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Objectives PHARMACIST TECHNICIAN Kidney Transplantation: • Describe mechanisms of • Identify medications used transplant in transplant recipients What Pharmacists & Technicians immunosuppression • Identify common adverse • Outline documentation Need to Know effects to transplant requirements for Amanda J. Condon, PharmD, BCPS immunosuppression transplant medications Solid Organ Transplant Pharmacist • Modify transplant University of New Mexico Hospitals regimens to ensure safety and efficacy

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Epidemiology – U.S. Epidemiology – New Mexico

95,124 13,992 24,213 522 52 2,310 people need lifesaving kidney kidney transplants have been Donors recovered so far in people need lifesaving kidney kidney transplants have been Patients have been transplanted transplants (total waitlist performed so far in 2018 2018 transplants in New Mexico performed in New Mexico since 1988 candidates) (January to August 2018) (January to August 2018)

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Epidemiology Indications for Transplant

Modifiable • Diabetes • Hypertension • NSAID overuse

Non-Modifiable • Genetics (polycystic kidney disease, etc) • Congenital Abnormalities (obstructive uropathy, etc) • Glomerular Disease (anti-GBM, IgA Nephropathy, etc)

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Transplant Course Goals of Immunosuppression

Infection Rejection Malignancy Monthly Adherence (ACR vs AMR) Weekly Visits Visits Toxicity Listing Transplant! ~ 1 month ~ 6 months

Pre- Waiting on List Biweekly Bimonthly q6-12 month Transplant ~ Months to Years Visits Visits Visits Graft Work Up ~ 1 month ~ 3 months ..Forever Patient & ~6 mos – 1 year Failure Graft Survival

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Sensitization & Risk Factors for Rejection Phases of Immunosuppression Transplant Rejection HLA DCD Organ Sensitizing Mismatch Delayed Risk Factors Events Previous Graft Transplant Function

Blood Rejection Transfusion Episodes Induction

Previous Graft African Pregnancy Loss American Desensitization Maintenance

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Determination of Regimens Induction Agents • Evaluation of Immunologic Risk Goal: To prevent early acute allograft rejection immediately • HLA mismatch • Blood group post-transplant using intense, prophylactic • Younger recipient and incompatibility immunosuppressive therapy older donor • Delayed onset of graft • African-American function (DGF) – Basiliximab (Simulect®) • Panel Reactive Antibody • Cold ischemia time > 24 ◦ 20 mg IV POD0 and POD4 (PRA) > 0 hours • Donor-specific Antibody – Antithymocyte Globulin (Thymoglobulin®) (DSA) ◦ 2 mg/kg (IBW) IV starting POD0 up to 6mg/kg total • Evaluation of Infectious Risk • Elderly • Previous chemotherapy – Alemtuzumab (Campath®) • HBV exposure • ganR CMV ◦ 30 mg IV POD0 • HCV exposure

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Basiliximab (Simulect®) • Mechanism of Action: – Blocks T-cell proliferation via Interleukin-2 (IL-2) receptor antagonism (anti-CD25 antibodies)

• Used in lowest immunologic risk patients

• Decreased infection rates when compared to thymoglobulin

• Does not lead to sustained depletion of lymphocytes and related CD4 helper T cells

N Engl J Med. 2004 Dec 23;351(26):2715-29.

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Antithymocyte Globulin Antithymocyte Globulin (Thymoglobulin®) (Thymoglobulin®) • Mechanism of Action: • Infusion reactions common – Binds to T-cell surface antigens leading to the elimination of T-cells – Associated with previous rabbit exposure – Premedicate: APAP 650mg PO, Benadryl 25mg IV, Steroids • Used in moderate to high immunologic risk patients • Can cause serum sickness • Increased risk for CMV and BKV – Occurs 10-21 days after administration • PJP and other invasive fungal pathogens have been associated with – Presentation: Myalgias, fever, fatigue, jaw pain thymoglobulin • Monitoring: – WBC, Platelets – Reduction if WBC < 3 or PLT < 75 – Hold if WBC < 2 or PLT < 50

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Alemtuzumab (Campath®) Phases of Immunosuppression • Mechanism of Action: Transplant Rejection – Binds to CD52 on T-cells, B-cells, NK cells, and monocytes/macrophages causing complement activation and antibody-dependent cellular toxicity

• “AIDS” in a bottle that can result in pan-T-cell depletion

• CD4/CD8 counts nadir at 4 weeks, 1 year for recovery • Associated with many opportunistic infections Induction

Desensitization

Maintenance

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Maintenance Agents Goal: To prevent early and late allograft rejection post- transplant using long-term prophylactic immunosuppressive therapy

• Corticosteroids • CTLA-4 Blockade (Belatacept) (Methylprednisolone, Prednisone) • mTOR Inhibitors (Sirolimus, • Calcineurin Inhibitors (Tacrolimus, Everolimus) Cyclosporine)

• Antimetabolites (Mycophenolate, Azathioprine)

N Engl J Med. 2004 Dec 23;351(26):2715-29.

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Corticosteroids (Prednisone, Corticosteroids (Prednisone, Methylprednisolone) Methylprednisolone) • Mechanism of Action: •Adverse Effects….. are plenty – Profound immune system augmentation including inhibition of IL-1, 2, 3, 4, 5, 6, 8, TNF involved in T-cell proliferation; decreased B-cell SHORT TERM LONG TERM clone expansion, and decreased antibody synthesis • Mood Change • Osteoporosis • Increased risk of bacterial, mycobacterial, viral and fungal infections • Hyperglycemia* • Adrenal Insufficiency • Hypertension* • Ulcerative Esophagitis • Routinely used to treat rejection • Increased Appetite • Hirsutism • Insomnia • Pacreatitis • Acne • Amenorrhea • Leukocytosis* • Diabetes Mellitus

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Calcineurin Inhibitors (Tacrolimus, Calcineurin Inhibitors (Tacrolimus, Cyclosporine) Cyclosporine) • Mechanism of Action: – Binds to immunophilins and block the function of calcineurin at different enzymatic sites, resulting in downstream impairment of T-cell IL-2 synthesis

• Tacrolimus is broader in inhibitory effect (IL-3, IL-4, IL-5, IFN-γ, other cytokines)

• CsA has antiviral properties – HIV, HSV, HCV

• Increased risk of CMV and BKV

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Calcineurin Inhibitors (Tacrolimus, Calcineurin Inhibitors (Tacrolimus, Cyclosporine) Cyclosporine) • Drug Interactions GUT – Primarily through hepatic metabolism (CYP3A4 inhibition or induction) ◦ ↑ Drug Level: ketoconazole, diltiazem, fluconazole, grapefruit juice ◦ ↓ Drug Level: phenytoin, rifampin

– P-gp Substrate

– Drug interactions have high inter- and intra-patient variability

– Consistent administration with or without food BLOOD

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When to Check Troughs? Tacrolimus Preparations • Depends on the clinical situation and when last trough was checked • Prograf – Immediate release capsule • Recommend erring on side of caution and checking a trough when in doubt – IV preparation ◦ Dose reduce to 1/3 of oral dose as a continuous infusion • Any AKI ◦ Please don’t do this – use sublingual instead (if possible) – Tacrolimus can be the cause of AKI – Can be used for SL administration – Tacrolimus is NOT renally excreted ◦ Dose reduce 1 mg PO : 0.5 mg SL • Any diarrhea • Astagraf – Tacrolimus levels are increased during episodes of diarrhea – Once-daily long-acting capsule – Really only used for tacrolimus-sensitive patients (ie, 0.5mg once a day = 0.25mg Prograf BID)

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Calcineurin Inhibitors (Tacrolimus, Tacrolimus Preparations Cyclosporine) • Envarsus XR • Tacrolimus Adverse Effects – Once-daily long-acting tablet – Fantastic pharmacokinetics! • Hypertension • Hyperglycemia* – Significantly less neurotoxicity • Diarrhea • Pruritis • Nephrotoxicity • Hyperkalemia • Headache • Hypomagnesemia • Hepatotoxicity • Infection • Neurotoxicity • Alopecia

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Calcineurin Inhibitors (Tacrolimus, Calcineurin Inhibitors (Tacrolimus, Cyclosporine) Cyclosporine) • Cyclosporine Adverse Effects • Adverse Effects Tacrolimus Cyclosporine LESS COMMON MORE COMMON Nephrotoxicity +++ ++ • Migraine • Hyperlipidemia Hyperglycemia & DM +++ ++ • • Nephrotoxicity Acne Neurotoxicity +++ ++ • GI effects • Tremor Electrolyte abnormalities +++ ++ • Gynecomastia • Hypertension • • Hyperkalemia Hyperglycemia Hypertension +++ +++ • Gingival hyperplasia • Hypomagnesemia Other Alopecia Hirsutism, • • Hepatotoxicity Hirsutism hyperlipidemia, gingival hyperplasia, hyperuricemia

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Antimetabolites (Mycophenolate, Antimetabolites (Mycophenolate, Azathioprine) Azathioprine) • Mechanism of Action: – Targets enzymes involved in de novo synthesis of purines leading to impairment of DNA replication in B- and T-cells

• Potential for bone marrow suppression

• Significantly increased risk for major viral, fungal and parasitic infections

• Usually the first agent pulled when patient has infection

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Antimetabolites (Mycophenolate, Antimetabolites (Mycophenolate, Azathioprine) Azathioprine) • Mycophenolate Conversion • Drug Interactions – Conversion: 180 mg Myfortic = 250 mg CellCept – Primarily through decreased absorption ◦ Cholestyramine, sucralfate • Myfortic is enteric coated for delayed release* Black Box Warning – ?Cations??? • Mycophenolate is teratogenic and cannot be used in pregnancy ◦ Studies show decreased AUC ◦ AUC not well correlated with graft outcomes • Azathioprine is reserved for mycophenolate intolerance or women who want ◦ Missed doses (due to 4x/day dosing regimens) HAVE been correlated with to become pregnant significantly worse outcomes – Azathioprine: ◦ Mercaptopurine – profound myelosuppression ◦ Allopurinol/Febuxostat – profound myelosuppression

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Antimetabolites (Mycophenolate, Antimetabolites (Mycophenolate, Azathioprine) Azathioprine) • Mycophenolate Adverse Effects • Azathioprine Adverse Effects

• GI Intolerance!! • Bone Marrow Suppression • Diarrhea Dose Limiting • Leukopenia • Nausea Adverse Effects! • Neutropenia • Bloating • Thrombocytopenia • Bone Marrow Suppression • Leukopenia • Increased LFTs • Neutropenia • AST, ALT, Alk Phos, Tbili • Thrombocytopenia • Myalgias • Back Pain • GI Intolerance • Hyperglycemia

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CTLA-4 Inhibitors (Belatacept) CTLA-4 Inhibitors (Belatacept) • Mechanism of Action: – Binds CD80 and CD86 receptors on APCs to block selective T-cell costimulation leading to lack of response by T-cell

• Risk of PTLD in EBV seronegative recipients

• Non-standard maintenance agent used to preserve renal function

• Part of a limited-distribution program

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CTLA-4 Inhibitors (Belatacept) mTOR Inhibitors (Sirolimus, Everolimus)

• Adverse Effects Black Box Warning – Post-Transplant Lymphoproliferative Disorder (PTLD) ◦ Must be EBV seropositive to receive medication – GI Disturbances – Hypertension – Peripheral Edema – Anemia

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mTOR Inhibitors (Sirolimus, mTOR Inhibitors (Sirolimus, Everolimus) Everolimus) • Mechanism of Action: • Adverse Effects – Binds mTOR inhibiting pathways needed for mRNA translation critical for – Edema cell division in T- and B-cells – Anemia • Antiviral properties – Impaired Wound Healing – Interstitial Lung Disease* • Decreased wound healing due to inhibition of fibroblasts – Proteinuria • Non-standard maintenance agent used to preserve renal function – Hyperlipidemia

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Practical Considerations for Maintenance Medications Phases of Immunosuppression • Do not need to separate from cations (calcium, magnesium, iron, etc) Transplant Rejection – Theoretical interaction, decreases compliance

• Take consistently with regards to food – Taking with food reduces nausea Induction • Do not hesitate to check a CNI/mTORi trough if patient gets admitted to hospital Desensitization

Maintenance

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Infectious Complications • Temporally distributed • Immunosuppressive regimen – Dose, duration, sequence • Comorbid conditions – Diabetes, malnutrition, neutropenia, alcoholic cirrhosis, autoimmune diseases, etc • Immunomodulating viral infections – CMV, EBV, HBV, HCV, HHV6 • Presence of foreign material – Intravenous catheters, foleys, etc

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Infection Prophylaxis Treatment of Infections • Treat similar to non-transplant patient – Except…Don’t give q8 vancomycin unless patient “earns it” or is very sick Bactrim Valganciclovir Oral Nystatin • Pay special attention to combinations – Vancomycin/Piperacillin-Tazobactam Pneumocystis Cytomegalovirus Oropharyngeal Candida ◦ Higher risk of AKI UTI Pathogens Herpes Simplex Varicella Zoster ◦ Consider Vancomycin/Cefepime +/- Metronidazole • Usually tend to be more broad and aggressive up front then deescalate

Day 0 = Day of Transplant

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Rejection Malignancy • Acute Cellular Rejection • Related to degree of immunosuppression – T-Cell Mediated – Increased risk with increased survival – Relatively Common – Easily Treated • Lung, breast, colon, and prostate cancer are not increased compared to general population • Antibody Mediated Rejection – Difficult to Treat • Increased risk of lymphomas and lymphoproliferative disorders, Kaposi’s sarcoma, renal carcinoma, and skin cancers – Usually Related to Non-Adherence • Chronic Rejection – No Treatment – Slow Progression to Graft Failure

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Goals of Immunosuppression Weekly Pill Box Post-Transplant Sun Mon Tues Wed Thurs Fri Sat

AM

Infection Rejection Malignancy NOON Adherence (ACR vs AMR) Toxicity X

PM Patient & Graft Survival BED

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Barriers to Adherence Barriers to Adherence • System • PHARMACISTS are the best provider to address adherence – Prior authorizations, transportation • As drug experts, it is our duty to own the entire process of medication • Motivation use – Depression, feeling “different” • If you see something abnormal, contact the transplant team! We love • Understanding fixing issues – Education level, language barriers • Recall – Variable schedule, distractions • Financial – Cost of medications

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Transplant Medication Billing Transplant Medication Billing

• Complicated! On Medicare at Time of Transplant On Medicare at Time of Transplant (≥65 yo) (< 65 yo) • Depends on patient insurance and Medicare status at time of transplant • Immunosuppressants billed • Receives Medicare B for 3 years through Medicare B and 80% is post-transplant covered • Requires specialized knowledge and infrastructure to bill for • At 3 years, patient loses Med B medications • Remaining 20% is billed through unless they have another reason for Medicare B supplement (paper billing) disability • Can really mess up a patient’s insurance situation if not billed correctly • Patient has $0 copay for immunos • Patient’s drug plan is now – Put someone in the donut hole L • No prior authorizations needed responsible for immunos • Eligible to bill immunos through • Prior authorizations usually needed Med B forever • Copays dictated by insurance carrier

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Transplant Medication Billing Limitations in Transplant • Every center practices differently No Medicare at Time of Transplant • Most evidence based on retrospective, single-center experiences • Immunosuppressants billed through prescription drug plan • Many medications are used “off-label” (Medicaid, NMMIP, private, etc) • Prior authorizations usually needed If billing Medicare You Need: • Copays dictated by insurance carrier • ICD10 Code: Z94.0 • Transplant Date • Discharge Date • Cannot be for >30 Day Supply • Cannot be on Automatic Refill …You could get audited

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Summary References

— Hale DA. Basic transplantation immunology. Surg Clin North Am. 2006 Oct;86(5):1103-25, v. • Immunosuppression is complex and patient specific — Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004 Dec 23;351(26):2715-29. — Lindenfeld J, Miller GG, Shakar SF, et al. Drug therapy in the heart transplant recipient: part II: immunosuppressive drugs. • Circulation. 2004 Dec 21;110(25):3858-65. Transplant providers and pharmacists work together to create the — Brennan DC, Daller JA, Lake KD, et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J most balanced regimen possible Med. 2006 Nov 9;355(19):1967-77. — Hanaway MJ, Woodle ES, Mulgaonkar S, et al. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011 May 19;364(20):1909-19. • Protocolization provides a framework for patient management, but — Raghavan R, Jeroudi A, Achkar K, et al. Bortezomib in kidney transplantation. J Transplant. 2010;2010. pii: 698594. doi: 10.1155/2010/698594. doesn’t fit every patient — Barnett AN, Asgari E, Chowdhury P, et al. The use of eculizumab in renal transplantation. Clin Transplant. 2013 Mar 21. doi: 10.1111/ctr.12102. — Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal • Understanding and appropriately billing transplant medications transplantation. N Engl J Med. 2008 Jul 17;359(3):242-51. ensures there are no gaps in care — Raghavan R, Jeroudi A, Achkar K, et al. Bortezomib in kidney transplantation. J Transplant. 2010;2010. pii: 698594. doi: 10.1155/2010/698594. — Hardinger KL, Rhee S, Buchanan P, et al. A prospective, randomized, double-blinded comparison of thymoglobulin versus Atgam for induction immunosuppressive therapy: 10-year results. Transplantation. 2008 Oct 15;86(7):947-52. — Martin ST, Tichy EM, Gabardi S. Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation. Pharmacotherapy. 2011 Apr;31(4):394-407. — Leca N. Leflunomide use in renal transplantation. Curr Opin Organ Transplant 2009 Aug;14(4):370-4. — Ruiz R, Klintmalm GB. Renal-sparing regimens employing new agents. Curr Opin Organ Transplant. 2012 Dec;17(6):619-25. — Jordan SC, Kahwaji J, Toyoda M, et al. B-cell immunotherapeutics: emerging roles in solid organ transplantation. Curr Opin Organ Transplant. 2011 Aug;16(4):416-24.

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Questions?

Amanda J. Condon, PharmD, BCPS Solid Organ Transplant Pharmacist University of New Mexico Hospitals

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