosuvastatin in HIV patients receiving protease inhibitors is not recommended.
    Antacid: The simultaneous dosing of Crestor 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 Crestor. The clinical relevance of this interaction has not been studied.
    Erythromycin: Concomitant use of Crestor and erythromycin resulted in a 20% decrease in AUC (0-t) and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.
    Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of Crestor and an oral contraceptive resulted in an increase in ethinyl estradiol and norgestrel AUC of 26% and 34%, respectively. These increased plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in subjects taking concomitant Crestor and HRT and therefore a similar effect cannot be excluded. However, the combination has been extensively used in women in clinical trials and was well tolerated.
    Other medicinal products: Based on data from specific interaction studies no clinically relevant interactions with digoxin is expected.
    Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. 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). Concomitant administration of itraconazole (an inhibitor of CYP3A4) and rosuvastatin resulted in a 28% increase in AUC of rosuvastatin. This small increase is not considered clinically significant. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected.
     Interactions requiring rosuvastatin dose adjustments : When it is necessary to co-administer Crestor with other medicinal products known to increase exposure to rosuvastatin, doses of Crestor should be adjusted. Start with a 5 mg once daily dose of Crestor if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of Crestor should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of Crestor taken without interacting medicinal products, for example a 20 mg dose of Crestor with gemfibrozil (1.9-fold increase), and a 10 mg dose of Crestor with combination ritonavir/atazanavir (3.1-fold increase).
    For full details see prescribing information.


    Pregnancy and Lactation

    Pregnancy: Crestor 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. Animal studies provide limited evidence of reproductive toxicity. If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.
    Lactation: Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans.


    Overdose

    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.


    Manufacturer
    AstraZeneca UK Ltd.
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