Certican Dosage/Direction for Use

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 levels monitoring.
Adults: An initial dose regimen of 0.75 mg twice daily is recommended for the general kidney and heart transplant population, administered as soon as possible after transplantation. The dose of 1 mg twice daily is recommended for the hepatic transplant population with the initial dose approximately 4 weeks after transplantation. The daily dose of Certican should always be given orally in 2 divided doses (twice daily), consistently given either with or without food (see Pharmacokinetics under Actions) and at the same time as ciclosporin for microemulsion or tacrolimus (see Therapeutic Drug Monitoring).
Patients receiving Certican may require dose adjustments based on blood levels achieved, tolerability, individual response, change in co-medications and the clinical situation. Dose adjustments can be made at 4-5 days interval (see Therapeutic Drug Monitoring).
Black Patients: The incidence of biopsy-proven acute rejection episodes was significantly higher in Black renal transplant patients than in non-Black patients. Limited information indicates that Black patients may require a higher Certican dose to achieve efficacy similar to that achieved in non-Black patients at the recommended adult dose (see Pharmacokinetics under Actions). Currently, the efficacy and safety data are too limited to allow specific recommendations for use of everolimus in Black patients.
Children and Adolescents: There are no adequate data of the use of Certican in children and adolescents to support its use in patients in these age groups. Limited information is, however, available in renal transplant paediatric patients (see Pharmacokinetics under Actions).
Elderly (≥65 years): Clinical experience is limited in patients ≥65 years. Nevertheless, there are no apparent differences in the pharmacokinetics of everolimus in patients ≥65-70 years as compared with younger adults (see Pharmacokinetics under Actions).
Renal Impairment: No dosage adjustment is required (see Pharmacokinetics under Actions).
Hepatic Impairment: Whole blood trough levels (C0) of everolimus should be closely monitored in patients with impaired hepatic function. For patients with mild hepatic impairment (Child-Pugh Class A), the dose should be reduced to approximately ²/₃ of the normal dose. For patients with moderate or severe hepatic impairment (Child-Pugh B or C), the dose should be reduced to approximately ½ of the normal dose. Further dose titration should be based on therapeutic drug monitoring (see Pharmacokinetics under Actions).
Therapeutic Drug Monitoring: Routine whole blood therapeutic drug level monitoring of everolimus is recommended. Based on exposure-efficacy and exposure-safety analysis, patients achieving everolimus whole blood trough levels (C0) ≥3 ng/mL have been found to have a lower incidence of biopsy-proven acute rejection in renal, cardiac and hepatic transplantation than patients whose trough levels (C0) are <3 ng/mL. The recommended upper limit of the therapeutic range is 8 ng/mL. Exposure >12 ng/mL has not been studied. These recommended ranges for everolimus are based on chromatographic method.
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 Interactions). Everolimus concentrations might be slightly lower following the dispersible tablet administration.
Ideally, dose adjustments of Certican should be based on trough levels (C0) obtained >4-5 days after the previous dosing change. Since ciclosporin interacts with everolimus, everolimus levels may decrease if ciclosporin exposure is markedly reduced (ie, trough concentration <50 ng/mL).
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 level windows as follows: See Table 14.

Click on icon to see table/diagram/image

Measured levels are shown under Clinical Studies under Pharmacology under Actions.
Prior to dose reduction of ciclosporin, it should be ascertained that steady-state everolimus whole blood trough concentrations (C0) are ≥3 ng/mL.
There are limited data regarding dosing Certican with reduced ciclosporin trough concentrations (C0) <50 ng/mL or C2 levels <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 ciclosporin dose reduced, beginning 1 month after transplantation 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. For cardiac transplant patients, the ciclosporin dose should be guided by the experience in study 2411 and confirmed in study 2310 in which Certican was administered with ciclosporin with recommended reduced target trough concentrations (C0) as follows: See Table 15.

Click on icon to see table/diagram/image

Measured levels are shown under Clinical Studies under Pharmacology under Actions.
Prior to dose reduction of ciclosporin, it should be ascertained that steady-state everolimus whole blood trough concentrations (C0) are ≥3 ng/mL.
In cardiac transplantation, there are limited data regarding dosing Certican with reduced ciclosporin trough concentrations (C0) of 50-100 ng/mL after 12 months. If the patient cannot tolerate reduction of ciclosporin exposure, the continued use of Certican should be reconsidered.
Tacrolimus Dose Recommendation in Hepatic Transplantation: Hepatic transplant patients should have the tacrolimus exposure reduced to minimize calcineurin-related renal toxicity. The tacrolimus dose should be reduced starting approximately 3 weeks after initiation of dosing in combination with Certican based on tacrolimus blood trough levels (C0) targeting 3-5 ng/mL. Certican has not been evaluated with full dose tacrolimus in controlled clinical trials.
Administration: For oral use only.
Certican tablets should be swallowed whole with a glass of water and not crushed before use. For patients unable to swallow whole tablets, Certican dispersible tablets are also available (see Certican dispersible tablets international package leaflet).