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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. 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 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 McCashland TM. Liver Transpl 2001; 7:S2. Steroids Tacrolimus (CNI) Cyclosporine (CNI) Mycophenalate mofetil Azathioprine Sirolimus 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 Neurotoxicity, hair loss, insomnia CVD GERD, nausea Metabolic abnormalities (DM, HLD) Diarrhea Reduced bone mineral density Nephrotoxicity Gout Long-Term Management of Adult Liver Transplant: 2012 Practice Guideline by AASLD and AST DRUGS ADVERSE EFFECTS Steroids Hypertension, 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 Sirolimus Neutropenia, anemia, liver inflammation, hair loss, acute pancreatitis Tremors, hyperlipidemia, thrombocytopenia, neutropenia, anemia, poor wound healing Numerous drugs that interact with immunosuppressants Check for drug-interactions before starting new medications P-glycoprotein Cyclosporine Tacrolimus CYP 3A4 Cyclosporine Tacrolimus Sirolimus Drug Pregnancy Category Concerns Steroids C/D First 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 C 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 D Congenital anomalies, hematologic toxicities, and intrauterine growth retardation. Better alternative than MMF. Sirolimus C Not teratogenic, lower birth weights, fetal mortality. Effective contraception must be started before therapy and continued for 12 weeks after d/c Pregnancies 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 A pregnancy registry has been established for pregnant women taking immunosuppressants following any solid organ transplant. National Transplantation Pregnancy Registry, 877-955-6877 Long-Term Management of Adult Liver Transplant: 2012 Practice Guideline by AASLD and AST 65 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? AYES Initiate atorvastatin 40 mg daily B YES Initiate simvastatin 40 mg daily CYES Initiate rosuvastatin mg daily 5 Per the lipid guidelines, this patient qualifies for a high intensity statin However, atorvastatin is contraindicated with cyclosporine Your patient develops rhabdomyolysis and is hospitalized Dagnabbit Doctor! Here’s to better luck next time… Per the lipid guidelines, this patient qualifies for a high intensity statin However, simvastatin is contraindicated with cyclosporine Your patient develops rhabdomyolysis and is hospitalized Dagnabbit Doctor! Here’s to better luck next time… Per 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. Congratulations Doctor! Continue to the next adventure… Statin Cyclosporine Tacrolimus Atorvastatin CONTRAINDICATED No dose adjustment, monitor Fluvastatin Limit fluvastatin to 20 mg BID Lovastatin CONTRAINDICATED Pitavastatin CONTRAINDICATED Pravastatin Limit pravastatin to 20 mg/day Rosuvastatin Limit rosuvastatin to 5 mg/day Simvastatin CONTRAINDICATED No dose adjustment, monitor No dose adjustment, monitor 65 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? AYES Initiate atorvastatin 40 mg daily B YES Initiate simvastatin 40 mg daily CYES Initiate rosuvastatin mg daily 5 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 BioDrugs 2001; 15 (4) Long-Term Management of Adult Liver Transplant:2012 Practice Guideline by AASLD and AST Pretransplantation CVD Hyperlipidaemia Hyperhomocysteinemia Hypertension Diabetes mellitus Smoking Acute rejection episodes Graft failure Direct effects of immunosuppressive agents BioDrugs 2001; 15 (4) BioDrugs 2001; 15 (4) Incidence of CAD 9-25% ALL agents require close follow-up Strict 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 Fouad T. Transplantation. 2009;87(5):763 54 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? A ACEI Initiate lisinopril 10 mg daily B HCTZ Initiate HCTZ 25 mg daily C DHPCCB Initiate amlodipine 5mg daily Patient 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 Congratulations Doctor! Continue to the next adventure… Hydrochlorothiazide 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… Patient 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 Congratulations Doctor! Continue to the next adventure… 54 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? A ACEI Initiate lisinopril 10 mg daily B HCTZ Initiate HCTZ 25 mg daily C DHPCCB Initiate amlodipine 5mg daily 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) Ann Pharmacother 2010;44:1259-70 Long-Term Management of Adult Liver Transplant:2012 Practice Guideline by AASLD and AST. 38 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? A YES Screen every 3 years B NO Does not have risk factors for diabetes screening C YES Screen every year The patient is screened for diabetes and does not have newonset 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… The 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… The 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… 38 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? A YES Screen every 3 years B NO She does not have risk factors for diabetes screening C YES Screen every year 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 2008 European Society for Organ Transplantation 22 (2009) 519–530 Long-Term Management of Adult Liver Transplant: 2012 Practice Guideline by AASLD and AST More common with the current obesity epidemic Associated with CVD, graft failure, and death 2008 European Society for Organ Transplantation 22 (2009) 519–530 Common among patients who have transplants Incidence of 50-60% Combination of Hypertension Insulin resistance/diabetes Dyslipidemia Obesity Immunosuppressant use is associated with all aspects of the metabolic syndrome 2008 European Society for Organ Transplantation 22 (2009) 519–530 Long-Term Management of Adult Liver Transplant: 2012 Practice Guideline by AASLD and AST The risk of fractures following transplantation is high DEXA 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 nontransplant general population Weight-bearing exercises Supplementation with calcium and vitamin D Bisphosphonates Long-Term Management of Adult Liver Transplant: 2012 Practice Guideline by AASLD and AST 63 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? A Protonix B Initiate pantoprazole 40mg daily Dexilant Initiate dexlansoprazole 30mg daily C Nexium Initiate esomeprazole 40mg daily 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… 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… 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… 63 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? A Protonix B Initiate pantoprazole 40mg daily Dexilant Initiate dexlansoprazole 30mg daily C Nexium Initiate esomeprazole 40mg daily Diarrhea Caused by mycophenolate and tacrolimus May 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 decrease the absorption of mycophenolate May increase concentration of tacrolimus Use of pantoprazole preferred H2RAs Use of ranitidine or famotidine preferred 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 Shibolet O. Transplantation 2004; 77:1576. 58 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? A NO She is already adequately protected against pneumococcal disease B YES One dose of PCV13 today, then second PPSV23 5 years from first C YES Another dose of PPSV23 five years after the original dose It 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… After 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… Recommended 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… If no previous pneumococcal vaccination: PCV13 now PPSV23 in 8 weeks PPSV23 5 years later If previous pneumococcal vaccination with PPSV23: PCV13 after at least 1 year PPSV23 5 years later ACIP 2016 Adult Immunization Schedule 58 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? A NO She is already adequately protected against pneumococcal disease B YES One dose of PCV13 today, then second PPSV23 5 years from first C YES Another dose of PPSV23 five years after the original dose Pre-Transplant Post-Transplant Influenza-inactivated Influenza-live attenuated Recommended X (may be given ≥2 weeks prior) Recommended X PCV13 PPSV23 Recommended Recommended Recommended* Recommended* Hep B Recommended Recommended* Hep A Recommended Recommended* Tdap, Td If indicated If indicated HPV If indicated If indicated Meningiococcal If indicated If indicated Polio If indicated If indicated MMR If indicated X Rotavirus If indicated X Varicella If indicated and ≥4 weeks prior X Zostavax If indicated and ≥4 weeks prior X *if not vaccinated prior to transplant ACIP 2016 Adult Immunization Schedule If possible, vaccinate prior to transplant Delay until prednisone dose is <20 mg/day Live-attenuated vaccines should be avoided after transplant Prophylactic pneumococcal and influenza vaccine for all American Journal of Transplantation 2013; 13: 311–317 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 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.