university of north carolina hospital scut monkey...

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



1. HCV+

Anti-Thymocyte Globulin 2mg/kg* IV on

POD 0, 1, 2


Mycophenolate 750mg PO BID





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


Mycophenolate 1000mg BID**





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)


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)


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.

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:


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):


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

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)

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:


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):


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.

19

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

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 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):


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

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 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)


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)


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.

22

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

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 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

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:




6 months










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

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.

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:




6 months










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)

27

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

28

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.



29

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






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 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.






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

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 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


Sirolimus* 9-12ng/mL 8-10ng/mL 6-8ng/mL

Sirolimus +Tac¥ Tac 4 – 6ng /mL Sirolimus 4 – 6 ng/mL



LIVER Tacrolimus 8-10 ng/mL* Until

Month 3

6-8 ng/mL * Starting Month 3

4-6 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


Nevirapine (NVP) Cyclosporine, Tacrolimus, Steroids

NVP induces P450 so will decrease CYA, TAC, and steroids


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)


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


Lopinavir/ritonavir (LPV/RTV)


LPV/RTV inhibits P450 3A and induces 1A2, 2C9, and 2C19


Nelfinavir (NFV) Cyclosporine, Tacrolimus, Steroids

NFV inhibits P450 so may increase CYA, TAC, and 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


Saquinavir (SQV) Cyclosporine, Tacrolimus, Steroids

SQV inhibits P450 so may increase CYA, TAC, and steroids


Tipranavir/ritonavir (TPV/RTV)


TPV/RTV inhibits 3A so may increase CYA, TAC, and 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


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)


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


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


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

http://www.ncbi.nlm.nih.gov/pubmed?term=%E2%80%A2%09Borobia%20AM.%20Trough%20tacrolimus%20concentration%20in%20the%20first%20week%20after%20kidney%20transplantation%20are%20related%20to%20acute%20rejection.%20Ther%20Drug%20Monit.%202009%3B%2031%3A%20436-42

http://www.ncbi.nlm.nih.gov/pubmed?term=Am%20J%20Transplant%202004%3B%204%20(6)%3A%20914-9


http://www.ncbi.nlm.nih.gov/pubmed?term=Influence%20of%20CYP3A5%20genetic%20polymorphism%20on%20tacrolimus%20daily%20dose%20requirements%20and%20acute%20rejection%20in%20renal%20graft%20recipients.%20Basic%20Clin%20pharmcaol%20Toxicol%202009%3B%20103%3A%20546-52.%20



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:

1. Evans WE, McLeod HL. Pharmacogenomics--drug disposition, drug targets, and side effects. N Engl J Med. 2003;348:538–49

2. Roy J et al. CYP3A5 genetic polymorphisms in different ethnic populations. Drug Metab Dispos. 2005 Jul;33(7):884-7. Epub 2005 Apr 15.

3. Seaghdha CM. Higher tacrolimus trough levels on days 2-5 post renal transplant are associated with reduced rates of

acute rejection. Clin Transplant 2009 ; 23: 462—8.

4. Undre et al. Low systemic exposure to tacrolimus correlates with acute rejection. Transplant Proc 1999; 31: 296-298

5. Thervet E et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clinical Pharmacology and

therapeticus. 2010: 87: 721-26

6. Borobia AM. Trough tacrolimus concentration in the first week after kidney transplantation are related to acute

rejection. Ther Drug Monit. 2009; 31: 436-42

http://www.ncbi.nlm.nih.gov/pubmed/15833928

51

7. 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):914-9.

8. Quteineh L. Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in

renal graft recipients. Basic Clin pharmcaol Toxicol 2009; 103: 546-52.

9. Staatz CE, Effects of CYP3A and ABCB1 single nucleotide polymorphisms on paharmacokinetics and pharmacodynamics

of calcinueirn inhibitors: Part I. Clini Pharmacokinet. 2010; 49: 141-75

10. Tzvetkov M. Pharmacogenetic screening for drug therapy: from single gene markers to decision making in the next

generation sequencing era. Pathology. 2012; 44: 166-180.

11. VanderVaart, S et al.Complicated Pain Management in a CYP450 2D6 Poor Metabolizer. Ther Drug Monit. 2011

Aug;33(4):425-32.

12. Allegri M et al. Pharmacogenetics and postoperative pain: a new approach to improve acute pain management. Minerva

Anestesiol. 2010 Nov;76(11):937-44.

13. Foster A et al. Complicated pain management in a CYP450 2D6 poor metabolizer. Pain Pract. 2007 Dec;7(4):352-6.

Epub 2007 Nov 6.

14. Mercadante S et al. Prospects and challenges in opioid analgesia for pain management. Curr Med Res Opin. 2011

Sep;27(9):1741-3. Epub 2011 Jul 19

15. http://www.pharmgkb.org/

16. http://www.cypalleles.ki.se/cyp2d6.htm

17. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Codeine Therapy in the Context of

Cytochrome P450 2D6 (CYP2D6) Genotype. Clinical Pharmacology and Therapeutics. December 2011; 91: 2

doi:10.1038/clpt.2011.287



http://www.ncbi.nlm.nih.gov/pubmed?term=Allegri%20M%5BAuthor%5D&cauthor=true&cauthor_uid=21102389

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http://www.ncbi.nlm.nih.gov/pubmed?term=allegri%20pharmacogenomicpain



http://www.cypalleles.ki.se/cyp2a6.htm

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