Home » Drug Information » FDA Approved Drugs » 2010
Medical Areas: Immunology | Nephrology
View By:YearCompanyConditionsTherapeutic AreasDrug Names
The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
Approval Status: Approved May 2010
Treatment Area: organ rejection following kidney transplant
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 prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant.
Zortress is supplied as tablet for oral 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.
The FDA approval of Zortress for kidney transplant rejection was based on the following studies:
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.
Adverse events associated with the use of Zortress may include, but are not limited to, the following:
- Peripheral edema
- Urinary tract infection
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.
Salvadori M, Scolari MP, Bertoni E, Citterio F, Rigotti P, Cossu M, Dal Canton A, Tisone G, Albertazzi A, Pisani F, Gubbiotti G, Piredda G, Busnach G, Sparacino V, Goepel V, Messa P, Berloco P, Montanaro D, Veroux P, Federico S, Bartezaghi M, Corbetta G, Ponticelli C Everolimus with very low-exposure cyclosporine a in de novo kidney transplantation: a multicenter, randomized, controlled trial. Transplantation 2009 Nov 27;88(10):1194-202
For additional information regarding Zortress or organ rejection following kidney transplant, please visit the Novartis web page.