MANAGING TRANSPLANT &

HEPATITIS CShiny Parsai

Froedtert Ambulatory Care Rotation – Medication ManagementUniversity of Iowa PharmD Candidate 2016

December 1, 2015

OUTLINE• Patient presentation • Disease background – hepatitis C and transplant• Drug interactions – hepatitis C and transplant • Summary/conclusions• Questions

PATIENT BACKGROUND

PATIENT PRESENTATION• BD, 54 year old, white male• Height: 5’7” Weight: 73kg (160lbs)• BMI: 25kg/m2 (normal)• CrCl > 60ml/min (normal renal function)• Drug allergies – spironolactone• Family history – diabetes, cerebral vascular disease, thyroid issues• Insurance – Medicare• Transplant in May 2014 – liver, left kidney secondary to hepatitis C genotype 4

•Chief complaint/diagnosis • Chronic hepatitis C & multi-organ transplant

PATIENT PRESENTATION • History of illness

• Chronic hepatitis C initial treatment• Interferon and ribavirin X 2 courses (1992)

• Non responder • Cirrhosis (2003)• Kidney and liver transplant (May 2014)• Chronic hepatitis C retreatment

• Viekira Pak (without dasabuvir) and ribavirin 400mg AM, 600mg PM X 12 weeks • Started 7/8/15, completed 10/1/15 (2 missed doses), SVR12 due 12/24/15• Ribavirin dose lowered to 400mg twice daily due to drop in hemoglobin

(7/31/15)• Insurance did not approve for 24 weeks

• Technivie and ribavirin X 12 weeks• Insurance did not approve for additional 12 weeks

PATIENT PRESENTATION •Physical Exam (10/2015)

•normal•Surgical History

•Hernia repair (2001)•Knee scope (2008)•Transplant (5/2014)•Kidney biopsy (10/2014)•Urinary procedure for urinary obstruction (5/2015)• Stent removed (7/2015)

•Past Medical History

•Anxiety•Cirrhosis (biopsy)•Depression•Degenerative disk disease•Diabetes mellitus •Diverticulitis•Hemorrhoids•Hearing loss in left year

PATIENT PRESENTATION Immunization history

• Hepatitis A (antibody reactive) immune• Hepatitis B surface antibody 2.32 (6/2015) immune • Influenza (11/3/2013) due

• Avoid live vaccines • Pneumococcal PPV23 (3/2011) PCV13 (8/2015) immune

• Anyone 2 through 64 years old with disease or condition lowering the body’s resistance to infection, such as: kidney failure; HIV infection or AIDS; organ transplant, etc…

• If already received one or more doses of PPSV23, the dose of PCV13 should be given at least 1 year the most recent dose of PPSV23

OUTPATIENT MEDICATIONS Drug Dose/Indication Acetaminophen 650mg every 12 hours PRN; painAmlodipine 10mg daily; hypertensionAspirin enteric coated 81mg daily; cardiovascular prevention Escitalopram 10mg daily; depressionFamotidine 20mg twice daily; gastric ulcer Glimepiride 1mg daily; diabetes Multivitamin 1 tablet daily; supplementationMycophenolate (Cellcept) 500mg twice daily; transplantPrednisone 2.5mg daily; transplantMagnesium plus protein 3 tablets three times daily; transplantSodium polystyrene 15g/60ml suspension, take 120mL when

directed; transplantSulfamethoxazole/trimethoprim

400/80mg mon, wed, fri; transplant

Tacrolimus 4mg twice daily; transplantTramadol 50mg every 8 hours PRN; pain/back injury/degenerative disc

diseaseVitamin A 8000 units mon, wed, fri; supplementation Viekira Pak without dasabuvir

12.5/75/50mg once daily; chronic hepatitis C

Ribavirin 400mg AM, 600mg PM X 12 weeks; chronic hepatitis C

TREATMENT GOALS• Prevent transplant loss

• Assess FK506 levels• Low levels associated with onset of rejection episodes• High levels associated with onset of adverse effects

• Nephrotoxicity, immunosuppression, hypertension, neurotoxicity, post transplant diabetes

• Resolve hepatitis C infection• Based on sustained virological response (SVR)

• Absence of detectable HCV RNA in the serum 12 weeks after completion of therapy (cure)

• Associated with RNA suppression, ALT normalization, quality of life improvement, reduced all-cause mortality, reduced risk of hepatocellular cancer, and reduced risk of decompensation

• Minimize drug interactions• Major interactions – Viekira Pak and tacrolimus• Minor interactions – Viekira Pak and amlodipine, tramadol, and mycophenolate

• Emphasize medication adherence

HEPATITIS C BACKGROUND

HEPATITIS C – background1

• Epidemiology • 3.2 million infected in United States• ~ 80% of develop chronic infection • 50% HCV patients are diagnosed • Less than 15% of patients treated

• Genotypes in the US• 1 ~ 75%• 2 ~ 15%• 3 ~ 10%• 4 ~ 2%

• Transmission • Primarily through skin exposures to infectious blood• IVDU (most common transmission in U.S.), donated blood products, and organs

prior to 1992, needlestick injuries, birth to an HCV-infected mother

HEPATITIS C – symptoms/diagnosis1

• Symptoms• Acute symptoms within 4 to 12 weeks from exposure• Most chronic hepatitis C patients are asymptomatic • Mild and flu like - fatigue, nausea or poor appetite, stomach pain, dark urine,

jaundice, fever, muscle and joint pains• Diagnosis

• Hepatitis C Antibody Test• Non-reactive or negative antibody test – does not have hepatitis C• Reactive or positive antibody test – exposed to hepatitis C virus

•  HCV RNA test  • Confirms chronic hepatitis C infection

• Biopsy • Gold standard at Froedtert• Liver staging/degree of fibrosis/etiology

AASLD/IDSA GUIDELINES2

•Post liver transplantation, treatment experienced, genotype 4• Recommended #1: daclatasvir + sofosbuvir + ribavirin x 12 weeks

• Only approved for genotype 3• Recommended #2: Harvoni (ledipasvir/sofosbuvir) + ribavirin X 12 weeks

• Not approved by insurance• Alternative #1: Technivie (ombitasvir/paritaprevir/ritonavir) + ribavirin x 12

weeks• Extend duration to 24 weeks in liver transplant patients

VIEKIRA PAK vs. TECHNIVIE3,4

• Viekira Pak• Ombitasvir, paritaprevir, ritonavir (12.5/75/50mg) once daily; dasabuvir 250mg

twice daily• Technivie

• Ombitasvir, paritaprevir, ritonavir (12.5/75/50mg) once daily • Approved July 2015• With ribavirin for genotype 4 patients

MONITORING1

• Hepatitis C labs • Safety Labs

• CBC, BMP, LFT• Baseline• 2 week (ribavirin – hemolytic anemia), 4 week, then monthly

• Efficacy Labs • 4 weeks, end of treatment, 12 and 24 weeks post treatment • RNA quant

TRANSPLANT BACKGROUND

TRANSPLANT – background5

•Chronic hepatitis C is the leading indication for liver transplantation

•United Network for Organ Sharing• Utilizes scoring system for organ transplant

•Donated organs• Deceased donors who have died recently

• DBD – donation after brain death • DCD – donation after cardiac death

•Success rates• Liver ~ 80% after one year• Kidney ~ 93% after one year

TRANSPLANT – rejection prophylaxis5

•Combination of drugs used to target different levels of the immune cascade and lower doses minimize toxicity

•Treatment phases• Induction• Common maintenance regimen

• Calcineurin inhibitor + Adjuvant Agent ± Corticosteroid• Acute rejection

Induction Calcineurin inhibitor

Antiproliferatives

mTOR inhibitors

Additional

Antithymocyte Globulin Basiliximab Alemtuzumab

CyclosporineTacrolimus

AzathioprineMycophenolate

SirolimusEverolimus

CorticosteroidsBelatacept

TRANSPLANT – monitoring5

•FK506 levels • Mechanism

• Tacrolimus binds cytoplasmic proteins – FK binding protein 12 which binds FK506• Drug protein complex binds to and inhibits calcineurin inhibitor phosphatase which

prevents T cell activation

• Kidney function, liver function, blood counts, electrolytes, glucose levels

•Signs of rejection • Liver – elevated liver enzymes, fatigue, appetite loss, nausea, abdominal

tenderness or pain, fever, jaundice, dark urine, or light colored stools• Kidney – decreased urine output, fever, hypertension, increased creatinine,

tenderness near kidney• Biopsy needed to confirm rejection

TRANSPLANT – monitoring5

•Side effects • Weight gain – prednisone• Diabetes – tacrolimus, cyclosporine• Hypertension – prednisone, tacrolimus, cyclosporine, sirolumus• Hyperlipidemia – cyclosporine, sirolimus • Osteoporosis – prednisone• Nephrotoxicity – tacrolimus, cyclosporine, sirolimus

DRUG INTERACTIONS

MAJOR DRUG INTERACTIONS6 • http://www.hep-druginteractions.org/• Tacrolimus and Viekira

• Tacrolimus is a substrate of CYP3A4• Viekira increased Cmax, AUC, and Cmin of tacrolimus by 4x, 86x, 25x

respectively•  Administer tacrolimus 0.5 mg once a week when coadministered with Viekira • Monitor tacrolimus levels and adjust dose and/or frequency as needed

• Tacrolimus dosing without CYP interactions• Approximately 0.1 mg/kg/day orally in 2 divided doses

• Availability • liquid, tablet sizes 0.5 MG, 1 MG, 5 MG

Rapid Recovery of Cytochrome P450 3A4 After Protease Inhibitor Withdrawal in Post Liver Transplant Patients7

• Case report of two HIV patients• Dose of tacrolimus requires an almost immediate adjustment after PI

withdrawal • Immediate reversibility of CYP3A4 after protease inhibitor withdrawal

MAJOR DRUG INTERACTIONS6

• Prior to Viekira• Tacrolimus 1mg tablets – take 2 mg twice daily

• Initiating Viekira (7/8/15)• PharmD intervention

• Administer tacrolimus 0.5mg/week X 1 dose with Viekira Pak• Monitor tacrolimus levels twice weekly and adjust as needed

• Tacrolimus 0.5mg on 7/8/15 X 1 dose morning then wait for labs

7/8/15 7/9/15 7/11/15 7/13/15 7/15/15 7/18/15 7/27/15 7/30/15FK 506 --- 9.6 6.9 7.3 11.4 ---- 6.0 5.4Tacrolimus dose

0.5mg ---- ---- 0.5mg ---- 0.5mg ---- ----

MAJOR DRUG INTERACTIONS6

• Maintenance • During treatment tacrolimus 0.5mg every 6 to 10 days based on levels

• take 0.5mg twice weekly on Mon, Thurs

9/1/15

9/2/5

9/3/15

9/5/15

9/8/15

9/10/15

9/14/15

9/15/15

9/17/15

9/21/15

9/23/15

9/24/15

9/28/15

9/30/15

FK 506 5.9 5.5 5.3 --- 8.8 7.0 5.1 ---- 6.4 5.7 ---- 7.9 6.2 ----Tacrolimus dose

---- --- ---- 0.5mg

---- ---- ---- 0.5mg

---- ---- 0.5mg

---- ---- 0.5mg

8/1/15

8/3/15

8/6/15

8/8/15

8/12/15

8/17/15

8/21/15

8/24/15

8/27/15

8/28/15

FK506 ---- 7.3 5.7 ---- 7.2 5.8 ---- 6.9 5.6 ----Tacrolimus Dose

0.5mg

---- ---- 0.5mg

---- ---- 0.5mg

---- ---- 0.5mg

MAJOR DRUG INTERACTIONS6

• Discontinuing Viekira 10/1/15

10/2/15

10/3/15

10/5/15 10/8/15 10/12/15

10/13/15

10/15/15

10/19/15

10/23/15

10/26/15

FK506 ---- 8.4 ---- 3.2 1.414 hr level

3.8 ---- 4.4 5.3 --- 9.4

Tacrolimusdose

Stop Viekira

---- 0.5mg Start 0.5mg BID

↑ to 2mg BID

2mg BID

↑ to 3mg BID with goal 4-7

↑ to 4mg BID

4mg BID

4mg BID

↑ to 5mg BID

MINOR DRUG INTERACTIONS6

• Viekira and amlodipine • May increase exposure of amlodipine• Decrease amlodipine dose by 50% and monitor patients for clinical

effects• Viekira and tramadol

• Tramadol is a substrate of CYP3A4 and CYP2D6 • Exposure may increase due to CYP3A4 inhibition by ritonavir

• Viekira and mycophenolate • Mycophenolic acid exposures may increase• Reduction in dose may be needed

SUMMARY

COUNSELING• Encourage hydration • Avoid alcohol• Adherence

• Hep C medications – missed dose within same day; do not double up doses • Transplant medication – take as directed• Labs – need regular transplant labs

• Do not start or stop any meds without PharmD consult• Adverse drug reactions• Pharmacy – FMLH with automatic refills

SUMMARY• BD, 54 year old, white male• Chronic hepatitis C infection • Non responder to interferon plus ribavirin • Kidney and liver transplantation • Viekira (without dasabuvir) + ribavirin X 12 weeks• Tacrolimus monitored adjusted at initiation, maintenance, and

discontinuation of Viekira

SUMMARY

•Tacrolimus • 4mg twice daily

• Transplant labs • Once a week• Per physician goal FK range - 5 to 8

• Recent abnormal labs (11/23/15)• Hemoglobin 12.5 (13.7 – 17.5 g/dL)• Glucose 149 (65 – 99 mg/dL)

TRANSPLANT 11/23/15

11/16/15 11/10/15 11/3/15 10/29/15

FK506 6.2 6.5 5.0 6.1 9.0

HEPATITIS C 12/24/15

8/3/15 7/6/15 6/29/15 5/22/15

Hep C RNA (IU/ML) SVR12 pending

Not detectable

2,644,547 3,190,647 966,324

CONCLUSIONS• Utilize guidelines to treat hepatitis C • Monitor drug interactions with hepatitis C and tacrolimus • Strategy most successful in adherent patients

REFERENCES1. Center for Disease Control: Viral Hepatitis C information. [Internet]. [cited 2015 Dec 1].

Available from: http://www.cdc.gov/hepatitis/hcv/2. Infectious Disease Society of America. [Internet]. [cited 2015 Dec 1]. Available from:

http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infection3. Viekira Pak [package insert]. North Chicago, IL. AbbVie Inc.; 2015.4. Technivie [package insert]. North Chicago, IL. AbbVie Inc.; 2015.5. Lee RA, Garbardi S. Current treands in immunosuppressive therapies for renal transplant

receipients. American Journal of Health-System Pharmacy; 2012, 69: 1961-1975. 6. Hep drug interactions. The University of Liverpool. [Internet]. [cited 2015 Dec 1]. Available

from: http://hep-druginteractions.org/7. Oo HY, Mutimer DJ. Rapid recovery of cytochrome P4503A4 after protease inhibitor withdrawal

in post-liver transplant patients. Liver transplantation; 2012(18):10, 1264-1265.

QUESTIONS?