EVEROLIMUS BIOCON TABLETS 0.25MG [SIN17583P]

Product Info

EVEROLIMUS BIOCON TABLETS 0.25MG

[SIN17583P]

Indication

INDICATIONS

Kidney and heart transplantation

Everolimus Biocon tablets are indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving an allogeneic renal or cardiac transplant. In kidney and heart transplantation, Everolimus Biocon tablets should be used in combination with ciclosporin for microemulsion and corticosteroids.

Liver transplantation
Everolimus Biocon tablets are indicated for the prophylaxis of organ rejection in adult patients receiving a hepatic transplant. In liver transplantation, Everolimus Biocon tablets should be used in combination with tacrolimus and corticosteroids.

Dosing

DOSAGE REGIMEN AND ADMINISTRATION
Treatment with Everolimus Biocon tablets 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 level monitoring. Everolimus should be used in combination with ciclosporin for microemulsion and corticosteroids with ciclosporin exposure reduced over time post-transplantation.

Dosage regimen

General target population

Adults

Kidney and heart transplantation
An initial dose regimen of 0.75 mg b.i.d., which is recommended for the general kidney and heart transplant population, should be administered as soon as possible after transplantation.

Liver transplantation
The dose of 1.0 mg b.i.d. is recommended for the hepatic transplant population with the initial dose approximately 4 weeks after transplantation.

Dosing considerations
The daily dose of Everolimus Biocon tablets should always be given orally in two divided doses (b.i.d.). Everolimus Biocon tablets should be consistently given either with or without food (see section PHARMACOKINETICS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information) and at the same time as ciclosporin for microemulsion or tacrolimus (see section Therapeutic drug monitoring – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Patients receiving Everolimus Biocon tablets 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 intervals (see section Therapeutic drug monitoring – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Special populations 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 Everolimus dose to achieve efficacy similar to that achieved in non-black patients at the recommended adult dose (see section CLINICAL PHARMACOLOGY, PHARMACOKINETICS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Currently, the efficacy and safety data are too limited to allow specific recommendations for use of everolimus in Black patients.

Pediatric patients (below 18 years)

• There are no adequate data of the use of Everolimus in children and adolescents to support its use in patients in these age groups.

• Limited information is, however, available in renal and hepatic transplant pediatric patients but no dosage recommendation can be made (see sections CLINICAL PHARMACOLOGY, PHARMACOKINETICS and CLINICAL STUDIES – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Geriatric patients (65 years or above)

• Clinical experience is limited in patients ≥ 65 years of age.

• Nevertheless, there are no apparent differences in the pharmacokinetics of everolimus in patients ≥65 to 70 years of age as compared with younger adults (see section PHARMACOKINETICS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Renal impairment
No dosage adjustment is required (see section CLINICAL PHARMACOLOGY, PHARMACOKINETICS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

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 two-thirds of the normal dose. For patients with moderate hepatic impairment (Child-Pugh B) the dose should be reduced to approximately one half of the normal dose. For patients with severe hepatic impairment (Child-Pugh C) the dose should be reduced to at least one half of the normal dose. Further dose titration should be based on therapeutic drug monitoring (see section CLINICAL PHARMACOLOGY, PHARMACOKINETICS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Method of administration
Everolimus Biocon tablets are for oral use only.

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

Therapeutic drug monitoring

Everolimus has a narrow therapeutic index which may require adjustments in dosing to maintain therapeutic response. 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) ≥ 3.0 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 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 INTERACTIONS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Everolimus concentrations might be slightly lower following the dispersible tablet administration.

Ideally, dose adjustments of Everolimus should be based on trough levels (C0) obtained > 4 to 5 days after the previous dose change. Since ciclosporin interacts with everolimus, everolimus levels may decrease if ciclosporin exposure is markedly reduced (i.e. trough concentration (C0) < 50 ng/mL).

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

Renal transplantation: recommended target ciclosporin blood trough-level windows

Prior to dose reduction of ciclosporin it should be ascertained that steady state everolimus whole blood trough concentrations (C0) are equal to or above 3 ng/mL.

There are limited data regarding dosing Everolimus with ciclosporin trough concentrations (C0) 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 Everolimus 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 should be guided by the experience in study 2411 and confirmed in study 2310 in which Everolimus was administered with ciclosporin with recommended reduced target trough concentrations (C0) as follows:

Cardiac transplantation: recommended target ciclosporin blood trough-level windows

Prior to dose reduction of ciclosporin it should be ascertained that steady state everolimus whole blood trough concentrations (C0) are equal to or above 3 ng/mL.

In cardiac transplantation, there are limited data regarding dosing Everolimus with reduced ciclosporin trough concentrations (C0) of 50 to 100 ng/mL after 12 months. If the patient cannot tolerate reduction of ciclosporin exposure, the continued use of Everolimus and reduced ciclosporin exposure 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 Everolimus based on tacrolimus blood trough levels (C0) targeting 3 to 5 ng/mL. Everolimus has not been evaluated with full dose tacrolimus in controlled clinical trials.

Contraindications

CONTRAINDICATIONS
Everolimus Biocon tablets are contraindicated in patients with a known hypersensitivity to everolimus, sirolimus or any of the excipients.