Zortress (everolimus) (PG033) Form

Zortress (everolimus), FDA approved in 2009, is indicated for prophylaxis of organ rejection in adult patients.

Everolimus inhibits the mammalian Target of Rapamycin (mTOR), a key regulatory kinase involved in activation and proliferation of T and B lymphocytes. Everolimus is available as 0.25mg, 0.5mg, 0.75mg, and 1mg strengths tablet forms. Zortress is considered medically necessary in specific circumstances related to organ transplantation.

Organ transplantation

Organ transplantation is the preferred treatment approach for end stage kidney/liver diseases. It involves replacing the native organ with a supposedly healthy organ from another body. The recipient's immune system recognizes the foreign organ and attacks it using its own immune system. Immunosuppressant drugs (such as Zortress) are used in organ transplant recipients to prevent the host from attacking the transplanted organ. This allows the recipient to live and function with the healthy, foreign organ.

Definitions

• Immunosuppressant: refers to a type of medication that modulates or suppresses the body's immune response. These drugs are critical in preventing the rejection of transplanted organs.
• mTOR (mammalian target of rapamycin) inhibitor: is a class of drugs that works by inhibiting the protein mTOR, which plays a key role in cell growth, cell proliferation, and the immune response. mTOR inhibitors are used in various medical conditions, including certain cancers and organ transplant rejection.
• Lymphocyte: is a subtype of white blood cell that plays a crucial role in the body's immune response. Lymphocytes, which include T cells and B cells, are involved in identifying and neutralizing foreign substances in the body.

Medical Necessity Criteria for Authorization

The Plan considers Zortress (everolimus) medically necessary when ALL of the following criteria are met:

1. The member is 18 years of age or older; AND
2. The requested medication is being prescribed by, or in consultation with, a transplant specialist; AND
3. The requested medication is for ONE of the following indications:
   1. Kidney transplant rejection prophylaxis for a member at low-to-moderate immunologic risk AND the member meets ALL of the following:
      1. has had Simulect (basiliximab) induction; and
      2. is using Zortress (everolimus) concurrently with tacrolimus (reduced doses) or cyclosporine (reduced doses) and corticosteroids; and
      3. is unable to use, or has tried and failed ALL of the following:
         1. calcineurin inhibitor (such as tacrolimus); and
         2. antiproliferative agent (such as mycophenolate); and
         3. sirolimus;
   2. Liver transplant rejection prophylaxis AND the member meets ALL of the following:
      1. is at least 30 days post-transplant; and
      2. is using Zortress (everolimus) in combination with tacrolimus (reduced doses), with or without corticosteroids; and
      3. is unable to use, or has tried and failed TWO of the following:
         1. calcineurin inhibitor (such as tacrolimus at a standard dose); and/or
         2. antiproliferative agent (such as mycophenolate); and/or
         3. Sirolimus;
   3. Heart transplant rejection prophylaxis AND the member meets ALL of the following:
      1. Is at least 3 months post-transplant; and
      2. Is using Zortress (everolimus) with reduced doses of an immunosuppressant; and
      3. Is unable to use, or has tried and failed mycophenolate;
   4. Lung transplant rejection prophylaxis AND the member meets ALL of the following:
      1. Is at least 1 month post-transplant; and
      2. Is using Zortress (everolimus) with concurrent corticosteroids and reduced doses of cyclosporine; and
      3. Is unable to use, or has tried and failed both mycophenolate and azathioprine;

Clinical documentation has been provided for review to substantiate the above listed requirements. If the above prior authorization criteria are met, Zortress will be approved indefinitely.

Experimental or Investigational / Not Medically Necessary

Zortress for any other indication is considered not medically necessary by the Plan, as it is deemed to be experimental, investigational, or unproven.

Appendix

Heart transplantation (≥3 months post-transplantation)

NOTE: The FDA issued a black box warning for everolimus because of the increased risk of mortality observed within the first three months post-transplantation among patients started on the higher dose (3 mg/day) of everolimus as de novo immunosuppression.

Zortress (everolimus) appears to be an effective medication for the prevention of cardiac allograft vasculopathy (CAV) and reducing rejection incidence in heart transplant patients, but its usage is recommended at least 3 months after transplantation due to increased risk of mortality within the first three months. Several studies indicate that everolimus, when administered in conjunction with reduced-dose cyclosporine, can reduce renal impairment post-transplant and decrease the incidence of CAV.

1. A clinical trial involving 634 de novo heart transplant recipients showed that those treated with everolimus (1.5 mg or 3.0 mg per day) had a smaller increase in coronary artery intimal thickness and intimal index compared to patients treated with azathioprine. This study also indicated that everolimus was associated with a significant reduction in the incidence of rejection.
2. A large, 24-month, multicenter clinical trial involving 721 de novo cardiac transplant recipients compared the effects of everolimus (1.5 mg or 3 mg per day) with mycophenolate mofetil (MMF). The primary efficacy endpoint was a composite of the incidence of biopsy-proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death, or loss to follow-up. Everolimus 1.5 mg daily was noninferior to MMF at one year for the composite end point and for the incidence of biopsy-proven acute rejection. Mortality at one year was higher for the everolimus 3 mg daily group.
3. The SCHEDULE trial demonstrated that everolimus, in combination with reduced-dose cyclosporine and MMF, was effective at reducing the incidence and severity of cardiac allograft vasculopathy and improving renal function compared to continued cyclosporine use.

Lung transplantation (≥1 month post-transplantation)

Everolimus has been shown to be effective for prophylaxis of organ rejection in lung transplant recipients based on data from three prospective, randomized controlled trials. The drug is typically initiated at least 1 month post-transplant, in combination with concurrent corticosteroids and reduced doses of cyclosporine.

1. The data from these trials highlight both the benefits and risks of everolimus use. Some studies found that everolimus treatment resulted in fewer episodes of acute rejection and less deterioration in forced expiratory volume in one second (FEV1), a marker for chronic rejection. However, everolimus treatment also resulted in more adverse effects including serious bacterial and fungal infections, pneumonia, hyperlipidemia, anemia, and thrombocytopenia.
2. Trials comparing everolimus with other drugs such as azathioprine and mycophenolate found comparable efficacy in the prevention of bronchiolitis obliterans syndrome (BOS), but they also noted a higher rate of adverse events with everolimus.
3. Several fatal cases of anastomotic bronchial dehiscence have been reported when sirolimus or everolimus was used in the first 30 to 90 days following lung transplantation. Thus, initiation of these drugs should be delayed until after the bronchial anastomosis is completely healed.
4. The addition of everolimus to standard calcineurin-based regimens to mitigate nephrotoxicity did not demonstrate improved safety or outcomes.

In fact, this strategy might even worsen outcomes by increasing thrombotic events and potential mortality.

References

1. Afinitor and Afinitor Disperz (everolimus) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; February 2022.
2. Andreassen AK, Andersson B, Gustafsson F, et al; SCHEDULE Investigators. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial. Am J Transplant. 2014;14(8):1828-1838.
3. Andreassen AK, Andersson B, Gustafsson F, et al; SCHEDULE investigators. Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study. Am J Transplant. 2016;16(4):1238-1247.
4. Bara C, Dengler T, Hack MA, Ladenburger S, Lehmkuhl HB. A 1-year randomized controlled study of everolimus versus mycophenolate mofetil with reduced-dose cyclosporine in maintenance heart transplant recipients. Transplant Proc. 2013;45(6):2387-2392.
5. DeSimone et al., Use of Everolimus in Liver Transplantation: Recommendations From a Working Group, Transplantation. 2017 Feb;101(2):239-251.
6. Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant. 2013;13(5):1203-1216.
7. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the Prevention of Allograft Rejection and Vasculopathy in Cardiac-Transplant Recipients. N Engl J Med. 2003;349(9):847-858.
8. Glanville AR, Aboyoun C, Klepetko W, et al. Three-year results of an investigator-driven multicenter, international, randomized open-label de novo trial to prevent BOS after lung transplantation. J Heart Lung Transplant. 2015;34(1):16-25.
9. Hollis IB, Reed BN, Moranville MP. Medication management of cardiac allograft vasculopathy after heart transplantation. Pharmacotherapy. 2015;35(5):489-501.
10. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9 (Suppl 3):S6-13.
11. Lucey MR, Terrault N, Ojo L, et al. Long-Term Management of the Successful Adult Liver Transplant: 2012 Practice Guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl. 2013;19(1):3-26
12. Pascual et al., Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation, JASN 2018, 29 (7) 1979-1991
13. Rashidi M, Esmaily S, Fiane AE, et al. Wound complications and surgical events in de novo heart transplant patients treated with everolimus: post-hoc analysis of the SCHEDULE trial. Int J Cardiol. 2016;210:80-84.
14. Snell GI, Valentine VG, Vitulo P, et al. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Am J Transplant. 2006;6(1):169-177.
15. Strueber M, Warnecke G, Fuge J, et al. Everolimus versus mycophenolate mofetil de novo after lung transplantation: a prospective, randomized, open-label trial. Am J Transplant. 2016;16(11):3171-3180.
16. Velleca A, Shullo MA, Dhital K, et al. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2023;42(5):e1-e141. doi:10.1016/j.healun.2022.10.015
17. Zortress (everolimus) [prescribing information]. East Hanover, NJ: Novartis Pharmaceutical Corporation; January 2021.

Clinical Guideline Revision / History Information

Original Date: 08/06/2020

Reviewed/Revised: 06/24/2021, 12/01/2021, 06/23/2022, 06/29/2023