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Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with atorvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens.
Pharmacodynamic interactions: Atorvastatin is metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the multi-drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin (see Pharmacology: Pharmacokinetics under Actions). Concomitant administration of medicinal products that are inhibitors of CYP3A4 or transport proteins may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. The risk might also be increased at concomitant administration of ATOZET with other medicinal products that have a potential to induce myopathy, such as fibric acid derivatives and ezetimibe (see Precautions).
Pharmacokinetic interactions: ATOZET: No clinically significant pharmacokinetic interaction was seen when ezetimibe was co-administered with atorvastatin.
Effects of other medicinal products on ATOZET: Ezetimibe: 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.
Cholestyramine: Concomitant cholestyramine 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 ATOZET to cholestyramine may be lessened by this interaction (see Dosage & Administration).
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 insufficiency who was receiving ciclosporin and multiple other medicinal products 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. Caution should be exercised when initiating ATOZET in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving ATOZET and ciclosporin (see Precautions).
Fibrates: Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations approximately 1.5 and 1.7 fold, respectively. Although these increases are not considered clinically significant, co-administration of ATOZET with fibrates is not recommended (see Precautions).
Atorvastatin: CYP3A4 inhibitors: Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of atorvastatin (see Table 5 and specific information as follows). Co-administration of potent CYP3A4 inhibitors (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, some antivirals used in the treatment of HCV (e.g. elbasvir/grazoprevir) and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided if possible. In cases where co-administration of these medicinal products with ATOZET cannot be avoided, lower starting and maximum doses of ATOZET should be considered and appropriate clinical monitoring of the patient is recommended (see Table 5).
Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see Table 5). An increased risk of myopathy has been observed with the use of erythromycin in combination with statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with ATOZET may result in increased exposure to atorvastatin. Therefore, a lower maximum dose of ATOZET should be considered and appropriate clinical monitoring of the patient is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor.
Inhibitors of Breast Cancer Resistant Protein (BCRP): Concomitant administration of products that are inhibitors of BCRP (e.g. elbasvir and grazoprevir) may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy; therefore, a dose adjustment of atorvastatin should be considered depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with atorvastatin increases plasma concentrations of atorvastatin 1.9-fold (see Table 5); therefore, the dose of ATOZET should not exceed 10/20 mg daily in patients receiving concomitant medications with products containing elbasvir or grazoprevir (see Dosage & Administration and Precautions).
Inducers of cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampicin, St. John's wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampicin, (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of ATOZET with rifampicin is recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction in atorvastatin plasma concentrations. The effect of rifampicin on atorvastatin concentrations in hepatocytes is, however, unknown and if concomitant administration cannot be avoided, patients should be carefully monitored for efficacy.
Transport inhibitors: Inhibitors of transport proteins (e.g. ciclosporin) can increase the systemic exposure of atorvastatin (see Table 5). The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant administration cannot be avoided, a dose reduction of ATOZET and clinical monitoring for efficacy is recommended (see Table 5).
Gemfibrozil / fibric acid derivatives: The use of fibrates alone is occasionally associated with muscle-related events, including rhabdomyolysis. The risk of these events may be increased with the concomitant use of fibric acid derivatives and atorvastatin.
Ezetimibe: The use of ezetimibe alone is associated with muscle-related events, including rhabdomyolysis. The risk of these events may therefore be increased with concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring of these patients is recommended.
Colestipol: Plasma concentrations of atorvastatin and its active metabolites were lower (by approx. 25%) when colestipol was co-administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were co-administered than when either medicinal product was given alone.
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, atorvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see Precautions.
Colchicine: Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
Daptomycin: The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors and daptomycin. Consideration should be given to suspending ATOZET temporarily in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk (see Precautions).
Boceprevir: Exposure to atorvastatin was increased when administered with boceprevir. When co-administration with ATOZET is required, starting with the lowest possible dose of ATOZET should be considered with titration up to desired clinical effect while monitoring for safety, without exceeding a daily dose of 10/20 mg. For patients currently taking ATOZET, the dose of ATOZET should not exceed a daily dose of 10/20 mg during co-administration with boceprevir.
Effects of ATOZET on the pharmacokinetics of other medicinal products: Ezetimibe: 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.
Anticoagulants: 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 ATOZET is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see Precautions).
Atorvastatin: Digoxin: When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady-state digoxin concentrations increased slightly. Patients taking digoxin should be monitored appropriately.
Oral contraceptives: Co-administration of atorvastatin with an oral contraceptive produced increases in plasma concentrations of norethisterone and ethinyl estradiol.
Warfarin: In a clinical study in patients receiving chronic warfarin therapy, co-administration of atorvastatin 80 mg daily with warfarin caused a small decrease of about 1.7 seconds in prothrombin time during the first 4 days of dosing, which returned to normal within 15 days of atorvastatin treatment. Although only very rare cases of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined before starting ATOZET in patients taking coumarin anticoagulants and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of ATOZET is changed or discontinued, the same procedure should be repeated. Atorvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
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