Lypstaplus Drug Interactions

Contraindications: Ciclosporin: During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Contraindications). Concomitant administration did not affect plasma concentrations of ciclosporin.
Co-administration of LYPSTAPLUS with ciclosporin is contraindicated (see Contraindications).
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 insufficiency 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: Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure (see Table 3). 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 C_max 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 Dosage & Administration, Precautions, and Table 3). The combination is not suitable for initial therapy.
Treatment initiation or dose adjustment if necessary should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible.
Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of LYPSTAPLUS with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy (see Dosage & Administration, Precautions, and Table 3).
Gemfibrozil and other lipid-lowering products: Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin C_max and AUC (see Precautions). Concomitant gemfibrozil administration modestly increased total ezetimibe concentrations (approximately 1.7-fold).
Based on data from specific interaction studies no pharmacokinetic relevant interaction between rosuvastatin and fenofibrate is expected, however a pharmacodynamic interaction may occur. Concomitant fenofibrate administration modestly increased total ezetimibe concentrations (approximately 1.5-fold).
Fenofibrate, and other fibrates increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone. In patients receiving fenofibrate and ezetimibe, physicians should be aware of the possible risk of cholelithiasis and gallbladder disease (see Precautions and Administration). If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see Adverse Reactions). 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 all species (see Pharmacology: Toxicology: Preclinical safety data under Actions). A lithogenic risk associated with the therapeutic use of ezetimibe cannot be ruled out.
The dose of rosuvastatin should not exceed 10 mg/day when given in combination with fibrates or niacin (see Dosage & Administration and Precautions).
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 Precautions.
Other interactions: 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.
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.
Erythromycin: Concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in AUC_0-t and a 30% decrease in C_max 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).
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.
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.
Concomitant administration of ezetimibe (10 mg once daily) had no 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 LYPSTAPLUS is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see Precautions).
Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of rosuvastatin and 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.
In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel).
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 Dosage & Admnistration).
Statins: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.
Ticagrelor can cause renal insufficiency and may affect renal excretion of rosuvastatin, increasing the risk for rosuvastatin accumulation. In some cases, co-administered ticagrelor and rosuvastatin led to renal function decrease, increased CPK level and rhabdomyolysis. Renal function and CPK control is recommended while using ticagrelor and rosuvastatin concomitantly.
Other medicinal products: Based on data from specific interaction studies no clinically relevant interaction between rosuvastatin and 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.
Interactions requiring rosuvastatin dose adjustments (see also Table 3 as follows): When it is necessary to co-administer rosuvastatin with other medicinal products known to increase exposure to rosuvastatin, doses should be adjusted. Start with a 5 mg once daily dose of rosuvastatin if the expected increase in exposure (AUC) is approximately 2-fold or higher. 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 atazanavir/ritonavir (3.1-fold increase). (See Table 3.)

Click on icon to see table/diagram/image

The combination is not suitable for initial therapy. Treatment initiation or dose adjustment if necessary should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible.