1 The Mystery of TransplantFocusing on solid-organ transplant patients Management of the transplant patient in the primary care setting Katee Lira, PharmD Ambulatory Care Clinical Pharmacist, St. Vincent Indianapolis Assistant Professor of Pharmacy Practice, Manchester University April 20, 2016 I have no actual or potential conflicts of interest to disclose.

2 Objectives: Identify the primary care providers’ role in management of solid organ transplant patients Describe how transplant medications contribute to metabolic disorders Develop a “checklist” for appropriate considerations in primary care patients with a solid organ transplant Identify common adverse effects of transplant medication Will be discussing mainly liver and kidney

3 How does this pertain to Primary Care?PCPs have an important role in improving outcomes of transplant recipients Outcomes after transplant have improved, with an increasing number of long-term survivors Metabolic syndrome, CVD, renal dysfunction, and malignancies are leading causes of morbidity/mortality Some centers defer management of metabolic syndrome and medical complications to PCPs --PCPs may see transplant recipients in their practice as many die with functioning grafts --CVD has become the leading cause of mortality in renal transplant recipients, accounting for over 50% of deaths --With advances in surgical techniques, careful selection of donors and recipients, and improvements in medical management of the recipient. The current 1-year, 5-year, and 10-year survival rates of OLT recipients are 84%, 68%, and 54%, respectively. --Many patients are cared for outside of a txp center which requires PCPs to be familiar with complications see in txp pts --Immediately following liver transplantation, patients are managed by transplant surgeons, hepatologists, nephrologists. However, after several months, the general medical care of a liver transplant recipient is often transferred back to the PCP --transplant center will monitor laboratory tests and levels of immunosuppressive drugs --Many patients are managed by primary care clinicians following liver transplantation. However, issues related to immunosuppression (including infections, organ rejection, and renal disease) and biliary complications are typically managed by a transplant hepatologist and/or surgeon --Survey looked at which elements of the patient's care transplant centers wanted the primary care clinician to manage: 100% preventive medicine, 65% annual examinations, 65% Vaccinations, 60% diabetes, 40% bone disease, 37% Hypertension McCashland TM. Liver Transpl 2001; 7:S2.

4 FDA Approved MedicationsSteroids Tacrolimus (CNI) Cyclosporine (CNI) Mycophenalate mofetil Azathioprine Sirolimus Will not go into specifics about each agents MOA/dosing etc. because the specialist will manage and select which agents to use

5 Typical Regimens Triple drug combination:Glucocorticoid Calcineurin inhibitor (CNIs) Purine antagonist (mycophenalate) Steroid is weaned off or decreased to lowest dose Once stable, can sometimes be only monotherapy Typically a calcineurin inhibitor CNIs such as tacrolimus Typical starting regimen: prednisone, tacrolimus, mycophenalate

6 Complications of Transplant MedicationsNeurotoxicity, hair loss, insomnia CVD GERD, nausea Metabolic abnormalities (DM, HLD) Diarrhea Complications of immunosuppression including hypertension, renal insufficiency, infection, malignancy, a variety of dermatologic conditions, and metabolic diseases such as diabetes mellitus, obesity, hyperlipidemia, and bone disease Nephrotoxicity Reduced bone mineral density Gout Long-Term Management of Adult Liver Transplant: 2012 Practice Guideline by AASLD and AST

7 Common Side Effects DRUGS ADVERSE EFFECTS SteroidsHypertension, diabetes, hyperlipidemia, bone disease, weight gain, impaired wound healing, cataracts, psychological changes Tacrolimus Tremors, nephrotoxicity, neurotoxicity, diabetes, hypertension, gout, hyperkalemia, hyperlipidemia Cyclosporine Tremors, nephrotoxicity, diabetes, hypertension, gout, hyperkalemia, hyperlipidemia, neurotoxicity, increased hair/gum growth Mycophenolate mofetil N/V/D, neutropenia, anemia Azathioprine Neutropenia, anemia, liver inflammation, hair loss, acute pancreatitis Sirolimus Tremors, hyperlipidemia, thrombocytopenia, neutropenia, anemia, poor wound healing Highlighted things that PCPs may manage

8 Common Side Effects Important to note which are most likely to be contributing

9 Medication InteractionsNumerous drugs that interact with immunosuppressants Check for drug-interactions before starting new medications P-glycoprotein CYP 3A4 Cyclosporine Tacrolimus Sirolimus Because there are numerous drugs that interact with immunosuppressive agents, at each visit patients should be asked about any new medications or supplements they are taking (including over the counter medications) and be reminded not to start any new medications or supplements without first talking to their clinicians Other CYP3A4s: azoles, verapamil, macrolides, statins, HIV medications (protease inhibitors), HCV medications (boceprevir, teleprevir)

10 Pregnancy Drug Pregnancy Category Concerns Steroids C/DFirst trimester use associated with oral clefts; decreased birth weight; recommended to use lowest dose for shortest duration Tacrolimus C Lower birth weights, fetal mortality, hyperkalemia in infants, renal toxicity, maternal toxicity Cyclosporine Not teratogenic. May be used in pregnant transplant patients Mycophenalate D Boxed Warning: increased risk of congenital malformations and first trimester pregnancy loss. Effective contraception must be started before and continued for 6 weeks after d/c Azathioprine Congenital anomalies, hematologic toxicities, and intrauterine growth retardation. Better alternative than MMF. Sirolimus Not teratogenic, lower birth weights, fetal mortality. Effective contraception must be started before therapy and continued for 12 weeks after d/c Following transplant, normal menstruation and fertility may be restored within months; however, appropriate contraception is recommended to prevent pregnancy until 1-2 years following the transplant to improve pregnancy outcomes (Cowan, 2012; EBPG Expert Group on Renal Transplantation, 2002; McGuire, 2009; Parhar 2012). In general, women who have had a kidney transplant should be instructed that fertility will be restored following the transplant but that pregnancy should be avoided for ~2 years. Tacrolimus may be used as an immunosuppressant during pregnancy. The risk of infection, hypertension, and pre-eclampsia may be increased in pregnant women who have had a kidney transplant (EPBG, 2002). [U.S. Boxed Warning]: Mycophenolate is associated with an increased risk of congenital malformations and first trimester pregnancy loss when used by pregnant women. Females of reproductive potential must be counseled about pregnancy prevention and planning. Alternative agents should be considered for women planning a pregnancy. Adverse events have been reported in animal reproduction studies. In humans, the following congenital malformations have been reported: external ear abnormalities, cleft lip and palate, anomalies of the distal limbs, heart, esophagus and kidney. Spontaneous abortions have also been noted. Females of reproductive potential (girls who have entered puberty, women with a uterus who have not passed through clinically confirmed menopause) should have a negative pregnancy test with a sensitivity of ≥25 mIU/mL immediately before therapy and the test should be repeated 8-10 days later. Pregnancy tests should be repeated during routine follow-up visits. Acceptable forms of contraception should be used during treatment and for 6 weeks after therapy is discontinued. The effectiveness of hormonal contraceptive agents may be affected by mycophenolate. For women with lupus nephritis taking mycophenolate and who are planning a pregnancy, mycophenolate should be discontinued at least 6 weeks prior to trying to conceive (Hahn, 2012).

11 National Transplantation Pregnancy Registry, 877-955-6877Pregnancies are considered high risk Delay pregnancy for 1-2 year(s) post-transplant CNIs should be continued and monitored closely Barrier method required with mycophenolate IUDs are less effective with azathioprine -Include discussion of sexual activity, and counseling about contraception and safe sex practices -Breastfeeding is controversial, but benefit may outweigh the risk with low-dose CNI -Recommend that MMF and enteric-coated mycophenolate sodium (EC-MPS) be discontinued or replaced with azathioprine before pregnancy is attempted. -It is important to avoid the use of potentially teratogenic immunosuppressive agents in women of child-bearing potential who wish to become pregnant -Pregnancy may effect blood levels of immunosuppressants and if not carefully monitored may lead to chronic rejection after childbirth Contraceptives (Estrogens): Mycophenolate may decrease the serum concentration of Contraceptives (Estrogens). Average AUC values were unchanged, but there was evidence of substantial patient-to-patient variability in response to this combination. Management: Women of childbearing potential who are receiving mycophenolate mofetil should consider using an alternative and/or additional form of contraception. Risk D: Consider therapy modification May use Oral contraceptives with caution in txp patients due to their increased risk of CVD A pregnancy registry has been established for pregnant women taking immunosuppressants following any solid organ transplant. National Transplantation Pregnancy Registry, Long-Term Management of Adult Liver Transplant: 2012 Practice Guideline by AASLD and AST

12 Patient Case: Cardiovascular Risk65 yoM with a kidney transplant is on cyclosporine and azathioprine. He also has T2DM, HTN, OA and depression. ASCVD 10-year risk of 21.5%, LDL 107 Is a statin indicated in this patient? If so, what regimen would you initiate? A YES Initiate atorvastatin 40 mg daily B C Initiate rosuvastatin 5 mg daily YES Initiate simvastatin 40 mg daily

13 Patient Case: Cardiovascular RiskPer the lipid guidelines, this patient qualifies for a high intensity statin However, atorvastatin is contraindicated with cyclosporine Your patient develops rhabdomyolysis and is hospitalized Concurrent use of cyclosporine with atorvastatin should be avoided due to an increased risk for atorvastatin-related toxicities such as myopathy and rhabdomyolysis with concurrent use. Consider changing to a statin that is less sensitive to this interaction (e.g., pravastatin or fluvastatin) The atorvastatin AUC and maximum serum concentration (Cmax) were increased an average of 8.7- and 10.7-fold Dagnabbit Doctor! Here’s to better luck next time…

14 Patient Case: Cardiovascular RiskPer the lipid guidelines, this patient qualifies for a high intensity statin However, simvastatin is contraindicated with cyclosporine Your patient develops rhabdomyolysis and is hospitalized According to the simvastatin prescribing information, concurrent use with cyclosporine should be avoided.1 Several published case reports describe myopathy or rhabdomyolysis in patients who received this combination the AUC of simvastatin was increased by an average of approximately 8-fold Dagnabbit Doctor! Here’s to better luck next time…

15 Patient Case: Cardiovascular RiskPer the lipid guidelines, this patient qualifies for a high intensity statin However, the max dose of rosuvastatin is 5 mg/day in patients who are also on cyclosporine The patient presents to your next visit in 3 months and her LDL is 68. She has no complaints or concerns. Monitor for toxic effects (e.g., myalgia, myopathy, rhabdomyolysis) of rosuvastatin if cyclosporine is being received/dose increased, or decreased effects if cyclosporine is discontinued/dose decreased CycloSPORINE (Systemic) may increase the serum concentration of Rosuvastatin. The average AUC and maximum serum concentration (Cmax) were 7.1- and 10.6-fold higher Congratulations Doctor! Continue to the next adventure…

16 Statins and Antirejection MedicationsCyclosporine Tacrolimus Atorvastatin CONTRAINDICATED No dose adjustment, monitor Fluvastatin Limit fluvastatin to 20 mg BID Lovastatin Pitavastatin Pravastatin Limit pravastatin to 20 mg/day Rosuvastatin Limit rosuvastatin to 5 mg/day Simvastatin Fluvastatin or pravastatin appears to have a lower risk of interaction with cyclosporine and may be preferred Increased statin concentrations and risk of statin toxicity including myotoxicity with cyclosporine Ezetimibe has also been studied alone or as an adjunct to a statin in liver and kidney transplant avoid treatment with cholestyramine because it can raise triglyceride levels and it may significantly impair the absorption of medications, including calcineurin inhibitors avoid nicotinic acid because it can decrease glucose tolerance and raise uric acid levels, leading to symptomatic gout in some patients

17 Patient Case: Cardiovascular Risk65 yoM with a kidney transplant is on cyclosporine and azathioprine. He also has T2DM, HTN, OA and depression. ASCVD 10-year risk of 21.5%, LDL 107 Is a statin indicated in this patient? If so, what regimen would you initiate? A YES Initiate atorvastatin 40 mg daily B C Initiate rosuvastatin 5 mg daily YES Initiate simvastatin 40 mg daily Because this patient is on cyclosporine, atorvastatin and simvastatin are contraindicated Even though patient requires high-intensity statin – max dose of rosuvastatin is 5mg/day – increase AUC of rosuvastatin so will still should get enough lipid lowering.

18 Dyslipidemia Incidence of HLD: 40-66%Significant elevations in total cholesterol are typical Changes seen 3-6 months after transplantation Annual fasting lipid profile Treatment is similar to treatment in non-transplant patient Statins are safe and effective Complicated by drug interactions --Increases in TC, LDL, VLDL, TGs, apo-lipoprotein B --Changes in lipids are typically observed during the first 3 to 6 months after transplantation, with initial changes either persisting over time or, more often, decreasing somewhat before remaining constant at an elevated level from baseline --Treatment is indicated in patients whose dyslipidemia does not improve with steroid withdrawal --However, treatment is complicated by interactions of the drugs used to treat dyslipidemia with immunosuppressive agents. These interactions can lead to alterations in immunosuppressant levels and/or increased toxicities, including rhabdomyolysis. Thus, agents to treat dyslipidemia must be chosen carefully based upon the patient's immunosuppressive regimen, and immunosuppressant levels should be monitored if interactions are anticipated --SRL, CSA, and corticosteroids are major factors contributing to hyperlipidemia, --in addition to other more usual factors (eg, obesity, genetic predisposition, hypothyroidism, diabetes mellitus, nephrotic-range proteinuria, and allograft dysfunction). --Recommendations include maintaining total cholesterol level <200mg/dL, LDL-C level <100mg/dL, and triglyceride levels <150mg/dL. --First-line therapy should include both a low-fat diet and statins. --However, to date, no studies have demonstrated that lipid lowering strategies significantly reduce CVD morbidity or mortality and improve allograft survival in transplant recipients. --There is an increased risk of myopathy or rhabdomyolysis because of the pharmacokinetic interaction of statins with CSA, TAC, and SRL. It has been recommended that the maximum dose of statins be reduced in patients receiving either CSA or TAC. --Consequently, the creatine kinase (CK) enzyme and alanine aminotransferase (ALT) levels should be monitored regularly. --If diet and statin treatment fail to control the hypercholesterolemia, other treatment measures include switching from SRL or CSA to TAC, and adding ezetimibe are recommended. BioDrugs 2001; 15 (4) Long-Term Management of Adult Liver Transplant:2012 Practice Guideline by AASLD and AST

19 Risk factors for post-transplant CVDPretransplantation CVD Hyperlipidaemia Hyperhomocysteinemia Hypertension Diabetes mellitus Smoking Acute rejection episodes Graft failure Direct effects of immunosuppressive agents --transplant recipients have a greater risk of cardiovascular death and ischemic events than age- and sex-matched nontransplanted patients --The relative risk of death due to cardiovascular disease in liver transplant recipients was 2.6 (95% CI ) compared with controls --no reason to consider risk factors for CVD such as hyperlipidaemia, hypertension and diabetes mellitus in transplant recipients differently from in the general population. Cardiovascular risk factors, often existing before transplantation, include hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, peripheral vascular disease, long duration on dialysis, obesity, physical inactivity, older age, smoking, and male gender.7,9 Cardiovascular risk reduction includes tight control of blood pressure (to <130/80 mm Hg), hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C] level <100 mg/dL), and diabetes mellitus, if present; smoking cessation, physical activity, and weight control or reduction are also important. BioDrugs 2001; 15 (4)

20 Impact of immunosuppressant agents on CVD risk factors--Unfortunately, there are no controlled studies showing as a primary endpoint the differences between immunosuppressive agents with regard to the risk of CVD BioDrugs 2001; 15 (4)

21 CVD Incidence of CAD 9-25% ALL agents require close follow-upStrict management of CVD risk factors is recommended Annual rate of fatal or nonfatal CVD events in kidney transplant patients is 2x higher than general population --CVD remains the leading cause of death in kidney transplant recipients. --The annual rate of fatal or nonfatal CVD events in kidney transplant patients is %, 50-fold higher than in the general --population. Evidence of carotid or peripheral arterial occlusive vascular disease should be checked at least annually on physical examination and followed with duplex ultrasound and pulse volume recordings, respectively. Stress testing is often needed for asymptomatic individuals who are also at high risk but may not experience chest pain Fouad T. Transplantation. 2009;87(5):763

22 Patient Case: Hypertension54 yo AA male s/p liver transplantation Antirejection regimen tacrolimus and mycophenalate Patients BP is 148/92 despite steroids being weaned What antihypertensive agent would you start in this patient? HCTZ Initiate HCTZ 25 mg daily A ACEI Initiate lisinopril 10 mg daily B C DHP-CCB Initiate amlodipine 5mg daily

23 Patient Case: HypertensionPatient is started on lisinopril 10mg and BP reaches goal with no complications ACEIs/ARBs can be used but with caution May have problematic effects on renal function and hyperkalemia After early post-transplant, ACEIs/ARBs may be beneficial Nephroprotective effect Antifibrotic effect Close monitoring for hyperkalemia is recommended for both ACEIs/ARBs when used in association with CNIs --ACEIs/ARBs can also be used in patients with difficult-to-control hypertension and may have additional benefits in diabetic patients with microalbuminuria. --May have negative effects renal function in patients taking CNI inhibitors and may induce hyperkalemia, so they should therefore be used with caution --May be preferred in patients with diabetes or proteinuria  nephroprotective effects --May benefit patients with recurrent HCV or NASH  may also have antifibrotic effects Congratulations Doctor! Continue to the next adventure…

24 Patient Case: HypertensionHydrochlorothiazide 25mg daily is started and patient develops hyperuricemia causing a gout flare Diuretics are not used as primary therapy for hypertension in transplant patients Concerns: Excerbate electrolyte disturbances Risk for hyperuricemia Renal dysfunction If thiazides or loop diuretics must be used, close follow-up is required Dagnabbit Doctor! Here’s to better luck next time…

25 Patient Case: HypertensionPatient is started on amlodipine 5mg and BP reaches goal with no complications DHP-CCBs are the preferred first-line agents Amlodipine Nifedipine Cause vasodilation of renal afferent arterioles Minimally interact with CNIs, and have limited side effects since part of the mechanism of hypertension is thought to be due to renal arteriolar vasoconstriction Although no single antihypertensive agent has been shown to be superior to others, DHP-CCBs are the preferred first-line agents Amlodipine, felodipine, and nicardipine are preferred as first-line agents since they are long-acting, minimally interact with CNIs, and have limited side effects Non-DHP CCBs agents such as diltiazem or verapamil should be avoided as they increase the level of CNIs Congratulations Doctor! Continue to the next adventure…

26 Patient Case: Hypertension54 yo AA male s/p liver transplantation Antirejection regimen tacrolimus and mycophenalate Patients BP is 148/92 despite steroids being weaned What antihypertensive agent would you start in this patient? HCTZ Initiate HCTZ 25 mg daily A ACEI Initiate lisinopril 10 mg daily B C DHP-CCB Initiate amlodipine 5mg daily Either answer could be correct as long as it wasn’t immediately post-txp

27 Hypertension Summary Incidence 40-85%Target blood pressure is <140/90 Up to 30% of patients require 2 or more agents Monitoring: weekly home monitoring and monthly office readings x6 months post-transplant, then Q6 months Preferred agents DHP CCBs (amlodipine, nifedipine) ACEIs/ARBs Use with caution Non-DHP CCBs (diltiazem, verapamil) Diuretics (hydrochlorothiazide, furosemide) Management is similar to general population No randomized controlled trials exist For the first six months following transplantation, self-monitoring every week and blood pressure monitoring by a health care provider every month. In patients without hypertension after six months, blood pressure monitoring by a health care provider every six months The cause of hypertension is multifactorial but is mostly related to the use of calcineurin inhibitors and steroids Post-transplantation hypertension appears to be a major risk factor determining graft and patient survival, and immunosuppressive agents have different effects on hypertension. Ann Pharmacother 2010;44: Long-Term Management of Adult Liver Transplant:2012 Practice Guideline by AASLD and AST.

28 Patient Case: Diabetes38 yo Hispanic female s/p kidney transplantation Antirejection regimen tacrolimus and mycophenalate Family history is not significant for DM and her BMI is 24.1 Do you need to screen her for diabetes? If so, what is the most appropriate frequency? NO Does not have risk factors for diabetes screening A YES Screen every 3 years B C Screen every year

29 Patient Case: DiabetesThe patient is screened for diabetes and does not have new-onset diabetes mellitus after transplantation (NODAT) upon initial screening Patient is not screened for three years and within that time she develops new-onset diabetes mellitus after transplantation (NODAT) that is unrecognized Her uncontrolled diabetes leads to graft failure Dagnabbit Doctor! Here’s to better luck next time…

30 Patient Case: DiabetesThe patient is not screened for diabetes until she is 45 She develops new-onset diabetes mellitus after transplantation (NODAT) that is unrecognized Her uncontrolled diabetes leads to graft failure Dagnabbit Doctor! Here’s to better luck next time…

31 Patient Case: DiabetesThe patient is screened and found to have new-onset diabetes mellitus after transplantation (NODAT) She is started on appropriate treatment and does not develop complications of uncontrolled diabetes Congratulations Doctor! Continue to the next adventure…

32 Patient Case: Diabetes38 yo hispanic female s/p kidney transplantation Antirejection regimen tacrolimus and mycophenalate Family history is not significant for DM and her BMI is 24.1 Do you need to screen her for diabetes? What is the most appropriate frequency? NO She does not have risk factors for diabetes screening A YES Screen every 3 years B C Screen every year Screen every year because they are at high risk and uncontrolled blood glucose can lead to worse outcomes

33 Diabetes Summary Incidence 30-40%Negatively affects graft and patient survival Annual screening is recommended Management is similar to general population Insulin may be required in the early post-txp period Oral hypoglycemic agents are safe and effective later The development of diabetes does not adversely affect survival in the first year following transplantation, but it is associated with decreased survival after 5 to 10 years conform to the guidelines (ADA) for treatment of type 2 diabetes mellitus in the general population 2008 European Society for Organ Transplantation 22 (2009) 519–530 Long-Term Management of Adult Liver Transplant: 2012 Practice Guideline by AASLD and AST

34 New-onset diabetes mellitus after transplantation (NODAT)More common with the current obesity epidemic Associated with CVD, graft failure, and death Factors that predispose to development include Age Weight and weight gain Ethnicity Family history Infection with hepatitis C Corticosteroids Calcineurin inhibitors (cyclosporine, tacrolimus) Associated with CVD, graft failure and death in both kidney and other solid organ transplant recipients Also called Transplant-associated hyperglycemia (TAH) or new-onset diabetes mellitus after transplantation (NODAT) Kasiske et al. studied Medicare beneficiaries who received first kidney transplants between 1996 and 2000 and reported a cumulative incidence of NODAT of 9%, 16%, and 24% at 3, 12, and 36 months, respectively [6] The cumulative incidence of post-transplantation new-onset diabetes mellitus (NODM) at 12 and 36 months after transplantation has been reported to be approximately 16% and 24%, respectively,10 but the true incidence is difficult to assess because of the absence of a uniform definition of NODM. Risk factors for NODM are age older than 50 years, obesity, African American and Hispanic ethnicities, family history of DM, hepatitis C, and use of CSA, TAC, and GC. The use of MMF, azathioprine, statins, and ACE inhibitors does not increase the risk for developing NODM. Initial therapy focuses on diabetes education, diet, exercise, and weight reduction. Selection of medications should take into consideration drugs affected by impaired renal function and interaction with immunosuppressants. Because of the surge in new drugs for diabetes treatment, NODM often requires management by an endocrinologist. Modification of the immunosuppressive regimen, if necessary, should be done with the aid of a transplantation nephrologist. GC tapering or discontinuation should be avoided or done with extreme caution because of the high risk of acute rejection 2008 European Society for Organ Transplantation 22 (2009) 519–530

35 Metabolic Syndrome Common among patients who have transplantsIncidence of 50-60% Combination of Hypertension Insulin resistance/diabetes Dyslipidemia Obesity Immunosuppressant use is associated with all aspects of the metabolic syndrome Hypertension: Glucocorticoids, cyclosporine> tacrolimus Diabetes mellitus: Glucocorticoids, tacrolimus>cyclosporine Obesity: Glucocorticoids, cyclosporine Dyslipidemia: Glucocorticoids, cyclosporine>tacrolimus, sirolimus 2008 European Society for Organ Transplantation 22 (2009) 519–530 Long-Term Management of Adult Liver Transplant: 2012 Practice Guideline by AASLD and AST

36 Osteoporosis The risk of fractures following transplantation is highDEXA scan Pre-transplant 6 months to 1 year after transplantation Then recommended every 2-3 years post transplant Management of osteoporosis is similar to that for the non-transplant general population Weight-bearing exercises Supplementation with calcium and vitamin D Bisphosphonates Prior to transplantation, all patients should receive 1000 mg/day of calcium and 800 int. units/day of vitamin D Bone mineral density measurement prior to transplantation and every other year after transplantation. no consensus on the optimal approach --In patients who require continued glucocorticoid therapy (eg, prednisone at ≥5 mg daily), BMD measurements every one to two years may be required. In patients who have successfully tapered off glucocorticoid therapy, we suggest annual BMD measurements for two years after transplantation with less frequent monitoring (every two to three years) thereafter. Risk factors for osteoporosis: age ≥65 years, Sedentary lifestyle, Cigarette smoking, Alcoholism The majority of bone loss and fractures occur within the first six months following transplantation, and fractures often involve the spine -- Osteopenia following transplantation mostly results from the use of glucocorticoids -> reducing the dose of glucocorticoids as soon as possible All patients should receive counseling regarding smoking cessation, early mobilization after transplantation Both female and male kidney recipients lose up to 8% of bone mass during the first 18 months after transplantation. An assessment of kidney transplant recipients at a mean of 6 years after transplantation has shown that bone loss, in the form of osteopenia or osteoporosis, affects 88% of recipients. Corticosteroid use is a major factor in bone loss, along with persistent hyperparathyroidism. Hypothyroidism and hypogonadism are other possible factors that need to be evaluated and treated if indicated. Guidelines from the American Society of Transplantation recommend a baseline dual-energy x-ray absorptiometry (DEXA) scan at the time of transplantation, at 6 months after transplantation in all patients, and then annually in patients with abnormal results. Prevention and treatment of osteoporosis include appropriate daily elemental calcium (1200 mg/day) and vitamin D (800 U/day) intake, along with daily exercise and avoidance of smoking, caffeine, and alcohol use. The use of bisphosphonates will often depend on the level of renal function. The emerging regimen of GC avoidance may be promising for limiting osteoporosis, whereas GC withdrawal creates a significant risk of rejection Long-Term Management of Adult Liver Transplant: 2012 Practice Guideline by AASLD and AST

37 Protonix Nexium Patient Case: GERD Dexilant63 yo Caucasian male with HCV due to IVDA received a liver transplant Anti-rejection regimen of mycophenolate/tacrolimus He is complaining of GERD symptoms. What PPI would you start? Dexilant Initiate dex-lansoprazole 30mg daily A Protonix Initiate pantoprazole 40mg daily B C Nexium Initiate esomeprazole 40mg daily

38 Patient Case: GERD This patient begins pantoprazole as directed and his GERD symptoms are relieved Patient has no interaction with tacrolimus and does not develop complications Congratulations Doctor! Continue to the next adventure…

39 Patient Case: GERD This patient begins dexlansoprazole as directed and his GERD symptoms are relieved Dexlansporazole interacts with tacrolimus and causes increased tacrolimus levels Patient develops tremors Dagnabbit Doctor! Here’s to better luck next time…

40 Patient Case: GERD This patient begins esomeprazole as directed and his GERD symptoms are relieved Esomeprazole interacts with tacrolimus and causes increased tacrolimus levels Patient develops tremors Dagnabbit Doctor! Here’s to better luck next time…

41 Protonix Nexium Patient Case: GERD Dexilant63 yo caucasian male with HCV due to IVDA received a liver transplant Anti-rejection regimen of mycophenolate/tacrolimus He is complaining of GERD symptoms. What PPI would you start? Dexilant Initiate dex-lansoprazole 30mg daily A Protonix Initiate pantoprazole 40mg daily B C Nexium Initiate esomeprazole 40mg daily

42 GI disorders Diarrhea GERD Caused by mycophenolate and tacrolimusMay treat with loperamide Switching CellCept  Myfortic (specialist to manage) GERD Antacids May decrease the absorption of mycophenolate Separate mycophenolate and antacids by at least 2 hours PPIs May increase concentration of tacrolimus Use of pantoprazole preferred H2RAs Use of ranitidine or famotidine preferred MMF: Abdominal pain (25% to 63%), nausea (20% to 55%), diarrhea (31% to 51%), constipation (19% to 41%), vomiting (33% to 34%), anorexia (25%), dyspepsia (22%) TACROLIMUS: Gastrointestinal: Diarrhea (25% to 72%), abdominal pain (29% to 59%; Astagraf XL <15%), nausea (13% to 46%), constipation (14% to 40%), anorexia (7% to 34%), vomiting (13% to 29%), dyspepsia (18% to 28%; Astagraf XL <15%) Very common to see patients on PPIs Monitor tacrolimus concentrations closely when using a proton pump inhibitor together with tacrolimus. Tacrolimus dose adjustment may be necessary. Patients with certain CYP2C19 and/or CYP3A5 genotypes may be at greater risk. Rabeprazole or pantoprazole may be less likely to significantly interact. Selected H2-receptor antagonists (i.e., ranitidine or famotidine) also appear less likely to interact.

43 Gout Incidence 10% to 20% Hyperuricemia occurs in a larger number of CNI-treated patients Acute attacks may be treated with colchicine or steroids Avoid NSAIDs due to risk of nephrotoxicity Allopurinol should be avoided/used with caution in patients who are taking azathioprine Colchicine and allopurinol require dose adjustments in patients with reduced renal function , primarily those receiving CSA, because of decreased glomerular filtration of uric acid In addition to the typical site of acute gout in the first metatarsophalangeal joint, post-transplantation gout may occur in the upper extremities and larger joints (e g , wrists, shoulders, elbows, knees, hips). Conversion from azathioprine to MMF avoids the problem and usually permits doses closer to those for nontransplantation patients. Shibolet O. Transplantation 2004; 77:1576.

44 Patient Case: Vaccinations58 yo white female with liver transplant due to hx of alcoholism Antirejection regimen includes tacrolimus PPV23 (Pneumovax) received 10/15/2012 Does the patient require further pneumococcal vaccination? YES One dose of PCV13 today, then second PPSV23 5 years from first A NO She is already adequately protected against pneumococcal disease B C YES Another dose of PPSV23 five years after the original dose

45 Patient Case: VaccinationIt is recommended that this patient receive a dose of PCV13 one year after the original PPSV23 vaccination It is also recommended that she be revaccinated with PPSV23 5 years from the first dose Without further vaccinations, this patient is not appropriately immunized and is at risk for pneumococcal infection Dagnabbit Doctor! Here’s to better luck next time…

46 Patient Case: VaccinationAfter receiving the PCV13 vaccination today, the patient is appropriately immunized against pneumococcal infection The patient receives the second dose of PPSV23 in 5 years, and has a reduced risk of pneumococcal infections Congratulations Doctor! Continue to the next adventure…

47 Patient Case: VaccinationRecommended that this patient receive a dose of PCV13 one year after the original PPSV23 vaccination Revaccinated with PPSV23 5 years from the first dose Without the PCV13 vaccination, this patient is not appropriately immunized and is at risk for pneumococcal infection Dagnabbit Doctor! Here’s to better luck next time…

48 Pneumococcal VaccinationPCV13 now PPSV in 8 weeks PPSV23 5 years later If no previous pneumococcal vaccination: If previous pneumococcal vaccination with PPSV23: PCV13 after at least 1 year PPSV years later Pneumovax Recommend Prevnar 13 x 1 dose + Pneumovax 8 weeks later + Pneumovax 5 years later – if no pneumococcal vaccine has been received Recommend PCV13 x 1 dose at least one year after PPV23 – if PPV23 has been received All should be revaccinated if > 5 years after first dose ACIP 2016 Adult Immunization Schedule

49 Patient Case: Vaccinations58 yo white female with liver transplant due to hx of alcoholism Antirejection regimen includes tacrolimus PPV23 (Pneumovax) received 10/15/2012 Does the patient require further pneumococcal vaccination? YES One dose of PCV13 today, then second PPSV23 5 years from first A NO She is already adequately protected against pneumococcal disease B C YES Another dose of PPSV23 five years after the original dose

50 Vaccinations Pre-Transplant Post-Transplant Influenza-inactivated Influenza-live attenuated Recommended X (may be given ≥2 weeks prior) X PCV13 PPSV23 Recommended* Hep B Hep A Tdap, Td If indicated HPV Meningiococcal Polio MMR Rotavirus Varicella If indicated and ≥4 weeks prior Zostavax A minimum of four weeks between live-virus vaccine administration and transplantation is suggested. Recommendations: Td booster every 10 years, at least one dose of tdap Annual flu vaccine – except live vaccine HPV vaccine series if indicated Hep A Hep B Inactivated influenza vaccine may be administered to solid organ transplant recipients despite intensive immunosuppression (eg, during the immediate posttransplant period), particularly in an outbreak situation (weak, low). Because immunosuppression can affect the patient's ability to mount an immune response to vaccinations, it is recommended that many of the vaccinations (eg, hepatitis A and B vaccines) be administered prior to transplantation when possible. In addition, live virus vaccinations should be avoided Immunosuppressed patients may not be able to mount an immune response adequate enough to achieve immunity. For this reason vaccinations are usually not recommended during the first year following transplantation ACIP 2016 Adult Immunization Schedule American Journal of Transplantation 2013; 13: 311–317 *if not vaccinated prior to transplant

51 Vaccinations If possible, vaccinate prior to transplantDelay until prednisone dose is <20 mg/day Live-attenuated vaccines should be avoided after transplant Prophylactic pneumococcal and influenza vaccine for all Clinicians' reluctant to administer vaccines to transplant recipients stems from a variety of factors including fear of precipitating allograft rejection. Despite anecdotal reports, there is minimal substantial evidence to support this association Inactivated vaccines are generally safe after solid organ transplantation while live-attenuated vaccines are not commonly administered after transplantation. It is recommended to administer live vaccines against viruses such as MMR, Zoster and Varicella prior to transplantation For the first 2-3 months after transplantation, a patient’s response to vaccinations may be diminished due to the high doses of anti-rejection medications used immediately after surgery. Accordingly, it may not be worthwhile to get vaccinations during this period. Thereafter, transplant recipients should receive certain vaccinations on a regular basis. Some vaccines are absolutely contraindicated in solid-organ transplant recipients. These include oral polio vaccine, vaccinia, BCG, and live oral typhoid American Journal of Transplantation 2013; 13: 311–317

52 The adventure continues…Many of these patients die with functioning grafts Primary care providers have an important role in improving outcomes of transplant recipients Important items to monitor in the primary care setting: Metabolic abnormalities Cardiovascular risks Contraceptive GI complaints Drug interactions Osteoporosis Vaccinations General health maintenance for liver transplant recipients is similar to that for the general population. However, require more intensive screening

53 The Mystery of TransplantFocusing on solid-organ transplant patients Management of the transplant patient in the primary care setting Katee Lira, PharmD Ambulatory Care Clinical Pharmacist, St. Vincent Indianapolis Assistant Professor of Pharmacy Practice, Manchester University April 20, 2016 I have no actual or potential conflicts of interest to disclose.