10/18/23, 12:48 PM Role of Posttransplant Immunosuppressive Agents

 COVID-19 Resources 

PUBLISHED JULY 18, 2023

Role of Posttransplant Immunosuppressive Agents

Yvette C. Terrie, BS Pharm, RPh

Consultant Pharmacist/Medical Writer
Haymarket, Virginia

US Pharm. 2023;48(7):26-32.

ABSTRACT: Patients who have undergone organ transplant surgery require

immunosuppressive therapy to decrease and/or prevent rejection episodes.
The therapy regimens often involve multiple medications, which require routine
monitoring and adjustments when warranted. Adherence to these therapies is
critical to successful clinical outcomes. As integral healthcare team members,
pharmacists are well poised to educate transplant patients about the drug
regimens generally prescribed post transplant, including immunosuppressive
agents, proper use, and potential adverse effects. Pharmacists can also be
instrumental in making clinical recommendations to optimize drug efficacy and
safety and to manage and diminish the incidence of adverse effects while
improving clinical outcomes and health-related quality of life.

For numerous individuals with end-stage organ failure, organ transplant

surgeries (e.g., kidney, liver, heart, lungs, and pancreas) have given these
patients an opportunity to save their lives and prolong their survival. Over the
past 60 years, organ transplants have been considered one of the most
noteworthy advances in medicine.1,2 According to preliminary data from the
United Network for Organ Sharing (UNOS), there were multiple milestones for
transplants in 2022.1 The organization reported that in 2022, there were more
than 42,887 organ transplants performed in the United States, marking a rise
of 3.7% compared with those performed in 2021.1 Additionally, UNOS states
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that 2022 marked the first year on record in which 24,498 kidney transplants
were performed in the United States, with a 3.4% increase over those
performed in 2021. In addition, annual records were documented for liver
(9,528), heart (4,111), and lung (2,692) transplants.1

Patients and their families often face numerous physical, psychological, and
financial challenges throughout the transplantation process, including
adapting to a complex regimen of various medications to decrease the
incidence of organ rejection, infections, and mortality. Therefore,
implementing a multidisciplinary approach to patient education by providing
information about the transplant process, available resources, and support
services is essential in assisting patients and family members to understand
expectations and adjust to life after the transplant.

In general, posttransplant patients are often discharged from the hospital

with complex drug regimens that involve multiple medications, including
lifelong use of immunosuppressant agents that are prescribed to decrease
and/or thwart the incidence of acute or chronic organ rejection as well as
medicines to manage other comorbidities and to reduce and/or prevent
certain infections.2 Pharmacists are essential members of the
multidisciplinary healthcare team for posttransplant patients and have
multifaceted roles such as drug monitoring, medication reconciliation, patient
counseling, and making clinical recommendations to optimize drug safety
and efficacy and minimize adverse effects.2

Various publications reveal that post transplant, some patients may take as
many as five to 10 medications or more.2-5 Regimens may also require
patients to take multiple medications one to four times daily. These complex
multidrug regimens are often associated with an increased risk of drug-drug
interactions, leading to an augmented incidence of adverse effects and risk
of nonadherence.2-5 The National Kidney Foundation indicates that due to the
complexity of drug regimens, an estimated 20% to 60% of transplant patients
have revealed that they may miss a medication dose or that they are
noncompliant with medication.5

It is well documented in the literature that noncompliance with posttransplant

drug therapy is correlated with a host of complications, including acute and
chronic rejection.2-5 Other research indicates that nonadherence during the
pretransplant phase is often a factor that may aid clinicians in predicting if a
patient will be nonadherent in the posttransplant phase, and it is imperative to

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identify and address these issues to improve clinical outcomes.6-9

Additionally, nonadherence with immunosuppressive medications is a major
risk factor for graft loss, morbidity, and mortality.6-9

Classification of Immunosuppressive Agents

Posttransplant immunosuppressive agents are prescribed for early-stage
immunosuppression, the management of late-stage immunosuppression, or
the maintenance of organ rejection; therefore, in general they are classified as
induction therapies, maintenance therapies, and antirejection therapies.10-12
Posttransplant immunosuppression classically incorporates a combination
of medications based on individualized patient factors, medical and
medication history, and the type of organ transplant.12,13

According to UNOS:
• Induction therapies are therapies administered immediately after transplant
in intensified doses to thwart episodes of acute rejection. While these
therapies may be continued post hospital discharge for at least 30 days after
transplant, these therapies are not prescribed for long-term
immunosuppressive maintenance.12
• Maintenance therapies consist of all immunosuppressive medications
prescribed before, during, or after transplant and with the purpose of long-
term use. Additionally, maintenance immunosuppression does not involve
any immunosuppressive medications administered to manage rejection
episodes or induction.12
• Antirejection immunosuppression involves all immunosuppressive
medications prescribed for dealing with an episode of acute rejection in the
initial posttransplant period or during a specific follow-up period, typically up
to 30 days after the diagnosis of acute rejection.12

According to the recently published consensus recommendations for the

usage of maintenance immunosuppression in solid organ transplantation
endorsed by the American College of Clinical Pharmacy, American Society of
Transplantation, and the International Society for Heart and Lung
Transplantation, tremendous progress has been made with regard to
maintenance immunosuppressive therapies (M-IMS), which in turn have
enhanced clinical outcomes in those who have undergone solid organ
transplantation over the past 30 years.13 The panel of experts for the
consensus recommendations states, “Uninterrupted access to
immunosuppression is paramount to minimize rejection and maintain

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allograft and patient survival.”13 The consensus panel experts also state, “The
need for lifelong maintenance immunosuppression (M-IMS) is nearly
universal as the risk of rejection is omnipresent. Nonadherence to M-IMS is a
contributing cause of poor post-transplant outcomes, with barriers to
medication access a leading risk factor for nonadherence.”13

The panel notes that these recommendations are aimed at offering

transplant clinicians a synopsis of the most current literature on M-IMS
therapies and supporting transplant team members who assist transplant
patients in accessing these lifesaving medications.13 The panel of experts
also indicates that there is no universal approach to M-IMS management, and
selected agents vary from institution to institution and are often contingent
on numerous factors, including transplanted organ, center-specific protocol,
provider expertise, insurance formularies, recipient characteristics and
tolerability, and patient insurance.13

Studies have indicated that posttransplant patients often deal with physical
and psychological issues as well as adjusting to day-to-day life and
productivity, which may be linked to the complexity of drug regimens that
involve multiple medications, managing the timing of doses, and the
increased risk of developing adverse effects.14,15 Findings from a cross-
sectional, qualitative study exploring self-management challenges and
wishes for patient support in transplant recipients revealed that they wanted
to receive more patient education, be able to share experiences with other
transplant patients, and talk about not only medical issues but also emotional
and social problems with their healthcare providers; they also needed positive
feedback from their healthcare providers.15 Finally, the authors indicated that
the “one size fits all” educational approach was not beneficial and that care
should be tailored to patient need and level of understanding.15

Studies reveal that as many as 70% of posttransplant patients do not adhere

to their medication regimens as directed for various reasons, including the
inability to afford medications due to high medication costs and lack of
proper patient education that resulted in a deficit of understanding of how
and when to take medications correctly due to multiple medication
regimens.16

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Posttransplant Immunosuppressants
Post transplant, patients may be prescribed immunosuppressive agents and
anti-infectives. The anti-infectives include an antimicrobial prophylaxis, which
may consist of one or more of the following: antibacterials, antifungals, and
antivirals to prevent infections, especially during the first month post
transplant since patients are at greater risk of developing opportunistic
infections such as Candida esophagitis, cytomegalovirus, herpes simplex
virus, and Pneumocystis jirovecii.17-19 It is essential that clinicians routinely
monitor patients since some antimicrobials can affect and/or interfere with
the metabolism of immunosuppressive agents by augmenting or reducing
serum levels of immunosuppressive agents that may heighten an individual’s
risk of severe adverse effects.18 Additionally, patients may be prescribed
medications for the treatment of other comorbidities and medications to
address the adverse drug reactions associated with immunosuppressive
agents, such as antiemetics for nausea and vomiting and/or medications for
sleep issues, depression, and anxiety.17,18 Some transplant clinicians may
also recommend the use of nutritional supplements tailored to patient need.

Studies reveal that long-term use of immunosuppressive agents is often

correlated with the onset of posttransplant diabetes, hypertension,
hyperlipidemia, cardiovascular disease, and infections. This, in turn,
augments mortality rates, therefore highlighting the significance of tailoring
therapy to patient need to optimize drug safety, minimize adverse effects, and
improve clinical outcomes.20,21 Different studies indicate a range of 10% to
40% incidence of posttransplant diabetes.20,21

Multiple publications indicate that the major M-IMS agents that are typically
prescribed include a combination of agents, including calcineurin inhibitors
(tacrolimus and cyclosporine), antimetabolites (mycophenolate mofetil and
azathioprine), mammalian target of rapamycin inhibitors (everolimus and
sirolimus), and corticosteroids.10-14,21 Transplant experts note that the
primary goal in posttransplant patients is to individualize therapy to include
the optimal combination of immunosuppressive agents, which can improve
patient survival by preventing acute rejection while also preventing or
decreasing the incidence of adverse effects.10-14,21

The 2019 Organ Procurement and Transplantation Network Annual Data

Report revealed that the most frequently prescribed posttransplant M-IMS
regimen included tacrolimus, mycophenolate mofetil (MMF), and

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corticosteroids for kidney (65%), pancreas (67%), liver (65%), heart (86%), and
lung (80%) transplant recipients.13 See TABLE 1 for additional information on
immunosuppressive agents used in solid-organ transplantation.

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According to the consensus recommendations mentioned above, the most

frequently prescribed corticosteroids for the prevention and treatment of
organ rejection are IV methylprednisolone and oral prednisone, and a large
percentage of transplant recipients are continued on corticosteroids
indefinitely.13 The panel of experts also indicates that early corticosteroid
discontinuation post transplant is a goal due to the considerable morbidity
risk correlated with chronic and long-term use of these agents.13

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Identifying and Addressing Nonadherence

Pharmacists can be instrumental in assisting patients in the management of
complex posttransplant regimens and make clinical recommendations to
improve adherence when possible. Various publications indicate that
nonadherence is common among posttransplant patients and may be
classified as intentional (conscious refusal to take prescribed medication) or
unintentional (nondeliberate, such as missing medication doses), and
contributing factors may be patient-related, therapy-related, disease-related,
socioeconomic, and/or healthcare-related.22-24

According to a study in the journal Nephrology, nonadherence to

immunosuppressant medications augments the likelihood of allograft
rejection and loss.22 In this study involving a cohort of 161 adult renal
transplant patients, researchers sought to explore the incidence of
nonadherence and barriers to adherence with immunosuppressant
medications.22 The results revealed that 55% were classified as nonadherent,
with 45% delaying doses and 25% missing doses. The authors indicated that
nonadherent patients were more prone to not remembering doses and more
prone to skip doses when their daily routine changed or when the cost of
medication was a factor. Additionally, nonadherent patients had less self-
reported knowledge than adherent patients; over 50% of patients self-
reported nonadherence, with the primary factors contributing to
nonadherence being forgetfulness and skipped doses. The authors
recommended that interventions tailored to patient need and level of
understanding may enhance adherence.22

Another study indicated that among adults greater than 12 months post
kidney transplant, nonadherence with immunosuppressive therapy was
recorded as 33.6% and was correlated with negative impacts on mental
health–related quality of life and anxiety and depression.23,24 Studies also
noted that adverse effects associated with immunosuppressive therapy may
affect patient adherence.23,24

A systematic review published in Clinical Kidney Journal indicated that

nonadherence to medication rates range from 2.3% to 72.2% among lung
transplant recipients.25

In a systematic review published in Transplantation Reviews, nonadherence to

immunosuppressive therapy among heart transplant patients may correlate
with an increased risk of transplant coronary artery disease and acute late
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rejection and mortality.26 The authors noted that simplified drug regimens,
including utilizing once-daily dosing immunosuppressives such as
tacrolimus, medication reminders, and mobile app reminders, were related to
greater adherence.26

According to another publication in Clinical Kidney Journal, authors

recommended strategies that may aid in thwarting and addressing
nonadherence; they include collaborative efforts between healthcare
providers involved in patient care, including interventions from pharmacists,
electronic reminders such as medication reminders via phone alarms and
applications, simplifying drug regimens when possible such as once-daily or
twice-daily regimens, and identifying patient risk factors via multidisciplinary
measures from the healthcare team.27

The Role of the Pharmacist

An abundance of clinical evidence indicates that pharmacists can enhance
outcomes in transplant patients through clinical recommendations and
patient education initiatives.28 Additionally, a study published in the
International Journal of Clinical Pharmacy indicates that pharmacists can be a
valuable resource and improve pharmaceutical care and optimize medication
safety, especially since transplant patients often require complex medication
regimens and medication changes, augmenting the risk for drug/drug
interactions and adverse effects.29 Patient education and adherence to
therapy are critical components to attaining successful clinical outcomes.
Patients should be encouraged to take an active part in their care, which may
improve adherence and overall health-related quality of life.

Pharmacist Roles in the Management of Transplant Patients

• Making clinical recommendations and monitoring potential drug-drug
interactions and contraindications, as well as patient response to complex
posttransplant medication regimens
• Recommending treatment regimens based on efficacy and safety data
tailored to patient needs
• Implementing patient education initiatives to enhance patient adherence
and improve clinical outcomes
• Conducting ongoing clinical monitoring and making changes when
warranted to optimize medication efficacy and safety
• Identifying and addressing adverse effects when warranted
• Educating patients on the drugs prescribed, dosage, administration,

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indication for use, monitoring parameters, and potential adverse effects

• Instructing patients on what to do in case of a missed dose
• Providing information on the handling and storage of medication
• Recommending measures such as medication reminders to ensure doses
are not missed
• Providing tips on staying organized, such as using pill boxes with labels and
refill reminders, to ensure that medications are filled on time.

Pharmacists can also suggest that patients obtain a MedicAlert ID tag or

bracelet indicating that they are transplant recipients and continue to
maintain a current list of all medicines, including nonprescription
medications. Patients should also be instructed to always discuss using any
new medications, including OTC products and supplements, with their
transplant care provider prior to using them.

Conclusion
The transplant process is a life-changing experience for both patients and
their families, especially during the posttransplant period. Empowering
patients with knowledge, encouragement, and support is essential as
patients adjust to life posttransplant and to improve health-related quality of
life.

REFERENCES
1. United Network for Organ Sharing. 2022 organ transplants again set annual records. January 10,
2023. https://unos.org/news/2022-organ-transplants-again-set-annual-records/. Accessed June 12,
2023.
2. Sam S, Guérin A, Rieutord A, et al. Roles and impacts of the transplant pharmacist: a systematic
review. Can J Hosp Pharm. 2018;71(5):324-337.
3. Denhaerynck K, Dobbels F, Cleemput I, et al. Prevalence, consequences, and determinants of
nonadherence in adult renal transplant patients: a literature review. Transpl Int. 2005;18(10):1121-1133.
4. Pinsky BW, Takemoto SK, Lentine KL, et al. Transplant outcomes and economic costs associated
with patient noncompliance to immunosuppression. Am J Transplant. 2009;9(11):2597-2606.
5. Anderson-Haag T. Transplant medications: forget me not! National Kidney Foundation.
www.kidney.org/transplantation/transaction/TC/summer09/TCsm09_ForgetMeNot. Accessed June
12, 2023.
6. Sandal S, Chen T, Cantarovich M. Evaluation of transplant candidates with a history of nonadherence:
an opinion piece. Can J Kidney Health Dis. 2021;8:1-7.
7. Martin P, DiMartini A, Feng S, et al. Evaluation for liver transplantation in adults: 2013 practice
guideline by the AASLD and the American Society of Transplantation. Hepatology. 2014;59:1144-1165.
8. EASL clinical practice guidelines: liver transplantation. J Hepatol. 2016;64(2):433-485.
9. Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society for Heart Lung
Transplantation listing criteria for heart transplantation: a 10-year update. J Heart Lung Transplant.
2016;35(1):1-23.

https://www.uspharmacist.com/article/role-of-posttransplant-immunosuppressive-agents 11/13
10/18/23, 12:48 PM Role of Posttransplant Immunosuppressive Agents

10. Pellegrino B, Schmidt RJ, Onder S, et al. Immunopsupression. Medscape. March 1, 2021.
https://emedicine.medscape.com/article/432316-overview#a3. Accessed April 24, 2023.
11. Hussain Y, Khan H. Immunosuppressive drugs. Encyclop Infect Immun. 2022:726-740.
12. United Network for Organ Sharing. Types of immunosuppressants. www.transplantliving.org/after-
the-transplant/preventing-rejection/types-of-immunosuppressants/. Accessed June 12, 2023.
13. Nelson J, Alvey N, Bowman L, et al. Consensus recommendations for the use of maintenance
immunosuppression in solid organ transplantation: endorsed by the American College of Clinical
Pharmacy, American Society of Transplantation, and the International Society for Heart and Lung
Transplantation. Pharmacotherapy. 2022;42(8):599-633.
14. Yang FC, Chen HM, Huang CM, et al. The difficulties and needs of organ transplant recipients during
postoperative care at home: a systematic review. Int J Environ Res Public Health. 2020;17(16):5798.
15. Been-Dahmen JMJ, Grijpma JW, Ista E, et al. Self-management challenges and support needs
among kidney transplant recipients: a qualitative study. J Adv Nurs. 2018;74(10):2393-2405.
16. Tschida S, Aslam S, Khan TT, et al. Managing specialty medication services through a specialty
pharmacy program: the case of oral renal transplant immunosuppressant medications. J Managed Care
Pharm. 2013;19(1):26-41.
17. de la Vega A, Luong D. Post-transplant patient education and medication adherence. Texas Kidney
Foundation. April 28, 2017. https://txkidney.org/wp-content/uploads/2017/03/Post-Transplant-Patient-
Education-and-Compliance-v.pdf?x15235. Accessed June 12, 2023.
18. Bhagat V, Pandit RA, Ambapurkar S, et al. Drug interactions between antimicrobial and
immunosuppressive agents in solid organ transplant recipients. Indian J Crit Care Med. 2021;25(1):67-
76.
19. Kumar R, Ison MG. Opportunistic infections in transplant patients. Infect Dis Clin North Am.
2019;33(4):1143-1157.
20. Ahmed SH, Biddle K, Augustine T, et al. Post-transplantation diabetes mellitus. Diabetes Ther.
2020;11:779-801.
21. Parlakpinar H, Gunata M. Transplantation and immunosuppression: a review of novel transplant-
related immunosuppressant drugs. Immunopharmacol Immunotoxicol. 2021;43(6):651-665.
22. Cossart AR, Staatz CE, Campbell SB, et al. Investigating barriers to immunosuppressant medication
adherence in renal transplant patients. Nephrology. 2019;24(1):102-110.
23. Covvey JR, Mancl EE. Pharmaceutical care in transplantation: current challenges and future
opportunities. Nanomedicine. 2019;14(20):2651-2658.
24. Scheel JF, Schieber K, Reber S, et al. Psychosocial variables associated with immunosuppressive
medication non-adherence after renal transplantation. Front Psychiatry. 2018;9:23.
25. Hu L, Lingler JH, Sereika SM, et al. Nonadherence to the medical regimen after lung transplantation:
a systematic review. Heart Lung. 2017;46(3):178-186.
26. Hussain T, Nassetta K, O’Dwyer LC, et al. Adherence to immunosuppression in adult heart transplant
recipients: a systematic review. Transplant Rev. 2021;35(4):100651.
27. Gandolfini I, Palmisano A, Fiaccadori E, et al. Detecting, preventing and treating non-adherence to
immunosuppression after kidney transplantation. Clin Kidney J. 2022;15(7):1253-1274.
28. Sam S, Guérin A, Rieutord A, et al. Roles and impacts of the transplant pharmacist: a systematic
review. Can J Hosp Pharm. 2018;71(5):324-337.
29. Mulder MB, Doga B, Borgsteede SD, et al. Evaluation of medication-related problems in liver
transplant recipients with and without an outpatient medication consultation by a clinical pharmacist: a
cohort study. Int J Clin Pharm. 2022;44(5):1114-1122.
30. Hertl M. Overview of transplantation. Merck Manual Professional Version. September 2022.
https://www.merckmanuals.com/professional/immunology-allergic-
disorders/transplantation/overview-of-transplantation?query=transplant. Accessed June 12, 2023.
31. Imuran (azathioprine) package insert. Hunt Valley, MD: Prometheus Labs Inc; May 2011.

https://www.uspharmacist.com/article/role-of-posttransplant-immunosuppressive-agents 12/13
10/18/23, 12:48 PM Role of Posttransplant Immunosuppressive Agents

32. Simulect (basiliximab) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation;
August 2020.
33. Nulojix (belatacept) package insert. Princeton, NJ: Bristol-Myers Squibb Company; July 2021.
34. Neoral (cyclosporine) package insert. East Hanover, NJ: Novartis; June 2021.
35. Gengraf (cyclosporine) package insert. North Chicago, IL: AbbVie Inc; February 2021.
36. Zortress (everolimus) package insert. East Hanover, NJ: Novartis Pharmaceutical Corporation;
January 2021.
37. CellCept (mycophenolate mofetil) package insert. South San Francisco, CA: Genentech USA Inc;
August 2022.
38. Myfortic (mycophenolate sodium) package insert. East Hanover, NJ: Novartis Pharmaceuticals
Corporation; March 2022.
39. Rapamune (sirolimus) package insert. Philadelphia, PA: Wyeth Pharmaceuticals LLC; August 2022.
40. Prograf (tacrolimus) package insert. Northbrook, IL: Astellas Pharma US Inc; November 2022.
41. Envarsus XR (tacrolimus) package insert. Cary, NC: Veloxis Pharmaceuticals Inc; September 2020.

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