Atozet Drug Interactions

ATOZET: No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with atorvastatin.
Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase atorvastatin plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.
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.
CYP3A4 Interactions: In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolizing enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolized by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase. Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4.
Inhibitors of cytochrome P3A4 increase the risk of myopathy by reducing the elimination of the atorvastatin component of ATOZET [see Myopathy/Rhabdomyolysis under Precautions].
Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of 80 mg atorvastatin with clarithromycin (500 mg twice daily) compared to that of atorvastatin alone. Therefore, in patients taking clarithromycin, caution should be used when the ATOZET dose exceeds 10/20 mg [see Myopathy/Rhabdomyolysis under Precautions and Cyclosporine, Clarithromycin, Itraconazole, or Certain HIV/HCV Antiviral Agents under Dosage & Administration].
Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin alone. Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of ATOZET should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing ATOZET, and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, or the hepatitis C protease inhibitor boceprevir, the dose of ATOZET should not exceed 10/20 mg and should be used with caution [see Myopathy/Rhabdomyolysis under Precautions and Cyclosporine, Clarithromycin, Itraconazole, or Certain HIV/HCV Antiviral Agents under Dosage & Administration]. In patients taking the HIV protease inhibitor nelfinavir the dose of ATOZET should not exceed 10/40 mg and close clinical monitoring is recommended.
Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg. Therefore, in patients taking itraconazole, caution should be used when the ATOZET dose exceeds 10/20 mg.
Grapefruit Juice: Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day).
Cyclosporine: In a study of eight post-renal transplant patients with creatinine clearance of >50 mL/min on a stable dose of cyclosporine, 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 from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m²) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls. 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 cyclosporine on Day 7 resulted in a mean 15% increase in cyclosporine AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of cyclosporine alone [see Myopathy/Rhabdomyolysis under Precautions].
Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone. The coadministration of ATOZET with cyclosporine should be avoided [see Myopathy/Rhabdomyolysis under Precautions].
Other Interactions: 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.
Coadministration of atorvastatin with an oral antacid suspension containing magnesium and aluminium hydroxides decreased plasma concentrations of atorvastatin and its active metabolites approximately 35%; however, LDL-C reduction was not altered.
Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be lessened by this interaction.
Fibrates [see Fibrates under Precautions]: Gemfibrozil: Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of ATOZET with gemfibrozil should be avoided.
In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. This increase is not considered clinically significant. No clinical data are available.
Fenofibrate: Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of fenofibrate, ATOZET should be administered with caution when used concomitantly with fenofibrate.
In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. This increase is not considered clinically significant.
Other fibrates: The safety and effectiveness of ezetimibe administered with other fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, coadministration of ATOZET with other fibrates is not recommended until use in patients is studied.
Fusidic Acid: The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of fusidic acid [see Myopathy/Rhabdomyolysis under Precautions].
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. There have been post-marketing reports of increased INR in patients who had ezetimibe added to warfarin or fluindione. Most of these patients were also on other medications. [See Anticoagulants under Precautions.]
Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.
The effect of ATOZET on the prothrombin time has not been studied.
Inhibitors of Breast Cancer Resistant Protein (BCRP): Atorvastatin is a substrate of the efflux transporter 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 may be necessary. Coadministration of elbasvir and grazoprevir with atorvastatin increases plasma concentrations of atorvastatin by 1.9-fold due in part to CYP3A and/or BCRP inhibition; therefore, the dose of ATOZET should not exceed 10/20 mg daily in patients receiving concomitant medication with products containing elbasvir or grazoprevir [see Myopathy/Rhabdomyolysis under Precautions].
Inducers of Cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous coadministration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
Antipyrine: Because atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isozymes are not expected.
Colestipol: Plasma concentrations of atorvastatin decreased approximately 25% when colestipol and atorvastatin were coadministered. However, LDL-C reduction was greater when atorvastatin and colestipol were coadministered than when either drug was given alone.
Digoxin: When multiple doses of atorvastatin and digoxin were coadministered, steady-state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
Oral Contraceptives: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
Amlodipine: In a drug-drug interaction study in healthy subjects, coadministration of atorvastatin 80 mg and amlodipine 10 mg resulted in an 18% increase in exposure to atorvastatin that was not clinically meaningful.
Niacin: The risk of skeletal muscle effects may be enhanced when ATOZET is used in combination with niacin; a reduction in ATOZET dosage should be considered in this setting [see Myopathy/Rhabdomyolysis under Precautions].
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing ATOZET with colchicine.
Daptomycin: The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors and daptomycin [see Myopathy/Rhabdomyolysis under Precautions].