• Skeletal muscle effects: effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in Rosuvastatin-treated patients with all doses. 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.
  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.
• Liver effects: as with other HMG-CoA reductase inhibitors, Rosuvastatin 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. Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal. In patients with secondary hypercholesterolemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with Rosuvastatin.
• Protease inhibitors: the concomitant use with protease inhibitors is not recommended.
• 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. 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: in patients with fasting glucose 5.6 to 6.9 mmol/L, treatment with Rosuvastatin has been associated with an increased risk of diabetes mellitus.
• Pediatric population: the evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in pediatric patients 10 to 17 years of age taking Rosuvastatin is limited to a one-year period. After 52 weeks of study treatment, no effect on growth, weight, BMI or sexual maturation was detected. The clinical trial experience in children and adolescent patients is limited and the long-term effects of Rosuvastatin (>1 year) on puberty are unknown.

PREGNANCY AND LACTATION
Rosuvastatin 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.
Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in
humans.

DRUG INTERACTIONS

• Ciclosporin: during concomitant treatment with Rosuvastatin and Ciclosporin, Rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers. 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 Rosuvastatin 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 Rosuvastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.
• Ezetimibe: concomitant use of Rosuvastatin and Ezetimibe resulted in no change to AUC or Cmax for either drug. However, a pharmacodynamic interaction, in terms of adverse effects, between Rosuvastatin and Ezetimibe cannot be ruled out.
• Gemfibrozil and other lipid-lowering products: concomitant use of Rosuvastatin and Gemfibrozil resulted in a 2-fold increase in Rosuvastatin Cmax and AUC. Based on data from specific interaction studies, no pharmacokinetic relevant interaction with Fenofibrate is expected, however a or equal to 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. 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 Rosuvastatin 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 Rosuvastatin. The clinical relevance of this interaction has not been studied.
• Erythromycin: concomitant use of Rosuvastatin 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 Rosuvastatin 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 Rosuvastatin 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 interaction 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.