DOSAGE AND ADMINISTRATION
Dosage in Adult Kidney T ransplant Patients
An initial everolimus dose of 0.75 mg orally twice daily (1.5 mg/day) is recommended for adult kidney transplant patients in combination with reduced dose cyclosporine, administered as soon as possible after transplantation. [ See Therapeutic Drug Monitoring
(2.2
and 2.3
)
, Clinical Studies
(14.1) ] Patients receiving everolimus may require dose adjustments based on everolimus blood concentrations achieved, tolerability, individual response, change in concomitant medications and the clinical situation. Dose adjustments can be made at 4-5 day intervals. [ See
Therapeutic Drug Monitoring
(2.2) ]
Oral prednisone should be initiated once oral medication is tolerated. Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft.
Therapeutic Drug Monitoring - Everolimus
Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients using appropriate assay methodology. The recommended everolimus therapeutic range is 3 to 8 ng/mL. [ See
Clinical Pharmacology
(12.5) ] Careful attention should be made to clinical signs and symptoms, tissue biopsies, and laboratory parameters.
It is important to monitor everolimus blood concentrations, in patients with hepatic impairment, during concomitant administration of CYP3A4 inducers or inhibitors, when switching cyclosporine formulations and/or when cyclosporine dosing is reduced according to recommended target concentrations. [ See
Clinical Pharmacology
(12.5 and 12.6) ]
Optimally, dose adjustments of everolimus should be based on trough concentrations obtained 4 or 5 days after a previous dosing change. There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced. [ See
Drug Interactions
(7
.2
) ]
Therapeutic Drug Monitoring- Cyclosporin e
Both cyclosporine doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with everolimus, in order to minimize the risk of nephrotoxicity. [ See Warnings and Precautions (5.8) and Drug Interactions (7.2), Clinical Pharmacology (12.6) ]
The recommended cyclosporine therapeutic range when administered with everolimus are 100 to 200 ng/mL through Month 1 post-transplant, 75 to 150 ng/mL at Months 2 and 3 post-transplant, 50 to 100 ng/mL at Month 4 post-transplant, and 25 to 50 ng/mL from Month 6 through Month 12 post-transplant. The median trough concentrations observed in the clinical trial ranged between 161 to 185 ng/mL through Month 1 post-transplant and between 111 to 140 ng/mL at Months 2 and 3 post-transplant. The median trough concentration was 99 ng/mL at Month 4 post-transplant and ranged between 46 to 75 ng/mL from Months 6 through Month 12 post-transplant. [ See
Clinical Pharmacology (12.6)
and Clinical Studies (14.1) ]
Cyclosporine, USP Modified is to be administered as oral capsules twice daily unless cyclosporine oral solution or i.v. administration of cyclosporine cannot be avoided. Cyclosporine, USP Modified should be initiated as soon as possible - and no later than 48 hours - after reperfusion of the graft and dose adjusted to target concentrations from Day 5 onwards.
If impairment of renal function is progressive the treatment regimen should be adjusted. In renal transplant patients, the cyclosporine dose should be based on cyclosporine whole blood trough concentrations. [S ee
Clinical Pharmacology (12
.6
) ]
In renal transplantation, there are limited data regarding dosing everolimus with reduced cyclosporine trough concentrations of 25 to 50 ng/mL after 12 months. Everolimus has not been evaluated in clinical trials with other formulations of cyclosporine. Prior to dose reduction of cyclosporine it should be ascertained that steady-state everolimus whole blood trough concentration is at least 3 ng/mL. There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced. [S ee
Drug Interactions (7
.2
) ]
Ad ministration
Everolimus tablets should be swallowed whole with a glass of water and not crushed before use.
Administer everolimus consistently approximately 12 hours apart with or without food to minimize variability in absorption and at the same time as cyclosporine. [ See
Clinical Pharmacology (12.3) ]
Hepatic Impairment
No dose adjustment is needed for patients with mild hepatic impairment (Child-Pugh Class A). In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose needs to be reduced by one-half the recommended initial daily dose and blood concentrations should be monitored to make further adjustments as necessary. There is no information on the effects of severe hepatic impairment (Child-Pugh Class C) on everolimus pharmacokinetics. [ See
Clinical Pharmacology
(
12.3) ]
DOSAGE FORMS AND STRENGTHS
Zortress is available as 0.25 mg, 0.5 mg, and 0.75 mg tablets.
Description of Zortress (everolimus) Tablets
|
Dosage Strength
|
0.25 mg
|
0.5 mg
|
0.75 mg
|
|
Appearance
|
White to yellowish, marbled, round, flat tablets with bevelled edge |
|
Imprint
|
“C” on one side and "NVR" on the other |
“CH” on one side and "NVR" on the other |
“CL” on one side and "NVR" on the other |
|
