Zortress (Page 7 of 12)

12.5 Drug-Drug Interactions

Everolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between everolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below [ s ee Warnings and Precautions ( 5.1 4 ), Drug Interactions (7)] .

Cyclosporine (CYP3A4/P-gp Inhibitor and CYP3A4 Substrate): Zortress should be taken concomitantly with cyclosporine in kidney transplant patients. Everolimus concentrations may decrease when doses of cyclosporine are reduced, unless the Zortress dose is increased [ s ee Dosage and Administration (2.1), Drug Interactions ( 7.2 ) ] .

In a single-dose study in healthy subjects, cyclosporine (Neoral) administered at a dose of 175 mg increased everolimus AUC by 168% (range 46% to 365%) and Cmax by 82% (range 25% to 158%) when administered with 2 mg Zortress compared with administration of Zortress alone [ s ee Drug Interactions (7.2) ] .

Ketoconazoleand OtherStrong CYP3A4 Inhibitors: Multiple-dose administration of 200 mg ketoconazole twice daily for 5 days to 12 healthy volunteers significantly increased everolimus Cmax , AUC, and half-life by 3.9-fold, 15-fold, and 89%, respectively, when coadministered with 2 mg Zortress. It is recommended that strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) should not be coadministered with Zortress [ s ee Warnings and Precautions ( 5.1 4 ) , Drug Interactions (7.3) ] .

Erythromycin (Moderate CYP3A4 Inhibitor) : Multiple-dose administration of 500 mg erythromycin 3 times daily for 5 days to 16 healthy volunteers significantly increased everolimus Cmax , AUC, and half-life by 2-fold, 4.4-fold, and 39%, respectively, when coadministered with 2 mg Zortress. If erythromycin is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [ s ee Drug Interactions (7.4) ] .

Verapamil(CYP3A4 Inhibitor and P-gp Substrate) : Multiple-dose administration of 80 mg verapamil 3 times daily for 5 days to 16 healthy volunteers significantly increased everolimus Cmax and AUC by 2.3-fold and 3.5-fold, respectively, when coadministered with 2 mg Zortress. Everolimus half-life was not changed. If verapamil is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary [ s ee Drug Interactions (7.5) ] .

Atorvastatin(CYP3A4 Substrate) and Pravastatin (P-gp Substrate): Following administration of a single dose of 2 mg Zortress to 12 healthy subjects, the concomitant administration of a single oral dose administration of atorvastatin 20 mg or pravastatin 20 mg only slightly decreased everolimus Cmax and AUC by 9% and 10%, respectively. There was no apparent change in the mean T1/2 or median Tmax . In the same study, the concomitant Zortress dose slightly increased the mean Cmax of atorvastatin by 11% and slightly decreased the AUC by 7%. The concomitant Zortress dose decreased the mean Cmax and AUC of pravastatin by 10% and 5%, respectively. No dosage adjustments are needed for concomitant administration of Zortress and atorvastatin and pravastatin [ s ee Drug Interactions (7.6) ] .

Midazolam (CYP3A4/5 Substrate): In 25 healthy male subjects, coadministration of a single dose of midazolam 4 mg oral solution with steady-state everolimus (10 mg daily dose for 5 days) resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC; whereas, the terminal half-life of midazolam and the metabolic AUC-ratio (1-hydroxymidazolam/midazolam) were not affected [ s ee Drug Interactions (7.9)] .

Rifampin (Strong CYP3A4 and P-gp Inducer):Pretreatment of 12 healthy subjects with multiple-dose rifampin (600 mg once-daily for 8 days) followed by a single dose of 4 mg Zortress increased everolimus clearance nearly 3-fold, and decreased Cmax by 58% and AUC by 63%. Combination with rifampin is not recommended [ s ee Drug Interactions ( 7. 8 )] .

12.6 Specific Populations

Hepatic Impairment

Relative to the AUC of everolimus in subjects with normal hepatic function, the average AUC in 6 patients with mild hepatic impairment (Child-Pugh Class A) was 1.6-fold higher following administration of a 10 mg single-dose. In 2 independently studied groups of 8 and 9 patients with moderate hepatic impairment (Child-Pugh Class B) the average AUC was 2.1-fold and 3.3-fold higher following administration of a 2 mg or a 10 mg single-dose, respectively; and in 6 patients with severe hepatic impairment (Child-Pugh Class C) the average AUC was 3.6-fold higher following administration of a 10 mg single-dose. For patients with mild hepatic impairment (Child-Pugh Class A), the dose should be reduced by approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic impairment (Child-Pugh B or C), the initial daily dose should be reduced to approximately one-half of the normally recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough concentration of everolimus, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL [ s ee Dosage and Administration (2.7)] .

Renal Impairment

No pharmacokinetic studies in patients with renal impairment were conducted. Posttransplant renal function (creatinine clearance range 11 to 107 mL/min) did not affect the pharmacokinetics of everolimus, therefore, no dosage adjustments are needed in patients with renal impairment.

Geriatrics

A limited reduction in everolimus oral CL/F of 0.33% per year was estimated in adults (age range studied was 16 to 70 years). There is no evidence to suggest that elderly patients will require a different dosage recommendation from younger adult patients.

Race

Based on analysis of population pharmacokinetics, oral clearance (CL/F) is, on average, 20% higher in black transplant patients.

12.7 Everolimus Whole Blood Concentrations Observed in Kidney and in Liver Transplant Patients

Everolimus in Kidney Transplantation

Based on exposure-efficacy and exposure-safety analyses of clinical trials and using an LC/MS/MS assay method, kidney transplant patients achieving everolimus whole blood trough concentrations greater than or equal to 3 ng/mL have been found to have a lower incidence of treated biopsy-proven acute rejection compared with patients whose trough concentrations were below 3 ng/mL. Patients who attained everolimus trough concentrations within the range of 6 to 12 ng/mL had similar efficacy and more adverse reactions than patients who attained lower trough concentrations between 3 to 8 ng/mL [ s ee Dosage and Administration (2. 3 ) ] .

In the kidney clinical trial [ s ee Clinical Studies (14.1) ] , everolimus whole blood trough concentrations were measured at Days 3, 7, and 14 and Months 1, 2, 3, 4, 6, 7, 9, and 12. The proportion of patients receiving 0.75 mg twice daily Zortress treatment regimen who had everolimus whole blood trough concentrations within the protocol specified target range of 3 to 8 ng/mL at Days 3, 7, and 14 were 55%, 71% and 69%, respectively. Approximately 80% of patients had everolimus whole blood trough concentrations within the 3 to 8 ng/mL target range by Month 1 and remained stable within range through Month 12 posttransplant. The median everolimus trough concentration for the 0.75 mg twice daily treatment group was between 3 and 8 ng/mL throughout the study duration.

Everolimus in Liver Transplantation

In the liver clinical trial [ s ee Clinical Studies (14.2)], Zortress dosing was initiated after 30 days following transplantation. Whole blood trough everolimus concentrations were measured within 5 days after first dose, followed by weekly intervals for 3 to 4 weeks, and then monthly thereafter. Approximately 49%, 37%, and 18% of patients, respectively, were below 3 ng/mL at 1, 2, and 4 weeks after initiation of Zortress dosing. The majority of patients (approximately 70% to 80%) had everolimus trough blood concentrations within the target range of 3 to 8 ng/mL from Month 2 through Month 24 posttransplant.

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