INDICATIONS AND USAGE（适应症）

Prophylaxis of Organ Rejection in Kidney Transplantation

Everolimus tablets are indicated for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. Everolimus tablets are to be administered in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and with corticosteroids. Therapeutic drug monitoring (TDM) of everolimus tablets and cyclosporine is recommended for all patients receiving these products.

Prophylaxis of Organ Rejection in Liver Transplantation

Everolimus tablets are indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Everolimus tablets are to be administered no earlier than 30 days post-transplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids. Therapeutic drug monitoring (TDM) of everolimus tablets and tacrolimus is recommended for all patients receiving these products.

DOSAGE（服用剂量）

Patients receiving everolimus tablets may require dose adjustments based on everolimus tablets blood concentrations achieved, tolerability, individual response, change in concomitant medications and the clinical situation. Optimally, dose adjustments of everolimus tablets should be based on trough concentrations obtained 4 or 5 days after a previous dosing change. Dose adjustment is required if the trough concentration is below 3 ng/mL. The total daily dose of everolimus tablets should be doubled using the available tablet strengths (0.25 mg, 0.5 mg, 0.75 mg or 1 mg). Dose adjustment is also required if the trough concentration is greater than 8 ng/mL on 2 consecutive measures; the dose of everolimus tablets should be decreased by 0.25 mg twice daily.

Dosage in Adult Kidney Transplant Patients

An initial everolimus tablets dose of 0.75 mg orally twice daily (1.5 mg per day) is recommended for adult kidney transplant patients in combination with reduced dose cyclosporine, administered as soon as possible after transplantation.

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.

Dosage in Adult Liver Transplant Patients

Start everolimus tablets at least 30 days post-transplant. An initial dose of 1.0 mg orally twice daily (2.0 mg per day) is recommended for adult liver transplant patients in combination with reduced dose tacrolimus.

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. The recommended everolimus therapeutic range is 3 to 8 ng/mL. 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.

There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced. There is little to no pharmacokinetic interaction of tacrolimus on everolimus, and thus, everolimus concentrations do not decrease if the tacrolimus exposure is reduced.

The everolimus recommended therapeutic range of 3 to 8 ng/mL is based on an LC/MS/MS assay method. Currently in clinical practice, everolimus whole blood trough concentrations may be measured by chromatographic or immunoassay methodologies. Because the measured everolimus whole blood trough concentrations depend on the assay used, individual patient sample concentration values from different assays may not be interchangeable. Consideration of assay results must be made with knowledge of the specific assay used. Therefore, communication should be maintained with the laboratory performing the assay.

Therapeutic Drug Monitoring - Cyclosporine in Kidney Transplant Patients

Both cyclosporine doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with everolimus tablets, in order to minimize the risk of nephrotoxicity.

The recommended cyclosporine therapeutic ranges when administered with everolimus tablets 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.

Cyclosporine, USP Modified is to be administered as oral capsules twice daily unless cyclosporine oral solution or intravenous 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.

In renal transplantation, there are limited data regarding dosing everolimus tablets with reduced cyclosporine trough concentrations of 25 to 50 ng/mL after 12 months. Everolimus tablets 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 tablets 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.

Therapeutic Drug Monitoring - Tacrolimus in Liver Transplant Patients

Both tacrolimus doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with everolimus tablets, in order to minimize the potential risk of nephrotoxicity [see Warnings and Precautions (5.6), Clinical Pharmacology (12.9)].

The recommended tacrolimus therapeutic range when administered with everolimus tablets are whole blood trough (C-0h) concentrations of 3 to 5 ng/mL by three weeks after the first dose of everolimus tablets (approximately Month 2) and through Month 12 post-transplant.

The median tacrolimus trough concentrations observed in the clinical trial ranged between 8.6 to 9.5 ng/mL at Weeks 2 and 4 post-transplant (prior to initiation of everolimus). The median tacrolimus trough concentrations ranged between 7 to 8.1 ng/mL at Weeks 5 and 6 post-transplant, between 5.2 to 5.6 ng/mL at Months 2 and 3 post-transplant, and between 4.3 to 4.9 ng/mL between Months 4 and 12 post-transplant.

Tacrolimus is to be administered as oral capsules twice daily unless intravenous administration of tacrolimus cannot be avoided.

In liver transplant patients, the tacrolimus dose should be based on tacrolimus whole blood trough concentrations.

In liver transplantation, there are limited data regarding dosing everolimus tablets with reduced tacrolimus trough concentrations of 3 to 5 ng/mL after 12 months. Prior to dose reduction of tacrolimus it should be ascertained that the steady-state everolimus tablets whole blood trough concentration is at least 3 ng/mL. Unlike the interaction between cyclosporine and everolimus, tacrolimus does not affect everolimus trough concentrations, and consequently, everolimus concentrations do not decrease if the tacrolimus exposure is reduced.

Administration

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

Administer everolimus tablets consistently approximately 12 hours apart with or without food to minimize variability in absorption and at the same time as cyclosporine or tacrolimus.

Hepatic Impairment

Whole blood trough concentrations of everolimus should be closely monitored in patients with impaired hepatic function. For patients with mild hepatic impairment (Child-Pugh Class A), the initial daily dose should be reduced by approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic impairment (Child-Pugh B or C), the initial daily dose should be reduced to approximately one-half of the normally recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough concentration of everolimus, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL.

ADVERSE REACTIONS（不良反应）

Hypersensitivity Reactions

Lymphomas and Other Malignancies

Serious Infections

Kidney Graft Thrombosis

Hepatic Artery Thrombosis

Everolimus and Calcineurin Inhibitor-Induced Nephrotoxicity

Heart Transplantation

Angioedema

Wound Healing and Fluid Accumulation

Interstitial Lung Disease/Non-Infectious Pneumonitis

Hyperlipidemia

Proteinuria

Polyoma Virus Infections

Thrombotic Microangiopathy/Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TMA/TTP/HUS)

New Onset Diabetes After Transplant

Male Infertility

For full information, please refer to:

https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/2693c497-a70b-4d00-b6db-602c872e5bed/spl-doc?hl=Everolimus

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