Everolimus is an inhibitor of cell proliferation and immunosuppressive agent that is used alone or in combination with calcineurin inhibitors to prevent cellular rejection after organ transplantation, and in combination with other anticancer agents as treatment of advanced renal cell and other cancers. Everolimus therapy can be associated with mild serum enzyme elevations, but has yet to be linked to instances of clinically apparent liver injury with jaundice.
Everolimus (e" ver oh' li mus) binds to the same intracellular receptor as tacrolimus and cyclosporine, but does not inhibit calcineurin; rather, it blocks the "mammalian target of rapamycin" (mTOR), which interrupts signaling pathways of several cytokines and growth factors including IL2 and causes a decrease in protein synthesis and cell cycle arrest. Everolimus therapy has been shown to improve graft survival after solid organ transplantation and to improve time to progression in several forms of cancer. Everolimus was approved for use in the United States in 2009 initially as an agent to prevent rejection after kidney and liver transplantaiton and later, in higher doses, as therapy of advanced renal cell, breast and pancreatic neuroendocrine cancers given alone or in combination with other antineoplastic agents. More recently, everolimus was approved as therapy of renal angiomyolipoma and subependymal giant cell astrocytoma associated with tuberous sclerosis complex (in which mTOR signaling is dysregulated). Everolimus like sirolimus is also used in drug eluting arterial stents, to prevent stenosis. Everolimus is available as tablets of 0.25, 0.50 and 0.75 mg under the brand name of Zortress for management of organ transplantation, and as tablets of 2.5, 5, 7.5 and 10 mg under the brand name of Afinitor, and tablets of 2, 3 and 5 mg for oral suspension under the brand name Afinitor-Disprez for use in cancer chemotherapy. The typical dose in organ transplantation is 1.5 mg in two divided doses daily; the dose in cancer chemotherapy being higher and variable, usually starting at 10 mg once daily. Everolimus is less nephrotoxic than the calcineurin inhibitors but does have many, largely dose dependent side effects including oral ulcers, diarrhea, nausea, poor appetite, fatigue, peripheral edema, rash, anemia, renal dysfunction and interstitial pneumonitis.
Serum enzyme elevations occur in up to a quarter of patients taking everolimus, but the abnormalities are usually mild, asymptomatic and self-limiting, rarely requiring dose modification or discontinuation. Liver test elevations above 5 times ULN occur in only 1% to 2% of treated patients. In contrast, idiosyncratic, clinically apparent acute liver injury has not been linked to everolimus therapy, but the total number of patients treated with this drug is limited. Thus, acute clinically apparent liver injury with jaundice due to everolimus is probably quite rare, if it occurs at all.
Importantly, everolimus is immunosuppressive and therapy in patients with cancer has been associated with episodes of reactivation of hepatitis B, which can be severe and even fatal. Reverse seroconversion (development of HBsAg in a person with preexisting antibody to hepatitis B, either anti-HBs or anti-HBc) has not been reported.
Mechanism of Injury
Everolimus undergoes extensive hepatic metabolism, largely via the cytochrome P450 system (CYP 3A4) and P-glycoprotein. Liver injury might be due to a direct effect of everolimus or to a toxic intermediate of its metabolism. Everolimus is prone to drug-drug interactions if used with inhibitors or inducers of the cytochrome P450 drug metabolizing enzymes.
Outcome and Management
Acute liver injury with jaundice associated with everolimus therapy has not been described, and the serum enzyme elevations associated with its use are usually mild and transient, resolving spontaneously or with dose modification. Because everolimus can lead to reactivation of chronic hepatitis B, routine screening of patients for HBsAg before starting therapy is advisable, particularly those undergoing organ transplantation. Patients who develop reactivation should be treated with an oral nucleoside analogue with potent activity against hepatitis B (entecavir or tenofovir). Everolimus is a macrolide similar in structure and function to sirolimus and temsirolimus, but these agents do not always exhibit cross sensitivity to adverse effects.
REPRESENTATIVE TRADE NAMES
Antineoplastic Agents; Transplant Drugs
Product labeling at DailyMed, National Library of Medicine, NIH
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References Last Updated: 08 April 2014
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Zuckermann A, Wang SS, Ross H, Frigerio M, Eisen HJ, Bara C, Hoefer D, et al. Efficacy and safety of low-dose cyclosporine with everolimus and steroids in de novo heart transplant patients: a multicentre, randomized trial. J Transplant 2011; 2011: 535983. PubMed Citation (Open label 6 month study of everolimus with standard or reduced doses of cyclosporine in 199 heart transplant recipients; no mention of ALT elevations or liver toxicity).
Grgic T, Mis L, Hammond JM. Everolimus: a new mammalian target of rapamycin inhibitor for the treatment of advanced renal cell carcinoma. Ann Pharmacother 2011; 45: 78-83. PubMed Citation (Systematic review of everolimus [5-10 mg/day] as therapy of renal cell carcinoma; major side effects are mucositis [40%], rash [25%], fatigue [20%] and liver test abnormalities [proportion not given]).
Oberstein PE, Saif MW. Safety and efficacy of everolimus in adult patients with neuroendocrine tumors. Clin Med Insights Oncol 2012; 6: 41-51. PubMed Citation (Review of safety and efficacy of everolimus as therapy of neuroendocrine tumors; common side effects are mucositis [64%], rash [49%], diarrhea [34%] and infections [23%], including reactivation of hepatitis B; no mention of ALT elevations or hepatotoxicity).
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Thompson LA, Kim M, Wenger SD, O'Bryant CL. Everolimus: a new treatment option for advanced pancreatic neuroendocrine tumors. Ann Pharmacother 2012; 46: 1212-9. PubMed Citation (Review of safety and efficacy of everolimus in advanced pancreatic endocrine tumors; side effects include mucositis, rash, diarrhea, fatigue, infections, nausea, edema, poor appetite and pneumonitis; no mention of ALT elevations or hepatotoxicity).
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multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013; 381(9869): 817-24. PubMed Citation (Among 118 adults with angiomyolipoma treated with everolimus or placebo for up to 2 years, common side effects were stomatitis, nasopharyngitis, acne, headache, cough and hypercholesterolemia; no mention of ALT changes or hepatotoxicity).
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Gastroenterol 2013; 6: 188-192. PubMed Citation (58 year old man with inactive HBsAg carrier state and refractory renal cell cancer developed reactivation of HBV 5 months after starting everolimus [bilirubin 11.0 mg/dL, ALT 878 U/L, HBV DNA 10 million copies/mL, INR 1.8], with progressive liver failure despite entecavir and methylprednisolone therapy and death 6 weeks after presentation).
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everolimus. World J Hepatol 2013; 5: 43-5. PubMed Citation (49 year old man with inactive HBsAg carrier state and refractory renal cell cancer developed reactivation of HBV 3-5 months after starting everolimus [bilirubin 16.3 mg/dL, ALT 1871 U/L, HBV DNA 1.2 billion copies/mL, protime 14.8 seconds], starting to resolve 20 days after stopping everolimus and starting tenofovir).
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transplantation. Am J Transplant 2014; 14: 701-10. PubMed Citation. (Among 203 liver transplant recipients switched to everolimus or maintained on calcineurin inhibitors 1 month after transplantation, 81 were enrolled in an extension study for up to 3 years; mean ALT, AST and GGT levels did not differ between those receiving or not receiving everolimus).
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Treat 2013; 141: 167-72. PubMed Citation. (56 year old woman with advanced metastatic breast cancer developed jaundice 4 months after starting everolimus [bilirubin 8.0 mg/dL, ALT 1758 U/L, Alk P 154 U/L, HBsAg and HBV DNA positive, IgM anti-HBc negative], with progression to hepatic failure and death despite tenofovir therapy).
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everolimus-induced steatohepatis: a case report. Eur J Med Res 2013; 18: 22. PubMed Citation. (76 year old man with metastatic neuroendocrine cancer developed ascites and liver test abnormalities 4 weeks after starting everolimus [bilirubin normal, ALT 16 U/L, GGT 1599 U/L] and CT scans of the liver suggested diffuse steatosis and expanding hepatic masses; the patient dying of multiorgan failure 2 weeks later, and there was no verification of steatosis histologically).
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