UNIVERSITY OF NORTH CAROLINA HOSPITAL SCUT MONKEY PROTOCOL FOR ABDOMINAL TRANAPLANT SERVICE Revised June 2013

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1 UNIVERSITY OF NORTH CAROLINA HOSPITAL SCUT MONKEY PROTOCOL FOR ABDOMINAL TRANAPLANT SERVICE Revised June 2013 IMMUNOSUPPRESSION PROTOCOLS Adult Kidney Transplant Induction and Maintenance Algorithm Adult Kidney Transplant Immunosuppression Protocol Adult Kidney Transplant ABO Incompatible Adult Kidney Transplant Donor Orders Adult Kidney Transplant HIV+ Recipients Adult Simultaneous Pancreas-Kidney or Pancreas Alone Transplant Adult Pancreas After Kidney Transplant Adult Liver Transplant Standard Adult Combined Liver/Kidney Transplant Pediatric Kidney Transplant Pediatric Liver Transplant PROPHYLAXIS PROTOCOLS Adult Kidney Transplant Adult Liver Transplant Adult Kidney-Pancreas & Pancreas Transplant Pediatric Kidney Transplant Pediatric Liver Transplant REJECTION PROTOCOLS Adult Kidney Transplant Adult Liver Transplant Pediatric Kidney Transplant Pediatric Liver Transplant ADJUNCT PROTOCOLS Pharmacogenetic Based Protocol Neutropenia Protocol Preemptive DSA Monitoring Protocol INFECTION PROTOCOLS CMV Treatment CMV Drug Resistance Algorithm BK Viremia and Polyoma Virus Nephropathy EBV Reactivation APPENDIX: A1: Mycophenolate mofetil (CellCept ) and Mycophenolic Sodium (Myfortic ) Conversion AII: Cyclosporine, Tacrolimus, Sirolimus Therapeutic Drug Monitoring Equivalency Table B: Common drug interactions with immunosuppression medication C: Common Drug Interactions with Anti-retroviral and Immunosuppression Post Transplantation D: Common Drug Interacctions with Anti-retroviral and Common Medications Used Post Transplantation E: Pharmacogenomic References

2 ADULT KIDNEY TRANSPLANT INDUCTION AND MAINTENANCE REGIMEN Adult Kidney Transplant Induction 1. Standard SCD, ECD, DCD 2. Previous abdominal transplant 3. Patient on >1 immunosuppressive agent 1. HCV+ 1. Previous heart or lung transplant 2. History of cyclophosphamide 3. 6 of 6 HLA match** STANDARD Alemtuzumab 30 mg* IV on POD 0 Anti-Thymocyte Globulin 2mg/kg* IV on POD 0, 1, 2 LOW RISK Basiliximab 20 mg IV on POD 0,4 Tacrolimus 0.02mg/kg PO BID at 06:00 and 18:00 Mycophenolate 750mg PO BID Methylpred 500 mg IV POD #0 Methylpred 250mg IV POD #1 Methylpred 125mg IV POD #2 Methylpred 125mg IV POD #3 Tacrolimus 0.05mg/kg PO BID at 06:00 and 18:00 Mycophenolate 750mg PO BID Methylpred 500 mg IV POD #0 Methylpred 250mg IV POD #1 Methylpred 125mg IV POD #2 Methylpred 125mg IV POD #3 Tacrolimus 0.05mg/kg PO BID at 06:00 and 18:00 Mycophenolate 1000mg BID** Methylpred 500 mg IV POD #0 Methylpred 250mg IV POD #1 Methylpred 125mg IV POD #2 Methylpred 125mg IV POD #3 Prednisone 5mg PO daily starting POD #4** HIV+ Recipients & ABO incompatible living donor pairs: See separate protocol * Requires premedication with methylprednisolone 500 mg, APAP 650mg, diphenhydramine 50mg intra-op ** Adult HLA 6 of 6 Match Kidney Transplant Induction: Basiliximab 20mg POD 0 and 4 Maintenance: Tacrolimus 0.05mg/kg PO BID at 06:00 and 18:00, mycophenolate 750mg BID, methylprednisolone 500mg Intra-Op, methylprednisolone 250mg POD 1, methylprednisolone 125mg POD 2 and 3 2

3 ADULT KIDNEY TRANSPLANT Patients enrolled in a drug study should be EXCLUDED from standard protocol o Consult study coordinators for further instructions (On call pager: ). Induction Therapy Corticosteroids Pre-operative (POD#0): Order 500 mg of methylprednisolone on-call to the OR. Please write in the order comments section that dose is to be administered intra-operatively to prevent administration on the floor. Post-operative: Patients receiving alemtuzumab & thymoglobulin will follow the steroid discontinuation protocol. If it is decided post-operatively to continue steroids, please refer to steroid continuation taper in the low-risk protocol. For patients receiving alemtuzumab and thymoglobulin, the post-operative steroid taper is as follows: POD 0: methylprednisolone 500 mg IVPB POD1: methylprednisolone 250 mg IVPB POD2: methylprednisolone 125 mg IV POD3: methylprednisolone 125 mg IV Monoclonal Antibody: Alemtuzumab, Campath (Standard) Pre-operative: Order alemtuzumab 30 mg IVPB on-call to the OR. Please write in the order comments section that the dose is to be given intra-operatively to prevent administration on the floor. This product is stable for 8 hours and should be protected from light. Please do not order this until you are 100% certain that the case will go within the next 4 hours (kidney at UNC, XM completed, OR seems to be running on-time ). Post-operative: Patients are not to receive any additional alemtuzumab. Polyclonal Antibody: Anti-Thymocyte Globulin, ATG, Thymoglobulin For renal transplant recipients with history of HCVand/or HIV+ recipients (not on raltegravir) Pre-operative (POD #0): Order rabbit anti-thymocyte globulin 2mg/kg using ideal body weight rounded to the nearest 25mg on-call to OR. This product is stable for 24 hours at room temperature. Please do not order this until you are 100% certain that the case will go within the next 4 hours (kidney at UNC, XM completed, OR seems to be running on-time ). Pre-operative pre-medications (POD #0) include acetaminophen 650mg PO or IV, diphenhydramine 50mg PO or IV and methylprednisolone 500mg IV all on-call to OR. Post-operative (POD 1,2): Total goal dose of anti-thymocyte globulin: 6 mg/kg given over 3 days at 2mg/kg/day. However, dosing subject to change according to WBC, platelet count, anaphylaxis/tolerability of medication and infectious signs and symptoms so do not order subsequent doses of anti-thymocyte globulin until after rounds on POD #1 and 2. Doses may be held/reduced at the discretion of the attending fellow on service based upon CD3 count, WBC, PLT, and other ADR. Please order the appropriate thymoglobulin preparation in CPOE based upon administration - central v peripheral, and make sure morning dose of steroids is given prior to administration CD3 count should not be ordered unless directed by the physician. CBC with diff and Chem7 should be ordered daily on POD # 1 and 2. Continue premedication with acetaminophen, diphenhydramine, and methylprednisolone 30 minutes prior to each antithymocyte globulin infusion. Methylprednisolone premedication dosing should be as follows: 3

4 POD1: methylprednisolone 250 mg IVPB POD2: methylprednisolone 125 mg IV POD3: methylprednisolone 125 mg IV Monoclonal Antibody: Basiliximab, Simulect Pre-operative (POD#0): Order basiliximab 20mg IVPB on-call to the OR. Please write in the order comments section that the dose is to be given intra-operatively to prevent administration on the floor. This product is stable for 4 hours at room temperature, Please do not order this until you are 100% certain that the case will go within the next 2 hours (kidney at UNC, XM completed, OR seems to be running on-time ). Post-operative (POD4): Patients are to receive a second dose of basiliximab 20mg IVPB x 1 dose on POD 3 or 4. Maintenance Immunosuppression Calcineurin Inhibitor (Drug of choice: tacrolimus) Pre-operative: Patients are not to receive any doses of tacrolimus. Post-operative: Patients are to receive tacrolimus dosed per algorithm above based on induction agent used. Time to initiation is per the attending/fellow on service, but will ideally commence within the first 24h post transplant. Doses may be initiated at a higher or lower dose depending upon concern for allograft function, concomitant medication interactions, pharmacogenetic profile. Doses are to be adjusted based upon trough levels as follows: 0 4 months: 8-10 ng/ml 5 12 months: 6-8 ng/ml > 12 months: 5-7 ng/ml (based upon patient-specific parameters) Antiproliferative (Drug of choice: mycophenolate mofetil in the peri-operative period) Post-operative: Patients are to receive mycophenolate mofetil PO BID starting on POD #0, dosed per algorithm above based on induction agent used. Corticosteroid taper for patients on chronic steroid therapy POD1: methylprednisolone 500 mg IVPB x 1 dose ( if > 50 kg) and 250 mg IVPB ( if < 50 kg) POD2: methylprednisolone 50 mg IV BID POD3: methylprednisolone 40 mg IV BID POD4: methylprednisolone 30 mg IV BID POD5: methylprednisolone 20 mg IV BID POD6-10: prednisone 10 mg PO QDay POD11-365: Prednisone 5 mg PO QDay >Month 12: Prednisone 2.5mg PO QDay 4

5 ABO INCOMPATIBLE KIDNEY TRANSPLANT PROTOCOL Titer Technique The schedule for the ABO-I treatment protocol is based on the initial ABO antibody (Ab) isohemagglutinin titer which will aid the physician in determining the number of therapeutic plasma exchange (TPE) treatments needed to decrease the ABO Ab titer. These titers will be performed using the Anti-Human Globulin (AHG) phase methodology for greater sensitivity (IgG antibody). In CPOE order test Antibody Titer (# 5340) and choose option AHG from drop down menu in comments. When ordering the titer, on the comment line, specify Isohemagglutinin titer, A1, A2, and B. All ABO antibody levels will be checked so all potential donor blood type antibodies are identified. All titers will be done at UNCH to maintain standardization of testing and result reporting. Note: Sensitivity of titers using AHG phase is increased by approximately x1 dilution on average as compared to the test tube method, e.g. 1:8 test tube method would result as 1:16 AHG method. The Ab titer is defined by the reciprocal of the highest dilution producing 1+ agglutination on 0-4 scale. ABO antibody Titers Pre Transplant: First titer should be drawn 1 month prior to transplant POD 0: Order ABO ab titers prior to each TPE session and on the day of surgery. Labs can be drawn in the plasmapheresis unit pretreatment. Acceptable ABO titers for transplant are 1:4 to 1:8 based on pre-transplant titer levels. The schedule below identifies the potential schedule need based on the initial titer. This schedule assumes a Tuesday surgery and will eliminate elective preoperative TPE over the weekend. (See calendar below for sample schedule.) Pre-transplant titer levels will determine the overall course of treatment; an initial titer below 1:8 may not require preoperative TPE; the treatment plan will be individually determined by the patient s transplant nephrologist. IVIG: If more than 4 TPE sessions are needed, IVIG 0.5g/kg will be administered following the fifth TPE session only. Never give IVIG before or during TPE treatment as TPE will remove the IVIg. How to schedule TPE prior to transplant: Ideally, TPE will be scheduled early in the morning to accommodate multiple visits on the same day (e.g., dialysis, etc.). Post-Transplant ABO ab Titer Schedule: POD #1 (Wednesday) and POD# 3 (Friday) Twice weekly x 4 weeks Monthly x 2, at scheduled with Month 2 and 3 post transplant visit With each kidney biopsy (indefinitely) 5

6 THERAPEUTIC PLASMA EXCHANGE (TPE) Initial AHG Titer # Pre-op TPE Pre-Op Days before surgery <1:8 TBD To be determined by MD 1:8 or 1:16 2 1, 4 [Mon. & Fri. pre transplant] 1:32 3 1, 4, 6 1:64 4 1, 4, 6, 8 1: , 4, 6, 8, 11 (IVIG after 5 th TPE treatment* ) 1: , 4, 6, 8, 11, 13 (IVIG after 5 th TPE treatment* ) Post Transplant (if initial titer is < 1:4) No Post Tx TPE is planned if Initial titer < 1:4. Post Transplant (if initial titer is > 1:4) 2 TPE tx on POD #1, and #3 6

7 Therapeutic plasma exchange is done to decrease the circulating ABO antibodies, by exchanging the patient s plasma with a colloidal substitute (e.g., albumin, or Fresh Frozen Plasma (FFP). Plasma is replaced volume for volume with 5% albumin; the estimated volume exchange per TPE session is 1x plasma volume (~3-4L). [Estimated plasma volume (in liters) = 0.07 x weight (kg) x (1 - hematocrit)]. (Note: these are typical plasmapheresis orders, which will be written by Transfusion Medicine MD.) If TPE procedure occurs < 48 hrs before surgery the patient will typically receive FFP (matched to donor blood type) as part or all of the volume for volume replacement to correct TPE induced coagulopathy. Orders for replacement will be written by Transfusion Medicine MD Note: any time the patient has an invasive procedure, e.g., kidney biopsy, and TPE within the same 48 hour period, FFP will be given as above to reverse potential coagulopathy/bleeding complications. If initial titer is 1 : 4, no post transplant pheresis will be planned. If the initial titer is > 1: 4, will undergo two post-transplant TPE sessions on POD 1 and POD 3; need for further post-transplant TPE will be determined individually. An increase in ABO ab titer post-transplant of > 1:64 or a two dilution increase (e.g., 1:8 1:16 1:32) should prompt a kidney biopsy. Based on results of kidney biopsy, TPE may be ordered. If unable to biopsy, physician will determine if TPE needed. Vascular Access for TPE: Patient s current fistula, or temporary dialysis catheter for access. If the patient does not have a dialysis access, please send the patient to apheresis before the starting treatment day to have a vascular access assessment. Insertion of two large bore IV s are required for each treatment, and if the patient does not have adequate venous access for this, it may be recommended that they have a temporary dialysis catheter placed in VIR before starting TPE. Induction agent- Basiliximab: Pre-operative (POD#0): Order basiliximab 20mg IVPB on-call to the OR. Please write in the order comments section that the dose is to be given intra-operatively to prevent administration on the floor. This product is stable for 4 hours at room temperature. Post-operative (POD4): Patients are to receive a second dose of basiliximab 20mg IVPB x 1 dose on POD 3 or 4. Methylprednisolone: POD 0 (day of surgery): 500mg IV intra-operatively POD1: methylprednisolone 250 mg IVPB POD2: methylprednisolone 125 mg IV POD3: methylprednisolone 125 mg IV Maintenance Immunosuppression (start pre-transplant): Patient should take mycophenolate mofetil and tacrolimus on the morning of surgery. Tacrolimus: 0.05 mg/kg po BID initiated 48 hrs pre transplant Start on the Sunday (POD -2) prior to day of surgery). Order tacrolimus trough the morning before surgery for baseline trough level. 7

8 Tacrolimus 12hr trough goals: 8-10 ng/ml x 0-3 months 6-8 ng/ml x 3-12 months 5-7 ng/ml >12 months Mycophenolate mofetil 1000 mg po BID starting 2 weeks prior to transplant. (If using mycophenolate sodium, dosing is 720 mg BID). Post transplant corticosteroid taper (Prednisone): POD 4: Prednisone 30mg PO daily Decrease prednisone dose to 20 mg daily once tacrolimus level is at goal range (8-10ng/mL) POD 30 : Prednisone 15 mg po daily POD 60 : Prednisone 10 mg po daily POD 90: Prednisone 5 mg po daily (final daily dose, do not withdraw prednisone) ID Prophylaxis Protocol: Refer to standard ID prophylaxis protocolkidney TRANSPLANT DONOR ORDERS Admit to SRF: surgeon Vitals: Q4H x 24 hours, then Q8H Activity: o OOB to chair evening of surgery o Ambulate POD1 w/assistance TID I/Os: Strict Q4H Nursing o Foley catheter to SD o D/C foley at 6 am on POD1 Check PVR/bladder scan if no void within 4 hours If > 150 cc, notify HO If > 300 cc, may need foley replacement, urology consult for urodynamics as outpatient o Call HO: Temp > 38.5 Pulse > 110 or < 50 RR > 30 or < 10 SBP > 160 or < 90 DBP > 100 or < 50 O 2 < 92% UOP < 50 cc/hr x 2 hours UOP volume decreases suddenly o Incentive spirometry x 10 Q1H o Wean O 2 to sats > 90% o SCDs continuous Diet o NPO except meds/ice chips, then diet when BF returns o IVF: D 5 8

9 Meds o Fentanyl PCA o Ondansetron 4 mg IV Q8H, scheduled x 24 hours o Bisacodyl suppository POD1, PRN thereafter o Senna 2 tabs PO QHS or miralax 17gm PO QDay o Docusate 100 mg PO BID o Esomeprazole PO Qday o Oxycodone/APAP PRN o Heparin 5,000 units SC Q8H (Per attending discretion) o Rectus muscle spasm: Lorazepam 2mg PO or promethazine 12.5mg PO (Per attending discretion) Labs o Full labs in PACU and H/H again at 6 pm o Chem7 and CBC POD 1 only KIDNEY TRANSPLANT HIV POSITIVE PROTOCOL Refer to Appendix D for HAART agents by class and abbreviations Eligibility: Patients must satisfy requirements prior to listing Stable on current HIV regimen x 6 months CD4 > 200 x 6 months HIV care provided at UNC No active infections HIV evaluation Coordinator should contact ID clinic requesting an HIV+Transplant evaluation. They will be scheduled on a Tuesday or Thursday, and care will be supervised by a designated Transplant ID/HIV physician (presently Dr. Quinlivan and ). If the patient is currently followed by the UNC ID clinic, they may continue care with their present physician or the designated HIV physicians. An evaluation of the need to change ART will be made if: o Regimen consists of a PI + /-NNRTI (due to unpredictable drug interactions) o Regimen contains zidovudine or stavudine (due to potential for antagonism with MMF) o Regimen contains tenofovir (due to nephrotoxicity with tacrolimus or cyclosporine) Pre-transplant PK/PD studies of ARTs or immunosuppressants will be considered Any special prophylaxis requirements will be established, including TB Patients will be assigned to an Enhanced Care nurse Pre-Transplant Evaluation Follow current UNC renal transplant work-up with transplant surgery, nephrology and pharmacy Patients to be notified of additional risks and possible difficulties of HIV+ transplantation Transplant Admission 9

10 Transplant nephrology and the transplant infectious disease service are to be notified immediately after the patient has agreed to come in for transplant. If transplant surgeon on service has concern over patient, may contact those services prior to contacting the patient. o These services will follow the patient throughout their hospital admission, though SRF will remain as the primary service. Admission orders to follow current protocols (labs, physical exam, OR scheduling, etc) Medication orders to follow HIV Transplant Protocol Anticipated transition from transplant surgery to nephrology/id care will occur around 1 month post-transplant Post-Transplant Nephrology and HIV care to be continue at UNC The patient s post-transplant coordinator will have primary responsibility for management and coordination of care. The patient s HIV Enhanced Care nurse will work with their post-transplant coordinator to maintain communication between the two services. It will be their responsibility to work with the appropriate attending physicians for patient care. Labs to follow current UNC protocols. The transplant coordinator is responsible for contacting appropriate nephrologist/id attending with abnormal values and any actions taken. These events are to be recorded in the TransChart Notes section as well (so as to feed into WebCis). o The ID attending/ Enhanced Care nurse may request additional labs/tests as necessary CD4/ RNA testing to be followed by ID: o within 30 days of transplant (pre-transplant to be ordered with admission labs if CRT) o at first post-hospital visit (~10-14 days) o with any med changes expected to alter ART levels o with any major change in health status ( i.e. hospitalizations) o at day intervals for 12m after transplant o at day intervals afterwards if fully suppressed and transplant condition is stable (per HIV guidelines) Additional considerations that would require the transplant coordinator to notify the Enhanced Care nurse: o Medication changes that may alter ART concentrations o Medication changes that may alter immunosuppressant concentrations o Changes to immunosuppression o The ordering of any non-protocol labs/tests (in the event the ID service has additional requests/considerations) Induction Agent: Refer to Appendix D for HAART agents by class and abbreviations If protease inhibitor is included in HAART Therapy: Pre-operative (POD #0): Order rabbit anti-thymocyte globulin 2 mg/kg using actual body weight rounded to the nearest 25mg on-call to OR. This product is stable for 24 hours at room temperature. Please do not order this until you are 100% certain that the case will go within the next 4 hours (kidney at UNC, XM completed, OR seems to be running on-time )Pre-operative pre-medications (POD #0) include acetaminophen 650mg PO or IV, diphenhydramine 50mg PO or IV and methylprednisolone 500mg IV all oncall to OR. All to be given 30 minutes prior to rabbit anti-thymocyte globulin Post-operative (POD 1,2): Total goal dose of anti-thymocyte globulin: 6 mg/kg given over 3 days at 2 mg/kg/day. Dosing subject to change according to WBC, platelet count, anaphylaxis/tolerability of medication and infectious signs and symptoms so do not order subsequent doses of anti-thymocyte globulin until after rounds on POD #1 and 2. Doses may be held/reduced at the discretion of the attending fellow on service based upon CD3 count, WBC, PLT, and other ADR. Please order the appropriate thymoglobulin preparation in CPOE based upon administration - central v peripheral, and make sure morning dose of steroids is given prior to administration. 10

11 Continue premedication with acetaminophen, diphenhydramine, and methylprednisolone 30 minutes prior to each antithymocyte globulin infusion. Methylprednisolone premedication dosing should be as follows: POD1: methylprednisolone 250 mg IVPB POD2: methylprednisolone 125 mg IV POD3: methylprednisolone 125mg IV POD4: prednisone 5mg daily CD3 count should not be ordered unless directed by the physician. CBC with diff and Chem7 should be ordered daily on POD # 1 and 2. If protease inhibitor is not included in HAART Therapy (Raltegravir based HAART for example): Preoperative (POD #0): Order basiliximab 20mg once the case is 100% confirmed as the product is only good for 4 hours and should not be administered outside of the OR. Methylprednisolone 500mg IV should also be ordered on call and given intra-operatively Post-operative day 4 (POD4): Patients are to receive a second dose of basiliximab 20mg IVPB POD1: methylprednisolone 250 mg IVPB POD2: methylprednisolone 125 mg IV POD3: methylprednisolone 125mg IV POD4: prednisone 5mg daily HIV PROTOCOL: Maintenance Immunosuppression: Calcineurin inhibitor: Patient to receive tacrolimus starting on POD1. Initiation may be delayed at the discretion of the attending on service. For patients receiving ARTs containing a PI ± NNRTI, the starting dose will be 1 mg PO once. Tacrolimus typically NOT dosed over two times per week on this regimen. Tacrolimus trough levels should be drawn daily immediately post-transplant For patients on an integrase inhibitor (No PI), the starting dose of tacrolimus should be 0.05 mg/kg PO BID. Goal tacrolimus trough concentrations as follows (based upon patient specific parameters): o Months 0-3: 9-11 ng/ml for PI based HAART (Thymo induction) : 8-10 ng/ml for non-pi containing regimens (Basiliximab induction) o Months 3-12: 6-8 ng/ml o Months > 12: 5-7 ng/ml For patients who require conversion to cyclosporine, use the following dosing considerations. May adjust up or down based upon clinical situation, however the correlation between tacrolimus and cyclosporine dosing is not as clear as for patients not on ARTs. For patients receiving ARTs containing a PI ± NNRTI, the starting dose will be mg PO twice daily. For patients on an integrase inhibitor (No PI), the starting dose will be 4mg/kg PO BID. Use 200 mg PO BID if the patient is on nevirapine; use 250 mg PO BID if the patient is on efavirenz. Goal cyclosporine trough concentrations as follows (based upon patient specific parameters): o Months 0-3: ng/ml o Months 3-12: ng/ml o Months > 12: ng/ml 11

12 Antiproliferative: Patient to receive mycophenolate mofetil 750mg PO BID if they received thymoglobulin induction. If basiliximab induction was given, mycophenolate mofetil dose should be1000 mg PO BID starting on POD# 0. Doses may be adjusted based upon tolerability and clinical judgment. Acute Rejection Treatment of rejection is to be based upon current standard of care, assessing the risk/benefit of any therapies utilized. The preferred therapy for cellular rejection is steroid therapy; lymphocyte-depleting agents should be administered only after careful consideration, and discussion between transplant surgery, nephrology, and infectious diseases. For humoral rejection, the decision to administer rituximab vs IVIG vs plasmapheresis should be similarly weighed. All patients should receive ID prophylaxis similar to post-transplant standards regardless of treatment modality used. General Prophylaxis GI: Patients not on atazanavir or indinavir are to receive esomeprazole 40 mg PO QHS for stress ulcer prophylaxis. For patients on these two ARTs, consultation must be made with the ID service to assess risk/benefit of introducing an H 2 - antagonist (requires boosting with ritonavir). CV: Patients are to receive an aspirin 81 mg PO daily starting on POD1. ID Prophylaxis: Surgical: Patients to have cefazolin 1 g IV x 1 dose ordered on-call to the OR. One dose should be given 6-8 hours postoperatively as well. For penicillin allergy: clindamycin 600 mg IVPB may be used in place of cefazolin. PCP: Patients to receive sulfamethoxazole/trimethoprim 800/160 mg PO QMWF. For sulfa allergy: May use dapsone 100 mg daily. If sulfa allergy & G6PD deficiency: consider aerosolized pentamidine 300 mg monthly or atovaquone 1500 mg PO daily. This is to be continued for six months after transplant or treatment of rejection (including with steroids). CMV: Per standard CMV prophylaxis protocol/ Patients with a history of CMV infection are to receive valganciclovir 900 mg PO daily for at least one month post-transplant or post-treatment of rejection. If these patients CD4 count goes < 100 (outside of the immediate post-transplant or post-rejection period), they are to receive valganciclovir until 6 months after their CD4 count recovers to > 200. EBV: Patients at high-risk for contracting EBV (donor +/recipient -) to receive ganciclovir 5 mg/kg IV daily while in the hospital. They are to continue on valganciclovir 900 mg PO daily x 1 year on discharge. This will take the place of CMV prophylaxis in these patients. Candidiasis: Nystatin 10 ml (1,000,000 units) PO TID while on steroids. If CD4 < 200, fluconazole 100 mg PO daily. HIV-specific Prophylaxis: MAC: Azithromycin 1200 mg PO qweek if CD4 75. Continue until 6 months after CD4 count is > 100. Patients with a history of MAC infection are to receive azithromycin 600 mg PO daily + ethambutol 15 mg/kg/day x 1 month posttransplant or post-treatment of rejection. If CD4 75 and patient is not within one month post-transplant or post-rejection period, prophylaxis is to be continued until 6 months after their CD4 count recovers to > 100. The use of rifabutin may also be continued by the infectious diseases service. Cryptococcosis, extrapulmonary: Patients with a history of crypto are to receive fluconazole 200 mg PO daily x 1 month post-transplant or post-treatment of rejection. If these patients have a CD4 count < 200, they are to receive prophylaxis until 6 months after their CD4 count recovers to >

13 Histoplasmosis: Patients with a history of histo are to receive itraconazole 200 mg PO BID (take with food) or fluconazole 400 mg PO daily for the rest of their life. Toxoplasmosis: If IgG + and CD4 count < 200, patients to receive sulfamethoxazole/trimethoprim 800/160 mg PO daily until six months after CD4 count recovers to > 200. In patients with a history of clinical toxo infection, prophylaxis is to be initiated with pyrimethamine 25 mg PO daily + sulfadiazine 100 mg/kg PO daily + leucovorin 25 mg PO daily x 1 month post-transplant or post-treatment of rejection. If CD4 count < 200, prophylaxis must continue until six months after CD4 count recovers to > 200. These patients do not need additional PCP coverage. In patients with a past infection and a sulfa allergy, prophylaxis is to be pyrimethamine 25 mg PO daily + clindamycin 600 mg PO TID. These patients must continue on an additional medication for PCP prophylaxis. Drug Interactions: Refer to Appendix E 13

14 SIMULTANEOUS PANCREAS-KIDNEY or PANCREAS ALONE TRANSPLANT Corticosteroids Pre-operative (POD0): Order 500 mg of methylprednisolone on-call to the OR. Please write in the order comments section that dose is to be administered intra-operatively to prevent administration on the floor. Post-operative: Patients receiving alemtuzumab will follow the steroid discontinuation protocol. If it is decided postoperatively to continue steroids, please refer to steroid continuation taper in the low-risk protocol. For patients receiving alemtuzumab, the post-operative steroid taper is as follows: POD1: methylprednisolone 250 mg IVPB x 1 dose POD2: methylprednisolone 125 mg IV x 1 dose POD3: methylprednisolone 125 mg IV x 1 dose Monoclonal Antibody Pre-operative: Order alemtuzumab 30 mg IVPB on-call to the OR. Please write in the order comments section that the dose is to be given intra-operatively to prevent administration on the floor. This product is only good for 8 hours, so please do not order this until you are 100% certain that the case will go within the next 4 hours (kp at UNC, XM completed, OR seems to be running on-time ). Calcineurin Inhibitor (Most patients will receive tacrolimus) Pre-operative: Patients are not to receive any doses of tacrolimus. Post-operative: Patients are to receive tacrolimus mg/kg PO BID. (Lower dose due to peri-operative fluconazole). Initiation to be decided per the attending/fellow on service, but will ideally commence within the first 24h after transplant. Doses may be initiated at a higher or lower dose depending upon concern for ATN or concomitant medication interactions. Doses are to be adjusted based upon trough levels as follows: 0 3 months: ng/ml 3 12 months: 7-9 ng/ml > 12 months: 6-8 ng/ml - barring mycophenolate dose is > 500mg BID Antiproliferative (most patients will receive mycophenolate mofetil in the peri-operative period) Pre-operative: Patients are to receive mycophenolate mofetil 1000 mg PO x 1 dose as soon as case is confirmed. Post-operative: Patients are to receive mycophenolate mofetil 1000 mg PO BID starting on POD0. 14

15 PANCREAS AFTER KIDNEY TRANSPLANT Corticosteroids Pre-operative (POD0): Order 500 mg of methylprednisolone on-call to the OR. Please write in the order comments section that dose is to be administered intra-operatively to prevent administration on the floor. Post-operative: Patients will follow the steroid discontinuation protocol. If it is decided post-operatively to continue steroids, please refer to steroid continuation taper in the low-risk kidney protocol. The post-operative steroid taper is as follows: POD1: methylprednisolone 250 mg IVPB x 1 dose POD2: methylprednisolone 125 mg IV x 1 dose POD3: methylprednisolone 125 mg IV x 1 dose Monoclonal Antibody Pre-operative: Order alemtuzumab 30 mg IVPB on-call to the OR. Please write in the order comments section that the dose is to be given intra-operatively to prevent administration on the floor. This product is only good for 8 hours, so please do not order this until you are 100% certain that the case will go within the next 4 hours (pancreas at UNC, OR seems to be running on-time ). Calcineurin Inhibitor (most patients will receive tacrolimus) Pre-operative: Patients are not to receive any doses of tacrolimus. Post-operative: Patients are to receive tacrolimus mg/kg PO BID. (Lower dose due to peri-operative fluconazole). Initiation to be decided per the attending/fellow on service, but will ideally commence within the first 24h after transplant. Doses may be initiated at a higher or lower dose depending upon concern for ATN or concomitant medication interactions. Doses are to be adjusted based upon trough levels as follows: 0 3 months: ng/ml 3 12 months: 7-9 ng/ml > 12 months: 6-8 ng/ml - barring mycophenolate dose is > 500mg BID Antiproliferative (most patients will receive mycophenolate mofetil in the peri-operative period) Pre-operative: Patients are to receive mycophenolate mofetil 1000 mg PO x 1 dose as soon as case is confirmed. Post-operative: Patients are to receive mycophenolate mofetil 1000 mg PO BID starting on POD0. 15

16 LIVER TRANSPLANT - STANDARD Most patients will ONLY receive steroids intra-operatively. For adult patients with a pre-operative SCr > 1.5 mg/dl order basiliximab 20mg on-call to OR once case confirmed. Blood Products: Use order sets and set up (on-call to OR) 10units PRBC 10units FFP 12units Platelets Corticosteroids: Pre-operative (POD0): Order methylprednisolone 500 mg IV on-call to the OR. Please write in the order comments section that dose is to be administered intra-operatively to prevent administration on the floor. Post-operative: Steroid taper is as follows POD1: methylprednisolone 500 mg IVPB x 1 dose POD2: methylprednisolone 50 mg IV BID POD3: methylprednisolone 40 mg IV BID POD4: methylprednisolone 30 mg IV BID POD5: methylprednisolone 20 mg IV BID POD6: Prednisone 20 mg PO POD7: Prednisone 15 mg PO POD8: Prednisone 10 mg PO POD9-14: Prednisone 5 mg PO QDay (leave HCV, AIH, PBC/PSC patients here) POD15-30: Prednisone 2.5 mg PO QDay, then discontinue Exceptions to this taper include: Patients admitted on steroids and /or have history of autoimmune hepatitis (AIH) will remain on steroids at a minimum of prednisone 5 mg PO daily Patients with history of HCV will remain on steroids at a minimum of prednisone 5 mg daily x 6 months, then discontinue Monoclonal Antibody- Basiliximab: Pre-operative (POD#0): Order basiliximab 20mg IVPB on-call to the OR. Please write in the order comments section that the dose is to be given intra-operatively to prevent administration on the floor. This product is stable for 4 hours at room temperature, Please do not order this until you are 100% certain that the case will go within the next 2 hours (kidney at UNC, XM completed, OR seems to be running on-time ). Post-operative (POD4): Patients are to receive a second dose of basiliximab 20mg IVPB x 1 dose on POD# 4. Calcineurin Inhibitor (drug of choice: tacrolimus): Pre-operative: Patients are not to receive any doses of tacrolimus. Post-operative: Patients are to receive tacrolimus 0.05 mg/kg PO BID. Initiation to be decided per the attending/fellow on service, but will ideally commence within the first 24h after transplant. Doses may be initiated at a higher or lower dose depending upon concern for ATN or concomitant medication interactions. Doses are to be adjusted based upon trough levels as follows: 0 3 months: 8-10 ng/ml 3 12 months: 6-8 ng/ml 16

17 > 12 months: 4-6 Antiproliferative (drug of choice: mycophenolate mofetil in the peri-operative period): Post-operative: Patients are to receive mycophenolate mofetil 500 mg PO BID starting on POD 0. Hepatitis B Prophylaxis (For HbsAg+ patients): Pre-operative: Order HBIG 10,000 units IV to be administered intra-operatively. Post-operative: Patients are to receive lamivudine 100 mg PO Q 24h (or whatever antiviral they were on at admission) resuming on POD1. They are also to receive HBIG 10,000 units IV Q 24h for 6 days post-transplant (total of 7 doses during transplant admission). Pre-med for the HBIG 30 minutes prior to infusion with acetaminophen 650 mg PO; diphenhydramine 25 mg PO. (Dosing frequency beyond the perioperative period will depend on antibody levels < 100 at a dose of 1560 IU (5mL) to be administered IM) 17

18 ADULT COMBINED LIVER/KIDNEY TRANSPLANT Addition of basiliximab 20mg on-call to methylprednisolone 500mg and pre-op antibiotic is standard for combined liver/kidney cases. Blood Products: Use order sets and set up (on-call to OR) 10units PRBC 10units FFP 12units Platelets Corticosteroids: Pre-operative (POD0): Order methylprednisolone 500 mg IV on-call to the OR. Please write in the order comments section that dose is to be administered intra-operatively to prevent administration on the floor. Post-operative: Steroid taper is as follows POD1: methylprednisolone 500 mg IVPB x 1 dose POD2: methylprednisolone 50 mg IV BID POD3: methylprednisolone 40 mg IV BID POD4: methylprednisolone 30 mg IV BID POD5: methylprednisolone 20 mg IV BID POD6: Prednisone 20 mg PO POD7: Prednisone 15 mg PO POD8: Prednisone 10 mg PO POD9 through the first year post transplant: Prednisone 5 mg PO QDay Monoclonal Antibody- Basiliximab: Pre-operative (POD#0): Order basiliximab 20mg IVPB on-call to the OR. Please write in the order comments section that the dose is to be given intra-operatively to prevent administration on the floor. This product is stable for 4 hours at room temperature, Please do not order this until you are 100% certain that the case will go within the next 2 hours (kidney at UNC, XM completed, OR seems to be running on-time ). Post-operative (POD4): Patients are to receive a second dose of basiliximab 20mg IVPB x 1 dose on POD# 4. Calcineurin Inhibitor (drug of choice: tacrolimus): Pre-operative: Patients are not to receive any doses of tacrolimus. Post-operative: Patients are to receive tacrolimus 0.05 mg/kg PO BID. Initiation to be decided per the attending/fellow on service, but will ideally commence within the first 24h after transplant. Doses may be initiated at a higher or lower dose depending upon concern for ATN or concomitant medication interactions. Doses are to be adjusted based upon trough levels as follows: 0 3 months: 8-10 ng/ml 3 12 months: 6-8 ng/ml > 12 months: 4-6 Antiproliferative (drug of choice: mycophenolate mofetil in the peri-operative period): Post-operative: Patients are to receive mycophenolate mofetil 750 mg PO BID starting on POD 0. 18

19 PEDIATRIC KIDNEY TRANSPLANT Pediatric Kidney Tranpslant Moderate - High-Risk: 1. African-American 2. PRA >20% 3. Prior transplant 4. >5 prior transfusions 5. HLA-B mismatch 6. Age <24 months (recipients of deceased donor only) Low-Risk: 1. Non-African American 2. Peak PRA <20% 3. Primary transplant Anti-thymocyte Globulin (ATG)* POD 0 (pre-op): 1.5mg/kg IV POD 1, 2, 3: 1.5mg/kg IVPB AND Solumedrol taper (give prior to ATG) POD 0 (pre-op): 10mg/kg (max of 1g) POD 1: 2mg/kg POD 2: 1mg/kg POD 3: 0.5mg/kg Basiliximab POD 0 (pre-op): 10mg IV (if <35kg) 20mg IV (if >35kg) POD 4: 10mg IV (if <35kg) 20mg IV (if >35kg) Methylpred 1mg/kg IV BID POD 1, 2 Tacrolimus mg/kg PO BID Tacrolimus mg/kg PO BID Mycophenolate 600mg/m 2 BID x 2-4 weeks Then decrease to 450mg/m 2 BID Mycophenolate 600mg/m 2 BID Prednisone 1mg/kg PO BID POD 3 Prednisone 0.5mg/kg PO BID POD 4 Prednisone 0.25mg/kg PO BID POD 5 Prednisone 0.25mg/kg PO daily POD 6 Discontinue steroids POD 7 *Round all doses to the nearest 25mg *Requires pre-medication with methylprednisolone, acetaminophen and diphenhydramine 19

20 Low Risk Recipients (Non-African American patients receiving first transplant with a peak PRA < 20%) Pre-operative (POD#0): Order basiliximab 10 mg IV x 1 if patient weighs <35kg. Order basiliximab 20mg if patient weighs >35kg IVPB on-call to the OR. Please write in the order comments section that the dose is to be given intraoperatively to prevent administration on the floor. This product is stable for 4 hours, so please do not order this until you are 100% certain that the case will go within the next 2 hours (kidney at UNC, XM completed, OR seems to be running on-time ). Post-operative (POD4): Patients are to receive a second dose of basiliximab 10 mg if patient weighs <35kg. Order basiliximab 20mg if patient weighs >35kg.IVPB x 1 dose on post-operative day 4. High Risk Recipients (PRA > 20%, repeat transplant, African American recipients) Pre-operative (POD#0): Order thymoglobulin 1.5 mg/kg (rounded to the nearest 25 mg) IVPB on-call to the OR. Please write in the order comments section that the dose is to be given intra-operatively to prevent administration on the floor. This product is good for 24 hours, and it may be ordered as soon as resident has seen patient and discussed them with the attending/fellow on service.post-operative (POD1,2,3): Patients are to receive thymoglobulin 1.5 mg/kg (rounded to the nearest 25 mg) IVPB daily on post-operative days 1, 2 and 3. Order a CD3 count on post-operative day 4, and do NOT order the thymoglobulin until after the attending/fellow on service has confirmed that the patient is to get it that day based on platelets, WBC and infectious parameters. Dosage reductions are recommended for the following: WBC < 2.0, ANC < 1000, Plt < 50 and/or signs and symptoms of infection. Order acetaminophen 650 mg and diphenhydramine 25 mg x 1 dose to be given minutes prior to these doses. Please order the appropriate thymoglobulin preparation in CPOE based upon administration - central v peripheral, and make sure morning dose of steroids is given prior to administration. Calcineurin Inhibitor (drug of choice: tacrolimus): Pre-operative: Patients are not to receive any doses of tacrolimus. Post-operative: Patients are to receive tacrolimus mg/kg PO BID. Initiation to be decided per the attending/fellow on service, but will ideally commence within the first 24h after transplant. Doses may be initiated at a higher or lower dose depending upon concern for allograft dysfunction or concomitant medication interactions. Doses are to be adjusted based upon trough levels as follows: 0 3 months: 8-10 ng/ml 3 12 months: 6-8 ng/ml 12 months: per Peds Nephrology (based upon patient-specific parameters) Antiproliferative (drug of choice: mycophenolate mofetil in the peri-operative period) Dosing as above. o Alternative Solid Dosage Forms According to BSA as follows: Cell Cept: If BSA m 2-750mg BID If BSA > 1.5mg/m mg BID Myfortic: If BSA m 2-540mg BID If BSA > 1.59m 2-720mg BID 20

21 PEDIATRIC LIVER TRANSPLANT Corticosteroids Pre-operative (POD0): Order methylprednisolone 10 mg/kg IV on-call to the OR. Please write in the order comments section that dose is to be administered intra-operatively to prevent administration on the floor. Post-operative: Patients are to receive a steroid taper as follows: POD1: methylprednisolone 10 mg/kg IV x 1 POD 2 methylprednisolone 2 mg/kg IV Q 12h POD 3 methylprednisolone 1.5 mg/kg IV Q 12h POD 4 methylprednisolone 1 mg/kg IV Q 12h POD 5 methylprednisolone 0.9 mg/kg IV Q 12h POD 6 prednisolone 0.8 mg/kg PO Q 24h POD 7 prednisolone 0.7 mg/kg PO Q 24h POD 8 prednisolone 0.6 mg/kg PO Q 24h POD 9-14 prednisolone 0.5 mg/kg PO Q 24h POD prednisolone 0.4 mg/kg PO Q 24h POD prednisolone 0.3 mg/kg PO Q 24h POD prednisolone 0.2 mg/kg PO Q 24h POD prednisolone 0.1 mg/kg PO Q 24h POD prednisolone 0.1 mg/kg PO Q 24h Polyclonal Antibody: Anti-thymocyte Globulin, ATG, Thymoglobulin (standard) Pre-operative (POD 0): Order thymoglobulin 1.5 mg/kg (rounded to the nearest 25 mg) IVPB on-call to the OR. Please write in the order comments section that the dose is to be given intra-operatively to prevent administration on the floor. This product is stable for 24 hours, and it may be ordered as soon as resident has seen patient and discussed them with the attending/fellow on service. Post-operative (POD1,3,5): Patients are to receive thymoglobulin 1.5 mg/kg (rounded to the nearest 25 mg) IVPB daily on post-operative days 1, 3, and 5. Order a CD3 count on post-operative day 4, and do NOT order the thymoglobulin until after the attending/fellow on service has confirmed that the patient is to get it that day based on platelets, WBC and infectious parameters. Dosage reductions are recommended for the following: WBC < 2.0, ANC < 1000, Plt < 50 and/or signs and symptoms of infection. Order acetaminophen 650 mg po x1 and diphenhydramine 25 mg po x 1 dose to be given minutes prior to these doses. Please order the appropriate thymoglobulin preparation in CPOE based upon administration - central v peripheral, and make sure patient receives morning dose of steroids prior to administration. Monoclonal Antibody: Basiliximab, Simulect (For living-related transplant patients) Pre-operative (POD#0): Order basiliximab 20mg IVPB on-call to the OR. Please write in the order comments section that the dose is to be given intra-operatively to prevent administration on the floor. This product is stable for 4 hours at room temperature, Please do not order this until you are 100% certain that the case will go within the next 2 hours (kidney at UNC, XM completed, OR seems to be running on-time ). Post-operative (POD4): Patients are to receive a second dose of basiliximab 20mg IVPB x 1 dose on POD# 4. Calcineurin Inhibitor (drug of choice: tacrolimus) Pre-operative: Patients are not to receive any doses of tacrolimus. Post-operative: Patients are to receive tacrolimus 0.05 mg/kg PO BID. Initiation to be decided per the attending/fellow on service, but will ideally commence within the first 24h after transplant. Doses may be initiated at a higher or lower dose depending upon concern for ATN or concomitant medication interactions. 21

22 Doses are to be adjusted based upon trough levels as follows: 0 3 months: ng/ml 3 12 months: ng/ml > 12 months: per Peds Hepatology Antiproliferative (drug of choice: mycophenolate mofetil) Pre-operative: Patients do not require any doses of mycophenolate mofetil. Post-operative: Patients are to receive mycophenolate mofetil PO BID starting on POD 0 per following dose: < 30 kg = 500 mg/m kg = 500 mg kg = 750 mg 60 kg = 1000 mg 22

23 KIDNEY TRANSPLANT PROPHYLAXIS Perioperative Antibiotics: Pre-operative: cefazolin 1grams IVPB (< 80 kg), 2 grams (> 80 kg) ordered on-call to OR. Pre-operative (PCN allergy): clindamycin 900mg IVPB on call to the OR. CMV: Risk Status Agent/Dose/Regimen Duration High risk valganciclovir 900 mg PO daily x 3 6 months Donor +/ Recipient -) months, then 450 mg PO daily x 3 Intermediate risk (Donor+/Recipient +) (Donor-/Recipient +) Low risk (Donor - / Recipient -) months Valganciclovir 450 mg PO daily acyclovir 400 mg PO BID 3 months 3 months **if patient is high-risk EBV/low-risk CMV, use valganciclovir 450 mg PO QDay Renal Dosing for Valganciclovir based on 900 mg daily dose Cl cr ml/minute: 450 mg once daily Cl cr ml/minute: 450 mg every 2 days Cl cr ml/minute: 450 mg twice weekly PCP: Sulfamethoxazole/trimethoprim 400/80 mg PO HS QMon, Weds, Fri x 6 months Sulfa allergy: give dapsone 100 mg QHS x 6 months. Check G6PD prior to initiation** Sulfa allergy + G6PD: consider pentamidine300 mg inhalation monthly Thrush: nystatin 10 ml PO TID. Discontinue at discharge unless peds patient. Stress ulcer: esomeprazole 40 mg PO QDay Cardiovascular: aspirin 81 mg PO QDay 23

24 LIVER TRANSPLANT PROPHYLAXIS Perioperative Antibiotics: Pre-operative: unasyn 3 grams ordered on-call to OR. Pre-operative (PCN allergy): clindamycin 900mg IVPB, levofloxacin 500 mg IVPB on call to the OR. Post-operative: unasyn 1.5 grams IVPB q8h x 2 doses Post-operative (PCN allergy): clindamycin 900mg IVPB q8h x 2 doses, levofloxacin 500 mg IVPB x 1 dose CMV: Risk Status Agent/Dose/Regimen Duration High risk valganciclovir 900 mg PO daily x 3 6 months Donor +/ Recipient -) months, then 450 mg PO daily x 3 Intermediate risk (Donor+/Recipient +) (Donor-/Recipient +) Low risk (Donor - / Recipient -) months Valganciclovir 450 mg PO daily acyclovir 400 mg PO BID 3 months 3 months **if patient is high-risk EBV/low-risk CMV, use valganciclovir 450 mg PO QDay Renal Dosing for Valganciclovir based on 900 mg daily dose Cl cr ml/minute: 450 mg once daily Cl cr ml/minute: 450 mg every 2 days Cl cr ml/minute: 450 mg twice weekly PCP: Sulfamethoxazole/trimethoprim 400/80 mg PO HS QMon, Weds, Fri x 6 months Sulfa allergy: give dapsone 100 mg QHS x 6 months. Check G6PD prior to initiation** Sulfa allergy + G6PD: consider pentamidine300 mg inhalation monthly Thrush: nystatin 10 ml PO TID. Discontinue at discharge unless peds patient. Stress ulcer: esomeprazole 40 mg PO QDay Cardiovascular: aspirin 81 mg PO QDay to be started when platelets >

25 KIDNEY-PANCREAS & PANCREAS TRANSPLANT PROPHYLAXIS Perioperative Antibiotics: Pre-operative: unasyn 3 grams ordered on-call to OR. Pre-operative (PCN allergy): clindamycin 900mg IVPB, levofloxacin 500 mg IVPB on call to the OR. CMV: Post-operative: unasyn 1.5 grams IVPB q8h x 3 doses Post-operative (PCN allergy): clindamycin 900mg IVPB q8h x 2 doses, levofloxacin 500 mg IVPB x 1 dose Risk Status Agent/Dose/Regimen Duration High risk valganciclovir 900 mg PO daily x 3 6 months Donor +/ Recipient -) months, then 450 mg PO daily x 3 Intermediate risk (Donor+/Recipient +) (Donor-/Recipient +) Low risk (Donor - / Recipient -) months Valganciclovir 450 mg PO daily acyclovir 400 mg PO BID 3 months 3 months **if patient is high-risk EBV/low-risk CMV, use valganciclovir 450 mg PO QDay Renal Dosing for Valganciclovir based on 900 mg daily dose Cl cr ml/minute: 450 mg once daily Cl cr ml/minute: 450 mg every 2 days Cl cr ml/minute: 450 mg twice weekly PCP: Sulfamethoxazole/trimethoprim 400/80 mg PO HS QMon, Weds, Fri x 6 months Sulfa allergy: give dapsone 100 mg QHS x 6 months. Check G6PD prior to initiation** Sulfa allergy + G6PD: consider pentamidine300 mg inhalation monthly Thrush: Pre-operative: Fluconazole 200 mg PO x 1 dose. Post-operative: Fluconazole 100 mg PO Daily x 7 days, then nystatin 10 ml PO TID. Discontinue at discharge Stress ulcer: Post-operative: esomeprazole 40 mg PO QDay CV/Thrombosis: Pre-operative: aspirin 325 mg PO x 1 dose ordered STAT. Post-operative: aspirin 325 mg PO QDay 25

26 Pediatric CMV Prophylaxis: PEDIATRIC KIDNEY TRANSPLANT Valganciclovir(mg)=7 x BSA x CrCl (Per modified Schwartz formula; cut-off at 150 ml/min/1.73 m 2 ) D+/R- (High Risk): Valganciclovir (dosed per above equation) x 6 months D+/R+ and D-/R- (Intermediate - low risk): Valganciclovir (dosed per above equation) x 3 months KIDNEY TRANSPLANT REJECTION Corticosteroid Treatment: Methylprednisolone 500 mg IV Q 24h for 3 days (*Taper based upon patient-specific criteria) Prednisone Taper Following methylprednisolone IV for rejection: Prednisone 80mg x 2 days Prednisone 60mg x 2 days Prednisone 40mg x 2 days Prednisone 20mg x 2 days Prednisone 10mg daily To be tapered on individual basis in clinic Rabbit Anti-Thymoglobulin Protocol for Severe or Steroid Resistant Rejection: Rabbit Anti-thymocyte globulin (ratg) - No longer based on absolute CD3 count due to lower rates of returning to baseline SCr and higher recurrent rejection episodes versus fixed dosing as outlined below. Always ensure central versus peripheral access is known prior to placing order Peripheral infusions must be admixed with heparin 1000units & hydrocortisone 20mg to prevent phlebitis Usual course of therapy is 7 to 14 days Each case to be individual per attending and pathologist review of biopsy, clinical status and other laboratory information (Donor specific antibody, underlying glomerular disease, etc) How to dose ratg based on patient weight (1.5mg/kg) Use actual body weight unless the patient is > 120% of their ideal body weight o o How to calculate IDEAL BODY WEIGHT: MALES: 50kg + (Inches over 60 x 2.3) FEMALES: 45.5kg + (Inches over 60 x 2.3) For patients > 120% of ideal body weight calculate & use adjusted body weight to dose ratg: ADJUSTED BODY WEIGHT: Ideal body weight + [ 0.4 (Total body weight ideal body weight) ] Round doses to the nearest 25mg (Example: 142mg should be rounded to 150mg) When ordering in CPOE make sure you select the correct product (Central versus peripheral administration) o The peripheral product has heparin and hydrocortisone in the bag to prevent phlebitis Maintenance Immunosuppression: o CNI (Tacrolimus, Cyclosporin): Decrease dose by 50% (Most tacrolimus goals will be 4 to 6 while on ratg) 26

27 o o o o 72hr prior to end of theapy increase CNI dose to attain 100% goal and reassess previous goal with attending Mycophenolate (Cell Cept, Myfortic): Discontinue until ratg is finished Restart full dose mycophenolate after last dose of ratg is administered If on maintenance prednisone: Discontinue : IV steroid doses and PO taper determined on case by case basis always yielding at least 1000mg methylprednisolone throughout ratg course Premedication Required: Methylprednisolone 500 mg IVPB (1st three doses ONLY), diphenhydramine 25 mg po x 1, acetaminophen 650 mg po x 1 o If patients have received methylprednisolone >1000mg prior to ratg doses only use 125mg of methylprednisolone as premedication o Administer all premedications 30 to 60 minutes before ratg doses o Most common adverse effects of ratg infusion: Hypotension, rigors, fever, anaphylaxis Dose ratg daily after reviewing daily CBC with attending on rounds WBC Platelets ratg Dose > 3000 > 50, % (1.5mg/kg ) ,000 50,000 Consider reduction by 50% (Reassess hold parameters daily) < 2000 < 30,000 HOLD ratg x 24 hours CD3s should only be ordered at attending request Always administer ratg after dialysis and plasma exchange in applicable cases Review of patient, clinical response and biopsy with attending should be discussed no later than 7 days into ratg therapy to determine total duration of ratg to be administered A minimum of 1000mg of methylprednisolone should be given during ratg course (Usually in the form of pre-medication during the first 3 doses of ratg) o Steroid taper will differ according to patient starting on day #4 and should be discussed with attending and pharmacist no later than day #3 (Example: Patients with DM, HCV may receive shorter taper of steroids) Most patients remain on 5 to 10mg of prednisone after ratg therapy Restart sulfamethoxazole/trimethoprim for PCP x 6 month Restart valganciclovir for CMV prophylaxis per below guidelines on day #1 of ratg therapy o Low to Intermediate Risk: 450mg daily x 3 months o High Risk: 900mg daily x 3 months followed by 450mg x 3 months o Dose adjustments permitted base on renal function *CD3 done by flow cytometry on weekdays ONLY (unless emergent), and must be drawn at least 6 hrs after the infusion* Order must be for CBC w/ differential and absolute CD3 count* B-CELL MEDIATED, HUMORAL REJECTION IVIG, plasmapheresis, +/- thymoglobulin or rituximab treatment IVIG should be selected as sucrose-free formulation and may be 5% or 10% concentration per attending request o Premedicate with acetaminophen and diphenhydramine pre-dose 27

28 Corticosteroid Treatment Taper: ADULT LIVER TRANSPLANT REJECTION Prednisone Taper Following methylprednisolone IV for rejection: Prednisone 80mg x 2 days Prednisone 60mg x 2 days Prednisone 40mg x 2 days Prednisone 20mg x 2 days Prednisone 10mg daily x 2 days Prednisone 5mg daily To be tapered on individual basis in clinic Steroid Resistant Rejection: Thymoglobulin 1.5mg/kg IV x 7-10 days (or until resolution of graft dysfunction) Order CD3 level only after the 3 rd dose of thymoglobulin is administered. Repeat dose when ABSOLUTE CD3 count is > 10 (There should not be more than a 48 hour lapse between doses regardless of ALC or abs CD3). Do NOT order the thymoglobulin until after the attending/fellow on service has confirmed that the patient is to get it that day based on platelets, WBC and infectious parameters. Dosage reductions are recommended for the following: WBC < 2.0, ANC < 1000, Plt < 50 and/or signs and symptoms of infection. An ALC of <0.1 USUALLY correlates with an Absolute CD3 count of <10 Premedicate with methylprednisolone 10 mg/kg IVPB (1st two doses ONLY), diphenhydramine, acetaminophen Both CNI and mycophenolate should be cut in half upon initiation of thymoglobulin and reinitiated 48 hours before the completion of treatment course to allow for therapeutic serum concentrations upon completion Patients must also receive valganciclovir for CMV prophylaxis for 3-6 months and sulfamethoxazole/trimethoprim for 6 months following therapy. *CD3 done by flow cytometry on weekdays ONLY (unless emergent), and must be drawn at least 6 hrs after the infusion* Order must be for CBC w/ differential and absolute CD3 count* 28

29 Corticosteroid Treatment Taper PEDIATRIC KIDNEY TRANSPLANT REJECTION Day 1-2 Methylprednisolone 10 mg/kg IV Q 24h x 2 days (max 500 mg/dose) Day 3 Methylprednisolone 4 mg/kg IV Q 12h Day 4 Methylprednisolone 3 mg/kg IV Q 12h Day 5 Methylprednisolone 2 mg/kg IV Q 12h Day 6 Methylprednisolone 1 mg/kg IV Q 12h Day 7 Methylprednisolone 0.5 mg/kg IV Q 12h Day 8 Methylprednisolone 0.5 mg/kg IV Q 24h Day 9 RETURN TO BASELINE PREDNISONE DOSE *If patient loses access or is to be discharged, intravenous methylprednisolone may be substituted with oral prednisone or oral prednisolone. Steroid Resistant Rejection: Thymoglobulin mg/kg IV x 7-10 days (or until resolution of graft dysfunction) Order CD3 level only after the 3 rd dose of thymoglobulin is administered. Repeat dose when ABSOLUTE CD3 count is > 10 (There should not be more than a 48 hour lapse between doses regardless of ALC or abs CD3). Do NOT order the thymoglobulin until after the attending/fellow on service has confirmed that the patient is to get it that day based on platelets, WBC and infectious parameters. Dosage reductions are recommended for the following: WBC < 2.0, ANC < 1000, platelet < 50 and/or signs and symptoms of infection. An ALC of <0.1 USUALLY correlates with an Absolute CD3 count of <10 Premedicate with methylprednisolone 10 mg/kg IVPB (1st two doses ONLY), diphenhydramine, acetaminophen Both CNI and mycophenolate should be cut in half upon initiation of thymoglobulin and reinitiated 48 hours before the completion of treatment course to allow for therapeutic serum concentrations upon completion Patients must also receive valganciclovir for CMV prophylaxis for 3-6 months and sulfamethoxazole/trimethoprim for 6 months following therapy. *CD3 done by flow cytometry on weekdays ONLY (unless emergent), and must be drawn at least 6 hrs after the infusion* Order must be for CBC w/ differential and absolute CD3 count* 29

30 PEDIATRIC LIVER TRANSPLANT REJECTION Corticosteroid Treatment Taper: Day 1-2 Methylprednisolone 10 mg/kg IV Q 24h x 2 days Day 3 Methylprednisolone 4 mg/kg IV Q 12h Day 4 Methylprednisolone 3 mg/kg IV Q 12h Day 5 Methylprednisolone 2 mg/kg IV Q 12h Day 6 Methylprednisolone 1 mg/kg IV Q 12h Day 7 Methylprednisolone 0.5 mg/kg IV Q 12h Day 8 Methylprednisolone 0.5 mg/kg IV Q 24h Day 9 RETURN TO BASELINE PREDNISONE DOSE *If patient loses access or is to be discharged, intravenous methylprednisolone may be substituted with oral prednisone or oral prednisolone. Steroid Resistant Rejection: Thymoglobulin mg/kg IV x 7-10 days (or until resolution of graft dysfunction) Order CD3 level only after the 3 rd dose of thymoglobulin is administered. Repeat dose when ABSOLUTE CD3 count is > 10 (There should not be more than a 48 hour lapse between doses regardless of ALC or abs CD3) An ALC of <0.1 USUALLY correlates with an Absolute CD3 count of <10. Do NOT order the thymoglobulin until after the attending/fellow on service has confirmed that the patient is to get it that day based on platelets, WBC and infectious parameters. Dosage reductions are recommended for the following: WBC < 2.0, ANC < 1000, Plt < 50 and/or signs and symptoms of infection. Premedicate with methylprednisolone 10 mg/kg IVPB (1st two doses ONLY), diphenhydramine, acetaminophen Both CNI and mycophenolate should be cut in half upon initiation of thymoglobulin and reinitiated 48 hours before the completion of treatment course to allow for therapeutic serum concentrations upon completion Patients must also receive valganciclovir for CMV prophylaxis for 3-6 months and sulfamethoxazole/trimethoprim for 6 months following therapy. *CD3 done by flow cytometry on weekdays ONLY (unless emergent), and must be drawn at least 6 hrs after the infusion* Order must be for CBC w/ differential and absolute CD3 count* 30

31 CMV TREATMENT GUIDELINES CMV Viremia: As defined by one of the following Asymptomatic patient with CMV PCR > 1000 Positive symptoms (leukopenia, thrombocytopenia, diarrhea, malaise, fatigue, fever) with detectable blood CMV PCR Induction therapy: Valganciclovir 900 mg po BID x 14 days (adjust for renal function) Maintenance therapy: Valganciclovir 900 mg po daily (adjust for renal function) x 2-4 additional weeks depending on clinical status of patient and/ or 1 week after 2 separate undetectable viral load (time frame to be determined by physician) Monitor CMV PCR weekly until negative, then biweekly x 2, then monthly x 2 months CMV Disease: As defined by tissue invasive disease or cannot tolerate PO Induction therapy: Ganciclovir 5 mg/kg IV BID x 21 days (adjust for renal function) Maintenance therapy: Ganciclovir 5 mg/kg IV daily OR Valganciclovir 900 mg po daily (adjust dose for renal function) x 2-4 additional weeks depending on clinical status of patient and/or 1 week after 2 separate undetectable viral load (time frame to be determined by physician) Cytogam should NOT be administered unless the following: o Clinical symptoms do not improve or worsen despite adequate anti-viral therapy o Viral load continues to rise despite adequate anti-viral therapy Severe or suspected life threatening illness or severe pneumonia Biopsy proven tissue invasive disease Recommended dose: mg/kg IV x 3 doses every 4 days at the discretion of physician. Supportive Care: Decrease or hold mycophenolate until viral load < 1000 and symptoms have resolved if at all possible Valganciclovir or ganciclovir dose should not be reduced for bone marrow suppression Reduction of mycophenolate, azathioprine, sulfamethoxazole, mtori Filgrastim (Neupogen) 5mg/kg may be used as inpatient for ANC < 1000 cell/mm 3 CMV Resistance: Suspect resistance when increasing or high level CMV viremia or progressive clinical drug resistance is observed during prolonged therapy (>2 weeks). Increases in viral loads in the first week of treatment are not reliable for drug resistance. Genotype assay testing should be sent and ID team should be consulted if resistance is detected. The following therapies should be considered if resistance occurs: o High dose IV ganciclovir, Foscarnet, Cytogam, Cidofovir, o See Appendix C for suggested resistance testing 31

32 Secondary Prophylaxis: To prevent recurrent infection after successful treatment of CMV disease: Low-Moderate Risk: Valganciclovir 450 mg po daily x 3 months High Risk Risk: Valganciclovir 900 mg po daily x 3 months Pediatric CMV Treatment: Do not reduce ganciclovir dose for leucopenia Consider reduction or holding mycophenolate if at all possible days IV ganciclovir 5mg/kg/BID Consider Cytogam for tissue invasive disease Secondary prophylaxis: valganciclovir PO (dosing per above equation) x 1-3 months Alternative dosing for hematologic toxicity from above dosing: Obtain CMV PCR prior to dosage reduction If T-cell depletion has been used for rejection within 90 days consider dose reduction of other myelosuppressive agents Reduce valganciclovir to 15-18mg/kg/day 32

33 CMV Drug Resistance Algorithm 33

34 PVAN (BKV) TREATMENT GUIDELINES FOR ADULTS Kuypers, D. R.Management of polyomavirus-associated nephropathy in renal transplant recipients Nat. Rev. Nephrol April doi: /nrneph Urine Cytology Decoy Cell Screening Week 2 and 4 Month 3, 6,9, 12, 15, 18, 24 and 36 - Repeat Decoy Cells Draw Quantitative BK PCR Reduce MMF/AZA by 50% Reduce CNI goal by 30% - - If PCR is increased, obtain renal biopsy If PCR is decreased, continue to monitor If PCR is unchanged, repeat in 2 weeks 34

35 EBV Reactivation Reactivation as defined by: UNC laboratory cut off for EBV PCR >250 copies/ml o If EBV PCR > 250 copies/ml serial EBV PCRs should be conducted every two weeks until two consecutive PCRs < 250copies/mL Due to heightened risk of PTLD in the setting of EBV reactivation patients should be closely monitored for new onset malaise, weight loss, abdominal pain, fever, headaches and/or lymphadenopathy o Imaging and oncology consult are recommended in the event of increasing EBV PCRs with or without the above symptoms General Principles for PTLD management: o Reduction of immunosuppression Common modifications of regimens in the setting of PTLD: CNI monotherapy Consider replacing current agent(s ) with sirolimus Complete cessation of immunosuppression during active chemotherapy cycles o Chemotherapy/radiation Most Common Chemotherapy Regimen: R-CHOP o Surgical intervention PHARMACOGENETIC BASED PROTOCOL If pharmacogenomics profile available, the following will take place: Single Nucleotide Polymorphism CYP3A5 *3/*3 CYP3A5*1 or CYP3A5 *1/*3 CYP2D6* 17, *29 Enzyme activity: drug affected Normal enzyme activity: standard of care Non Expressor Increased enzyme activity: calcineurin inhibitor Expressor: Results in reduced overall CNI clearance and exposure by approximately 2 fold. Low enzyme activity: Oxycodone, Hydrocodone, Codeine Intermediate metabolizer: May not metabolize to active metabolize inadequate pain control Alteration of therapy Initiate Prograf 0.05 mg/kg/day in 2 divided doses Initiate Prograf 0.15 mg/kg/day in 2 divided doses Oxycodone 5-10 mg po every 4-6 hours as needed for pain Consider using alternative pain management if inadequate control 35

36 CYP2D6 *3,*4, *6, *7 CYP2D6*1, *2 Decreased enzyme activity: Oxycodone, Hydrocodone, Codeine Poor metabolizer: Cannot metabolize to active metabolite inadequate pain control Normal enzyme activity: Oxycodone, Hydrocodone, Codeine Extensive metabolizer: Standard of care Hydromorphone/Dilaudid 2-4 mg po every 4-6 hours as needed for pain Decreased activity: Oxycodone 5-10 mg po every 4-6 hours as needed for pain 36

37 PREEMPTIVE DSA MONITORING PROTOCOL FOR RENAL TRANSPLANT RECIPIENTS According to the humoral theory of transplantation, donor specific HLA antibodies are the major cause of chronic rejection and allograft loss. Despite this and a large body of evidence that links HLA antibodies to allograft dysfunction and loss, doubt remains about the cause-and-effect relationship. Although several studies support the humoral theory, confirmation of this evidence is necessary to help facilitate change in transplant practice. Prospective monitoring for de novo DSA may allow for evaluation, detection and removal of antibodies prior to the development of clinical manifestations of graft dysfunction. Additionally, investigations into the best approach to removal of antibodies are necessary. DSA Monitoring: DSAs to be collected at month 1, 3, 6, 9, 12, 15, 18, 21, 24, 28, 32, 36, 40, 44, 48 post transplant Biopsies will be performed per center specific protocol and upon detectable DSA or if clinically indicated. A biopsy with pathological findings should be followed by a repeat biopsy in 2 weeks. DSA Treatment: MFI >2000 without signs and symptoms of graft dysfunction Optimization of immunosuppression o Increase Prograf goal to ng/ml x 3 months or until 50% reduction or removal of DSA (defined by DSA MFI < 2000 MFI) Increase mycophenolate dose to 1000 mg po twice daily x 12 months from the time of DSA detection or until reduction or removal of DSA (unless toxicities/intolerance occurs) Increase to biweekly DSA monitoring until reduction or removal of DSA Detectable DSA with presence of light microscopic histologic changes consistent with acute antibody mediated rejection and/or presence of C4d in the peritubular capillaries or glomeruli Center specific treatment of antibody mediated rejection Increase to biweekly DSA monitoring until clinical and histological improvement is demonstrated and reduction or removal of DSA has occured. 37

38 NEUTROPENIA PROTOCOL Grade 1 or 2 (ANC <2000/mm 3 or <1500/mm 3 ) Consider 50% MPA dose reduction Verify valganciclovir is dose adjusted for renal function, consider decreasing to 450mg daily if on 900mg daily Consider stopping TMP/SMX if within 1 month of planned stop date Grade 3 or 4 (ANC <1000/mm 3 or <500/mm 3 ) Hold MPA. Restart 50% dose at day 5 or when ANC >2000 Verify valganciclovir is dose adjusted for renal function, consider decreasing to 450mg daily if on 900mg daily Consider stopping TMP/SMX if within 1 month of planned stop date Give G-CSF (300mcg for pt <70kg, 480mcg for pt >70kg) daily until ANC >2000, maximum of 7 doses Monitor ANC daily before doses 2 & 3, then every other day until ANC> 2000 or 7 doses. Recheck ANC 1-2 weeks after last G-CSF dose 38

39 APPENDIX A: I: Mycophenolate mofetil (Cell Cept ) and Mycophenolic Sodium (Myfortic ) Dosage Equivalents Mycophenolic Acid Derivative Formulation Standard High Dose Low Dose MMF (Cell Cept ) 750mg BID 1000mg BID 500mg BID MPS (Myfortic ) 540mg BID 720mg BID 360mg BID Alternative agent: Substitute azathioprine 1.5mg/kg PO daily in place of mycophenolate derivatives for persistent leukopenia or GI intolerance. II: Equivalent goal levels of cyclosporine, tacrolimus, sirolimus: Organ Agent Goal Month 0-6 Goal Month 6-12 Goal Month >12 KIDNEY Tacrolimus 8-10 ng/ml 6-8 ng/ml 5-7 ng/ml Cyclosporine ng/mL ng/ml ng/ml Sirolimus* 8-10 ng/ml 6-8 ng/ml 4-6 ng/ml Sirolimus +Tac Tac 4 6ng /ml Sirolimus 4 6 ng/ml Tac 3 5ng /ml Sirolimus 3 5ng/mL Tac 2 4ng /ml Sirolimus 2 4 ng/ml KIDNEY PANCREAS/ PANCREAS ALONE Tacrolimus 9-12 ng/ml 6-10 ng/ml 4-8 ng/ml Cyclosporine ng/mL ng/ml ng/ml Sirolimus* 9-12ng/mL 8-10ng/mL 6-8ng/mL Sirolimus +Tac Tac 4 6ng /ml Sirolimus 4 6 ng/ml Tac 3 5ng /ml Sirolimus 3 5 ng/ml Tac 2 4ng /ml Sirolimus 2 4 ng/ml LIVER Tacrolimus 8-10 ng/ml* Until Month ng/ml * Starting Month ng/ml Cyclosporine ng/mL ng/ml ng/ml Sirolimus* 8-10 ng/ml 6-8 ng/ml 4-6 ng/ml Sirolimus +Tac SUM= 8-10 ng/ml SUM= 6-8 ng/ml SUM= 4-6 ng/ml 39

40 *Sirolimus dosing above not intended for patients with malignancy or concomitant CNI use. For malignancy goal of sirolimus should not exceed 6-8 in combination with reduced overall immunosuppression Sirolimus + Tac :Combination is synergistically nephrotoxic, reserve for patients with severe toxicities to monotherapy with either agent APPENDIX B: COMMON DRUG INTERACTIONS WITH IMMUNOSUPPRESSION CYP3A4 Inhibitors Cardiac: Diltiazem, Verapamil, Amiodarone, Dronedarone, Erythromycin, Azithromycin, Clarithromycin, Boceprevir, Telaprevir, Ritonavir AntiFungal: Fluconazole, Itraconazole, Voriconazole, Ketoconazole, Posaconazole Dietary: Grapefruit CYP3A4 Inducers Anti-Epileptics: Carbamazepine, Phenobarbital, Phenytoin Antibiotics: Rifampin, Rifabutin Herbal: St. John s Wort APPENDIX C: CMV RESISTANCE TESTING ALGORITHM Kotton CN. International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation Transplantation. April 2010; 89: APPENDIX D: Common Drug Interaction with Anti-retroviral and Common Immunosuppression ART Interacting Transplant Medications Monitoring Considerations Additional Care Measures NRTIs (Nucleoside reverse transcriptase inhibitor) Stavudine (d4t) Mycophenolate Potential for antagonism Try to avoid use of d4t with MMF. Monitor for reduced effects of MMF 40

41 Zidovudine (ZDV) (also Combivir and Trizivir) NNRTIs (Non-nucleoside reverse transcriptase inhibitor) Delavirdine (DLV) Efavirenz (EFV) Etravirine (ETV) Nevirapine (NVP) PIs (Protease Inhibitor) Atazanavir (ATV) Darunavir/ritonavir (DRV/RTV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir/ritonavir (LPV/RTV) Nelfinavir (NFV) Mycophenolate Potential for antagonism Try to avoid use of ZDV with MMF. Monitor for reduced effects of MMF Cyclosporine, Tacrolimus, Steroids Cyclosporine, Tacrolimus, Steroids Cyclosporine, Tacrolimus, Steroids Cyclosporine, Tacrolimus, Steroids - Cyclosporine, Tacrolimus, Steroids - Mycophenolate (?) Cyclosporine, Tacrolimus, Steroids Cyclosporine, Tacrolimus, Steroids Cyclosporine, Tacrolimus, Steroids Cyclosporine, Tacrolimus, Steroids Cyclosporine, Tacrolimus, Steroids DLV inhibits P450 so may increase CYA, TAC, and steroids EFV induces P450 so will decrease CYA, TAC, and steroids ETV inhibits P450 3A and induces 2C9 and 2C19; may decrease CYA, TAC, and steroids NVP induces P450 so will decrease CYA, TAC, and steroids ATV inhibits P450 so may increase CYA, TAC, and steroids; also inhibits UGT 1A1 so may (but not likely) increase MMF (UGT 1A9 substrate) DRV/RTV inhibits P450 so may increase CYA, TAC, and steroids FPV induces P450 so may decrease CYA, TAC, and steroids; however, with RTV likely inhibits 3A4 so may increase CYA, TAC, and steroids IDV inhibits P450 so may increase CYA, TAC, and steroids LPV/RTV inhibits P450 3A and induces 1A2, 2C9, and 2C19 NFV inhibits P450 so may increase CYA, TAC, and steroids Monitor for increased toxicity of CYA, TAC and steroids Monitor for rejection Monitor for rejection Monitor for rejection Monitor for increased toxicity of CYA, TAC, steroids, and MMF Monitor for increased toxicity of CYA, TAC, steroids - Monitor for rejection OR - Monitor for increased toxicity of CYA, TAC, steroids, and MMF Monitor for increased toxicity of CYA, TAC, steroids Monitor for increased toxicity of CYA, TAC, steroids Monitor for increased toxicity of CYA, TAC, steroids 41

42 Ritonavir (RTV) Saquinavir (SQV) Tipranavir/ritonavir (TPV/RTV) Cyclosporine, Tacrolimus, Steroids Cyclosporine, Tacrolimus, Steroids Cyclosporine, Tacrolimus, Steroids Low doses of RTV ( mg QD-BID) potently inhibits P450 so will increase CYA, TAC, and steroids SQV inhibits P450 so may increase CYA, TAC, and steroids TPV/RTV inhibits 3A so may increase CYA, TAC, and steroids Monitor for increased toxicity of CYA, TAC, steroids Monitor for increased toxicity of CYA, TAC, steroids Monitor for increased toxicity of CYA, TAC, steroids 42

43 APPENDIX E: Common Drug Interaction with Anti-retroviral and Common Medications Used Post Transplantation Other Therapies Interacting ART Monitoring Considerations Additional Care Measures Acid Suppression Agents Proton Pump Inhibitors H2-blockers (Ranitidine, etc) Antiepileptics Phenytoin, Phenobarbital, carbamazepine, oxcarbazepine Antifungals Ketoconazole, itraconzole Atazanavir and Indinavir Atazanavir and Indinavir NNRTIs and PIs CSA, FK, Rapa NNRTIs and PIs CSA, FK, Rapa ATV and IDV have ph dependent absorption so PPIs interact ATV and IDV have ph dependent absorption so H2 blockers interact These antiepileptics greatly decrease rx concentrations Monitor trough values of anti-rejection meds closely Keto and itra may increase ART concentrations and vice versa Will increase levels of anti-rejection meds Avoid concomitant use. If use is required page HIV provider. Do not use w/o RTV. Do not use more than dose equivalent of famotidine 40mg BID ATV 300mg + RTV 100mg should be given simultaneously or 10 hrs after H2 blocker In ART experienced pts also taking tenofovir, use ATV 400mg + RTV 100mg QD Avoid concomitant use with ARTs Monitor for toxicity of both azole and ARTs Monitor CSA, FK, & Rapa troughs closely 43

44 Voriconazole NNRTIs and PIs CSA, FK, Rapa Vori may increase ARTs & antirejection meds NNRTIs may decrease Vori PIs may increase Vori Fluconazole CSA, FK, Rapa Fluc will increase antirejection meds Antihypertensives Calcium channel blockers Non-dihydropyridine CCBs Beta-blockers (metoprolol, propranolol) Antituberculosis Meds Rifampin If concomitant use is required consult with ID Avoid use with Rapa Decrease CSA & FK to 25-30% of starting doses Decrease doses to 50% of starting doses if on 400 mg (or renally dosed equivalent) For doses < 400 mg, can monitor trough levels closely or empirically decrease doses by < 50% Atazanavir ATV can prolong QT interval. If used concomitantly with CCB baseline EKG is suggested. FK, CSA, Rapa Diltiazem & verapamil can Monitor trough Protease inhibitors (especially RTV) NNRTIs and PIs CSA, FK, Rapa increase levels Pis may increase some betablockers RIF will decrease these meds levels closely Atenolol is OK to use. If use is required consult with ID. Monitor trough levels closely with antirejection meds Increase dose of raltegravir to 800mg BID 44

45 Rifabutin Asthma Therapies Inhaled or nasal steroids Long acting beta blockers (salmeterol, formoterol) Benzodiazepines Midazolam, triazolam Erectile Dysfunction Meds Sildenfafil, Tadalafil, Vardenafil HMG CoA reductase inhibitors Simvastatin, lovastatin, fluvastatin, pravastatin, atorvastatin Simvastatin, lovastatin, fluvastatin, Atorvastatin >20mg QD NNRTIs and PIs CSA, FK, Rapa Protease inhibitors (especially RTV) Protease inhibitors (especially RTV) Protease inhibitors (especially RTV) Protease inhibitors (especially RTV) CSA, FK, RAPA Efavirenz, nevirapine, and etravirine (NNRTIs) Protease inhibitors (especially RTV) RBT usually has little effect on ARTs NNRTIs decrease RBT PIs increase RBT May decrease levels of antirejection meds PIs can greatly increase inhaled steroid concentrations systemically (most data with fluticasone) PIs may increase LABAs PIs are contraindicated with these BDZs All of these medications will increase concentrations of ED meds. EFV, NVP, and ETR may decrease exposure to statins (except rosuvastatin). PIs greatly increase these particular statins Dose adjustments for RBT are needed for concomitant use with NNRTIs and PIs. Consult ID Monitor trough levels closely with antirejection meds If inhaled steroid needed consider beclomethasone or budesonide (no data for this). If fluticasone required monitor cortisol reqularly. Monitor for toxicity of LABA or avoid concomitant use Avoid concomitant use Dose modifications for ED meds are required. Do not start at more than 25 mg of sildenafil (or the equivalent) Higher doses of statins will likely be needed. Do not use concomitantly with PIs. OK to use pravastatin, atorvastatin up to 20mg QD, and rosuvastatin 45

46 Simvastatin, lovastatin, fluvastatin, atorvastatin CSA, FK, RAPA These medications may increase exposure to statins. Do not use more than 40 mg of any of these. Okay to use atorvastatin 40 mg unless on PI (see above) APPENDIX F: PHARMACOGENOMIC LITERATURE SUMMARY Pharmacogenetics: The study of how genetic variations influence drug activity or an organism s reactions to a drug. Overview: It has been shown that people respond different to drug therapy despite traditional factors that influence bioavailability. It is estimated that genetic variation can account for 20-95% of drug disposition and effects. A priori knowledge of individual susceptibility and individualizing post-transplant pharmacotherapy based on genetic profiling may allow for more precise dosing than empirical dosing followed by incessant therapeutic drug monitoring. Drug metabolism: can be broken down into 2 phases: Phase I: drug is chemically activated. Typical enzymes involved in phase I of drug metabolism are cytochrome P450 oxidoreductases. Phase II: chemically activated drug is conjugated with a highly water soluble molecule increasing the water solubility of the drug and enabling elimination from the body through urine or bile. Typical phase II enzymes are UGT Single Nucleotide Polymorphism involved in post-transplant medications: Common single base pair variation in a genetic sequence. Greater than 11 million SNPs are known in humans today. CYP3A5: Cyp3A5 is reported in detectable amounts in only 10 to 30% of adult white people and Asians, whereas 60% of African Americans express the protein. Tacrolimus is metabolized by CYP3A in gut and liver and transported in the gut by p-glycoprotein (encoded by ABCB1 gene) CYP3A5*1 (wild type)= expressor CYP3A5*3/*3 (mutant allele; homozygous for *3 mutation) = non expressor Two recent studies using modern immunosuppression post kidney transplant showed that lower tacrolimus troughs in the first week post-transplant were associated with greater risk of rejection [1,2]. It is also well established through literature that P450 CYP3A5*1 variant allele is associated with higher clearance and lower systemic exposure. Furthermore, because of the growing use of steroid sparing and avoidance protocols, the importance of early immunosuppression intensity provided by CNI or other immunosuppressive exposure is important in minimizing risk of acute rejection [3]. Trial Design Result Borobia et al. N= 57 KTR UVA showed the following as the 46

47 Trough tacrolimus concentration in the first week after kidney transplantation are related to acute rejection Ther Drug Monit Aug;31(4): [5] Holt DW et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant Jun;4(6):914 [6] Quteineh L et al. Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. Basic Clin Pharmacol Toxicol Dec;103(6):546 [7] Descriptive analytic study IS: basiliximab, Tac dose of 0.1 mg/kg /day, MMF 500 mg bid, prednisone Primary outcome: Evaluate the relationship between tacrolimus trough concentrations within the first week after transplantation and the rate of acute rejection N=178 renal transplant recipients (expressors = 53, nonexpressors = 125) Purpose: assess the relationship between concentration-controlled dosing during the early period after transplantation, the time to achieve target concentrations N= 136 renal graft recipients Genotypes were correlated to tacrolimus daily dose at 1-week, 1-, 6- and 12-month posttransplantation and with transplantation outcome Purpose : determine influence of CYP3A5 and ABCB1 genetic polymorphisms on tac daily requirements and on transplantation outcome. following as significant differences between rejectors and non rejectors: Donor age Duration of hospital stay CrCL at 3 months Mean tacrolimus trough concentrations on day 5 (p=0.009), 7 (p=0.012), mean of days 1-7 (p=0.006) and mean of days 5-7 (0.035) In KMA, patients with tacrolimus trough concentrations below 9.3 mg/ml on day 5 showed lower survival time without AR (p 0.048) Expressors required twofold higher tacrolimus dose to achieve target blood concentrations than individuals nonexpressors Expressors had lower mean tac concentrations during first week (13.5 vs microg/l, p < ) with significant delay in achieving target concentrations (15-20 microg/l during week 1, then microg/l). More non expressor patients had tac concentrations above target during the first week (73.6% vs. 35.8%, p = 0.003). No difference in the rate of BPAR, but rejection occurred earlier in expressors (median 7 d vs. 13 d, p = 0.005). At 1-month post-transplantation, tacrolimus daily dose was higher for patients with CYP3A5*1/*1 genotype (exressor) vs CYP3A5*3/*3 genotype (nonexpressor), (0.26 +/ versus / mg/kg/day, respectively, P < ). Similar results were obtained at 6- and 12-month. CYP3A5*1/*1 were associated with increased risk of AR episodes vs patients 47

48 Thervet et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clinical Pharmacology and therapeutics [4] N= 280 KTR Single center prospectively assigned either to: Genotype based dosing for CYP3A5*1: 0.3 mg/kg/day Genotype based dosing for Non CYP3A5*3/*3 : 0.15 mg/kg /day Standard dosing: 0.2 mg/kg/day basiliximab induction + cellcept 2-3 grams/day, prednisone to 10 mg Primary endpoint : proportion of patients within target C0 Secondary endpoint: number of dose modifications and delay in achieving the targeted C0 with CYP3A5*1/*3 and*3/*3 (38% versus 10% and 9%, respectively, P = 0.01) Proportion that reached targeted C0 at day 3: Genotype based dosing : 43.2% vs. Standard dosing: 29.1%, (p = 0.03) Required fewer dose modifications, and the targeted C(0) was achieved by 75% of these patients more rapidly See table and figure below. 48

49 CYP2D6: Acute pain is a complex and subjective experience that is a predictable consequence of surgery. Untreated, it is associated with significant physiological, mental, and economic consequences. Despite the vast amount of current knowledge, uncontrolled postoperative pain is reported by approximately 50% of patients. Uncontrolled pain increases the risk of long hospital stays and complications, however too much pain relief can slow recovery and increase the risk of falls. Individualizing therapy for pain control my better predict drug non-response and adverse toxicities. Oxycodone is metabolized into oxymorphone by CYP2D6 and noroxycodone by CYP3A4 and CYP3A5 Oxymorphone is meant to be more potent at the mu opiate receptor than oxycodone In CYP2D6 poor metabolizers (PM), the conversion to oxymorphone does not take place. In those cases, and including our patient, accumulation of oxycodone or noroxycodone may lead increased toxicity. At the same time, a 2D6 PM would not have the benefit of analgesic effect from the metabolite oxymorphone, which is thought to be more potent at the m opiate receptor than oxycodone. Hydrocodone is metabolized to hydromorphone by CYP2D6 and norhydrocodone by CYP3A4 Hydromorphone has 7-33 times more binding potency to the mu receptor than hydrocodone. CYP2D6 poor metabolizers may experience a decrease in analgesic response due to lack of conversion to potent metabolite. Allele variant CYP2D6*1, *2 CYP2D6*17, *29 CYP2D6 Metabolism Activity Extensive metabolizer- normal activity Intermediate metabolizer- low activity Frequency data 77-92% Caucasian 2-11% Caucasian 49