ZORTRESS- everolimus tablet
Novartis Pharmaceuticals Corporation
WARNING : MALIGNANCIES AND SERIOUS INFECTIONS, KIDNEY GRAFT THROMBOSIS; NEPHROTOXICITY; AND MORTALITY IN HEART TRANSP L ANTATION
Malignancies and Serious Infections
Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe Zortress. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [ see Warnings and Precautions (5.1)] .
Increased susceptibility to infection and the possible development of malignancies such as lymphoma and skin cancer may result from immunosuppression [ see Warnings and Precautions
Kidney Graft Thrombosis
An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, was reported, mostly within the first 30 days posttransplantation [ see Warnings and Precautions ( 5.4 )] .
Nephrotoxicity
Increased nephrotoxicity can occur with use of standard doses of cyclosporine in combination with Zortress. Therefore reduced doses of cyclosporine should be used in combination with Zortress in order to reduce renal dysfunction. It is important to monitor the cyclosporine and everolimus whole blood trough concentrations [ see Dosage and Administration (2. 4 , 2. 5 ) ,Warnings and Precautions ( 5. 6 ) , Clinical Pharmacology (12. 7 , 12. 8 )] .
Mortality in Heart Transplantation
Increased mortality, often associated with serious infections, within the first three months posttransplantation was observed in a clinical trial of de novo heart transplant patients receiving immunosuppressive regimens with or without induction therapy. Use in heart transplantation is not recommended [ see Warnings and Precautions (5. 7 )] .
INDICATIONS AND USAGE
1.1 Prophylaxis of Organ Rejection in Kidney Transplantation
Zortress is indicated for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant [ see Clinical Studies (14.1)] . Zortress is to be administered in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and with corticosteroids. Therapeutic drug monitoring (TDM) of everolimus and cyclosporine is recommended for all patients receiving these products [ see Dosage and Administration (2.2 , 2.3)] .
1.2 Prophylaxis of Organ Rejection in Liver Transplantation
Zortress is indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Zortress is to be administered no earlier than 30 days posttransplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids [ s ee Warnings and Precautions (5. 5 ) , Clinical Studies (14.2) ] . Therapeutic drug monitoring (TDM) of everolimus and tacrolimus is recommended for all patients receiving these products [ s ee Dosage and Administration (2.3 , 2.5)] .
1.3 Limitations of Use
The safety and efficacy of Zortress has not been established in the following populations:
Kidney transplant patients at high immunologic risk
Recipients of transplanted organs other than kidney and liver [ s ee Warnings and Precautions (5. 7 ) ]
Pediatric patients (less than18 years)
2 DOSAGE AND ADMINISTRATION
Patients receiving Zortress may require dose adjustments based on everolimus blood concentrations achieved, tolerability, individual response, change in concomitant medications and the clinical situation. Optimally, dose adjustments of Zortress 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 Zortress should be doubled using the available tablet strengths (0.25 mg, 0.5 mg or 0.75 mg). Dose adjustment is also required if the trough concentration is greater than 8 ng/mL on 2 consecutive measures; the dose of ZORTRESS� should be decreased by 0.25 mg twice daily [ s ee Dosage and Administration (2.3) , Clinical Pharmacology (12.3)] .
2.1 Dosage in Adult Kidney Transplant Patients
An initial Zortress 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 [ s ee Dosage and Administration ( 2.3 , 2.4 ) , Clinical Studies (14.1) ] .
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.
2.2 Dosage in Adult Liver Transplant Patients
Start Zortress at least 30 days posttransplant. 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 [ s eeDosage and Administration (2.3 , 2.5), Clinical Studies (14.2)] .
Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft.
