Transplant Primer for ICU Pharmacists

Transcription

1 HISTORICAL OVERVIEW Margaret Fernandez, PharmD, BCPS Transplant Primer for ICU Pharmacists Jackson Memorial Hospital Miami, Florida First long term surviving kidney transplant performed in identical twins First heart First liver transplantation performed in Colorado First lung transplant performed in Mississippi transplant performed in Capetown, South Africa 1967 DISCLOSURE STATEMENT HISTORICAL OVERVIEW I have no actual or potential conflicts of interest in relation to this presentation. 1960s Azathioprine first used in organ transplantation 1970s & 1980s Antithymocyte globulin developed FDA approves cyclosporine 1990s FDA approves cyclosporine microemulsion, mycophenolate mofetil and tacrolimus OBJECTIVES Describe the classifications of rejection Review immunosuppressive agents used in induction, maintenance and acute rejection protocols Describe monitoring strategies to optimize pharmacotherapy in transplant patients Identify regimens to prevent and treat common posttransplant infections DONATION & TRANSPLANTATION STATISTICS More than 24,000 patients began new lives in 2014 thanks to organ transplants Nearly 124,000 people in the U.S. are currently waiting for an organ transplant On average, 150 people are added to the nation s largest organ transplant waiting (UNOS) list each day 21 people die each day because the organs they need are not donated in time UNOS: United Network for Organ Sharing 1

2 UNOS 2015: U.S. ANNUAL NUMBER OF TRANSPLANTS CATEGORIES OF REJECTION Number of Transplants 30,969 Transplants Performed in U.S. in 2015 Hyperacute Acute Chronic SCIENTIFIC REGISTRY OF TRANSPLANT RECIPIENTS (SRTR): FLORIDA SOT BY CENTER VOLUME FL SOT CENTER VOLUME 7/1/ /31/2014 3,480 SOT performed in Florida HYPERACUTE REJECTION Occurs within minutes to hours post transplantation Pre existing anti donor antibodies circulating in the host Results in intravascular thrombosis and rapid occlusion of graft vasculature and rapid rejection Rarely seen in current practice due to pre transplant immunologic screening and advances in crossmatch technique as well as potent induction medications ICU PHARMACIST ROLE Majority of solid organ transplantations (SOT) require immediate care in a critical care setting The ICU accommodates invasive monitoring strategies, use of IV drips, intensive nursing care and hemodynamic support ICU pharmacists play an integral role in the care of SOT recipients Prevent allograft rejection Monitoring of drug levels Advocate and educator Minimize adverse events Selection of immunosuppressive agents Prevent and treat opportunistic infections ACUTE REJECTION Occurs within weeks to several months post transplantation Mediated by cellular (T cells) and/or humoral (B cells) immunity Clinical manifestations vary according to the type of organ transplanted and type of rejection Definitive diagnosis involves confirmation by biopsy 2

3 CHRONIC REJECTION RECOGNIZING REJECTION Appears several months to years after transplant and generally leads to irreversible late graft failure Fibrosis and scarring in transplant organ Multifactorial etiology inflammation, ischemia and other processes play a role Clinical manifestations vary according to the type of organ transplanted Lung Cough/Dyspnea/Fever Hypoxemia Rales Ground glass opacities, septal thickening, pleural effusions on CT Multivisceral Abdominal pain, distension Ileus Increased fecal volume and stomal output Pancreas Elevated amylase/lipase Dull abdominal pain Decreased urine output DIAGNOSIS OF REJECTION CLASSIFICATIONS OF ACUTE REJECTION Patients may present with no signs or symptoms When symptoms are present, may be non specific Biopsy is gold standard for diagnosis T cell Mediated Rejection (TCR) Most common form of rejection Generally responsive to anti T cell agents T cell and macrophage infiltration that leads to cellular injury, hemorrhage +/ necrosis Antibody Mediated Rejection (AMR) Less common, less responsive to anti T cell agents Antibody induced & complement mediated activation of endothelial cells, results in vascular injury RECOGNIZING REJECTION RISK FACTORS Younger age African Americans and Hispanics Previous transplant recipient Previous rejection episodes Kidney Decreased urine output Flu like symptoms Fever Increase in Scr Fluid retention Liver Elevated liver enzymes Jaundice Dark colored urine, light colored stools Fatigue, loss of appetite Nausea, abdominal pain Heart Shortness of breath Enlarged heart Onset of hypotension Arrhythmias Edema JVD T cell mismatch Previous pregnancies Blood transfusions 3

4 GOALS OF PHARMACOTHERAPY Prevent organ rejection INDUCTION Maintain drug efficacy Minimize drug toxicity Depleting Agents Antithymocyte globulin, Alemtuzumab, Rituximab Requires pre medications CMV, PCP prophylaxis recommended Minimize risk of malignancy Minimize risk of infection Prolong and improve quality of life Non depleting Agents Basiliximab Does not require pre medications Prophylaxis not required Benign side effect profile IMMUNOSUPPRESSIVE STRATEGIES Induction Corticosteroids Antibody Therapy Corticosteroids Calcineurin inhibitors Maintenance Antiproliferatives mtor Inhibitors Rejection Corticosteroids Antibody Therapy ANTITHYMOCYTE GLOBULIN (THYMOGLOBULIN ) Rabbit ATG produced by isolating gamma globulin fractions of serum obtained from rabbits after immunization with human T cells Polyclonal antibody acts primarily through depletion of T cells via apoptosis, antibody mediated cytotoxicity and complement mediated lysis Dose 1 2 mg/kg/day IV over 6 hours Administration Pre medication required due to infusion related reactions: Diphenhydramine, acetaminophen, and corticosteroids Central and peripheral formulations available Adverse Effects Hematologic (leukopenia, thrombocytopenia) Infusion related reactions cytokine release syndrome Fever, chills, headache, nausea, diarrhea, myalgias, hypotension, tachycardia, cardiorespiratory events INDUCTION Initial, aggressive, augmented form of immunosuppression to create partial tolerance in the recipient and delay early acute rejection Administered IV during perioperative period Includes intra operative and postoperative doses Rituximab Antithymocyte globulin Basiliximab Alemtuzumab Corticosteroids ALEMTUZUMAB (CAMPATH ) Humanized monoclonal antibody Binds to CD 52 on surface of B&T lymphocytes, monocytes, macrophages, NK cells, and granulocytes causing lymphocyte lysis and depletion Dose 30 mg IV x1 dose Administration Infused over 2 hours via central or peripheral line. NOT for IV bolus Pre medication required: Diphenhydramine, acetaminophen, +/ corticosteroids Adverse Effects HSV, CMV, Fungal infections Severe and prolonged leukopenia, neutropenia and thrombocytopenia Infusion related reactions cytokine release syndrome Fever, chills, headache, nausea, diarrhea, myalgias, hypotension, tachycardia, cardiorespiratory events 4

5 RITUXIMAB (RITUXAN ) Chimeric monoclonal antibody Binds to CD20 on pre, mature and memory B cells Induces B cell lysis through complement dependent and antibody mediated cytotoxicity Blocks B cell activation and maturation to plasma cells Dose 375 mg/m mg x 1 dose Administration Rate is started at 50 mg/hr, increased by 50 mg/hr increments every 30 min, to a max rate of 400 mg/hr Adverse Effects Hematologic leukopenia, thrombocytopenia Infectious complications CMV, varicella, polyomavirus, hepatitis, fungus Infusion related reactions Urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, ARDS, MI, cardiogenic shock Severe mucocutaneous reactions MAINTENANCE Baseline immunosuppression used to prevent rejection Multiple agents may be used together from different classes Goal is to improve long term graft survival Costimulation Blockade mtor Inhibitors Calcineurin Inhibitors Corticosteroids BASILIXIMAB (SIMULECT ) SITES OF ACTION Non depleting chimeric monoclonal antibody Binds and inhibits interleukin (IL) 2 mediated activation and proliferation of T cells Dose 20 mg IV POD 0 and 4 Administration Infused over minutes via central or peripheral line Does not require pre medications Adverse Effects Does not appear to increase the incidence or severity of adverse effects in clinical trials Adverse effects were reported in 96% of both placebo and basiliximab groups Everolimus INDUCTION SUMMARY: ANTIBODY THERAPY DRUG MOA DOSE/ADMIN ADE PRE MEDS Anti Thymocyte globulin (Thymoglobulin ) Polyclonal antibody T cell depleting agent 1 2 mg/kg IV over 4 6 hr Leukopenia Thrombocytopenia Infusion related reaction Alemtuzumab (Campath ) Rituximab (Rituxan ) Basiliximab (Simulect ) Monoclonal antibody, T & B cell depleting agent Monoclonal antiobody, B cell (CD20) depleting agent Monoclonal antibody, IL 2 receptor antagonist, non depleting agent 30 mg IV over 2 hr Lymphocytopenia Infusion related reaction 375 mg/m 2 IV infusion time based on tolerability Cytopenias Hypertension Peripheral edema Infusion related reaction 20 mg IV over 30 min Hypertension Peripheral edema Yes Yes Yes No MAINTENANCE Corticosteroids Calcineurin Inhibitors Antiproliferatives Proliferation Signal Inhibitors Costimulatory Blocker Methylprednisolone Prednisone Cyclosporine (CsA) Tacrolimus (FK) Azathioprine Mycophenolates (MMF) Sirolimus Everolimus Belatacept 5

6 CORTICOSTEROIDS Nonspecific inhibitor of IL 1, IL 2, IL 3, IL 6, IL 15, TNF α, and IFN γ Role in induction, maintenance, and rejection protocols Dose Variable dosing strategies Highest doses at induction ( mg) tapered over days to weeks Long term maintenance doses usually range from mg daily Adverse Effects Hypertension, Hypertriglyceridemia Insulin resistance, osteoporosis N/V, diarrhea, abdominal pain, dyspepsia, gastritis, weight gain Impaired wound healing, water retention Hand tremor, mood disturbances, psychosis Cataracts Clinical Pearls Antibody induction with FK + MMF, allows for early corticosteroid withdrawal (first 7 days) CYCLOSPORINE Prevents IL 2 mediated CD4+ T cell activation. Binds to cyclophilin which prevents calcineurin dephosphorylation of nuclear factor of activated T cells (NFAT) Dosage Forms Sandimmune (non modified) original formulation Corn oil based formula, bile dependent for absorption Unpredictable oral absorption Neoral (modified) microemulsion formulation Self emulsifying, less bile dependent for absorption Better bioavailability of 30 45% Dose & Administration PO (Sandimmune or Neoral): Dose is dependent upon type of transplant Oral formulations are not bioequivalent and cannot be used interchangeably IV (Sandimmune only): ⅓ oral dose in divided doses or as a con nuous infusion Administer over 2 6 hours or as a 24 hr continuous infusion Anaphylactic risk Reserved only for patients who cannot take oral form Glass bottle or polyethylene bags (drug binds to PVC tubing) Clinical Pearls CYP3A4/Pgp substrate (many DDIs) TO WITHDRAW OR NOT TO WITHDRAW Corticosteroids remain a key component of most immunosuppressive protocols Benefits derived are offset by long term complications Withdrawal may minimize these complications Important to determine target population and timing of withdrawal Postmenopausal women, prior history of malignancy, history of diabetes and pediatric patients Early vs. late withdrawal TACROLIMUS Inhibits T lymphocyte activation Binds to FKBP 12 (intracellular protein) and complexes with calcineurin inhibiting calcineurin phosphatase Dose Oral/Feeding Tube: q 12 hr Conversion to: ER: 1:1 ratio given once daily Sublingual: 2:1 ratio IV: ¼ to ⅓ of PO total daily dose IV: mg/kg/day as a continuous infusion over 24 hours Do not use PVC tubing Anaphylactic reactions reported Administration Best absorption is on an empty stomach Antacids & cholestyramine impair absorption SL can be given to intubated and enterally fed patients Clinical Pearls CYP3A4/Pgp substrate (many DDIs) CALCINEURIN INHIBITORS Generic Brand Name Dosage Forms Routes of Administration Cyclosporine (CsA) Tacrolimus (Tac, FK) Gengraf, Neoral, Sandimmune Prograf, Hecoria, Astagraf XL Capsule Oral solution IV solution Capsule Oral solution IV solution Oral Feeding tube IV Oral, Sublingual Feeding Tube IV Special Routes Oral solution only for feeding tubes Oral solution only for feeding tubes Capsules can be given sublingually Drug Level Monitoring Yes Yes SUBLINGUAL ADMINISTRATION: TACROLIMUS Advantages of SL IV route associated with more nephrotoxicity, neurotoxicity and anaphylaxis Alternative to oral route if: N/V Risk of aspiration Decreased absorption due to delayed gastric emptying Disadvantages of SL Exact dose conversion is unknown High interpatient variability Must wear gloves and mask Content of capsule deposited into bottom half of capsule Powder is deposited under patient s tongue Allow to dissolve for 10 minutes 6

7 CALCINEURIN INHIBITORS: ADVERSE EFFECTS CsA and Tac (6 H S) Hyperuricemia Hyperlipidemia Hypertension Hyperglycemia Hyperkalemia Hypomagnesemia CsA and Tac (2 N s) Nephrotoxicity Neurotoxicity Cyclosporine only Hirsutism Hyperplasia (gingival) Tacrolimus only Alopecia QT prolongation Torsade de pointes ANTIPROLIFERATIVES: AZATHIOPRINE Antagonizes purine metabolism and inhibits synthesis of DNA, RNA and proteins Dose Initial PO or IV: 2 5 mg/kg once daily; Maintenance: 1 3 mg/kg once daily 1:1 IV to PO conversion Renal dose adjustment: CrCl ml/min: 75% of normal dose CrCl < 10 ml/min: 50% of normal dose Hemodialysis: dialyzable ~45% (administer 50% of normal dose) Administration IV: may be infused over 5 min or as a min infusion PO: administer after meals or in divided doses to decrease adverse GI effects Adverse Effects BMS, leukopenia, thrombocytopenia Nausea, vomiting, diarrhea Pancreatitis, hepatotoxicity Clinical Pearls Significant dose reductions required in the presence of xanthine oxidase inhibitors or with TPMT deficiency TPMT: thiopurine S methyltransferase CALCINEURIN INHIBITORS: COMMON DRUG INTERACTIONS Amiodarone Azole antifungals Clarithromycin Erythromycin Diltiazem Verapamil Nicardipine Concentration Concentra on Nephrotoxic Risk Grapefruit juice Indinavir Ritnovair Nelfinavir Sertraline Metronidazole Rifampin Phenytoin Phenobarbital Carbamazepine St. John s Wort Aminoglycosides Acyclovir (IV) Amphotericin B NSAIDs ACE I/ARBs Dosage Forms/Dose ANTIPROLIFERATIVES: MYCOPHENOLATES Inhibits inosine monophosphate dehydrogenase, preventing the de novo pathway of purine synthesis Mycophenolate mofetil (MM) (Cellcept ) Available IV & PO (500 mg tablet, 250 mg capsule, 200mg/mL suspension) 1:1 IV to PO conversion Dose: g IV/PO/NGT q 12 hr Mycophenolic acid (MPA) (Myfortic ) Enteric coated formulation Available in 180 mg, 360 mg tablets (no liquid) Dose: 720 mg PO BID Administration IV: Infuse over 2 hours PO/NGT: Capsules, tablets cannot be crushed, split Best absorbed on empty stomach Adverse Effects Leukopenia, thrombocytopenia Nausea, vomiting, diarrhea, abdominal pain, dyspepsia, gastritis Clinical Pearls GI symptoms similar between MM and MPA THERAPEUTIC DRUG MONITORING MYCOPHENOLATE DOSING CONVERSION Certain immunosuppressants require blood level monitoring Trough levels are drawn minutes prior to the dose Level must be correlated to the administration time and route Organ and protocol specific target levels Drug Cyclosporine Tacrolimus Sirolimus Everolimus Therapeutic Drug Monitoring ng/ml 5 15 ng/ml ng/ml* 3 12 ng/ml *Combined with mycophenolate: 6 10 ng/ml Combined with CNI: 4 8 ng/ml Cellcept (Mycophenolate Mofetil) Suspension, tablets and capsules Myfortic (Mycophenolic Acid) Delayed release tablets 1000 mg 720 mg 750 mg 540 mg 500 mg 360 mg 250 mg 180 mg 7

8 PROLIFERATION SIGNAL INHIBITORS: SIROLIMUS & EVEROLIMUS Sirolimus Everolimus Inhibits mammalian target of rapamycin (mtor), resulting in a reduction in IL 2 driven lymphocyte proliferation Dose PO/NGT: 2 5 mg daily Based on 24 hr trough levels 1 mg, 2 mg tabs & 1 mg/ml solution Administration Consistency with/without food PO/NGT: mg PO q 12 hr Based on 12 hr trough levels 0.25 mg, 0.75 mg tabs Oral solution available for NGT Tablets can be given via NGT Clinical Pearls Used to minimize CNI exposure and in malignancy recurrence Doses should be adjusted if needed at 5 day intervals due to long half life CYP3A4/Pgp substrate (many DDIs) Strongly consider holding therapy (convert to CNI) in patients undergoing surgical procedures because of risk of impaired wound healing SIROLIMUS & EVEROLIMUS: DRUG INTERACTIONS Amiodarone Azole antifungals Clarithromycin Erythromycin Diltiazem Verapamil Nicardipine Concentration Concentra on Nephrotoxic Risk Grapefruit juice Indinavir Ritnovair Nelfinavir Sertraline Metronidazole Rifampin Phenytoin Phenobarbital Carbamazepine St. John s Wort Aminoglycosides Acyclovir (IV) Amphotericin B NSAIDs ACE I/ARBs NGT ADMINISTRATION: EVEROLIMUS Must wear gloves and mask Place whole tablets in a 20 ml oral syringe Draw 10 ml sterile water into syringe Pull the plunger back to 15 ml and cap syringe Gently shake until tablets are dispersed Immediately give via NGT and flush with 20 ml sterile water COSTIMULATORY BLOCKADE: EVIDENCE Prophylaxis of organ rejection concomitantly with basiliximab induction, mycophenolate and corticosteroids in adult Epstein Barr Virus (EBV) seropositive kidney transplant recipients Used ONLY in EBV seropositive patients Use for prophylaxis in organs other than the kidney has not been established Ferguson et al 2011 Belatacept not proven more effective than tacrolimus Compared with cyclosporine, belatacept improved GFR despite a higher incidence of rejection Rostaing et al 2013 SIROLIMUS & EVEROLIMUS: ADVERSE EFFECTS Hypertension Lymphocele Hypertriglyceridemia Mucositis Hyperlipidemia Aseptic pneumonitis Hyperglycemia N/V, diarrhea Leukopenia Rash/acne Thrombocytopenia Proteinuria Prolonged DGF Tremor, headache, insomnia Impaired wound healing DGF: Delayed graft function COSTIMULATORY BLOCKER: BELATACEPT Fusion protein; selective Tcell co stimulation blocker resulting in T cell anergy Dose Initial: 10 mg/kg IV x 6 doses Maintenance: 5 mg/kg IV q 4 weeks Conversion from CNI 5 mg/kg IV x 5 doses, then q 4 weeks CNI dose is slowly tapered over 1 month Dose is based on actual body weight and rounded to closest multiple of 250 mg Administration 30 minute infusion with in line 0.22 micron filter No pre medications required Adverse Effects Hyperkalemia, hypomagnesemia N/V, diarrhea Headache Clinical Pearls Used as maintenance Contraindicated in EBV naïve patients or patients with an unknown EBV status because of the risk of PTLD 8

9 REMS REQUIREMENTS Mycophenolate Associated with increased risk of first trimester pregnancy loss Prescribers are required to provide extensive counseling to females of childbearing potential Belatacept Risk of developing Progressive Multifocal Leukoencephalopathy (PML) and Post Transplant Lymphoproliferative Disorder (PTLD) Prescribers are required to provide patients with a medication guide and pre infusion checklist IMMUNOSUPPRESSION RELATED COMPLICATIONS Allograft Rejection Infection PTLD REMS REQUIREMENTS REJECTION Eculizumab The purpose of the SOLIRIS REMS is to mitigate the occurrence and morbidity associated with meningococcal infections by informing healthcare providers and patients about the: Increased risk of meningococcal infections Early signs of invasive meningococcal infections Need for immediate medical evaluation of signs and symptoms consistent with possible meningococcal infections T cell Mediated Rejection (TCMR) Optimize maintenance + Steroid Bolus +/ Thymoglobulin +/ Alemtuzumab PP: Plasmapheresis Antibody Mediated (Humoral) Rejection (AMR) Optimize maintenance + Steroid Bolus +/ Thymoglobulin PLUS IVIG, PP, Rituximab or IVIG, PP, Bortezomib or IVIG, PP, Eculizumab MAINTENANCE THERAPY SUMMARY AGENTS USED FOR REJECTION IF AE to FKswitch to Cyclosporine Tacrolimus + CNI exposure or malignancy Sirolimus Maintenance Mycophenolate + CNI exposure or malignancy Everolimus +/ Corticosteroid If continued, tapered over 3 months Agent TCMR Dosing Guidelines General Recommendations or AMR Corticosteroids TCMR Methylprednisolone 500 mg 1000mg IV 1 st line low severity TCMR daily x 3 5 doses Antithymocyte TCMR 1.5 mg/kg IV daily x 4 14 doses 1 st line mod and high severity Globulin Alemtuzumab Both mg IV x 1 2 doses For AMR +PP +IVIG +/ rituximab IVIG AMR 100 mg/kg after PP + PP considered 1 st line for AMR Rituximab AMR 375 mg/m mg IV x1 dose CD20 not on pro B cells or plasma cells, do not use as monotherapy Bortezomib AMR 1.3 mg/m 2 IV on days 1, 4, 8 and 11 +PP and IVIG in refractory AMR or recurrence Eculizumab AMR 1200 mg IV x 1 dose, followed 1 week later by 4 weekly doses of 900 mg, with a final dose of 1200 mg at week 5 +PP AND IVIG in refractory AMR Meningococcal infection vaccination 14 days before therapy 9

10 REJECTION TREATMENT SUMMARY Rejection T cell mediated Antibody mediated Corticosteroids O R Antithymocyte globulin IVIG +PP + Alemtuzumab +/ Rituximab O R Bortezomib O R Eculizumab INFECTIOUS COMPLICATIONS Most common life threatening complication of long term immunosuppression Contributes to graft loss RISK FACTORS Technical & surgical complications of procedure Reduces long term survival Increases the risk for post transplant malignancy Immunosuppression is reduced or withheld during infection Net state of recipient immunosuppression Recipient s environmental exposures TIMELINE OF POST TRANSPLANT INFECTIONS First month post transplant Same infections as those observed in immunocompetent patient 2 6 months post transplant Opportunistic infections Immunomodulating viruses Greater than 6 months post transplant Depend on patient s clinical course Community acquired or persistent infections TREATMENT & PREVENTION: PCP Medication Prophylaxis Dosing Treatment Dosing Clinical Pearls SMZ/TMP 1 SS or DS tablet three times weekly mg/kg/day of TMP component IV divided q 6 8 hr x 21 days May need to stop early due to hyperkalemia and myelosuppression Atovaquone 1500 mg PO daily 750 mg PO BID x 21 days Available only as liquid Administer with food Dapsone mg PO daily 100mg PO daily + trimethoprim 15 mg/kg/day PO in three divided doses x 21 days Pentamidine Primaquine/ Clindamycin 300 mg inhaled q 4 weeks Not recommended G6PD: glucose 6 phosphate dehydrogenase Should never be administered to a patient with a significant sulfa allergy or G6PD deficiency 4 mg/kg IV daily x 21 days Prophylaxis dose can be given IV if necessary mg PO daily mg IV q 6 8 hr x 21 days Long term clindamycin can predispose to C. diff 10

11 DURATION OF ANTIMICROBIAL PROPHYLAXIS Solid Organ PCP CMV Antifungal Kidney 3 months D+R :6 months Continued while on steroids All other serotypes: 3 months Liver 12 months D+R/ : 6 months All other serotypes: 3 months Intestine/ Multivisceral Low risk: none High risk: 7 14 days Indefinite 12 months Azole continued until steroid discontinued Heart 3 months D+R :6 months All other serotypes: 3 months Lung 12 months D+R : 12 months All other serotypes: 6 months 3 months 12 months **Patients that have completed their course of prophylaxis and receive treatment for rejection should restart PCP, CMV and antifungal prophylaxis for a period of 3 months TREATMENT & PREVENTION: CMV POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS (PTLD) Medication Prophylaxis Dosing Treatment Dosing Clinical Pearls Ganciclovir 5 mg/kg IV daily 5 mg/kg IV q 12 hr Oral form no longer available Can be initiated IV and then converted to PO valganciclovir Valganciclovir 900 mg PO daily 900 mg PO q 12 hr Can be initiated with IV ganciclovir and then converted to PO valganciclovir Cidofovir Not recommended 5 mg/kg IV once weekly x2; then every 2 weeks Ganciclovir resistant CMV disease 1 L of NS given before and at the time of each infusion Probenecid 2 g 3 hr before infusion; 1g given at both 2 and 8 hr after infusion Foscarnet Not recommended Ganciclovir resistant CMV disease EBV: Epstein Barr Virus Heterogeneous group of lymphoproliferative disorders Most commonly of B cell origin with 60 80% of total PTLD cases found to be EBV positive Most serious and potentially fatal complication post transplantation Associated with a mortality of 40 60% Solid Organ Type Incidence Liver 2.2% Multivisceral 7 11% Heart 3.4% Lung % Kidney 1% TREATMENT & PREVENTION: FUNGAL Medication Prophylaxis Dosing Treatment Dosing Clinical Pearls Nystatin K, H: 500,000 unit/5 ml S/S QID N/A Only use if SOT is low risk Fluconazole Li, M, P: 400 mg PO daily 800 mg IV x1, then 400 Monitor CNI drug levels mg IV daily Itraconazole Lu, H: 200 mg PO BID mg PO daily Solution and capsule not to be used interchangeably Posaconazole Lu: 200 mg NGT TID with full meal or nutritional supplement or 300 mg PO daily with high fat meal 200 mg PO QID initially, then 400 mg PO BID Liquid and Tablet not to be used interchangeably DDI with liquid and PPI or H2 Voriconazole Lu, H: 200 mg PO BID 6 mg/kg IV q 12 hr x 1day, Monitor CNI drug levels 4mg/kg IV q 12 hr Micafungin Li: 50 mg IV daily mg IV daily Refractory or salvage Amphotericin B Lu: Inhaled AmphoB 25 mg daily x 4 days, then once weekly Li, M, P: 3 5 mg/kg Abelcet IV daily K: Kidney; H: Heart, Li: Liver; Lu: Lung; M: Multivisceral; P: Pancreas 5 mg/kg IV daily Higher dosages are not more effective PTLD RISK FACTORS Advanced age Type of transplant High degree of immunosuppression Primary EBV infection after transplant Type of immunosuppressive agents used Allograft rejection Cytomegalovirus co infection CLINICAL PRESENTATION Unexplained fever Mononucleosis like syndrome Gastrointestinal bleeding, obstruction or perforation Abdominal mass lesions Infiltrative disease of the allograft Hepatocellular or pancreatic dysfunction Central nervous system disease 11

12 PTLD: TREATMENT Based on case reports or a limited series of patients Initial strategy reduction or discontinuation of immunosuppressive drug therapy Most effective for EBV associated PTLDs occurring within the 1 st year of transplantation Rituximab is the first line if initial strategy fails 375 mg/m 2 IV weekly x 4 weeks QUESTIONS CONCLUSION UNOS amended its bylaws to include a clinical pharmacist as an essential member of the healthcare team ICU pharmacists play an integral role in the management of immunosuppression related issues in SOT recipients Valuable source in identifying and preventing immunosuppressant related adverse effects, drug interactions and providing alternative regimens when needed Important to be familiarized with management of rejection and infectious complications commonly seen in the SOT population REFERENCES 1. Reed MJ, Dhanyamraju S, Schultz MF, et al. Solid organ transplantation in the ICU. Comprehensive Critical Care: Adult. Chapter 42: Moten MA, Doligalski CT. Postoperative transplant immunosuppression in the critical care unit. 2013;24(4): Statistics from Organ Procurement and Transplantation Network as of January 16, Accessed April 18, Thompson ML, Flynn JD, Clifford TM. Pharmacotherapy of lung transplantation: an overview. J Pharm Practice 2012; 26(1): Gabardi S, Roger C. Long term management after kidney transplantation. PSAP 2014 Chronic Illnesses Ferguson R, Grinyo J, Vincenti F, et al. Immunosuppression with belatacept based, corticosteroid avoiding regimens in de novo kidney transplant recipients. Am J Transplant 2001;11: Rostaing L, Vincenti F, Grinyo J, et al. Long term belatacept exposure maintains efficacy and safety at 5 years: results from the longterm extension of the BENEFIT study. Am J Transplant 2013; 13: Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long term outcomes in kidney transplantation. N Engl J Med 2016; 374: Shah N, Meouchy J, Qazi Y. Bortezomib in kidney transplantation. Curr Opin Organ Transplant 2015;20: Kocak B, Demiralp AE, Karatas C, et al. Eculizumab for salvage treatment of refractory antibody mediated rejection in kidney transplant patients: case reports. Transplantation Proceedings 2013; 45: Fishman JA. Infection in solid organ transplant recipients. N Engl J Med 2007; 357: Razonable RR, Humar A. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013; 13: Silveira FP, Kusne S. Candida infections in solid organ transplantation. Am J Transplant 2013; 13: Petrara MR, Giunco S, Serraino D, et al. Post transplant lymphoproliferative disorders: from epidemiology to pathogenesis driven treatment. Cancer Letters 2015; 369: Andreone P, Gramenzi A, Lorenzini S, et al. Post transplantation Lymphoproliferative Disorders. Arch Intern Med 2003; 163: Rubin LG, Levin MJ, Ljungman P, et al Infectious Diseases Society of America guidelines for the vaccination of the immunocompromised host Alloway RR, Dupuis R, Gabardi S, et al. Evolution of the role of the transplant pharmacist on the multidisciplinary transplant team. Am J Transplant 2011; 11: