Zortress (everolimus) - 2 indications 

Scroll down for more information on each indication:

• for the prevention of organ rejection following a kidney transplant; approved April of 2010
• for the prevention of organ rejection following a liver transplant; approved October of 2016

General Information

Zortress (everolimus) is a macrolide immunosuppressant. It inhibits the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase, as well as antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes.

Zortress is specifically indicated for the following:

• the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. Zortress should be administered in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and with corticosteroids. Therapeutic drug monitoring of everolimus and cyclosporine is recommended for all patients receiving these products.
• the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Zortress is to be administered no earlier than 30 days post-transplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids. Therapeutic drug monitoring of everolimus and tacrolimus is recommended for all patients receiving these products.

Zortress is supplied as tablet for oral administration. Scroll down for recommended dosing/administration for each indication.

Mechanism of Action

Everolimus binds to the immunophilin FK Binding Protein-12 (FKBP-12) to generate an immunosuppressive complex that binds to and inhibits the activation of the mammalian Target of Rapamycin (mTOR), a key regulatory kinase. Inhibition of mTOR activation results in the inhibition of T lymphocyte activation and proliferation associated with antigen and cytokine (IL-2, IL-4, and IL-15) stimulation and the inhibition of antibody production.

Side Effects

Adverse events associated with the use of Zortress for kidney transplant may include, but are not limited to, the following:

• Peripheral edema
• Constipation
• Hypertension
• Nausea
• Anemia
• Urinary tract infection
• Hyperlipidemia

Adverse events associated with the use of Zortress for liver transplant may include, but are not limited to, the following:

• diarrhea
• headache
• peripheral edema
• hypertension
• nausea
• pyrexia
• abdominal pain
• leukopenia
• hypercholesterolemia

The Zortress drug label comes with the following Black Box Warning: Only physicians experienced in immunosuppressive therapy and management of transplant patients should use Zortress. Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression. Increased incidence of kidney graft thrombosis. Reduced doses of cyclosporine are required for use in combination with Zortress in order to reduce nephrotoxicity. Increased mortality in a heart transplant clinical trial. Use in heart transplantation is not recommended.

Indication 1 - for the prevention of organ rejection following a kidney transplant

approved April of 2010

Dosing/Administration

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

Clinical Trial Results

The FDA approval of Zortress for kidney transplant rejection was based on the following studies:

Study One

This 24-month, multi-national, open-label, randomized study enrolled 833 low to moderate risk renal transplant recipients undergoing their first transplant. The subjects received everolimus regimens of 1.5 mg per day starting dose (targeting 3 to 8 ng/mL) and 3.0 mg per day starting dose (targeting 6 to 12 ng/mL) with reduced doses of cyclosporine and corticosteroids OR 1.44 gm per day of mycophenolic acid with standard doses of cyclosporine and corticosteroids. The mean cyclosporine starting dose was 5.2, 5.0 and 5.7 mg/kg body weight/day in the everolimus 1.5 mg, 3.0 mg and in mycophenolic acid groups, respectively. Results at 12 months indicated that everolimus 1.5 mg per day is comparable to Myfortic with respect to efficacy failure, defined as treated biopsy-proven acute rejection, graft loss, death or loss to follow-up. The incidence of efficacy failure was 25% and 24% in the everolimus and Myfortic groups, respectively. The calculated mean glomerular filtration rate (using the MDRD equation) for everolimus 1.5 mg (target trough concentrations 3 to 8 ng/mL) and mycophenolic acid were comparable at Month 12.

Studies Two and Three

Two multicenter, double-blind (for first 12 months), randomized trials compared fixed doses of everolimus 1.5 mg per day and 3 mg per day, without therapeutic drug monitoring, combined with standard doses of cyclosporine and corticosteroids to mycophenolate mofetil 2.0 gm per day and corticosteroids. A total of 588 and 583 de novo renal transplant patients were enrolled. The 12 month analysis of GFR showed increased rates of renal impairment in both the everolimus groups compared to the mycophenolate mofetil group in both studies. Therefore, reduced doses of cyclosporine should be used in combination with everolimus in order to avoid renal dysfunction.

Indication 2 - for the prevention of organ rejection following a liver transplant

approved October of 2016

Dosing/Administration

Start Zortress 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.

Clinical Trial Results

Zortress was approved based on 12-month data from a phase III trial involving 719 liver transplant patients who had received treatment with the calcineurin inhibitor tacrolimus and corticosteroids, with or without mycophenolate mofetil, for the first 30 days following transplant. After the 30-day period, they were randomized to receive Zortress plus reduced-exposure tacrolimus, Zortress followed by tacrolimus withdrawal at four months, or standard-exposure tacrolimus only. Results showed that giving Novartis' drug alongside reduced-dose tacrolimus provided comparable efficacy and improved renal function as measured by estimated glomerular filtration rate (eGFR) compared to standard tacrolimus at 12 months.