Posology : מינונים

4.2   Posology and method of administration
Treatment with Certican should only be initiated and maintained by physicians who are experienced in immunosuppressive therapy following organ transplantation and who have access to everolimus whole blood concentration monitoring.

Posology
Adults
An initial dose regimen of 0.75 mg twice daily in co-administration with ciclosporin is recommended for the general kidney and heart transplant population, administered as soon as possible after transplantation.
The dose of 1.0 mg twice daily in co-administration with tacrolimus is recommended for the hepatic transplant population with the initial dose approximately 4 weeks after transplantation.
Patients receiving Certican may require dose adjustments based on blood concentrations achieved, tolerability, individual response, change in co-medications and the clinical situation. Dose adjustments can be made at 4-5 day intervals (see Therapeutic drug monitoring).

Special population

Black patients
The incidence of biopsy-proven acute rejection episodes was significantly higher in black renal transplant patients compared with non-black patients. There is limited information indicating that black patients may require a higher Certican dose to achieve similar efficacy to non-black patients (see section 5.2). Currently, the efficacy and safety data are too limited to allow specific recommendations for use of everolimus in black patients.

Paediatric population
Certican is not indicated for children and adolescents under 18 years old.

Elderly patients (≥65 years)
Clinical experience in patients >65 years of age is limited. Although data are limited, there are no apparent differences in the pharmacokinetics of everolimus in patients ≥65-70 years of age (see section 5.2).

Patients with renal impairment
No dosage adjustment is required (see section 5.2).

Patients with impaired hepatic function
Everolimus whole blood trough concentrations should be closely monitored in patients with impaired hepatic function. The dose should be reduced to approximately two thirds of the normal dose for patients with mild hepatic impairment (Child-Pugh Class A), to approximately one half of the normal dose for patients with moderate hepatic impairment (Child Pugh Class B), and to approximately one third of the normal dose for patients with severe hepatic impairment (Child Pugh Class C). Further dose titration should be based on therapeutic drug monitoring (see section 5.2). Reduced doses rounded to the nearest tablet strength are tabulated below:

Table 1      Certican dose reduction in patients with hepatic impairment Normal hepatic       Mild hepatic          Moderate               Severe hepatic function          impairment             hepatic                impairment (Child-Pugh A)         impairment             (Child-Pugh C)
(Child-Pugh B)

Renal and cardiac       0.75 mg b.i.d.        0.5 mg b.i.d.        0.5 mg b.i.d.         0.25 mg b.i.d.
transplantation
Hepatic                   1 mg b.i.d.        0.75 mg b.i.d.        0.5 mg b.i.d.         0.5 mg b.i.d.
transplantation

Therapeutic drug monitoring
The use of drug assays with adequate performance characteristics when targeting low concentrations of ciclosporin or tacrolimus is recommended.

Certican has a narrow therapeutic index which may require adjustments in dosing to maintain therapeutic response. Routine everolimus whole blood therapeutic drug concentration monitoring is recommended. Based on exposure-efficacy and exposure-safety analysis, patients achieving everolimus whole blood trough concentrations ≥3.0 ng/ml have been found to have a lower incidence of biopsy-proven acute rejection in renal, cardiac and hepatic transplantation compared with patients whose trough concentrations are below 3.0 ng/ml. The recommended upper limit of the therapeutic range is 8 ng/ml. Exposure above 12 ng/ml has not been studied. These recommended ranges for everolimus are based on chromatographic methods.

It is especially important to monitor everolimus blood concentrations in patients with hepatic impairment during concomitant administration of strong CYP3A4 inducers and inhibitors, when switching formulation, and/or if ciclosporin dosing is markedly reduced (see section 4.5).

Ideally, dose adjustments of Certican should be based on trough concentrations obtained >4-5 days after the previous dosing change. There is an interaction between ciclosporin and everolimus, and everolimus concentrations may therefore decrease if ciclosporin exposure is markedly reduced (i.e.
trough concentration <50 ng/ml).

Patients with hepatic impairment should preferably have trough concentrations in the upper part of the 3-8 ng/ml exposure range.

After starting treatment or after a dose adjustment, monitoring should be performed every 4 to 5 days until 2 consecutive trough concentrations show stable everolimus concentrations, as the prolonged half-lives in hepatically impaired patients delay the time to reach steady state (see sections 4.4 and 5.2). Dose adjustments should be based on stable everolimus trough concentrations.

Ciclosporin dose recommendation in renal transplantation
Certican should not be used long-term together with full doses of ciclosporin. Reduced exposure to ciclosporin in Certican-treated renal transplant patients improves renal function. Based on experience gained from study A2309, ciclosporin exposure reduction should be started immediately after transplantation with the following recommended whole blood trough concentration windows: 
Table 2      Renal transplantation: recommended target ciclosporin blood trough concentration windows

Target ciclosporin C0 (ng/ml)        Month 1         Months 2-3         Months 4-5        Months 6-12 Certican groups                      100-200          75-150             50-100             25-50 
(Measured C0 and C2 concentrations are shown in section 5.1).

Prior to dose reduction of ciclosporin it should be ascertained that steady-state everolimus whole blood trough concentrations are equal to or above 3 ng/ml.

There are limited data regarding dosing Certican with ciclosporin trough concentrations below 50 ng/ml, or C2 concentrations below 350 ng/ml, in the maintenance phase. If the patient cannot tolerate reduction of ciclosporin exposure, the continued use of Certican should be reconsidered.

Ciclosporin dose recommendation in cardiac transplantation
Cardiac transplant patients in the maintenance phase should have their ciclosporin dose reduced as tolerated in order to improve kidney function. If impairment of renal function is progressive or if the calculated creatinine clearance is <60 ml/min, the treatment regimen should be adjusted. In cardiac 
transplant patients, the ciclosporin dose may be based on ciclosporin blood trough concentrations. See section 5.1 for experience with reduced ciclosporin blood concentrations.

In cardiac transplantation, there are limited data regarding dosing Certican with ciclosporin trough concentrations of 50-100 ng/ml after 12 months.

Prior to dose reduction of ciclosporin it should be ascertained that steady-state everolimus whole blood trough concentrations are equal to or above 3 ng/ml.

Tacrolimus dose recommendation in hepatic transplantation
Hepatic transplant patients should have their tacrolimus exposure reduced to minimise calcineurin- related renal toxicity. The tacrolimus dose should be reduced starting approximately 3 weeks after initiating co-administration with Certican, based on targeted tacrolimus blood trough concentrations (C0) of 3-5 ng/ml. In a controlled clinical trial, complete withdrawal of tacrolimus has been associated with an increased risk of acute rejections.

Certican has not been evaluated with full-dose tacrolimus in controlled clinical trials.

Method of administration
Certican is for oral use only.
The daily dose of Certican should always be given orally in two divided doses consistently either with or without food (see section 5.2) and at the same time as ciclosporin for microemulsion or tacrolimus (see Therapeutic drug monitoring).

Certican tablets should be swallowed whole with a glass of water and not crushed before use.