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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
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ADULT KIDNEY TRANSPLANT – INDUCTION AND MAINTENANCE REGIMEN
¥ 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
Adult Kidney Transplant Induction
1. Standard SCD, ECD, DCD
2. Previous abdominal transplant
3. Patient on >1 immunosuppressive agent
STANDARD
Alemtuzumab 30 mg* IV on POD 0
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
1. HCV+
Anti-Thymocyte Globulin 2mg/kg* IV on
POD 0, 1, 2
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
1. Previous heart or lung transplant
2. History of cyclophosphamide
3. 6 of 6 HLA match**
LOW RISK
Basiliximab 20 mg IV on POD 0 ,4
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**
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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: 216-3617). 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 anti-thymocyte globulin infusion. Methylprednisolone premedication dosing should be as follows:
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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
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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)
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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
1:128 5 1, 4, 6, 8, 11 (IVIG after 5th TPE treatment* )
1:256 6 1, 4, 6, 8, 11, 13 (IVIG after 5th 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
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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.,
1:81:161:32) 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.
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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
O2 < 92%
UOP < 50 cc/hr x 2 hours
UOP volume decreases suddenly o Incentive spirometry x 10 Q1H o Wean O2 to sats > 90% o SCDs continuous
Diet o NPO except meds/ice chips, then diet when BF returns o IVF: D51/2NS @ ____________
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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
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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 60-90 day intervals for 12m after transplant o at 90-120 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 on-call 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.
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Continue premedication with acetaminophen, diphenhydramine, and methylprednisolone 30 minutes prior to each anti-thymocyte 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): Pre-operative (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 25-50 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: 250-300 ng/mL o Months 3-12: 150-250 ng/mL o Months > 12: 100-200 ng/mL
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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 H2-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 post-operatively 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 post-transplant 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 > 200.
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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
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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 post-operatively 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 0.025 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: 10-12 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.
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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 0.025 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: 10-12 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.
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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
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> 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)
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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.
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PEDIATRIC KIDNEY TRANSPLANT
*Round all doses to the nearest 25mg
*Requires pre-medication with methylprednisolone, acetaminophen and diphenhydramine
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)
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
Tacrolimus 0.05-0.15mg/kg PO BID
Mycophenolate 600mg/m2 BID
x 2-4 weeks
Then decrease to 450mg/m2 BID
Low-Risk:
1. Non-African American
2. Peak PRA <20%
3. Primary transplant
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 0.05-0.1mg/kg PO BID
Mycophenolate 600mg/m2 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
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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 intra-operatively 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 30-60 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 0.05-0.1mg/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 1.25-1.5m2 -750mg BID If BSA > 1.5mg/m2 -1000mg BID
Myfortic: If BSA 1.19-1.58m2 -540mg BID
If BSA > 1.59m2 - 720mg BID
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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 15-30 prednisolone 0.4 mg/kg PO Q 24h POD 30-60 prednisolone 0.3 mg/kg PO Q 24h POD 60-90 prednisolone 0.2 mg/kg PO Q 24h POD 90-120 prednisolone 0.1 mg/kg PO Q 24h POD 120-180 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 30-60 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.
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Doses are to be adjusted based upon trough levels as follows: 0 – 3 months: 11-13 ng/mL 3 – 12 months: 10-12 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/m2
30-39 kg = 500 mg
40-59 kg = 750 mg
60 kg = 1000 mg
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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 Donor +/ Recipient -)
valganciclovir 900 mg PO daily x 3 months, then 450 mg PO daily x 3 months
6 months
Intermediate risk (Donor+/Recipient +) (Donor-/Recipient +)
Valganciclovir 450 mg PO daily 3 months
Low risk (Donor - / Recipient -)
acyclovir 400 mg PO BID 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
Clcr 40-59 mL/minute: 450 mg once daily Clcr 25-39 mL/minute: 450 mg every 2 days Clcr 10-24 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
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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 Donor +/ Recipient -)
valganciclovir 900 mg PO daily x 3 months, then 450 mg PO daily x 3 months
6 months
Intermediate risk (Donor+/Recipient +) (Donor-/Recipient +)
Valganciclovir 450 mg PO daily 3 months
Low risk (Donor - / Recipient -)
acyclovir 400 mg PO BID 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
Clcr 40-59 mL/minute: 450 mg once daily Clcr 25-39 mL/minute: 450 mg every 2 days Clcr 10-24 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 > 100
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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.
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 CMV:
Risk Status Agent/Dose/Regimen Duration
High risk Donor +/ Recipient -)
valganciclovir 900 mg PO daily x 3 months, then 450 mg PO daily x 3 months
6 months
Intermediate risk (Donor+/Recipient +) (Donor-/Recipient +)
Valganciclovir 450 mg PO daily 3 months
Low risk (Donor - / Recipient -)
acyclovir 400 mg PO BID 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
Clcr 40-59 mL/minute: 450 mg once daily Clcr 25-39 mL/minute: 450 mg every 2 days Clcr 10-24 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
26
PEDIATRIC KIDNEY TRANSPLANT Pediatric CMV Prophylaxis:
Valganciclovir(mg)=7 x BSA x CrCl (Per modified Schwartz formula; cut-off at 150 mL/min/1.73 m2)
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 How to calculate IDEAL BODY WEIGHT:
MALES: 50kg + (Inches over 60 x 2.3)
FEMALES: 45.5kg + (Inches over 60 x 2.3)
o 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)
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o 72hr prior to end of theapy increase CNI dose to attain 100% goal and reassess previous goal with attending
o Mycophenolate (Cell Cept, Myfortic): Discontinue until rATG is finished
o Restart full dose mycophenolate after last dose of rATG is administered
o 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 > 50,000 100% (1.5mg/kg¥)
2000 – 3000 30,000 – 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
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ADULT LIVER TRANSPLANT REJECTION Corticosteroid Treatment Taper: 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 3rd 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*
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PEDIATRIC KIDNEY TRANSPLANT REJECTION
Corticosteroid Treatment Taper
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 1.5-2 mg/kg IV x 7-10 days (or until resolution of graft dysfunction)
Order CD3 level only after the 3rd 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*
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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 1.5-2 mg/kg IV x 7-10 days (or until resolution of graft dysfunction)
Order CD3 level only after the 3rd 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*
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: 100- 150 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/mm3
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
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
14-21 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
33
CMV Drug Resistance Algorithm
34
PVAN (BKV) TREATMENT GUIDELINES FOR ADULTS
Kuypers, D. R .Management of polyomavirus-associated nephropathy in renal transplant recipients Nat. Rev. Nephrol April 2012.
doi:10.1038/nrneph.2012.64
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
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
Enzyme activity: drug affected Alteration of therapy
CYP3A5 *3/*3 Normal enzyme activity: standard of
care
Non Expressor
Initiate Prograf 0.05 mg/kg/day in 2
divided doses
CYP3A5*1 or
CYP3A5 *1/*3
Increased enzyme activity:
calcineurin inhibitor
Expressor: Results in reduced
overall CNI clearance and exposure
by approximately 2 fold.
Initiate Prograf 0.15 mg/kg/day in 2
divided doses
CYP2D6* 17, *29 Low enzyme activity: Oxycodone,
Hydrocodone, Codeine
Intermediate metabolizer: May not
metabolize to active metabolize
inadequate pain control
Oxycodone 5-10 mg po every 4-6
hours as needed for pain
Consider using alternative pain
management if inadequate control
36
CYP2D6 *3,*4, *6,
*7
Decreased enzyme activity:
Oxycodone, Hydrocodone, Codeine
Poor metabolizer: Cannot
metabolize to active metabolite
inadequate pain control
Hydromorphone/Dilaudid 2-4 mg po
every 4-6 hours as needed for pain
Decreased activity:
CYP2D6*1, *2 Normal enzyme activity:
Oxycodone, Hydrocodone, Codeine
Extensive metabolizer: Standard of
care
Oxycodone 5-10 mg po every 4-6
hours as needed for pain
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 10-15 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.
38
NEUTROPENIA PROTOCOL
Grade 1 or 2 (ANC <2000/mm3 or <1500/mm3)
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/mm3 or <500/mm3)
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
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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 200-250ng/mL 150-200 ng/mL 100-150 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 250-300ng/mL 150-250 ng/mL 125-175 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 3
6-8 ng/mL * Starting Month 3
4-6 ng/mL
Cyclosporine 200-250ng/mL 150-200 ng/mL 100-150 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
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 CYP3A4 Inducers
Cardiac: Diltiazem, Verapamil, Amiodarone,
Dronedarone, Erythromycin, Azithromycin,
Clarithromycin, Boceprevir, Telaprevir, Ritonavir
Anti-Epileptics: Carbamazepine, Phenobarbital,
Phenytoin
AntiFungal: Fluconazole, Itraconazole,
Voriconazole, Ketoconazole, Posaconazole
Antibiotics: Rifampin, Rifabutin
Dietary: Grapefruit 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: 779-795
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
41
Zidovudine (ZDV) (also Combivir and Trizivir)
Mycophenolate Potential for antagonism Try to avoid use of ZDV with MMF. Monitor for reduced effects of MMF
NNRTIs (Non-nucleoside
reverse transcriptase
inhibitor)
Delavirdine (DLV) Cyclosporine, Tacrolimus, Steroids
DLV inhibits P450 so may increase CYA, TAC, and steroids
Monitor for increased toxicity of CYA, TAC and steroids
Efavirenz (EFV) Cyclosporine, Tacrolimus, Steroids
EFV induces P450 so will decrease CYA, TAC, and steroids
Monitor for rejection
Etravirine (ETV) Cyclosporine, Tacrolimus, Steroids
ETV inhibits P450 3A and induces 2C9 and 2C19; may decrease CYA, TAC, and steroids
Monitor for rejection
Nevirapine (NVP) Cyclosporine, Tacrolimus, Steroids
NVP induces P450 so will decrease CYA, TAC, and steroids
Monitor for rejection
PIs (Protease Inhibitor)
Atazanavir (ATV) - Cyclosporine, Tacrolimus, Steroids - Mycophenolate (?)
ATV inhibits P450 so may increase CYA, TAC, and steroids; also inhibits UGT 1A1 so may (but not likely) increase MMF (UGT 1A9 substrate)
Monitor for increased toxicity of CYA, TAC, steroids, and MMF
Darunavir/ritonavir (DRV/RTV)
Cyclosporine, Tacrolimus, Steroids
DRV/RTV inhibits P450 so may increase CYA, TAC, and steroids
Monitor for increased toxicity of CYA, TAC, steroids
Fosamprenavir (FPV)
Cyclosporine, Tacrolimus, Steroids
FPV induces P450 so may decrease CYA, TAC, and steroids; however, with RTV likely inhibits 3A4 so may increase CYA, TAC, and steroids
- Monitor for rejection OR - Monitor for increased toxicity of CYA, TAC, steroids, and MMF
Indinavir (IDV) Cyclosporine, Tacrolimus, Steroids
IDV inhibits P450 so may increase CYA, TAC, and steroids
Monitor for increased toxicity of CYA, TAC, steroids
Lopinavir/ritonavir (LPV/RTV)
Cyclosporine, Tacrolimus, Steroids
LPV/RTV inhibits P450 3A and induces 1A2, 2C9, and 2C19
Monitor for increased toxicity of CYA, TAC, steroids
Nelfinavir (NFV) Cyclosporine, Tacrolimus, Steroids
NFV inhibits P450 so may increase CYA, TAC, and steroids
Monitor for increased toxicity of CYA, TAC, steroids
42
Ritonavir (RTV) Cyclosporine, Tacrolimus, Steroids
Low doses of RTV (100-200mg QD-BID) potently inhibits P450 so will increase CYA, TAC, and steroids
Monitor for increased toxicity of CYA, TAC, steroids
Saquinavir (SQV) Cyclosporine, Tacrolimus, Steroids
SQV inhibits P450 so may increase CYA, TAC, and steroids
Monitor for increased toxicity of CYA, TAC, steroids
Tipranavir/ritonavir (TPV/RTV)
Cyclosporine, Tacrolimus, Steroids
TPV/RTV inhibits 3A so may increase CYA, TAC, and steroids
Monitor for increased toxicity of CYA, TAC, steroids
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
Atazanavir and Indinavir ATV and IDV have pH dependent absorption so PPIs interact
Avoid concomitant use. If use is required page HIV provider.
H2-blockers (Ranitidine, etc)
Atazanavir and Indinavir ATV and IDV have pH dependent absorption so H2 blockers interact
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
Antiepileptics
Phenytoin, Phenobarbital, carbamazepine, oxcarbazepine
NNRTIs and PIs
CSA, FK, Rapa
These antiepileptics greatly decrease rx concentrations
Monitor trough values of anti-rejection meds closely
Avoid concomitant use with ARTs
Antifungals
Ketoconazole, itraconzole
NNRTIs and PIs
CSA, FK, Rapa
Keto and itra may increase ART concentrations and vice versa
Will increase levels of anti-rejection meds
Monitor for toxicity of both azole and ARTs
Monitor CSA, FK, & Rapa troughs closely
44
Voriconazole NNRTIs and PIs
CSA, FK, Rapa
Vori may increase ARTs & antirejection meds
NNRTIs may decrease Vori
PIs may increase Vori
If concomitant use is required consult with ID
Avoid use with Rapa
Decrease CSA & FK to 25-30% of starting doses
Fluconazole CSA, FK, Rapa Fluc will increase antirejection meds
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%
Antihypertensives
Calcium channel blockers
Atazanavir ATV can prolong QT interval. If used concomitantly with CCB baseline EKG is suggested.
Non-dihydropyridine CCBs
FK, CSA, Rapa Diltiazem & verapamil can increase levels
Monitor trough levels closely
Beta-blockers (metoprolol, propranolol)
Protease inhibitors (especially RTV)
Pis may increase some beta-blockers
Atenolol is OK to use.
Antituberculosis Meds
Rifampin NNRTIs and PIs
CSA, FK, Rapa
RIF will decrease these meds If use is required consult with ID.
Monitor trough levels closely with anti-rejection meds
Increase dose of raltegravir to 800mg BID
45
Rifabutin NNRTIs and PIs
CSA, FK, Rapa
RBT usually has little effect on ARTs
NNRTIs decrease RBT
PIs increase RBT
May decrease levels of antirejection meds
Dose adjustments for RBT are needed for concomitant use with NNRTIs and PIs.
Consult ID
Monitor trough levels closely with anti-rejection meds
Asthma Therapies
Inhaled or nasal steroids
Protease inhibitors (especially RTV)
PIs can greatly increase inhaled steroid concentrations systemically (most data with fluticasone)
If inhaled steroid needed consider beclomethasone or budesonide (no data for this). If fluticasone required monitor cortisol reqularly.
Long acting beta blockers (salmeterol, formoterol)
Protease inhibitors (especially RTV)
PIs may increase LABAs Monitor for toxicity of LABA or avoid concomitant use
Benzodiazepines
Midazolam, triazolam Protease inhibitors (especially RTV)
PIs are contraindicated with these BDZs
Avoid concomitant use
Erectile Dysfunction Meds
Sildenfafil, Tadalafil, Vardenafil
Protease inhibitors (especially RTV)
CSA, FK, RAPA
All of these medications will increase concentrations of ED meds.
Dose modifications for ED meds are required. Do not start at more than 25 mg of sildenafil (or the equivalent)
HMG CoA reductase inhibitors
Simvastatin, lovastatin, fluvastatin, pravastatin, atorvastatin
Efavirenz, nevirapine, and etravirine (NNRTIs)
EFV, NVP, and ETR may decrease exposure to statins (except rosuvastatin).
Higher doses of statins will likely be needed.
Simvastatin, lovastatin, fluvastatin, Atorvastatin >20mg QD
Protease inhibitors (especially RTV)
PIs greatly increase these particular statins
Do not use concomitantly with PIs. OK to use pravastatin, atorvastatin up to 20mg QD, and rosuvastatin
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
47
Trough tacrolimus concentration in the first week after kidney transplantation are related to acute rejection Ther Drug Monit. 2009 Aug;31(4):436-42. [5]
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
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)
Holt DW et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant. 2004 Jun;4(6):914 [6]
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
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. 18.5 microg/L, p < 0.0001) with significant delay in achieving target concentrations (15-20 microg/L during week 1, then 10-15 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).
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. 2008 Dec;103(6):546 [7]
N= 136 renal graft recipients Genotypes were correlated to tacrolimus daily dose at 1-week, 1-, 6- and 12-month post-transplantation and with transplantation outcome Purpose : determine influence of CYP3A5 and ABCB1 genetic polymorphisms on tac daily requirements and on transplantation outcome.
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 +/- 0.03 versus 0.16 +/- 0.01 mg/kg/day, respectively, P < 0.0001). Similar results were obtained at 6- and 12-month. CYP3A5*1/*1 were associated with increased risk of AR episodes vs patients
48
with CYP3A5*1/*3 and*3/*3 (38% versus 10% and 9%, respectively, P = 0.01)
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
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.
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 Metabolism Activity
Frequency data
CYP2D6*1, *2 Extensive metabolizer- normal activity
77-92% Caucasian
CYP2D6*17, *29 Intermediate metabolizer- low activity
2-11% Caucasian
50
CYP2D6*3, *4, *6 , *7 Poor metabolizer- no activity 5-10% Caucasian 2-5% African American
Individuals carrying 2 functional alleles
Ultra rapid metabolizer – high activity
1-2% Caucasian
Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic liver enzyme of the cytochrome P450 super family involved with the metabolism and elimination of many commonly prescribed drugs. Genetic polymorphism in CYP2D6 is common and can affect therapeutic response to these drugs. The enzyme activity is expressed at highly variable levels. CYP2D6 is considered a low-capacity, high-affinity enzyme and CYP2D6 will preferentially metabolize drugs at lower concentrations. As the concentration of a drug increases, the metabolism spills over to CYP3A4 and CYP1A2, which are high-capacity, low-affinity enzymes. Thus if a drug that has several metabolic pathways but relies on CYP2D6 as its major pathway is given to a patient with poor CYP2D6 activity, the other P-450 enzymes that are high capacity, low affinity will clear the drug, but clearance will be slower and less efficient, and drug levels will increase, increasing the risk for adverse drug reactions.
Four phenotypes are identified: Extensive metabolizers (EMs) have one or two functional copies of the CYP2D6 gene and metabolize CYP2D6 substrates normally. Intermediate metabolizers (IMs) have one nonfunctional and one low activity allele and metabolize substrates at a low rate potentially requiring lower than average drug dose of optimal therapeutic response to medications. Poor metabolizers (PMs) have two nonfunctional alleles and cannot metabolize substrates, yielding increased risk of adverse effects. Alternative treatment should be considered. Ultrarapid metabolizers (UMs) have three or more copies of a functional 2D6 gene, causing them to metabolize substrates rapidly, which can lead to poor response to standard doses of a drug, therapeutic failure and may require an increased dose of drugs. All metabolizer groups vary among different racial and ethnic groups. There are ethnic differences in distribution of PMs, IMs and UMs. Approximately 7-14% of Caucasians are poor metabolizers (PM) and lack functional CYP2D6. The genetic basis for poor metabolizers is now well defined. The four most common mutant alleles are CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6 and account for 93-97% of the PM phenotypes in the Caucasian population. A recent review indicated that Asians, Pacific Islanders, African and African Americans have higher percentages of reduced functional or non-functional CYP2D6 alleles (between 40% and 50%) vs Caucasians (26%). Therefore the percentages of PMs in Asians and African Americans are most likely higher. Non-functional PMs and reduced function IMs represent about 50% of African populations (non functional CYP2D6*17 represents 35% of allele variation). African Americans show twice the allele frequency of PMs compared with Africans (14.5% vs 6.3%). References:
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