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 Rovastin with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy.
Ciclosporin: Rovastin is contraindicated in patients receiving concomitant ciclosporin.
Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure. 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 seven-fold increase in rosuvastatin AUC and Cmax respectively. The concomitant use of Rovastin and some protease inhibitor combinations may be considered after careful consideration of Rovastin dose adjustments based on the expected increase in rosuvastatin exposure.
Gemfibrozil and other lipid-lowering products: Concomitant use of Rovastin and gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and AUC (see Precautions).
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 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. These patients should also start with the 5 mg dose.
Ezetimibe: Concomitant use of 10 mg Rovastin and 10 mg ezetimibe resulted in a 1.2 fold increase in AUC of rosuvastatin in hypercholesterolaemic subjects. A pharmacodynamic interaction, in terms of adverse effects, between Rovastin and ezetimibe cannot be ruled out (see Precautions).
Antacid: The simultaneous dosing of Rovastin 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 Rovastin. The clinical relevance of this interaction has not been studied.
Fusidic Acid: Interaction studies with rosuvastatin and fusidic acid have not been conducted. As with other statins, muscle related events, including rhabdomyolysis, have been reported in post-marketing experience with rosuvastatin and fusidic acid given concurrently. Patients should be closely monitored and temporary suspension of rosuvastatin treatment may be appropriate.
Erythromycin: Concomitant use of Rovastin 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.
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. Therefore, 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).
Interactions requiring rosuvastatin dose adjustments: When it is necessary to co-administer Rovastin with other medicinal products known to increase exposure to rosuvastatin, doses of Rovastin should be adjusted. Start with a 5 mg once daily dose of Rovastin if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of Rovastin should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of the recommended maximum daily dose of Rovastin taken without interacting medicinal products. For example, where the recommended dose of Rovastin is 20mg; the dose of Rovastin taken with a ritonavir/atazanavir combination (3.1-fold increase) should not exceed 5mg, and the dose of Rovastin taken with gemfibrozil (1.9 fold increase) should not exceed 10mg.
Other medications: Concurrent use of fibrates may cause severe myositis and myoglobinuria.
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 Rovastin 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 Rovastin 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 Rovastin and an oral contraceptive may increase ethinyl estradiol and norgestrel. These increased plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in subjects taking concomitant Rovastin 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: Digoxin: No clinically relevant interaction with digoxin is expected.
Paediatric population: The extent of interactions in the paediatric population is not known.