9/30/2016 Disclosure • None Medication Management and Beyond David J. Quan, Pharm.D., BCPS Pharmacist Specialist-Solid Organ Transplantation UCSF Medical Center Health Sciences Clinical Professor School of Pharmacy University of California, San Francisco Goal and Objectives Introduction • Solid organ transplantation is a life saving procedure 1 • Goal: – Discuss the optimal medication management in transplant • Immunosuppressive drugs are life sustaining 2,3 recipients. • Transplant medications are essential (WHO) 4 – Cyclosporine, azathioprine, prednisone • Objectives: – Valganciclovir, fluconazole, trimethoprim/sulfamethoxazole – Review drug selection/dosing • Immunosuppressive drugs have side effects – Review medication reconciliation process – Over immunosuppression: Infections, malignancies – Discuss medication access issues – Renal failure, diabetes, hypertension, etc. – Review strategies to improve medication adherence 1. Rana A. JAMA. 2015;150:252-259., 2. Merion. NEJM. 1984;310:148-154., 3. US Multicenter FK 506 Liver Study Group. NEJM. 1994;22:1110-11115., 4. http://www.who.int/medicines/publications/essentialmedicines/en/ 1
9/30/2016 Transplant Medications Managing Medications Polypharmacy • Immunosuppressive drugs are essential to prevent Collaborative approach to optimize medication use to improve patient outcomes allograft rejection – Narrow therapeutic “window” • Choose the right drug – Many factors affect drug levels • Find the right dose – Multiple and unique side effects • Get the drug to the patient • Medications to counteract side effects • Keep taking the medications – Antibiotic prophylaxis to prevent infections • Reconciling medications across the continuum – Antihypertensives for high blood pressure – Insulin for diabetes Transplant Medications Transplant Medications Choosing the Right Immunosuppressive Choosing the Right Prophylaxis Drug • Stratify according to donor/recipient serology • Immunologic risk – High risk (D+/R-): Valganciclovir – Induction regimen (HLA, cPRA, DSAs, h/o transplant) • Add cytomegalovirus Ig (CMVIG) in lung transplant recipients – Steroid maintenance (DGF, African American, GN) • Hepatitis B Immune Globulin (liver transplant) • Avoid specific side effects – High risk: HBV viremia, resistance, HIV/HDV-co-infection – Cosmetic side effects: Tacrolimus vs cyclosporine 1 • PCP Prophylaxis (varies with service) – Diabetes: Cyclosporine vs tacrolimus 2 – Heart: TMP/SMX DS MWF x1 year – Belatacept: Avoid nephrotoxicity from CNI 3 – Kidney: TMP/SMX DS daily x1 month then MWF x5 months – Liver: TMP/SMX SS MWF x1 year • “Side effect” with benefits – Lung: TMP/SMX DS MWF for life – mTOR (antitumor activity) in patients with HCC 4 – BMT: TMP/SMX DS BID on Saturday & Sundays only 1. Webster A. Cochrane Database Syst Rev. 2005, 2. Velleca A. J Heart Lung Transplant. 2013;32:S202. 3. Rostaing L. Clin J Am Soc Nephrol. 2011;6:430., 4. Menon KV. Aliment Pharmacol Therap. 2012;37:411. HLA=Human Leukocyte Antigen, cPRA=calculated Panel of Reactive Antibodies, DSA=Donor-Specific Antibody, DGF=Delayed Graft Function, GN=Glomerulonephritis, CNI=Calcineurin Inhibitor, HCC=Hepatocellular Carcinoma 2
9/30/2016 Hepatitis B Immune Globulin CMV Prophylaxis Protocol Liver Transplant Varies With Transplanted Organ Patient population Antiviral Initial Dose Maintenance Kidney Transplant: Low risk CMV Antibody Status Basiliximab Antithymocyte globulin HBV DNA <100 IU/mL AND Entecavir 5000 Units None NO resistance Tenofovir D+ / R- Valganciclovir x6 months Valganciclovir x6 months NO HIV or HDV Tenofovir/emtricitabine D+ / R+ Acyclovir x3 months Valganciclovir x3 months HIGH RISK D- / R+ Acyclovir x3 months Valganciclovir x3 months HBV DNA < 100 IU/mL Entecavir 5000 Units Yes D- / R- Acyclovir x3 months Valganciclovir x3 months AND Tenofovir Tenofovir/emtricitabine Resistance OR Lung Transplant: HDV or HIV-co-infection CMV Antibody Status Valganciclovir Cytomegalovirus Ig (Cytogam) HBV DNA ≥100 IU/mL Entecavir 10,000 Units Yes AND Tenofovir D+ / R- Valganciclovir for >12 mos. Cytomegalovirus Ig x16 weeks Tenofovir/emtricitabine NO Resistance OR D+ / R+ Valganciclovir for >12 mos. NO HDV or HIV-co-infection HBV DNA ≥100 IU/mL Entecavir 10,000 Units Yes D- / R+ Valganciclovir for >12 mos. AND Tenofovir D- / R- Valganciclovir x6 months Resistance OR Tenofovir/emtricitabine HDV or HIV-co-infection Transplant Protocols Narrow Therapeutic Window Keeping It All Together • Protocols vary with transplant service 1400 Concentration (ng/ml) At risk of toxicity: Nephrotoxicity – Tailored for specific situations Neurotoxicity 1200 Opportunistic infection • KTU: TMP/SMX DS daily x1 month (UTI prophylaxis), then MWF x5 Malignancy 1000 months (PCP prophylaxis) • Lung: Voriconazole/Posaconazole + Inhaled amphotericin B 800 ( Aspergillus sp. prophylaxis) 600 • Protocols 400 – Standardized regimens 200 Subtherapeutic: At risk of rejection 0 – Periodically updated 0 1 2 3 4 5 6 7 8 9 10 11 12 – Published in transplant manuals, Agile MD Time (hours) 3
9/30/2016 Transplant Medications Many Factors Affect Drug Levels Finding the Optimal Dose • Weight/body size • Timing of sample – Calcineurin inhibitors (CNIs), corticosteroid (taper) – True trough? • Desired therapeutic range – Missed doses? – CNIs, mTOR inhibitors • Type of assay • Organ function • Dose (age, weight) – CNIs, mTOR inhibitors, valganciclovir • Organ function • Side effects • Drug-drug interactions (drug, herbal, food) – CNIs, Mycophenolate, valganciclovir • Drug-drug interactions • Genetic variability – CNIs, mTOR inhibitors, voriconazole/posaconazole CNI=Calcineurin inhibitor, mTOR=mammalian Target of Rapamycin Typical Drug-drug Interactions Drug Interactions • Pharmacokinetic (“ADME”) Tacrolimus Tacrolimus Valganciclovir Valganciclovir Amlodipine Amlodipine – Absorption (PPIs decrease absorption of posaconazole) Mycophenolate Mycophenolate TMP/SMX TMP/SMX Metoprolol Metoprolol – Distribution Prednisone Prednisone Fluconazole Fluconazole Mag Oxide Mag Oxide – Metabolism (fluconazole decreases metabolism of tacrolimus) Omeprazole Omeprazole Calcium Carb. Calcium Carb. – Excretion (enterohepatic recirculation of MPAG) Antithymocyte Antithymocyte Aspirin Aspirin Vitamin D Vitamin D • Pharmacodynamic globulin globulin Simvastatin Simvastatin – Antagonism / synergy (NSAIDs worsen renal toxicity of CNIs) • Pharmaceutical – Chemical/physical incompatibility (antacids decrease absorption of mycophenolate) PPI=Proton Pump Inhibitor, MPAG=Mycophenolic acid glucuronide, NSAID=Non-Steroidal Anti-Inflammatory Drug, CNI=Calcineurin inhibitor 4
9/30/2016 Drug-Drug Interactions Medication Reconciliation Managing it All Across the Continuum • At home • Be vigilant • Admission to the hospital – When starting a new medication • Stop/start medications • Power of information is key • Formulary alternatives (home � hospital) – Accurate list of current medications is critical • To/from a different level of care – Utilize resources to check for interactions • ICU floor • Avoid interactions if possible • Phases of care – If unavoidable: Just deal with it • Discharge home/another facility – Utilize interactions to your advantage • Resume home meds • Be consistent • Formulary alternatives (hospital � home) Medications (Liver Transplant) Transition of Care Across the Hospital Stay Discharge Begins on Admission Admission Post-Op Day #1 Post-Op Day#7 Discharge Home • Reconcile medications on admission Lactulose syrup Norepinephrine drip Tacrolimus Tacrolimus Rifaximin Mycophenolate Mycophenolate Mycophenolate • Identify pharmacy for discharge medications Zinc Sulfate Methylprednisolone Prednisone 20mg Prednisone 10mg, 5mg – Insurance Furosemide Valganciclovir Valganciclovir Valganciclovir Spironolactone TMP/SMX TMP/SMX TMP/SMX – Geography Ciprofloxacin Fluconazole Fluconazole Fluconazole Omeprazole Pantoprazole Lansoprazole Omeprazole • Prescriptions sent to pharmacy for processing Levothyroxine Levothyroxine Levothyroxine Levothyroxine – Prior authorization Fentanyl Aspirin Aspirin Regular insulin drip Aspart Lispro – Formulary alternatives Dextrose 50% Glargine Glargine Pureflow dialysate Docusate sodium Docusate sodium • Patient education Magnesium sulfate Hydrocodone/APAP Hydrocodone/APAP Potassium chloride • Discharge day Calcium gluconate Sodium phosphate D5W0.45%NS drip 5
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