Interactions : אינטראקציות

4.5       Interaction with other medicinal products and other forms of interaction

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 Crestor with medicinal products 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 seven-fold 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 sections 4.2, 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 Cmaxand AUC (see Section 4.4).

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 (see Section 4.3 and Section 4.4). These patients should also start with the 5 mg dose.

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 (see Section 4.4).

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 and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.

Ticagrelor: Ticagrelor might affect renal excretion of rosuvastatin, increasing the risk for rosuvastatin accumulation. Although the exact mechanism is not known, in some cases, concomitant use of ticagrelor and rosuvastatin led to renal function decrease, increased CPK level and rhabdomyolysis.

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 (see also Table 1): 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 atazanavir/ ritonavir (3.1-fold increase).
If medicinal product is observed to increase rosuvastatin AUC less than 2-fold, the starting dose need not be decreased but caution should be taken if increasing the Crestor dose above 20mg.

Table 1 Effect of co-administered medicinal products on rosuvastatin exposure (AUC; in order of decreasing magnitude) from published clinical trials
2-fold or greater than 2-fold increase in AUC of rosuvastatin
Interacting drug dose regimen                        Rosuvastatin dose         Change in regimen                   rosuvastatin AUC*
Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100      10mg single dose          7.4 -fold ↑ mg-100 mg) + Voxilaprevir (100 mg) once daily for 15 days
Ciclosporin 75 mg BID to 200 mg BID, 6 months        10 mg OD, 10 days         7.1-fold  Darolutamide 600 mg BID, 5 days                      5mg, single dose          5.2-fold ↑ Regorafenib 160 mg, OD, 14 days                      5 mg single dose          3.8-fold ↑ Atazanavir 300 mg/ritonavir 100 mg OD, 8 days        10 mg, single dose        3.1-fold  Velpatasvir 100 mg OD                                10 mg, single dose        2.7-fold ↑ Ombitasvir 25 mg/paritaprevir 150 mg/ Ritonavir      5 mg, single dose         2.6-fold ↑ 100 mg OD/ dasabuvir 400 mg BID, 14 days
Teriflunomide                                        Not Available             2.5-fold ↑ Grazoprevir 200 mg/elbasvir 50mg OD, 11 days         10 mg, single dose        2.3-fold ↑ Glecaprevir 400 mg/pibrentasvir 120 mg OD, 7         5 mg OD, 7 days           2.2-fold ↑ days
Lopinavir 400 mg/ritonavir 100 mg BID, 17 days       20 mg OD, 7 days          2.1-fold  Capmatinib 400mg BID                                 10 mg, single dose        2.1-fold ↑ Clopidogrel 300 mg loading, followed by 75 mg        20 mg, single dose        2-fold at 24 hours
Fostamatnib 100 mg twice daily                       20 mg, single dose        2.0-fold ↑ Fabuxostat 120mg OD                                  10 mg, single dose        1.9-fold ↑ Gemfibrozil 600 mg BID, 7 days                       80 mg, single dose        1.9-fold  Less than 2-fold increase in AUC of rosuvastatin
Interacting drug dose regimen                        Rosuvastatin              Change in dose regimen              rosuvastatin
AUC*
Eltrombopag 75 mg OD, 5days                          10 mg, single dose        1.6-fold  Darunavir 600 mg/ritonavir 100 mg BID, 7 days        10 mg OD, 7 days          1.5-fold  Tipranavir 500 mg/ritonavir 200 mg BID, 11 days      10 mg, single dose        1.4-fold  Dronedarone 400 mg BID                               Not available             1.4-fold  Itraconazole 200 mg OD, 5 days                       10 mg, single dose        **1.4-fold  Ezetimibe 10 mg OD, 14 days                             10 mg, OD, 14 days       **1.2-fold  Decrease in AUC of rosuvastatin
Interacting drug dose regimen                           Rosuvastatin             Change in dose regimen             rosuvastatin
AUC*
Erythromycin 500 mg QID, 7 days                         80 mg, single dose       20%  Baicalin 50 mg TID, 14 days                             20 mg, single dose       47%  *Data given as x-fold change represent a simple ratio between co-administration and rosuvastatin alone. Data given as % change represent % difference relative to rosuvastatin alone.
Increase is indicated as “↑”, decrease as “↓”.
**Severalinteraction studies have been performed at different Crestor dosages, the table shows the most significant ratio
AUC= area under curve; OD = once daily; BID = twice daily; TID = three times daily; QID = four times daily


The following medical product/combinations did not have a clinically significant effect on the AUC ratio of rosuvastatin at coadministration: Aleglitazar 0.3 mg 7 days dosing; Fenofibrate 67 mg 7 days TID dosing; Fluconazole 200mg 11 days OD dosing; Fosamprenavir 700 mg/ritonavir 100 mg 8 days BID dosing; Ketoconazole 200 mg 7 days BID dosing; Rifampin 450 mg 7 days OD dosing; Silymarin 140 mg 5 days TID dosing.

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 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.

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, 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: Based on data from specific interaction studies no clinically relevant interactions with digoxin is expected.

Fusidic Acid: Interaction studies with rosuvastatin and fusidic acid have not been conducted. 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, Crestor treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4.