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 1.0 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 two divided doses consistently either with or without food (see Pharmacology: Pharmacokinetics under Actions) and at the same time as ciclosporin for microemulsion or tacrolimus (see Therapeutic drug monitoring as follows).
Certican is 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.
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 day intervals (see Therapeutic drug monitoring as follows).
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 Pharmacology: Pharmacokinetics under Actions). Currently, the efficacy and safety data are too limited to allow specific recommendations for use of everolimus in black patients.
Paediatric population: There is insufficient experience to recommend the use of Certican in children and adolescents. Limited information is available in renal transplant paediatric patients (see Pharmacology: Pharmacokinetics under Actions).
Elderly patients (≥ 65 years): The 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 Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment: No dosage adjustment is required (see Pharmacology: Pharmacokinetics under Actions).
Patients with impaired hepatic function: Everolimus whole blood trough levels 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 ), approximately one half of the normal dose for patients with moderate hepatic impairment (Child-Pugh Class B), and 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 Pharmacology: Pharmacokinetics under Actions). Reduced doses rounded to the nearest tablet strength are tabulated as follows: (See Table 17.)

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Therapeutic Drug Monitoring: Routine everolimus whole blood therapeutic drug level monitoring is recommended. Based on exposure-efficacy and exposure-safety analysis, patients achieving everolimus whole blood trough levels ≥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 the patients whose trough levels are below 3.0 ng/ml. The upper limit to the therapeutic range is recommended at 8 ng/ml. Exposure above 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.
Optimally, dose adjustments of Certican should be based on trough levels obtained >4-5 days after the previous dosing change. There is an interaction of ciclosporin on everolimus, and consequently, everolimus levels may decrease if ciclosporin exposure is markedly reduced (i.e. trough concentration <50 ng/ml).
Patients with hepatic impairment should preferably have trough levels in the upper part of the 3-8 ng/ml exposure range.
Monitoring should be performed every 4 to 5 days until 2 consecutive trough levels have shown stable everolimus concentrations after starting treatment or after a dose adjustment because the prolonged half-lives in hepatic impaired patients delay the time to reach steady state (see Precautions and Pharmacology: Pharmacokinetics under Actions). 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 level windows: (See Table 18.)

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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 levels 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 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 levels. See Pharmacology: Pharmacodynamics under Actions for experience with reduced ciclosporin blood levels.
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 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. 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.