Policy: Post-Liver Transplant Outpatient Immunosuppression Protocol
Statement:
1. Activation date: 4/28/08
2. Affected Department: Liver Transplant Program
3. Vision Strategy: Patient care
4. Policy Statement: The Emory Transplant Center will comply with all applicable federal, state
and local laws, regulations and policies regarding the management of prescribing medications
and refills.
5. Basis: This policy is necessary for the protection of patients, physicians and staff.
6. Administrative Responsibility: Section heads, physicians, practitioners and staff are
responsible for compliance with this policy.
Scope/Procedure:
1. Tacrolimus (Prograf)
a. Tacrolimus is the preferred initial agent utilized in post-liver transplant immunosuppression.
Dosage will be adjusted based on disease process and serum tacrolimus levels. Tacrolimus
dosage should be decreased in the presence of adverse events as clinically warranted. Dosage
adjustments should be balanced between severity and timing of rejection episodes in relation to
date of transplant.
b. In the first 3 months post-transplant, tacrolimus levels should be targeted to 8-12ng/ml. See
the chart below for other goal trough levels. Trough level goals should be individualized to the
patient.
c. Tacrolimus conversion to other immunosuppressive agents may be considered if toxicities
persist. Dosing of any additional immunosuppressive agents will be individualized to a particular
patient depending upon the clinical events leading to conversion. Reasons to convert from
tacrolimus to a different immunosuppressive agent (such as sirolimus or cyclosporine) include
the following:
i. Nephrotoxicity
ii. GI toxicity
iii. Neurotoxicity not responsive to reasonable attempts at dosage adjustments or other
intervention
iv. Hyperglycemia not responsive to dosage adjustments or treatment with oral antidiabetic
agents
v. Hemolytic Uremic Syndrome (HUS)
vi. Severe alopecia
d. When converting tacrolimus to sirolimus, the dose of tacrolimus should be reduced by onehalf and sirolimus should be initiated at a dose of 2 or 3 mg daily. Sirolimus levels should be
checked approximately 5-7 days after initiation and tacrolimus should be discontinued once
sirolimus level is therapeutic. Sirolimus is not recommended as monotherapy due to a potential
increase in acute cellular rejection.
e. When converting tacrolimus to everolimus, the dose of tacrolimus should be reduced by onehalf and everolimus should be initiated at 1.5 mg BID. Everolimus levels should be checked
approximately 5 days after initiation and tacrolimus should be discontinued once the everolimus
level is therapeutic. Everolimus is not recommended as monotherapy due to a potential increase
in acute cellular rejection.
2. Cyclosporine (Gengraf)
a. Cyclosporine is often utilized in patients who do not tolerate tacrolimus well (see Section 1b
above). Dosage should be individualized for each patient based on disease process and serum
cyclosporine levels. Cyclosporine dosage should be decreased in the presence of adverse events
as clinically warranted. Dosage adjustments should be balanced between severity and timing of
rejection episodes in relation to date of transplant.
b. Patients newly started on cyclosporine should be started on modified cyclosporine (Gengraf or
Neoral) equivalent formula of cyclosporine. Non-modified cyclosporine (Sandimmune) should
not be used for patients starting on cyclosporine.
c. In the first 3 months post-transplant, cyclosporine levels should be targeted 150-180. See the
chart below for other goal trough levels. Trough level goals should be individualized to the
patient.
d. Dose adjustment of cyclosporine or conversion to another immunosuppressive agent such as
sirolimus (Rapamune) should be considered for adverse events such as gingival hyperplasia,
persistent hypertension, excessive growth of hair and nephrotoxicity.
e. When converting from cyclosporine to sirolimus, reduce the cyclosporine dose by one-half,
and initiate sirolimus at 2 or 3 mg daily. Sirolimus levels should be checked approximately 5-7
days after initiation and cyclosporine should be discontinued once sirolimus level is therapeutic.
Sirolimus is not recommended as monotherapy due to a potential increase in acute cellular
rejection.
f. When converting cyclosporine to everolimus, the dose of cyclosporine should be reduced by
one-half and everolimus should be initiated at 1.5 mg BID. Everolimus levels should be checked
approximately 5 days after initiation and cyclosporine should be discontinued once the
everolimus level is therapeutic. Everolimus is not recommended as monotherapy due to a
potential increase in acute cellular rejection.
3. Mycophenolate mofetil (CellCept)
a. Mycophenolate mofetil (MMF or CellCept) can be used as part of a dual or triple
immunosuppressive regimen. MMF will be dosed at 1 gram Q12hr initially post-transplant.
b. MMF should be avoided in patients desiring to become pregnant. A REMS program has been
developed due to higher risk of miscarriage within the first 3 months of pregnancy and higher
risk of birth defects with MMF.
c. MMF should be reduced in the following situations:
i. WBC < 3
1. Decrease dose by 50%
2. Obtain differential
ii. WBC < 2
1. Hold MMF
2. Obtain differential
iii. ANC < 500
1. Hold MMF
2. Administer filgastrim (Neupogen) 480 mcg SQ
iv. Severe diarrhea/nausea/vomiting
1. Change interval to four times daily, maintaining current
dose
2. Decrease dose by 50%
v. Severe Infection
1. Decrease dose by 50%
d. Reasons to discontinue MMF early include the following:
i. Bone marrow suppression not responsive to dose reduction
ii. GI toxicity not responsive to dose interval changes (i.e. 4 times daily) or dosage reduction (i.e.
500mg BID)
ii. Severe infection
e. Dosage may be increased to 1500mg BID at the discretion of the transplant team for higher
immunosuppressive levels.
f. Myfortic (mycophenolic acid)
i. Mycophenolic acid may be considered as an alternative to MMF for those patients that
continue to have GI intolerance to MMF or do not tolerate the dose reduction of MMF
ii. Dosing: MMF 1000mg PO BID = Myfortic 720mg PO BID
Myfortic is available in 180mg and 360mg tablets
4. Sirolimus (Rapamune)
a. Sirolimus may be considered in patients 30 days or more from transplant due to the potential
risk for delayed wound healing and hepatic artery thrombosis. It may be used as a substitute for
tacrolimus in the event of persistent renal insufficiency. Sirolimus conversion should be
considered if a patient has a creatinine clearance consistently below 60 mL/min or increased Scr
from baseline (see Renal Sparing Protocol). Sirolimus may also have beneficial anti-tumor
effects as well and may have a role in patients with skin cancer, HCC, renal cell carcinoma or
other malignancies.
b. If sirolimus is utilized it will be at an initial dose of 2 - 3 mg per day. Doses should be
individualized for each patient based on disease process and serum sirolimus levels. Sirolimus is
not recommended as monotherapy due to a potential increase in acute cellular rejection.
c. Prior to initiating sirolimus, the following laboratory values should be obtained: spot urine
protein, baseline fasting glucose, HbgA1c, fasting lipid profile with triglycerides. A fasting lipid
profile should be obtained in 1-3 months after initiation of sirolimus therapy. mTOR inhibitors
should not be used if the urine protein is > 800 mg/dL. If a patient is receiving an mTOR
inhibitor with increased triglycerides, consider changing immunosuppression if triglycerides
unable to be controlled. See Concomitant Medication Protocol for more information.
d. Conversion to a calcineurin inhibitor (CNI) should be considered in any patient on sirolimus
undergoing a surgical operation, such as a hernia repair, prior to the scheduled surgical date to
help promote better wound healing post procedure. Patients may be converted back to sirolimus
after the wound has healed.
5. Everolimus (Zortress)
a. Everolimus may be considered in patients 30 days or more from transplant due to the potential
risk for delayed wound healing and of hepatic artery thrombosis. It may be used as a substitute
for tacrolimus in the event of persistent renal insufficiency. Everolimus conversion should be
considered if a patient has a creatinine clearance consistently below 60 mL/min or increased Scr
from baseline (see Renal Sparing Protocol). Everolimus may also have beneficial anti-tumor
effects as well and may have a role in patients with skin cancer, HCC, renal cell carcinoma or
other malignancies.
b. Usual starting dose of everolimus is 1-1.5mg PO q12hr. Initial goal trough levels should range
8-12ng/ml. Everolimus is not recommended as monotherapy due to a potential increase in acute
cellular rejection.
c. Prior to initiating everolimus, the following laboratory values should be obtained: spot urine
protein, baseline fasting glucose, HbgA1c, fasting lipid profile with triglycerides. A fasting lipid
profile should be obtained in 1-3 months after initiation of everolimus therapy. The wound
should be healed prior to initiation of everolimus. mTOR inhibitors should not be used if the
urine protein is > 800 mg/dL. If a patient is receiving an mTOR inhibitor with increased
triglycerides, consider changing immunosuppression if triglycerides unable to be controlled. See
Concomitant Medication Protocol for more information.
e. Conversion to a CNI should be considered in any patient on everolimus undergoing a surgical
operation, such as a hernia repair, prior to the scheduled surgical date to help promote better
would healing post procedure. Patients may be converted back to everolimus after the wound is
healed.
6. Steroids (prednisone)
a. Steroids may be used as part of the initial post-transplant induction phase (see Inpatient
Immunosuppressive Protocol).
b. Patients are to be weaned off steroids based on their primary disease and freedom from
rejection. Weaning of steroids is based entirely on the clinical presentation of patients. Patients
with autoimmune hepatitis (AIH) may not benefit from steroid weans and may be maintained on
5-10mg prednisone daily.
7. Use of generic immunosuppression
a. The use of generic immunosuppression is allowed. The transplant team encourages patients to
take generics from the same manufacturer, when possible, to minimize potential effects on
trough levels.
Table 1. Immunosuppressive Levels and Steroid Taper
0-3
3-6
6-12
Drug
months
months
months
> 1 year
Tacrolimus (Prograf)
levels 8-12 levels 6-8 levels 6-8 levels 3-5
Cyclosporine (Gengraf)
MMF (Cellcept)
Sirolimus (Rapamune) or
Everolimus (Zortress)
levels 150180
1000mg
BID
1month 812
levels 100150
1000mg
BID
levels 75125
1000mg
BID
levels 4levels 6-12 10
levels 50100
1000mg
BID*
levels 3-8
6
>1
10 days
1 month
2 months 3 months months year
20mg
Off at day
QAM
10mg
5mg
90
off
20mg
AIH
QAM
10mg
5 mg
5mg
5mg
5mg
*Consider decreasing or eliminating mycophenolate after 1 year post-transplant on a case by
case basis.
Immunosuppressive regimens will be individualized on a case by case basis based on creatinine,
serum potassium, liver function profile, history of rejection or CMV status, and underlying
disease process.
Prednisone
Non-Viral Hepatitis,
HBV/Others, PSC, PBC
References:
Simone PD, Nevens F, DeCarlis L, et al. Everolimus with reduced tacrolimus improves renal
function in de novo liver transplant recipients: a randomized controlled trial. AJT 2012; 12:
3008-3020.
Fisher L, Klempnauer J, Beckebaum S, et al. A randomized, controlled study to assess the
conversion from Calcineurin inhibitors to everolimus after liver transplantation – PROTECT.
AJT 2012;12: 1855-1865.
Masetti M, Montalti R, Rompianesi, et al. Early withdrawal of Calcineurin inhibitors and
everolimus monotherapy in de novo liver transplant recipients preserves renal function. AJT
2010;10: 2252-2262.
Neupogen® (filgrastim) [package insert]. Thousand Oaks, CA: Amgen Inc.; 2015.
Related Policies/Procedures: Concomitant medications, Renal-sparing protocol
Approved by: Liver Transplant Leadership Group
__________________________________
Joseph Magliocca, MD
Chair, Liver Transplant Leadership Group
Director, Liver Transplant Program
____________________________________
Ram Subramanian, MD
Medical Director, Liver Transplant Program
Approval Dates: 4/28/08, 3/8/10, 4/2011, 5/13/2011, 7/2013, 6/24/2014, 5/19/2016
Regulatory References:
Related Policies/Procedures: