Disclosure None Medication Management and Beyond David J. Quan, - - PowerPoint PPT Presentation

9/30/2016 1

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

Disclosure

• None

Goal and Objectives

• Goal:

– Discuss the optimal medication management in transplant recipients.

• Objectives:

– Review drug selection/dosing – Review medication reconciliation process – Discuss medication access issues – Review strategies to improve medication adherence

Introduction

• Solid organ transplantation is a life saving procedure1
• Immunosuppressive drugs are life sustaining2,3
• Transplant medications are essential (WHO)4

– Cyclosporine, azathioprine, prednisone – Valganciclovir, fluconazole, trimethoprim/sulfamethoxazole

• Immunosuppressive drugs have side effects

– Over immunosuppression: Infections, malignancies – Renal failure, diabetes, hypertension, etc.

• 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/

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Managing Medications

Collaborative approach to optimize medication use to improve patient outcomes

• Choose the right drug
• Find the right dose
• Get the drug to the patient
• Keep taking the medications
• Reconciling medications across the continuum

Transplant Medications

Polypharmacy

• Immunosuppressive drugs are essential to prevent

allograft rejection

– Narrow therapeutic “window” – Many factors affect drug levels – Multiple and unique side effects

• Medications to counteract side effects

– Antibiotic prophylaxis to prevent infections – Antihypertensives for high blood pressure – Insulin for diabetes

Transplant Medications

Choosing the Right Immunosuppressive

• Immunologic risk

– Induction regimen (HLA, cPRA, DSAs, h/o transplant) – Steroid maintenance (DGF, African American, GN)

• Avoid specific side effects

– Cosmetic side effects: Tacrolimus vs cyclosporine1 – Diabetes: Cyclosporine vs tacrolimus2 – Belatacept: Avoid nephrotoxicity from CNI3

• “Side effect” with benefits

– mTOR (antitumor activity) in patients with HCC4

• 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

Transplant Medications

Choosing the Right Prophylaxis Drug

• Stratify according to donor/recipient serology

– High risk (D+/R-): Valganciclovir

• Add cytomegalovirus Ig (CMVIG) in lung transplant recipients
• Hepatitis B Immune Globulin (liver transplant)

– High risk: HBV viremia, resistance, HIV/HDV-co-infection

• PCP Prophylaxis (varies with service)

– Heart: TMP/SMX DS MWF x1 year – Kidney: TMP/SMX DS daily x1 month then MWF x5 months – Liver: TMP/SMX SS MWF x1 year – Lung: TMP/SMX DS MWF for life – BMT: TMP/SMX DS BID on Saturday & Sundays only

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Hepatitis B Immune Globulin

Liver Transplant

Patient population Antiviral Initial Dose Maintenance Low risk

HBV DNA <100 IU/mL AND NO resistance NO HIV or HDV Entecavir Tenofovir

Tenofovir/emtricitabine

5000 Units None HIGH RISK HBV DNA < 100 IU/mL AND Resistance OR HDV or HIV-co-infection Entecavir Tenofovir

Tenofovir/emtricitabine

5000 Units Yes HBV DNA ≥100 IU/mL AND NO Resistance OR NO HDV or HIV-co-infection Entecavir Tenofovir

Tenofovir/emtricitabine

10,000 Units Yes HBV DNA ≥100 IU/mL AND Resistance OR HDV or HIV-co-infection Entecavir Tenofovir

Tenofovir/emtricitabine

10,000 Units Yes

CMV Prophylaxis Protocol

Varies With Transplanted Organ

CMV Antibody Status Basiliximab Antithymocyte globulin D+ / R- Valganciclovir x6 months Valganciclovir x6 months D+ / R+ Acyclovir x3 months Valganciclovir x3 months D- / R+ Acyclovir x3 months Valganciclovir x3 months D- / R- Acyclovir x3 months Valganciclovir x3 months CMV Antibody Status Valganciclovir Cytomegalovirus Ig (Cytogam) D+ / R- Valganciclovir for >12 mos. Cytomegalovirus Ig x16 weeks D+ / R+ Valganciclovir for >12 mos. D- / R+ Valganciclovir for >12 mos. D- / R- Valganciclovir x6 months

Kidney Transplant: Lung Transplant:

Transplant Protocols

Keeping It All Together

• Protocols vary with transplant service

– Tailored for specific situations

• KTU: TMP/SMX DS daily x1 month (UTI prophylaxis), then MWF x5

months (PCP prophylaxis)

• Lung: Voriconazole/Posaconazole + Inhaled amphotericin B

(Aspergillus sp. prophylaxis)

• Protocols

– Standardized regimens – Periodically updated – Published in transplant manuals, Agile MD

Narrow Therapeutic Window

200 400 600 800 1000 1200 1400 1 2 3 4 5 6 7 8 9 10 11 12 Concentration (ng/ml) Time (hours)

At risk of toxicity: Nephrotoxicity Neurotoxicity Opportunistic infection Malignancy Subtherapeutic: At risk of rejection

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Transplant Medications

Finding the Optimal Dose

• Weight/body size

– Calcineurin inhibitors (CNIs), corticosteroid (taper)

• Desired therapeutic range

– CNIs, mTOR inhibitors

• Organ function

– CNIs, mTOR inhibitors, valganciclovir

• Side effects

– CNIs, Mycophenolate, valganciclovir

• Drug-drug interactions

– CNIs, mTOR inhibitors, voriconazole/posaconazole

CNI=Calcineurin inhibitor, mTOR=mammalian Target of Rapamycin

Many Factors Affect Drug Levels

• Timing of sample

– True trough? – Missed doses?

• Type of assay
• Dose (age, weight)
• Organ function
• Drug-drug interactions (drug, herbal, food)
• Genetic variability

Drug Interactions

• Pharmacokinetic (“ADME”)

– Absorption (PPIs decrease absorption of posaconazole) – Distribution – Metabolism (fluconazole decreases metabolism of tacrolimus) – Excretion (enterohepatic recirculation of MPAG)

• Pharmacodynamic

– 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

Typical Drug-drug Interactions

Tacrolimus Valganciclovir Amlodipine Mycophenolate TMP/SMX Metoprolol Prednisone Fluconazole Mag Oxide Omeprazole Calcium Carb. Antithymocyte Aspirin Vitamin D globulin Simvastatin Tacrolimus Valganciclovir Amlodipine Mycophenolate TMP/SMX Metoprolol Prednisone Fluconazole Mag Oxide Omeprazole Calcium Carb. Antithymocyte Aspirin Vitamin D globulin Simvastatin

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Drug-Drug Interactions

Managing it All

• Be vigilant

– When starting a new medication

• Power of information is key

– Accurate list of current medications is critical – Utilize resources to check for interactions

• Avoid interactions if possible

– If unavoidable: Just deal with it – Utilize interactions to your advantage

• Be consistent

Medication Reconciliation

Across the Continuum

• At home
• Admission to the hospital
• Stop/start medications
• Formulary alternatives (home hospital)
• To/from a different level of care
• ICU floor
• Phases of care
• Discharge home/another facility
• Resume home meds
• Formulary alternatives (hospital home)

Medications (Liver Transplant)

Across the Hospital Stay

Admission Post-Op Day #1 Post-Op Day#7 Discharge Home Lactulose syrup Norepinephrine drip Tacrolimus Tacrolimus Rifaximin Mycophenolate Mycophenolate Mycophenolate Zinc Sulfate Methylprednisolone Prednisone 20mg Prednisone 10mg, 5mg Furosemide Valganciclovir Valganciclovir Valganciclovir Spironolactone TMP/SMX TMP/SMX TMP/SMX Ciprofloxacin Fluconazole Fluconazole Fluconazole Omeprazole Pantoprazole Lansoprazole Omeprazole Levothyroxine Levothyroxine Levothyroxine Levothyroxine Fentanyl Aspirin Aspirin Regular insulin drip Aspart Lispro Dextrose 50% Glargine Glargine Pureflow dialysate Docusate sodium Docusate sodium Magnesium sulfate Hydrocodone/APAP Hydrocodone/APAP Potassium chloride Calcium gluconate Sodium phosphate D5W0.45%NS drip

Transition of Care

Discharge Begins on Admission

• Reconcile medications on admission
• Identify pharmacy for discharge medications

– Insurance – Geography

• Prescriptions sent to pharmacy for processing

– Prior authorization – Formulary alternatives

• Patient education
• Discharge day

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Payors

• Government

– Medicare A/B, D – Medi-Cal – Veteran’s Affairs Health System

• Commercial

– Private insurance – Kaiser Permanente

• Foreign nationals
• Cash

Cost of Transplant Medications

Medication Cost/month Tacrolimus 6mg PO BID $1846 Mycophenolate mofetil 1000mg PO BID $1098 Prednisone 5mg PO daily $15 Valganciclovir 900mg PO daily $4128 Fluconazole 100mg QWeek $46 Trimethoprim/sulfamethoxazole QMWF $17 Omeprazole 20mg PO daily $123 Amlodipine 10mg PO daily $98 Total $7371 “Retail price”: 8/2016

Medicare

Alphabet Soup

• Part A

– Hospital insurance (Hospital, SNF, hospice)

• Part B

– Medical insurance (Labs, DME, 80% of immunosuppressives)

• Part C

– Medicare advantage plans

• Part D

– Prescription drug coverage (not covered under “B”)

• Parts F & G

– Supplemental plans

SNF=Skilled Nursing Facility, DME=Durable Medical Equipment

Coordination of Benefits

“Who’s on First?”

“Medi-Medi”: Medicare A/B & D + Medi-Cal

Medication: Payor: Tacrolimus Mycophenolate mofetil Prednisone Medicare part B (pays 80%) then Medi-Cal (TAR for the remaining 20%) Valganciclovir Part D

Trimethoprim/Sulfamethoxazole

Part D Fluconazole Part D Omeprazole Part D Aspirin Over-the-counter

Hydrocodone/acetaminophen

Part D Docusate sodium Over-the-counter Aspart insulin Part D Insulin pen needles Medicare part B

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Transplant Medications

Prescribing Process

Prescriber restriction

Pharmacy

Day Supply

Prior Auth. Required eRx

Community Designated 30 90

Medicare B ✓

±

✓

• ±

✓ Medicare D ✓

±

✓

±

✓ ✓ Medi-Cal ✓ ✓ ✓ ✓ ✓ Managed Medi-Cal

± ±

✓ ✓ ✓ Private Insurance ✓

±

✓

±

✓ ✓ Kaiser Permanente

±

• ✓

✓ ✓

±

Veterans Affairs ✓

• ✓

✓ ✓ Foreign national

± ±

✓

± ±

✓ Cash ✓ ✓ ✓ ✓

“Drugs don’t work in patients who don’t take them.”

• C. Everett Koop

Epidemiology of Nonadherence

50% of US population are prescribed medications for chronic conditions Of those prescribed medication,

• nly 50% are taking it as directed.

Angell SY et al. City Health Information. 2009;28:1-8; Haynes RB. Compliance in Health Care. Johns Hopkins University Press;1979.

Nonadherence

• Nonadherence is a major risk factor for rejection and

allograft loss.1,2

• ~20% of kidney transplant recipients demonstrate

significant nonadherence. 3

– Similar rates for lung and liver recipients4,5

• Medication nonadherence can be improved

– Multimodal patient-tailored approach6

• Self-improvement interventions
• Medication counseling
• Simplification of drug regimen
• 1. Denhaerynck K. Transpl Int. 2005;18:1121., 2. Didlake RH. Transplant Proc. 1988;20:63., 3. Prendergast MB.

CJASN 2010;5:1305., 4. Berquist RK. Pediatr Transplant 2006;10:304., 5. Dew MA. Transplantation. 2008;85:193.,

• 6. Low JK. Nephrol Dial Transplant. 2014;0:1.

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Predictors of Nonadherence

• Frequency of drug dosing

– Complex regimen

• Side effects
• Access to medications

– Cost of medications (e.g. copays)

• Age

– Adolescence, senior

• Poor insight, lack of education about illness

– Shorter time to transplant – Multiple medical conditions

Prendergast MB. CJASN. 2010;5:1305

Value of a Good Education

• Educate providers
• Educate the patient and care givers

– Pre-transplant

• Evaluation phase (what to expect, out of pocket costs)

– Transplant

• Inpatient teaching (why, what, when, how)
• Transition to home (medication card)

– Post-transplant

• Clinic visits, telephone encounters
• Assess medication adherence
• Positive reinforcement

Strategies to Improve Adherence

Simplify the regimen Impart knowledge Modify patient beliefs and human behavior Provide communication and trust Leave the bias Evaluate adherence

Medication Cards

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Medication Cards

Specific

Transplant Medications

Scylla and Charybdis

Gillray, James. Britannia between Scylla & Charybdis. 1793. Engraving, color. Library of Congress, Washington D.C. Accessed 2/10/16. http://cdn.loc.gov/service/pnp/cph/3g00000/3g03000/3g03100/3g03137v.jpg

It Takes a Team

pr

NP/PA Pharmacist RN Nutritionist PT/OT Case manager Social worker Medical asst. Coordinators Financial coord. Behavioral hlth.

• Admin. Assts.

Staff IT

Physician Patient Practice team Family

Caregivers Immediate family Extended family Friends

Adapted from Defining Primary Care: An Interim Report IOM 1994.

Balance

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Transplant Medications

Event Horizon

• Tacrolimus pharmacokinetic modeling1,2
• Personalized medicine

– Biomarkers, gene arrays to predict rejection

• C1 esterase inhibitor for treatment of antibody

mediated rejection3

• Medicare Part D “donut hole” closing in 20204
• Smart phone apps for medication management5
• 1. Zhan C. Br J Pharmacol 2016;81:891., 2. Passey C. Br. J Pharmacol. 2011;72:948., 3. Montgomery RA. Am J Transplant
• 2016. doi:10.1111/ajt.13871., 4. https://www.medicare.gov/Pubs/pdf/11493.pdf, 5. Browning RB. j Am Pharm Assoc.

2016;56:40.

Summary

• Choosing the right drug/dose can be complex
• Many factors affect drug levels/doses
• Reconciling the medications is critical at transitions

points of care

• Access to medications and patient education can

affect medication adherence

Conclusions

• Many different medications are necessary for organ

transplantation to be successful

• Managing medications in a transplant recipient can

be challenging

• Close collaboration across many different disciplines

is required for the optimal care in this patient population