Related | Appendix A: Liver Transplant
Copyright © 2021 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission
Contact: CCKM@uwhealth.org Last Revised: 07/2021
Tacrolimus – liver transplant
Recommendations Notes/Evidence
Initiation Post-operative day 1 • Initiation of tacrolimus should on post-
operative day 1 after transplant (UW Health,
Very Low, Conditional)
Dosing
(initial)
Standard dosing Fixed dose 2 mg by mouth twice daily • Capsules and suspension may be taken with or
without food. Since the presence of food affects
the bioavailability of tacrolimus, if taken with
food, it should be taken consistently the same
way each time. (UW Health, Very Low,
Conditional)
• Tacrolimus may be given sublingually in patients
unable to adequately absorb enteral
formulations or in those unable to take oral. If a
patient is being transitioned to tacrolimus
sublingual from tacrolimus IR, each dose should
be divided by 2 and given sublingually. (UW
Health, Very Low, Conditional)
• Use of IV should be considered rare and risky
and only considered in the inpatient setting.
Only after discussion with an experienced
transplant pharmacist and the faculty of record
can it be considered. Conversion from IV to oral
tacrolimus is recommended as soon as enteral
therapy can be tolerated to minimize risk of
anaphylactic reactions that occur with
injectables containing castor oil derivatives.
(UW Health, Very Low, Conditional)
• LCP-Tacrolimus (Envarsus®) may be utilized in
patients with documented intolerable adverse
effects with tacrolimus IR or who are unable to
obtain a therapeutic drug concentration with
the IR formulation. If a patient is being
transitioned to LCP-tacrolimus from tacrolimus
IR, the total daily dose should be multiplied by
0.8, then rounded to the nearest tablet size.
Astagraf, Envarsus, and Prograf are not
interchangeable (UW Health, Very Low,
Conditional)
Increased sensitivity (on CYP3A4 inhibitor - see list
below)
Fixed dose 1 mg by mouth twice daily
Drug-drug
Interactions
(not an all-
inclusive
list)
Increases tacrolimus concentration
*Check Lexicomp for dose adjustments*
Adjust tacrolimus dose empirically for the
following CYP4 inhibitors:
• Fluconazole
• Posaconazole
• Voriconazole
• Ritonavir
• Letermovir
Monitor tacrolimus levels and adjust as needed:
• Clarithromycin
• Erythromycin
Decreases tacrolimus concentration
*Check Lexicomp for dose adjustments*
Monitor tacrolimus levels and adjust as needed:
• Rifampin
• Phenytoin
• Carbamazepine
• Phenobarbital
Target levels
Dose
Adjustments
Labs
Autoimmune
disease and
not on MPA
NOT
autoimmune
OR on MPA
0-3 months: 8-10 ng/mL 5-7 ng/mL
3-6 months: 8-10 ng/mL 5-7ng/mL
6-12 months: 6-8 ng/mL 3-5 ng/mL
>12 months: 4-6 ng/mL 2-5 ng/mL
*Above trough goals are general guidance, and
immunosuppression should be tailored to
patient’s immunologic risk and tolerance of
medications*
Below/Above
Target
>50% Adjust dose by 25-50%*
<50% Adjust dose by 25%
*Holding doses may be necessary
Laboratory Monitoring:
Tacrolimus (trough), potassium, and creatinine
Inpatient: Daily
Outpatient:
Day after discharge Frequency
0-30 Twice weekly
31-90 Not less than weekly
91-180 Not less than twice
monthly
181-365 Not less than once
monthly
Modify as Needed on a Patient-by-Patient basis:
• Change in medication formulation, patient
status, or creatinine increase >0.3 mg/dL
above baseline
• 3 to 7 days (ideally 4 days) following dose
adjustment
Effective 6-17-2021. Contact CCKM@uwhealth.org for previous versions.
Copyright © 2021 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission
Contact: CCKM@uwhealth.org Last Revised: 07/2021
Adverse
effects
Acute kidney injury • Assess tacrolimus trough level for correlation with elevated creatinine
• If trough level is above goal and creatinine has increased > 0.3 mg/dL above baseline:
o Decrease tacrolimus dose if trough is <4 ng/mL above goal
o Hold tacrolimus if trough >5 ng/mL above goal and consider increasing current prednisone
dose
• Consult transplant physician regarding further work up elevated creatinine
Neurological symptoms (tremor, headache) • Assess tacrolimus trough level for correlation with tremors or headache
• If trough level is above goal, adjust tacrolimus dose and follow up with patient
• If trough level within target range, no dose adjustment is recommended, follow-up with patient in 1
week to assess continued symptoms and trend severity
• If adverse effects are persistent, not improving, or interfering with daily activities and there is no
other known cause:
• Consult the transplant physician to consider splitting IR tacrolimus to three times daily or
converting the patient to LCP-tacrolimus or cyclosporine
• Addition of a low dose propranolol may also be considered if heart rate >60 BPM, systolic blood
pressure >120 mmHg, and patient is not already on a beta blocker
New onset diabetes after transplantation
(NODAT)
Diagnosis (2 of the following)
• Sx of DM + casual PG concentrations >200
mg/dL
• FPG >126 mg/dL
• 2-hr PG >200 mg/dL during an oral glucose
tolerance test
• Hba1c > 7.0% for more than 2 months
• No tacrolimus dose adjustment is recommended
• Consult diabetes management & nutrition services
• Diagnosis of new onset diabetes after transplant (NODAT) is defined by the World Health
Organization (WHO) and American Diabetes Association (ADA) that develops for the first time after
transplantation
• Continue planned discontinuation of glucocorticoids by 2 months
• If there is no improvement in glucose control 6 months after transplant (NODAT requiring insulin OR
A1c >7% with glucose lowering agent):
o Consult transplant physician and consider reassessment of steroid dosing or conversion to LCP-
tacrolimus
Effective 6-17-2021. Contact CCKM@uwhealth.org for previous versions.
Copyright © 2021 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission
Contact: CCKM@uwhealth.org Last Revised: 07/2021
Cyclosporine – liver transplant
Recommendations Notes/Evidence
Initiation Post-operative day 1 • The initiation of cyclosporine should start post-
operative day 1 after transplant (UW Health, Very
Low, Conditional)
Dosing
(initial)
Standard dosing Fixed dose 150 mg by mouth twice daily • Neoral/Gengraf (cyclosporine modified) and
Sandimmune (cyclosporine non-modified) are not
bioequivalent and cannot be used
interchangeably (UW Health, Very Low,
Conditional)
• Cyclosporine modified is preferred over
cyclosporine non-modified (UW Health, Very Low,
Conditional)
• Capsules and suspension may be taken with or
without food. However, since the presence of
food affects the bioavailability of cyclosporine, if
taken with food, it should be taken consistently
the same way each time. (UW Health, Very Low,
Conditional)
Increased sensitivity (on CYP3A4 inhibitor - see list
below)
Fixed dose 100 mg by mouth twice daily
Drug-Drug
Interactions
(not an all-
inclusive
list)
Increases cyclosporine concentration
*Check Lexicomp for dose adjustments*
Adjust cyclosporine dose empirically for the
following CYP4 inhibitors:
• Fluconazole
• Posaconazole
• Voriconazole
• Ritonavir
• Letermovir
Monitor cyclosporine levels and adjust as needed:
• Clarithromycin
• Erythromycin
Decreases cyclosporine concentration
*Check Lexicomp for dose adjustments*
Monitor cyclosporine levels and adjust as
needed:
• Rifampin
• Phenytoin
• Carbamazepine
• Phenobarbital
Target levels
Dose
Adjustments
Labs
Autoimmune
disease and
not on MPA
NOT
autoimmune
OR on MPA
0-3 mo: 150-200 ng/mL 125-175 ng/mL
3-6 mo: 125-150 ng/mL 125-150 ng/mL
6-12 mo: 100-125 ng/mL 75-100 ng/mL
>12 mo: 100 ng/mL 50-75 ng/mL
*Above trough goals are general guidance, and
immunosuppression should be tailored to
patient’s immunologic risk and tolerance of
medications*
Below/Above
Target
>50% Adjust dose 25% to 50%
<50% Adjust dose by 25%
*Holding doses may be necessary
Laboratory Monitoring:
Cyclosporine (trough), potassium, and
creatinine
Inpatient: Daily
Post-Discharge:
Day Frequency
0-30 Twice weekly
31-90 Not less than weekly
91-180 Not less than twice
monthly
181-365 Not less than once
monthly
Modify as Needed on a Patient-by-Patient
basis:
• Change in medication formulation, patient
status, or creatinine increase >0.3 mg/dL
above baseline
• 3 to 7 days (ideally 4 days) following dose
adjustment
Effective 6-17-2021. Contact CCKM@uwhealth.org for previous versions.
Copyright © 2021 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission
Contact: CCKM@uwhealth.org Last Revised: 07/2021
Adverse
effects
Acute kidney injury • Assess cyclosporine trough level for correlation with elevated creatinine
• If trough level is above goal and creatinine has increased > 0.3 mg/dL above baseline:
o Decrease cyclosporine dose if trough is <50 ng/mL above goal
o Hold cyclosporine if trough >50 ng/mL above goal and consider increasing current prednisone
dose
• Consult transplant physician regarding further work up elevated creatinine
Neurological symptoms (tremor, headache) • Assess cyclosporine trough level for correlation with tremors or headache
• If trough level is above goal, adjust cyclosporine dose and follow up with patient
• If trough level within target range, no dose adjustment is recommended, follow-up with patient in 1
week to assess continued symptoms and trend severity
• If adverse effects are intolerable or interacting with daily activities and there is no other known cause
of symptom:
o Consult the transplant physician to consider converting the patient to LCP-tacrolimus
o Addition of a low dose propranolol may also be considered if heart rate >60 BPM, systolic blood
pressure >120 mmHg, and patient is not already on a beta blocker
New onset diabetes after transplantation
(NODAT)
Diagnosis (2 of the following)
• Sx of DM + casual PG concentrations >200
mg/dL
• FPG >126 mg/dL
• 2-hr PG >200 mg/dL during an oral glucose
tolerance test
• Hba1c > 7.0% for more than 2 months
• No cyclosporine dose adjustment is recommended
• Consult diabetes management & nutrition services
• Diagnosis of new onset diabetes after transplant (NODAT) is defined by the World Health Organization
(WHO) and American Diabetes Association (ADA) that develops for the first time after transplantation
• Continue planned discontinuation of glucocorticoids by 60 days
• If there is no improvement in glucose control 6 months after transplant (NODAT requiring insulin OR
A1c >7% with glucose lowering agent):
• Consult transplant physician and consider reassessment of steroid dosing or conversion to other
immunosuppressant
Effective 6-17-2021. Contact CCKM@uwhealth.org for previous versions.
Copyright © 2021 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission
Contact: CCKM@uwhealth.org Last Revised: 07/2021
Mycophenolate – liver transplant
Recommendation Notes/Evidence
Initiation Post-operative day 0 • Full dose mycophenolic acid is the preferred anti-
proliferative medication used for liver transplant
patients (UW Health, Very Low, Conditional)
• IV mycophenolate mofetil is indicated if the patient
has an acute condition that affects gastrointestinal
absorption (i.e., GI bleed or obstruction,
malabsorption syndromes, severe diarrhea or
severe vomiting) (UW Health, Very Low,
Conditional)
• Mycophenolate mofetil suspension is utilized for
patients receiving medications via nasogastric or
orogastric tube
Dosing
(initial)
Mycophenolate mofetil
1000 mg IV x 1 dose POD0
1000 mg IV twice daily x 4 doses POD1-2
Mycophenolate sodium 720 mg PO twice daily and after POD3
Drug-drug
interactions
(not an all-
inclusive
list)
Medications that decrease mycophenolate concentration
• Cyclosporine
• Bile acid sequestrants
Mycophenolate decreases concentration of estrogen derivatives. Women of childbearing potential
who are receiving mycophenolate mofetil should consider using an alternative and/or additional
form of contraception.
*Check Lexicomp for dose adjustments*
Target
levels
Labs Laboratory Monitoring:
• Lab monitoring of MPA levels is not recommended to assess for toxicity or efficacy
• If levels are requested, they are only appropriate for mycophenolate mofetil and should be
drawn as a trough
Goal MPA Trough
CsA or TAC based regimens 1.0-3.5 mg/L
• MPA AUC is a better predictor of clinical events
than MPA trough. Trough levels are poorly
correlated with AUC and are not recommended
(UW Health, Very Low, Conditional)
• Levels may be utilized for assessing safety; not
recommended to assess efficacy
Adverse
effects
Diarrhea
If a patient has ≥50% increase in their frequency of daily
bowel movements for ≥ 5-7 days
• 0-3 months post-transplant:
o C. difficile, C. difficile toxin B PCR
o CMV PCR
• ≥3 months post-transplant:
o CMV PCR
o Complete blood count
o Clostridium difficile toxin B PCR
o Cryptosporidium
o Giardia PCR
o Norovirus PCR
o Rotavirus AG
o Stool culture, with E. Coli (Shiga) toxin
o Stool O&P (parasitology, isospora, cyclospora,
pinworm)
o Consider colonoscopy if diarrhea persists and all
stool studies are negative
*In any patient post-liver transplant with diarrhea in the
first 6 months, consider graft-versus-host disease
• If diarrhea work-up is negative for an infectious cause of diarrhea and it is affecting activities of daily
living or the patient is having limited and/or decreased oral intake:
o Decrease mycophenolate by 25% and increase dosing frequency (ex. 720 mg BID → 360 mg
TID)
▪ If fails, decrease mycophenolate by 50%
o Follow up with patient in 1 week to assess continued symptoms and trend severity
o If dose is decreased to 180 mg twice daily (MYF) or 250 mg twice daily (MMF) consult
provider to determine if other immunosuppression needs to be adjusted
o Consider adding the following:
▪ Add loperamide (Imodium®) 2 mg as needed after each loose stool (max dose: 16
mg daily)
▪ Diphenoxylate/atropine (Lomotil®) 5 mg four times daily as needed (max dose: 20
mg/day)
▪ Psyllium fiber (Metamucil®) 3.4 g daily as needed
• If patient is continuing to have symptoms despite lowering immunosuppression, discuss with
transplant provider
Leukopenia • Consult transplant physician regarding further work up leukopenia
• Adjust dose based on following recommendations:
o WBC 2-4 x 109/L: Could consider decrease in total daily dose by 50%
o WBC <2 x 109/L: Hold doses until leukopenia resolves
Effective 6-17-2021. Contact CCKM@uwhealth.org for previous versions.
Copyright © 2021 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission
Contact: CCKM@uwhealth.org Last Revised: 07/2021
• Consider dose modifications or discontinuations of other medications that may cause leukopenia
• If leukopenia persists despite medication changes, consider graft-versus-host disease
Heartburn/nausea • Counsel patient on taking MYF or MMF with food if not already doing so
• Convert from MMF to MYF if only upper GI complaints (heartburn, nausea)
• Add calcium carbonate as needed, or the addition of an H2RA or PPI if not already on
• If symptoms continue following 1 week of daily therapy increase H2RA or PPI dose to twice daily,
reassess in 1 week
• If symptoms persist for ≥1 week, consider EGD to rule out infection vs. ulceration
Effective 6-17-2021. Contact CCKM@uwhealth.org for previous versions.
Copyright © 2021 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission
Contact: CCKM@uwhealth.org Last Revised: 07/2021
Azathioprine – liver transplant
Recommendation Notes/Evidence
Initiation Failure to tolerate mycophenolate • Azathioprine is recommended for use in patients
unable to tolerate adverse effects of mycophenolate
(UW Health, Very Low, Conditional)
Dosing
(initial)
1-3 mg/kg by mouth daily rounded to nearest 25 mg dose • Azathioprine is considered to be less effective than
MPA in preventing rejection. Prior to initiating
azathioprine, consider the total immunosuppression
for the patient and timing out from transplant
• Azathioprine 50 mg tablets should be prescribed as
azathioprine 75 and 100 mg tablets are not available
as generic and are more expensive
Drug-drug
interactions
(not an all-
inclusive
list)
Increases azathioprine concentration:
*Check Lexicomp for dose adjustments*
Avoid concurrent use:
• Febuxostat
Adjust azathioprine dose empirically:
• Allopurinol
Labs Laboratory Monitoring:
• Monitor CBC with differential and platelets weekly during first month, twice monthly for
months 2 and 3, then monthly thereafter; monitor more frequently with dose modifications
• Monitor LFTs every 3 months while on treatment
• There is no recommended azathioprine level for monitoring purposes. However, if toxicity is
suspected, check thiopurine methyltransferase (TPMT)
Adverse
effects
Leukopenia • Consult transplant provider if WBC <3 and consider checking thiopurine methyltransferase (TPMT)
Gastrointestinal
If a patient has ≥50% increase in their frequency of daily
bowel movements for ≥ 5-7 days
• 0-3 months post-transplant:
o C. difficile, C. difficile toxin B PCR
o CMV PCR
• ≥3 months post-transplant:
o CMV PCR
o Complete blood count
o Clostridium difficile toxin B PCR
o Cryptosporidium
o Giardia PCR
o Norovirus PCR
o Rotavirus AG
o Stool culture, with E. Coli (Shiga) toxin
o Stool O&P (parasitology, isospora, cyclospora,
pinworm)
Consider colonoscopy if diarrhea persists and all stool
studies are negative
• See diarrhea work-up algorithm
Pancreatitis • Consult transplant provider if suspected based on patient symptoms
Effective 6-17-2021. Contact CCKM@uwhealth.org for previous versions.
Copyright © 2021 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission
Contact: CCKM@uwhealth.org Last Revised: 07/2021
Sirolimus/everolimus – liver transplant
Recommendations Notes/Evidence
Initiation For use in patients with:
• CNI toxicity
• Skin cancer
• Recurrent hepatocellular carcinoma
• Renal dysfunction
Quadruple therapy
• Sirolimus/everolimus may impair or delay wound healing,
and should be used with caution in the peri-surgical
period (UW Health, Very Low, Conditional)
• Sirolimus should not be used within 30 days of liver
transplant due to risk of hepatic artery thrombosis (UW
Health, Very Low, Conditional)
• May be indicated for use in patients with recurrent skin
cancers as a replacement for azathioprine, MPA, or CNIs
(UW Health, Very Low, Conditional)
Dosing (initial) Sirolimus 2 mg by mouth once daily
Everolimus 0.75 mg by mouth twice daily
Drug-drug
interactions (not
an all-inclusive
list)
Increase mTOR concentration (not an all-
inclusive list):
*Check Lexicomp for dose adjustments*
Avoid concurrent use:
• Posaconazole
• Voriconazole
• Ritonavir
Monitor mTOR levels and adjust as needed:
• Fluconazole
• Ritonavir
• Letermovir
• Clarithromycin
• Erythromycin
Decrease mTOR concentration (not an all-
inclusive list)
*Check Lexicomp for dose adjustments*
Monitor mTOR levels and adjust as needed:
• Rifampin
• Phenytoin
• Carbamazepine
• Phenobarbital
Target levels
Dose
Adjustments
Labs
Goal Trough Levels (Siro/Evr+FK) Goal Trough Levels (Siro/Evr+MPA)
0-3 mo: Siro/Evr: 4-7 ng/mL; FK: 5-7 ng/mL Siro/Evr: 8-10 ng/mL
3-6 mo: Siro/Evr: 4-7 ng/mL; FK: 5-7 ng/mL Siro/Evr: 8-10 ng/mL
6-12 mo: Siro/Evr: 3-5 ng/mL; FK: 3-5 ng/mL Siro/Evr: 5-8 ng/mL
>12 mo: Siro/Evr: 3-5 ng/mL; FK: 3-5 ng/mL Siro/Evr: 5-8 ng/mL
*Above trough goals are general guidance, and immunosuppression should be tailored to
patient’s immunologic risk and tolerance of medications*
Laboratory Monitoring:
• Recommended monitoring trough level once weekly upon initiation and with any dose
changes
• When target trough level has been attained, recommend monitoring levels once monthly
• Monitor fasting lipids profile annually, proteinuria at 6 months and then annually post-
transplant, and LFTs and CBC while on therapy.
Effective 6-17-2021. Contact CCKM@uwhealth.org for previous versions.
Copyright © 2021 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission
Contact: CCKM@uwhealth.org Last Revised: 07/2021
Adverse Effects Proteinuria • Consider administration of angiotensin-converting enzyme (ACE)-inhibitors and angiotensin II receptor
antagonists and reducing mTOR levels
Mouth ulcers • Development of mouth ulcers seems to be dose-related because they usually appear after the loading
dose and often improve after a dose reduction
• Addition of a high-potency topical steroid may be considered
Hyperlipidemia • Follow current guidelines for management (diet, exercise, lipid lowering agents)
• Immunosuppressive strategies minimizing doses of mTORs, CNIs, or corticosteroids may help in
controlling hyperlipidemia
Leukopenia • Consider dose reduction or temporary drug suspension if appropriate
Thrombocytopenia • Consider dose reduction or temporary drug suspension if appropriate
Anemia • Consider dose reduction or temporary drug suspension if appropriate
Effective 6-17-2021. Contact CCKM@uwhealth.org for previous versions.
Copyright © 2021 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission
Contact: CCKM@uwhealth.org Last Revised: 07/2021
Prednisone – liver transplant
Recommendations Notes/Evidence
Initiation Post-operative day 5 following dexamethasone taper • Prednisone 10 mg twice daily will be
started on POD 5 following
dexamethasone taper and may be
continued on discharge
Dosing
(initial)
Standard steroid taper
• Prednisone taper should occur following
POD5
• Assessment for prednisone taper should
occur at 3-4 weeks post-operatively for
patients without autoimmune disease
• Factors that may influence the duration of
prednisone taper:
o Current and historical CNI levels
o Current and historical MPA dosing
o Current liver function
o Episodes of rejection
o Perceived rejection and infection risk
Dexamethasone 100 mg POD0
50 mg POD1
25 mg POD2
12 mg POD3
6 mg POD4
Prednisone 10 mg BID POD5
Without
autoimmune
disease
Decrease by 5 mg every 2 weeks until gone
With
autoimmune
disease
Decrease by 5 mg every 2 weeks to a dose
of 5 mg daily
• Prednisone doses should be split to
twice daily dosing for patients requiring
insulin for glucose control (UW Health,
Very Low, Conditional)
• Patient should be off prednisone by 2
months post-transplant and
maintained on tacrolimus and
mycophenolate but is based on
provider discretion
• For patients on doses higher than 20
mg daily for anticipated duration of
greater than 2 weeks, PJP prophylaxis
should be initiated
Labs Laboratory Monitoring:
Glucose, bone mineral density
Adverse
effects
Hyperglycemia • Prednisone doses should be split to twice daily dosing for patients requiring insulin for glucose control
Heartburn/reflux • Start a proton pump inhibitor (PPI) at time of transplant
• If a patient complains of heartburn on daily dosing of the PPI, frequency may be increased to twice daily
(pending renal function)
• Discontinue PPI in patients with no history of heartburn/gastroesophageal reflux disease (GERD) prior to
transplant if prednisone is discontinued
Osteoporosis • Recommend calcium 1200 mg daily (based on elemental calcium dosing)
• Recommend vitamin D 2000 units daily
Effective 6-17-2021. Contact CCKM@uwhealth.org for previous versions.