Solid Organ Transplant Pearls for the Non-Transplant Pharmacist Katie Cunningham, PharmD, BCPSAssistant Professor, Pharmacy PracticeRosalind Franklin University of Medicine & Science Clinical Specialist, Solid Organ Transplant PGY2 Solid Organ Transplant Pharmacy Residency Director Northwestern Memorial Hospital
1st COVID-19 Lung Transplant Recipient
Objectives
• Understand the role of the pharmacist and pharmacy technician in solid organ transplant
• Describe important medication counseling points for transplant patients
• Review the importance of drug shortages, formulation changes and insurance coverage issues in transplant patients
• Explain the significance of select immunosuppression related drug-drug interactions
Solid Organ Transplant (SOT)
Every 10 min someone is
added to the transplant waiting list
~20 people die each day awaiting an
organ transplant
~74,805 people active
on the transplant waiting list
36,528 organ transplants
performed in 2018
1 organ donor can
save 8 lives!!
Transplanted Organs
UNDERSTAND THE ROLE OF THE PHARMACIST & PHARMACY TECHNICIAN IN SOLID ORGAN TRANSPLANT
Post-Transplant Care
• Interprofessional Transplant Team • Surgeon + Fellow(s)
• Nephrologist + Fellow
• Hepatologist + Fellow
• Pulmonologist + Fellow
• Cardiologist + Fellow
• Infectious Diseases Team
• Nurse Practitioners/Physician Assistants
• Dietician
• Social Worker
• Transplant Nurse Coordinator
• Clinical Coordinator on the transplant unit (RN)
• Transplant Pharmacist + Resident/Fellow
SOT Pharmacist: Inpatient Responsibilities
Daily Rounding
Order Verification
Immunosuppression Management
Discharge Medication Reconciliation
Patient Education
Student and Resident Precepting
SOT Pharmacist: Outpatient Responsibilities
• Pre-Transplant: • Attend all selection meetings
• Medication reconciliation and preliminary patient education
• Post-Transplant: • Surgical visit, 1 month & 3 month patient
appointments• As needed thereafter or requested by MD/NP
• Facility discharge medication education
SOT Pharmacist
• Other Responsibilities:
• Quality Assurance and Performance Improvement Committee
• Protocol Review & Development
• Research
• College of Pharmacy Transplant Lecture(s)
• Residency Program Director
• Organization Involvement
SOT Pharmacist Training
• PGY1 Residency
• Transplant center experience preferred
• PGY2 Residency in Solid Organ Transplant
• 1+ year(s)
• 49 SOT Residency Programs
• Board Certification
• First examination planned for Fall 2021
Role of Pharmacy Technicians
• Inpatient roles & responsibilities:
• Insurance authorization, billing & troubleshooting common coverage denials
• Coordination of vouchers, collecting payment from patients, discussing future fills & delivery options
• Outpatient transplant clinic and/or Specialty Pharmacy
• Prior authorizations
• Refills, coordination of delivery
• Formulation switches due to insurance issues (in conjunction with transplant PharmD)
DESCRIBE IMPORTANT MEDICATION COUNSELING POINTS FOR TRANSPLANT PATIENTS
Post-Transplant Medications
• Induction Immunosuppression
• Maintenance Immunosuppression
• 2-3 medications (lifelong)
• Anti-Infective Prophylaxis
• 2-4 medications
• Acid Suppression
• Pain Medication
• Bowel Regimen
• Blood Pressure Medications
• Miscellaneous Medications
Sample Medication List
Mycophenolate mofetil (Cellcept®) Mycophenolate Sodium (Myfortic®)
• Use and benefit: Anti-rejection
• Administration Instructions:
– Take twice daily
– Important to take at consistent times (~12 hours apart)
– May take concurrently with other medications
– Can take with or without food
• Recommend a small meal/snack for nausea
• Important to be consistent with amount of food since food affects absorption
17
Mycophenolate mofetil (Cellcept®) Mycophenolate Sodium (Myfortic®)
• Adverse effects: • Gastrointestinal:
• Nausea, vomiting, diarrhea• Most common adverse effects
• Hematologic:
• Anemia, leukopenia, thrombocytopenia
**Note**- Some patients may have mycophenolate trough levels checked
- On lab draw days, patients should not take morning dose before getting blood drawn (ok if morning dose is late that day)
• Teratogenicity Risk:
• Females who take mycophenolate while pregnant have a higher risk of miscarriage and birth defects
• Risk Evaluation and Mitigation Strategy (REMS):
• Informational handout provided to all women of childbearing age
• Discussion with patients about birth control methods
• Routine pregnancy tests in clinic
• Patients should notify their provider to alter immunosuppression if pursuing pregnancy
19
MycophenolateBrand name: Cellcept®, Myfortic®
Sample Medication List
Tacrolimus Brand name: Envarsus XR®, Astragraf®, Prograf®
21
• Use and benefit: Anti-rejection • Historically has been the cornerstone of
immunosuppressive regimens
• Administration instructions: • Take twice daily (Prograf®), once daily (Astagraf®
or Envarsus®)
• Important to take at consistent times (~12 hours apart)
• May take concurrently with other medications
• Can take with or without food
• Important to be consistent with amount of food since food affects absorption
• Adverse effects:
• Hypertension
• Hyperglycemia & new onset diabetes
• Hyperkalemia & hypomagnesemia
• Neurotoxicity
• Nephrotoxicity
• Importance of therapeutic drug monitoring
22
TacrolimusBrand name: Envarsus XR®
Prednisone
• Use: Anti-rejection
• Note: not ALL patients will be on prednisone post-transplant
• Administration instructions:
• Take once daily in the morning
• Can take at same time as other medications
• Take with food if possible
23
Anti-Infective Medications
Anti-Infective Medications
• Cytomegalovirus (CMV)/Herpes Simplex Virus (HSV):
• Valganciclovir (Valcyte®) or Valacyclovir (Valtrex®)
• Agent selection per donor/recipient serologies
• Dosing: daily
• Requires renal adjustment
• Duration: 3 months – 1 year
• Based on organ type and risk stratification
• Adverse effects: leukopenia
25
Anti-Infective Medications
• Pneumocystis jiroveci pneumonia (PJP):
• Sulfamethoxazole/Trimethoprim (Bactrim®)
• Dosing: daily or three times weekly
• Requires renal adjustment
• Duration: 6 months – lifelong
• Adverse effects: leukopenia
• Alternative therapies: • Atovaquone
• Dapsone
• Aerosolized pentamidine
Anti-Infective Medications
• Anti-Fungal Prophylaxis:
• Historically all organ types received anti-fungal prophylaxis
• Nystatin and clotrimazole shortages lead to prophylaxis changes
• Prophylaxis strategy dependent on organ type
• Medications used:
• Nystatin, clotrimazole
• Fluconazole, posaconazole, voriconazole
• Inhaled amphotericin
Other Medications
Acid suppression
Statin therapy
Pain medication
Bowel regimen
Maintenance medications
REVIEW THE IMPORTANCE OF DRUG SHORTAGES AND FORMULATION CHANGES IN TRANSPLANT PATIENTS
Drug Shortages
Recent Drug Shortages
Tacrolimus
• Immediate release (IR) generic products
• Active ingredient shortage
Clotrimazole
• Increased demand
• One manufacturer did not provide a reason for the shortage
Nystatin
• One manufacturer ceased production
• FDA listed one manufacturer with GMP-related issue
https://www.ashp.org/Drug-Shortages/Current-Shortages/https://www.accessdata.fda.gov/scripts/drugshortages
Drug Shortage Management
• Nystatin & Clotrimazole:
1. Switch to alternative agent:
• Nystatin → clotrimazole
• Clotrimazole→ nystatin
• Fluconazole
• NOTE: drug-drug interaction
2. Limit prophylaxis to specific patients:
• Pediatric patients
• High dose steroids
• Inpatient use only
Drug Shortage Management
• Immediate release tacrolimus (generic products):
1. Transition to brand products
• Financial & insurance considerations
• Need for therapeutic drug monitoring
2. Stockpile generic tacrolimus
• Ethical considerations
3. Convert to extended release (ER) product
• Dosing considerations & potential for errors
• Need for therapeutic drug monitoring & patient counseling
• Financial & insurance considerations
Formulation Changes: Tacrolimus
• Indications for conversion: • Adverse effects
• Difficulty obtaining target trough levels
• Improved adherence
• Drug shortages
• Dosing conversion: • Astagraf®: 1:1
• Envarsus®: 80% of total daily IR dose
• Review drug levels
• Available tablet/capsule strength
Patient Education:Dose & frequency changes
Product differentiation Lab monitoring
Formulation Changes: Mycophenolate
• Indications for conversion:
• Adverse effects:
• Gastrointestinal
• Affordability • Co-pay card
(Myfortic®)
• Dosing conversion: • Mycophenolate mofetil
250 mg capsule = Mycophenolate sodium 180mg tablet
Patient Education:Dose change
Product differentiation
REVIEW THE IMPORTANCE OF COMMON INSURANCE ISSUES IN TRANSPLANT PATIENTS
Medicare Review
Part A* • Covers inpatient needs and hospice care- i.e. transplant
• No monthly premium
Part B*• Covers outpatient care, medical supplies, and a few
medications under specific circumstances.
• Monthly premium
Part C Medicare
Advantage
• Medicare advantage plan; administered by private company that must follow rules set by Medicare
• “Bundled plan” includes Part A, B, and usually D
• Monthly premium
• Variable out of pocket costs and rules for services
Part D• Covers prescription drugs, unless the drug is covered by Part B
• Monthly premium
• Certain patients may qualify for low income subsidy/extra help based on annual income
*Medigap: optional supplement to original Medicare (Part A/B); can be purchased through private companies
https://www.medicare.gov/
Immunosuppressant Drug Coverage: Medicare
https://www.medicare.gov/
(1) Medicare Part A in place or retroactive prior to transplant date, AND
(2) Patient enrolled in Medicare Part B when immunosuppressant claim(s) processed
Immunosuppressants billed through Part B
Criteria not met
Immunosuppressants billed through Part D
It is important for the transplant team and recipient to understand whether Part B or D is the correct payer for immunosuppressants to ensure proper billing and payment
FDA-Approved Indications & CMS Compendia Endorsed Off-Label Indications for Immunosuppressants
Kidney Liver Heart Lung Pancreas Intestine
Tacrolimus FDA FDA FDA Comp-D Comp-D Comp-D
Cyclosporine FDA FDA FDA Comp-D Comp-A *
Belatacept FDA * * * * *
Mycophenolate
mofetil
FDA FDA FDA Comp-A Comp-D *
Mycophenolate
sodium
FDA * * Comp-A * *
Azathioprine FDA Comp-D * * Comp-D *
Leflunomide Comp-A Comp-A Comp-A Comp-A Comp-A Comp-A
Sirolimus FDA * * * * *
Everolimus FDA FDA * * * *
*Vulnerable to coverage denial by Medicare Part D
FDA: use per FDA approved labeling; Comp-A: off-label use supported by AHFS Drug Information; Comp-D: off-label use
supported by DRUGDEX Information System
Lushin EN, et al. Am J Transplant 2021;21:889-96
Prior Authorizations
● Often required for transplant medications ○ Common reasons:
• High-cost medications (High “Tier”)
• Brand name medications
• Step therapy requirements
• Quantity and dosage limits
• Non-formulary
• Coordination of benefits (i.e. Medicare Part B vs D Determination)
Prior Authorizations: Medicare Part D
0%
5%
10%
15%
20%
25%
30%
2007 2019
Prior Authorization Requirements for Medicare Part D Plans
Medicare Part D Denials of Immunosuppressants in SOT Recipients
• 39 patients experienced 66 immunosuppressant denials for off-label use not supported by CMS approved compendia
• In 74% of first level appeals, 96% of second level appeals, and 100% of those reviewed by an administrative law judge, denials were upheldResneck JS. JAMA 2020;323:703-704
Lushin EN, et al. Am J Transplant 2021;21:889-96.
Pri
or
Au
tho
riza
tio
n
De
nie
d n
=66 Approved n=11
Denied n=31
Approved n=1
Denied n=22
Approved n=0
Denied n=6
Not Pursued n=16
Not Pursued n=8
Not Pursued n=24
1st Level Appeal
2nd Level Appeal
Administrative Law Judge
Lung Transplant Patient: Commercial Insurance →Medicare eligible AFTER transplant
Commercial insurance at time of transplant
Turns 65, now eligible for Medicare: Medicare Part D plan responsible for IS coverage
Prior authorization required with new Part D plan: DENIED
First level appeal:DENIED
Second level appeal:DENIED
Appeal to Medicare Administrative Law Judge: DENIED
Obtain drug by alternativemethod: • Pay out of
pocket• GoodRx
coupon• Patient
assistance program
Medication Access Resources
Discounted coupons through Good Rx
Manufacturer sponsored
• Free 30-day trials
• Copay cards (commercial insurance only)
• Prescription assistance programs
State specific medication assistance programs
Foundation support
American Society of Transplantation Resources:
• Medication Access Resource Guide
EXPLAIN THE SIGNIFICANCE OF SELECT IMMUNOSUPPRESSION RELATED DRUG-DRUG INTERACTIONS
Potential Consequences of Drug Interactions
Low Levels High Levels
Significant Drug-Drug Interactions
CYP 3A4 Inhibitors & Inducers
Statins
Colchicine
Allopurinol & febuxostat
Calcineurin Inhibitor (CNI)Metabolism and Elimination
Taylor AL. Crit Rev Oncol Hematol. 2005 Oct;56(1):23-46. Clinical Pharmacology [database online]. URL: www.clinicalpharmacology.com
Cyclosporine Tacrolimus
Metabolism- Cytochrome P450 (CYP) 3A4
and P-glycoprotein - CYP3A4 and P-glycoprotein
inhibitors -> increase cyclosporine bioavailability
Elimination - Elimination half-life highly
variable (10-40 hr)- Prolonged in hepatic disease
or disorders of biliary excretion
Metabolism- Cytochrome P450 (CYP) 3A4- CYP3A4 inhibitors -> increase
tacrolimus bioavailability
Elimination- Elimination half-life 12-18 hr- Prolonged in hepatic disease
or disorders of biliary excretion
Drug Interactions: CYP Enzymes
Adapted from: WrightonSA et al. CritReview Toxicology. 1992;22:1-22.Kashubaand Bertino. Mechanisms of drug interaction. In Drug Interactions in Infectious Diseases. Humana Press. 2001.
CYP3A4 Inducers
Anticonvulsants Anti-TuberculosisAgents
Antibiotics Other
Phenytoin Rifampin Nafcillin Ticlodipine
Phenobarbital Rifabutin St. Johns Wort
Carbamazepine Isoniazid Sirolimus
Caspofungin
CYP3A4 Inhibitors
Tri-azole Antifungals
Protease Inhibitors
Macrolide Antibiotics
Calcium Channel Blockers
Other
Fluconazole Indinavir Erythromycin Diltiazem Amiodarone
Isavuconazole Ritonavir Clarithromycin Verapamil Grapefruit
Itraconazole Saquinavir
Ketoconazole Nelfinavir
Posaconazole
Voriconazole
Dose Adjustments
Drug Tacrolimus Cyclosporine Sirolimus
Fluconazole (Doses >200mg/day)
40% 40% 50-70%
Posaconazole 75-80% 30% ---
Itraconazole 50-60% 50-60% ---
Voriconazole 66% 50% 90%**
Isavuconazole --- --- ---
**Combination not recommended per manufacturer
Saad, et al. Pharmacotherapy. 2006:26(12):1730-44.; NivoixY, et al. ClinPharmacokin. 2008:47(12).; Grollet al. ClinPharmacolDrug Dev. 2017; 6(1):76-85.
Statins
• Cardiovascular disease = leading cause of death in patients with a functioning kidney transplant • Risk factors increase post transplant: • Hypertension • Diabetes• Dyslipidemia
• Long term benefit of statin therapy demonstrated in heart transplant recipients
Lancet. 2003;361:1265J Heart Lung Transplant. 2005;24:1736-40.
Drug Tacrolimus* Cyclosporine**
CYP 3A4 Mediated (Major)
Atorvastatin Patient specific vs. no dose adjustment*
Avoid
Simvastatin No dose adjustment Avoid
Lovastatin No dose adjustment Avoid
Pitavastatin No dose adjustment Avoid
CYP 3A4 Mediated (Minor)
Pravastatin No dose adjustment Limit to 20mg daily
Fluvastatin No dose adjustment Limit to 5mg daily
Rosuvastatin No dose adjustment Limit to 20mg twice daily
*Mechanism: tacrolimus inhibition of CYP3A4-mediated statin metabolism**Mechanism: cyclosporine inhibition of the CYP3A4-mediated metabolism of statins &
cyclosporine inhibition of the OATP1B1/SLCO1B1-mediated hepatic uptake of statins
P-glycoprotein (P-gp)
• Expressed in certain cell types in the liver, pancreas, kidney, colon and jejunum
• Cell membrane associated protein →transports drug substrates
• P-gp substrates are transported back into the intestinal lumen as they are absorbed
• Cyclosporine = P-gp substrate + inhibitor
Colchicine
• FDA reported 169 colchicine related deaths in 2009
• Patients were on concomitant clarithromycin therapy in 51% of cases
• Colchicine toxicities:
• Polyneuropathy
• Myopathy
• Rhabdomyolysis
• Neutropenia
• Heart Failure
Food and Drug Administration: Information for healthcare professionals: new safety information for colchicine; 2009.Transplant Proceedings. 2012;44:2851-2852.
Colchicine
• Colchicine: substrate of CYP 3A4 & P-glycoprotein
• Colchicine + cyclosporine → significant increases in colchicine concentrations
• Consider avoidance in renal or hepatic impairment
• Dosing recommendations:
• Acute gout flare: 0.6mg once, dose can be repeated in 3 days
• Gout prophylaxis: 0.3mg once daily or every other day
Clinical Pharmacology [database online]. URL: www.clinicalpharmacology.com
Allopurinol & Febuxostat
• Allopurinol & febuxostat inhibit xanthine oxidase
Results in reduced elimation of 6-MP → significant leukopeniaAzathioprine dose should be reduced by 50-75%
•. 2001 Jan;12(1):170-176.
J Am Soc Nephrol. 2001 Jan;12(1):170-176.
Questions?
