Everolimus

EVEROLIMUS- everolimus tablet
Par Pharmaceutical, Inc.

1 INDICATIONS AND USAGE

1.1 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 [see Clinical Studies (14.1) ] Everolimus is to be administered in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and with corticosteroids. 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

Everolimus is indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Everolimus is to be administered no earlier than 30 days post-transplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids [See Warnings and Precautions (5.5) and Clinical Studies (14.2)]. Therapeutic drug monitoring (TDM) of everolimus and tacrolimus is recommended for all patients receiving these products. [See Dosage and Administration (2.3, 2.5)]

1.3 Limitations of Use

The safety and efficacy of everolimus has not been established in the following populations:

• Kidney transplant patients at high immunologic risk
• Recipients of transplanted organs other than kidney or liver [See Warnings and Precautions (5.7) ]
• Pediatric patients (less than 18 years).

2 DOSAGE AND ADMINISTRATION

Patients receiving everolimus 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 everolimus 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 3ng/mL. The total daily dose of everolimus 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 should be decreased by 0.25 mg twice daily [See Dosage and Administration (2.3), Clinical Pharmacology (12.3)]

2.1 Dosage in Adult Kidney Transplant Patients

An initial everolimus 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. [see 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 everolimus at least 30 days post-transplant. An initial dose of 1 mg orally twice daily (2 mg per day) is recommended for adult liver transplant patients in combination with reduced dose tacrolimus. [See Dosage 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.

2.3 Therapeutic Drug Monitoring (TDM) — 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. [See Clinical Pharmacology (12.7) ] 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 [see Clinical Pharmacology (12.7, 12.8)].

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. [See Drug Interactions (7.12) ]

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.