Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Contraindicated combinations:
Ciclosporin: Concomitant administration of Rosetemib S.K with ciclosporin is contraindicated because of the rosuvastatin (see section 4.3). During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). Concomitant administration did not affect plasma concentrations of ciclosporin.

In a study of eight post-renal transplant patients with creatinine clearance of>50 ml/min on a stable dose of ciclosporin, a single 10-mg dose of ezetimibe resulted in a 3.4-fold (range 2.3 to 7.9-fold) increase in the mean AUC for total ezetimibe compared to a healthy control population, receiving ezetimibe alone, from another study (n=17). In a different study, a renal transplant patient with severe renal impairment who was receiving ciclosporin and multiple other medications, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls receiving ezetimibe alone. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100 mg dose of ciclosporin on Day 7 resulted in a mean 15 % increase in ciclosporin AUC (range 10 % decrease to 51 % increase) compared to a single 100 mg dose of ciclosporin alone. A controlled study on the effect of co-administered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted.

Not-recommended combinations:

Fibrates and other lipid-lowering products: In patients receiving fenofibrate and ezetimibe, physicians should be aware of the possible risk of cholelithiasis and gallbladder disease (see sections 4.4 and 4.8). If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see section 4.8). Concomitant fenofibrate or gemfibrozil administration modestly increased total ezetimibe concentrations (approximately 1.5- and 1.7-fold respectively).

Co-administration of ezetimibe with other fibrates has not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In animal studies, ezetimibe sometimes increased cholesterol in the gallbladder bile, but not in all species (see section 5.3). A lithogenic risk associated with the therapeutic use of ezetimibe cannot be ruled out.

Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and 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/10 mg dose is contraindicated with concomitant use of a fibrate (see sections 4.3 and 4.4).
Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure (see Table 1). 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 rosuvastatin and some protease inhibitor combinations may be considered after careful consideration of rosuvastatin dose adjustments based on the expected increase in rosuvastatin exposure (see sections 4.2, 4.4 and 4.5 Table 1).

Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of rosuvastatin 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).

Fusidic acid: 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, rosuvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4.

Other interactions:

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).

In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.

Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.

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.

Colestyramine: Concomitant colestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental low density lipoprotein cholesterol (LDL C) reduction due to adding ezetimibe to colestyramine may be lessened by this interaction (see section 4.2).

Anticoagulants, Vitamin K antagonists: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had ezetimibe added to warfarin or fluindione. If Rosetemib S.K is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see section 4.4).

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.

Clopidogrel: Clopidogrel has been shown to increase rosuvastatin exposure in patients by 2-fold (AUC) and 1.3-fold (Cmax) after administration of 300 mg clopidogrel dose, and by 1.4-fold (AUC) without effect on Cmax after repeated administration of 75 mg clopidogrel dose.

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.

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 women 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.
In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel).

Other medicinal products: Based on data from specific interaction studies with rosuvastatin no clinically relevant interaction with digoxin is expected. In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, glipizide, tolbutamide, or midazolam, during co-administration. Cimetidine, co-administered with ezetimibe, had no effect on the bioavailability of ezetimibe.

Rosuvastatin/ezetimibe: Concomitant use of 10 mg rosuvastatin 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 rosuvastatin and ezetimibe cannot be ruled out (see section 4.4).

Interactions requiring rosuvastatin dose adjustments (see also Table 1): When it is necessary to co-administer rosuvastatin with other medicinal products known to increase exposure to rosuvastatin, doses should be adjusted. The maximum daily dose should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of rosuvastatin taken without interacting medicinal products, for example a 20 mg dose of rosuvastatin with gemfibrozil (1.9-fold increase), and a 10 mg dose of rosuvastatin with combination ritonavir/atazanavir (3.1-fold increase).
Table 1 Effect of co-administered medicinal products on rosuvastatin exposure (AUC; in order of decreasing magnitude) from published clinical trials
Interacting drug dose regimen       Rosuvastatin dose regimen Change in rosuvastatin AUC*
Ciclosporin 75 mg BID to 200 mg      10 mg OD, 10 days         7.1-fold ↑ BID, 6 months
Regorafenib 160 mg, OD, 14 days      5 mg single dose          3.8-fold ↑ Atazanavir 300 mg/ritonavir 100 mg   10 mg, single dose        3.1-fold ↑ OD, 8 days
Velpatasvir 100 mg OD                10 mg, single dose        2.7-fold ↑ Ombitasvir 25 mg/paritaprevir 150    5 mg, single dose         2.6-fold ↑ mg/ritonavir 100 mg OD/ dasabuvir
400 mg BID, 14 days
Grazoprevir 200 mg/ elbasvir 50 mg   10 mg, single dose        2.3-fold ↑ OD, 11 days
Glecaprevir 400 mg/ pibrentasvir 120 5 mg OD, 7 days           2.2-fold ↑ mg OD, 7 days
Lopinavir 400 mg/ritonavir 100 mg    20 mg OD, 7 days          2.1-fold ↑ BID, 17 days
Clopidogrel 300 mg loading,          20 mg, single dose        2-fold ↑ followed by 75 mg at 24 hours
Clopidogrel 300 mg                   40 mg, OD                 2-fold ↑, loading dose,
 followed by 75 mg                                              1.4-fold ↑ OD, 7 days
Gemfibrozil 600 mg BID, 7 days       80 mg, single dose        1.9-fold ↑ Eltrombopag 75 mg OD, 5 days         10 mg, single dose        1.6-fold ↑ Darunavir 600 mg/ritonavir 100 mg    10 mg OD, 7 days          1.5-fold ↑ BID, 7 days
Tipranavir 500 mg/ritonavir 200 mg   10 mg, single dose        1.4-fold ↑ BID, 11 days
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 ↑ Fosamprenavir 700 mg/ritonavir       10 mg, single dose        ↔
100 mg BID, 8 days
Aleglitazar 0.3 mg, 7 days           40 mg, 7 days             ↔
Silymarin 140 mg TID, 5 days         10 mg, single dose        ↔
Fenofibrate 67 mg TID, 7 days        10 mg, 7 days             ↔
Rifampin 450 mg OD, 7 days           20 mg, single dose        ↔
Ketoconazole 200 mg BID, 7 days      80 mg, single dose        ↔
Fluconazole 200 mg OD, 11 days       80 mg, single dose        ↔
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 “↑“, no change as “ ”, decrease as “↓”.
**
Several interaction studies have been performed at different rosuvastatin dosages, the table shows the most significant ratio
OD = once daily; BID = twice daily; TID = three times daily; QID = four times daily