Pharmacology Update
Everolimus Tablets (Zortress®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
Everolimus, a derivative of sirolimus, is a mammalian target of rapamycin (mTOR) inhibitor. The drug has been approved by the FDA for prophylaxis of organ rejection after kidney transplantation. It was originally approved for the treatment of advanced renal cell carcinoma and marketed as Afinitor®. For the new indication, everolimus is marketed by Novartis as Zortress® and at a much lower dose. Everolimus has been approved for renal and heart transplantation by the European Agency for the Evaluation of Medicinal Products since 2004.
Indications
Everolimus is indicated for prophylaxis of organ rejection in adults at low-moderate immunologic risk who are receiving a kidney transplant.1 It is given in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and corticosteroids.
Dosage
The initial dose is 0.75 mg orally twice daily in combination with reduced-dose cyclosporine started as soon as possible after transplantation. Everolimus may be taken without regard to meals and at the same time as cyclosporine. The recommended whole blood therapeutic range is 3-8 ng/mL. Routine monitoring is recommended and dose adjustments can be made at 4-5 day intervals. Adjustments are based on blood level, tolerability, individual response, concomitant drugs, and clinical situation.1 Oral prednisone should be started as soon as oral medications are tolerated and may be tapered based on the clinical status of the patient and function of the graft.1
Everolimus (Zortress) is available as 0.25 mg, 0.5 mg, and 0.75 mg tablets.
Potential Advantages
Everolimus with a reduced calcineurin inhibitor provides an effective alternative antigraft rejection regimen.1,2
Potential Disadvantages
Moderate to strong inhibitors and inducers of CYP3A may affect the blood levels of everolimus and dose adjustment may be required.1 Non-infectious pneumonitis, angioedema, risk for delayed wound healing, and graft thrombosis have been associated with everolimus. Proteinuria, hyperlipidemia, and hyperglycemia can occur; therefore, monitoring is recommended. Male infertility has also been associated with everolimus. The combination of everolimus and cyclosporine may increase the risk of thrombotic, microangiopathy/thrombotic thrombocytopenia purpura/hemolytic uremic syndrome.
Comments
Everolimus is a derivative of sirolimus with greater water solubility, shorter elimination half-life, and better bioavailability.2 The mechanism of action is based on mTOR inhibition, leading to an antiproliferative effect of T and B lymphocytes. Everolimus potentiates cyclosporine-associated nephrotoxicity and is used with reduced-dose cyclosporine.
The approval was based on a 24-month, multinational, open-label, randomized trial comparing everolimus with mycophenolate.1 Study participants were 18-70 years of age, undergoing their first transplant with low-to-moderate immunologic risk. This was defined as an ABO blood type-compatible first organ or tissue transplant with anti-HLA Class I PRA < 20% by a complement-dependent cytotoxicity-based assay, or < 50% by a flow cytometry or ELISA-based assay, and with a negative T-cell cross-match. All participants received basiliximab induction and were randomized to everolimus 1.5 mg per day (n = 279), everolimus 3 mg per day (n = 277), or mycophenolate (Myfortic®) 1.44 g per day (n = 277). Everolimus was given with reduced doses of cyclosporine and corticosteroids, and mycophenolate with standard doses of cyclosporine and corticosteroids. The primary endpoint was treatment failure defined as a composite of biopsy-proven acute rejection, death, graft loss, or loss to follow-up. The percent failures were 25.3% for everolimus 1.5 mg and 24.2% for mycophenolate. Data presented to the FDA suggest everolimus may be less effective in female patients.4 The incidences of adverse events were similar although psychiatric disorders (33% vs 26%), peripheral edema (45% vs 40%), wound healing-related reactions (33% vs 26%), and dyslipidemia (15% vs 9%) were higher with everolimus.1 Incidence of viral infections (CVM and BK) were lower with everolimus (10% vs 21%). The discontinuation rate in the 3 mg study arm was 34%; therefore, that dose is not recommended. Data on another mTOR inhibitor, sirolimus, suggest that conversion from calcineurin inhibitors may reduce the risk of post-transplant cancer.5,6 Recent data suggest that everolimus may be dosed once-daily.7
Clinical Implications
Everolimus provides an alternative antigraft rejection regimen with a reduced dose of calcineurin inhibitor (e.g., cyclosporine). It is currently being evaluated in addition to calcineurin inhibitor reduction or discontinuation for the maintenance of renal transplant recipients.8
References
1. Zortress Product Information. East Hanover, NJ: Novartis Pharmaceuticals Corp.; March 2010.
2. Nashan B, et al. Everolimus and reduced-exposure cyclosporine in de novo renal-transplant recipients. Transplantation 2004;78:1332-1340.
3. Dunn C, Croom KF. Everolimus: A review of its use in renal and cardiac transplantation. Drug 2006;66:547-570.
4. Panel recommends everolimus in kidney transplant. Available at: www.medpagetoday.com/Nephrology/KidneyTransplantation/17376. Accessed July 8, 2010.
5. Campistol JM, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol 2006;17:581-589.
6. Schena FP, et al. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients. Transplantation 2009;87:233-242.
7. Corbetta G, Ponticelli C. Once-a-day administration of everolimus, cyclosporine, and steroid after renal transplantation. Transplantation Proc 2010;42:1303-1307.
8. National Institutes of Health. Available at: www.clinicaltrial.gov/ct2/show/NCT00170846?term=nct00170846&rank=1. Accessed July 4, 2010.
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