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Home , Dasabuvir, Elbasvir, Ledipasvir, Ombitasvir, Paritaprevir

3/2/2016

Pharmacists Objectives

• Describe the route of transmission and provide recommendations to prevent the transmission of Treatment of C (HCV)

• Identify high risk patients who would benefit from screening and how to interpret diagnostic testing Jay Hazelcorn, Pharm.D. PGY-1 Pharmacy Resident Develop a guideline-based treatment approach that Broward Health Medical Center • includes a monitoring plan for adherence, drug interactions, adverse effects, and sustained virologic response www.fshp.org 3

Disclosure Technicians Objectives

• Recognize the different classes of direct-acting • I have no financial nor non financial antiviral for the treatment of hepatitis C relationships to disclose regarding the content of this presentation • Recall specific drug-drug interactions and common side effects

• Summarize risk factors that could lead to contracting and the spread of hepatitis C

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Resources Hepatitis

• American Association For the Study of Liver Diseases • Hêpar: Greek meaning “liver” (AASLD) / Infectious Diseases Society of America (IDSA) • -itis: Greek suffix meaning “inflammation” – http://hcvguidelines.org/full-report-view – Last updated February 24 th 2016 Viral Hepatitis • CDC Viral Hepatitis • Hepatitis A – http://www.cdc.gov/hepatitis/ • Hepatitis B • Hepatitis C Package inserts • • • Drug interaction database • Hepatitis E – http://hep-druginteractions.org/ http://healer24.com/wp-content/uploads/2015/07/cause_liver_cancer.jpg 5 7

Functions of the Liver Prevalence

• Many different functions • The CDC estimates that 2.7 million people are infected • Filters blood with hepatitis C (HCV) in the United States – Waste products from cells – National Health and Nutrition Examination Survey – Medications & alcohol • Major limitation does not include homeless and incarcerated • Production of bile • Estimation including homeless and incarcerated – Helps digest fats – 4.6 million to 4.9 million people in the United States • Metabolism

http://www.humanillnesses.com/photos/cirrhosis-of-the-liver- – Carbohydrates 2418.jpg – Fats/Cholesterol – Proteins/Clotting factors

6 Edlin, Brian R., et al. "Toward a more accurate estimate of the prevalence of hepatitis C in the United States." Hepatology 62.5 (2015): 1353-1363. 8 “Viral Hepatitis The Liver” Centers for Disease Control and Prevention., 2016. Web. 21 Feb. 2016

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Frequently Asked Transmission High Risk of HCV and Testing Questions • Born between 1945 - 1965 • Chronic hemodialysis • What are ways HCV is NOT spread? • Injection drug use (History) patients – Sharing eating utensils, breastfeeding, hugging, kissing, coughing, sneezing, food, and water • Intranasal illicit drug use • Known exposures to HCV – Needlesticks • Receiving a tattoo in • How should blood be cleaned to ensure virus is gone? – Recipients of blood or organs unregulated settings – Virus can live on surfaces for up to 3 weeks • Receiving clotting factor • Human immunodeficiency virus (HIV) – Clean using 1 part household bleach to 10 parts water concentrates before 1987 • ¼ cup bleach with 2 ¼ cup water • Received blood or solid • Children born to HCV- organ transplant before positive mothers (~ 6%) • Can I donate blood, or organs if cured from HCV? 1992 • Incarceration – No; Not if you have ever tested positive for HCV

American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. "Recommendations for testing, managing, and treating9 11 hepatitis C." (2015) "Hepatitis C FAQs for the Public." Centers for Disease Control and Prevention., 2016. Web. 21 Feb. 2016.

Frequently Asked Transmission Progression of HCV Questions • How is HCV spread? 100 Patients infected with HCV – Percutaneous/permucosal (Blood to blood contact) – Less common sharing of personal care items 75-85 Develop chronic infection • Razors or toothbrushes

• Can HCV be transmitted through sex? 60-70 Develop chronic liver disease – Yes; however risk is very low with heterosexual sex • Barrier protection may not be necessary in monogamous partners 5-20 Develop cirrhosis – Risk  in individuals with: HIV, STD, rough sex, and MSM • Barrier protection is recommended 1-5 Die of cirrhosis or liver cancer STD= sexually transmitted diseases MSM= men who have sex with men 10 12 "Hepatitis C FAQs for the Public." Centers for Disease Control and Prevention., 2016. Web. 21 Feb. 2016. "Hepatitis C FAQs for Health Professionals." Centers for Disease Control and Prevention, 2016. Web. 21 Feb. 2016.

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Clinical Presentation HCV Genome

• Most patients will be asymptomatic • 20-30% of people develop symptoms of acute illness – 4-12 weeks from exposure Symptoms Direct-Acting Antiviral Drugs Fever Fatigue Dark urine Drug Class NS3/4A Inhibitors NS5A Inhibitors NS5B Inhibitors Abdominal pain Loss of appetite Clay-colored stool Drug Nausea & Vomiting Joint pain Jaundice • Chronic HCV – Asymptomatic until decompensated Mechanism Protease inhibitor Replication complex Polymerase of Action inhibitor inhibitor – Screened for blood or elevated liver enzymes Suffix -previr -asvir -buvir

NS= non-structural protein 13 15 "Hepatitis C FAQs for Health Professionals." Centers for Disease Control and Prevention, 2016. Web. 21 Feb. 2016. Feeney, Eoin R., and Raymond T. Chung. "Antiviral treatment of hepatitis C." (2014): g3308.

Life Cycle of HCV Genotypes

• 6 different genotypes with 50 subtypes – Genotype 1 highest prevalence in the United States • Historically the most difficult to treat

• Genotyping will determine treatment and duration

• Once identified it does not need to be tested again – Will not change during course of infection

14 16 Feeney, Eoin R., and Raymond T. Chung. "Antiviral treatment of hepatitis C." (2014): g3308. "Hepatitis C FAQs for Health Professionals." Centers for Disease Control and Prevention, 2016. Web. 21 Feb. 2016.

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CDC Testing Sequence to Identify HCV Management of Acute HCV

• Monitor HCV RNA every 4-8 weeks for 6 -12 months – To assess for spontaneous clearance • Avoid hepatotoxic insults (i.e. acetaminophen) and alcohol consumption • Council on taking precautions to reduce the risk of HCV transmission to others • Addiction specialists if related to IVDU • Treatment is the same as for chronic infection

IVDU= intravenous drug use

17 American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. "Recommendations for testing, managing, and treating19 Source: CDC. Testing for HCV infection: An update of guidance for clinicians and laboratorians. MMWR 2013;62(18). hepatitis C." (2015)

Diagnostic Testing Goal of Treatment

Test Outcome Interpretation Further Actions • Reduce all-cause mortality Test for HCV RNA to Positive HCV Antibody Presumed HCV infection and adverse consequences confirm diagnosis No further action • Prevent clinical progression Negative HCV Antibody No HCV infection required* End stage liver disease Positive HCV Antibody • Current HCV infection Link patient to care HCV RNA Detected • Hepatocellular carcinoma Prior exposure and Positive HCV Antibody No current HCV cleared virus. Can be • How? HCV RNA Undetectable infection naturally or from – Sustained virologic response treatment

*If exposed within in the last 6 months or immunocompromised test for HCV RNA

RNA= Ribonucleic acid 18 American Association for the Study of Liver Diseases, and Infectious Diseases Society of http://cdn.hepwebstudy.org/doc/34-1/natural-history- 20 Source: CDC. Testing for HCV infection: An update of guidance for clinicians and laboratorians. MMWR 2013;62(18) America. "Recommendations for testing, managing, and treating hepatitis C." (2015) following-initial-infection-hcv.jpg

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Sustained Virologic Response (SVR) When and Whom to Treat

• SVR • All patients with chronic HCV – A marker for cure – Earlier the better to prevent disease progression – Defined as undetectable HCV RNA in the patient's blood

• SVR 24 • Except those with a short life expectancy – Undetectable HCV RNA 24 weeks after completion of treatment – Treatment of HCV with medications or by transplantation would not extend the patients life • SVR 12 – Patients should receive expert consultation – Undetectable HCV RNA 12 weeks after completion of treatment

• 99 % of SVR 12 patients remained undetectable at 5 yrs

– SVR 12 used to determine “virologic cure”

American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. (2015) 21 American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. "Recommendations for testing, managing, and treating23 "Hepatitis C FAQs for Health Professionals." Centers for Disease Control and Prevention, 2016. Web. 21 Feb. 2016. hepatitis C." (2015)

When and Whom to Treat Treatment Options

Previously was stratified into priorities FDA-Approved Medications High priority groups To Prevent Transmission Daclatasvir ( Daklinza® ) Simeprevir ( Olysio® ) Elbasvir-Grazoprevir ( Zepatier® ) Sofosbuvir ( Sovaldi® ) • Advanced fibrosis • Intravenous drug use Ledipasvir-Sofosbuvir ( Harvoni® ) Peginterferon alfa-2a (Pegasys®) • Liver transplant recipients • High risk sexual practices Ombitasvir-Paritaprevir- Peginterferon alfa-2b (PegIntron®) • Extrahepatic manifestations • Incarcerated people (Technivie® ) • HIV or HBV co-infection • Hemodialysis patients Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir ( Viekira Pak® ) (Copegus®, Rebetol®, Ribasphere®) • Women who wish to become pregnant Discontinued Medications (Victrelis®) (Incivek®)

HBV= hepatitis B virus

American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. "Recommendations for testing, managing, and treating22 24 hepatitis C." (2015)

6 3/2/2016

Daclatasvir (Daklinza®) Elbasvir-Grazoprevir (Zepatier®)

• Non-structural viral protein 5A (NS5A) inhibitor • Combination of a NS5A and NS3/4A inhibitor ─ Replication complex inhibitor ─ Replication complex inhibitor & Protease inhibitor • Indication and Usage • Duration • Indication and Usage • Duration – Genotype 1 and 3 – 12 week treatment – Genotype 1 and 4 – 12-16 week treatment – HCV/HIV co-infection • Preparations – HCV/HIV co-infection • Preparations – Always dosed with – Resistance testing – 60 mg and 30 mg tablets – Co-formulated tablet sofosbuvir Genotype 1a SVR ↓ from • 12 – 50 mg of elbasvir – With and without 98% to 70% Add ribavirin ↑ SVR to 100% – 100 mg of grazoprevir cirrhosis ± ribavirin • 12 With and without cirrhosis – Post-transplant with – ribavirin ± ribavirin

25 27 Daclatasvir (Daklinza®) package insert. Bristol-Myers Squibb Company, Princeton, NJ 08543, USA Elbasvir-Grazoprevir (Zepatier®) package insert. Merck & CO., INC., Whitehouse Station, NJ 08889, USA

Daclatasvir (Daklinza®) Elbasvir-Grazoprevir (Zepatier®) • Dosing: 1 tablet (50 mg/100 mg) by mouth once daily • Dosing: 60 mg tablet daily with sofosbuvir • Contraindications: • Dose Modifications: – Child Pugh B or C; ↑ drug levels and risk of ↑ liver enzymes – Strong CYP3A inhibitors ↑ drug levels – Organic anion transporting polypeptides (OATP1B1/3) inhibitors • Reduce dose to 30 mg once daily – Cytochrome P450 3A (CYP3A) inducers and – Moderate CYP3A inducers and nevirapine ↓ drug levels CYP3A inducers OATP1B1/3 inhibitors • Increase dose to 90 mg once daily Phenytoin Rifampin • Strong inducers are contraindicated HIV protease inhibitors – No renal adjustments St. John’s Wort Cyclosporine • Highly protein bound, unlikely removed by dialysis Please refer to package insert for complete list • Common adverse effects • Adverse effects – Headache, fatigue, nausea, and diarrhea – Fague, headache, nausea, ↑ alanine aminotransferase 5x normal (1%)

26 28 Daclatasvir (Daklinza®) package insert. Bristol-Myers Squibb Company, Princeton, NJ 08543, USA Elbasvir-Grazoprevir (Zepatier®) package insert. Merck & CO., INC., Whitehouse Station, NJ 08889, USA

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Ombitasvir-Paritaprevir-Ritonavir and Ledipasvir-Sofosbuvir (Harvoni ®) Dasabuvir (Viekira Pak®) • Combination of a NS5B and NS5A inhibitor • NS5A, NS3/4A, and NS5B inhibitor with booster ─ Polymerase inhibitor & Replication complex inhibitor ─ Replication complex, protease, and polymerase inhibitor • Indication and Usage • Duration • Indication • Duration – Genotype 1, 4, 5 or 6 – 12-24 week treatment – Genotype 1 – 12-24 week treatment – HCV/HIV co-infection – HCV/HIV co-infection • Preparations • Preparations – Post-transplant with ribavirin – With and without cirrhosis – Ombitasvir-Paritaprevir- – Co-formulated tablet – With and without cirrhosis ± Ritonavir (fixed dose ± ribavirin – 90 mg of ledipasvir ribavirin 12.5/75/50 mg) Post-transplant with Dose – – 400 mg of sofosbuvir • – Dasabuvir 250 mg ribavirin – 2 tablets of Ombitasvir- Paritaprevir-Ritonavir daily – 1 tablet of dasabuvir twice a day – Given with food 29 31 Ledipasvir-Sofosbuvir (Harvoni®) package insert. , Inc. Foster City, CA 94404 Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®) package insert. AbbVie Inc., North Chicago, IL 60064

Ledipasvir-Sofosbuvir (Harvoni®) Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®) • Dosing: 1 tablet (90 mg/400 mg) by mouth once daily • Drug interactions • Lots of drug interactions – Acid-reducing agents can ↓ ledipasvir concentraons Drug Interactions – AVOID Drug Interactions- MONITOR

• Antacids, H 2 antagonists, PPI (refer to package insert) Anticonvulsants Antiarrhythmics – Amiodarone Statins – Lovastatin and Simvastatin Statins – Rosuvastatin and Pravastatin PDE5 inhibitors Immunosuppressants • Symptomatic bardycardia (avoid co-administration) Antiretrovirals Amlodipine – Pgp inducers can ↓ ledipasvir-sofosbuvir concentrations Oral contraceptives Omeprazole • St. John’s Wort, rifampin, carbamazepine, etc. (avoid co-administration) Gemfibrozil Furosemide Herbal products Alprazolam – Tenofovir disoproxil fumarate (can ↑ tenofovir levels) Please refer to package insert for complete list • Monitor renal function • Adverse effects • Adverse effects ─ Fatigue, nausea, pruritus, insomnia – Fatigue, headache, and nausea 30 32 Ledipasvir-Sofosbuvir (Harvoni®) package insert. Gilead Sciences, Inc. Foster City, CA 94404 Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®) package insert. AbbVie Inc., North Chicago, IL 60064

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Ombitasvir-Paritaprevir-Ritonavir Sofosbuvir (Sovaldi®) (Technivie®) • NS5A, and NS3/4A inhibitor with booster • NS5B inhibitor • Duration ─ Replication complex and protease inhibitor ─ Polymerase inhibitor – 12 to 24 week treatment • Indication and Usage • Duration • Indication and Usage • Preparations – Genotype 4 without – 12 week treatment – Combination therapy ONLY – Sofosbuvir 400 mg tablet cirrhosis • Preparations – Genotype 1 and 4 – Given with ribavirin – Ombitasvir-Paritaprevir- • Given with peginterferon + ribavirin • Dose Ritonavir (fixed dose – Genotype 2 and 3 – 2 tablets daily with food 12.5/75/50 mg) • Given with ribavirin – HCV/HIV co-infection

33 35 Ombitasvir-Paritaprevir and Ritonavir (TECHNIVIE®) package insert. AbbVie Inc., North Chicago, IL 60064 Sofosbuvir (Sovaldi®) package insert. Gilead Sciences, Inc. Foster City, CA 94404

Ombitasvir-Paritaprevir-Ritonavir Sofosbuvir (Sovaldi®) (Technivie®) • Viekira Pak – dasabuvir = Technivie® • Dosing: 400 mg daily by mouth with or without food – Dasabuvir intrinsically resistant to genotype 1 • Drug interactions – P-glycoprotein inducers decrease drug concentrations • Lots of drug interactions • Examples: St. John’s Wort, rifampin – CYP3A substrates • Adverse effects – CYP3A inducers – Nausea, fatigue, headache, insomnia, anemia • Patients awaiting liver transplantation • Adverse effects – With hepatocellular carcinoma Given with ribavirin for up to 48 weeks to prevent post- – Fatigue, nausea, potential hepatoxicity – transplant HCV reinfection

34 36 Ombitasvir-Paritaprevir and Ritonavir (TECHNIVIE®) package insert. AbbVie Inc., North Chicago, IL 60064 Sofosbuvir (Sovaldi®) package insert. Gilead Sciences, Inc. Foster City, CA 94404

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Simeprevir (Olysio®) Ribavirin and Peginterferon

• NS3/4A inhibitor • Duration • Ribavirin (Copegus®) dosing: ─ Protease inhibitor – 12-24 week treatment – < 75 kg: 1000 mg/day (400 mg AM / 600 mg PM) Preparations – 75 kg: 1200 mg/day (600 mg twice a day) • Indication and Usage • – Simeprevir 150 mg tablet – Genotype 1 and 4 (Pegasys ®) (Pegintron ®) – Given with peginterferon + Peginterferon alfa-2a Peginterferon alfa-2b ribavirin • 180 mcg subQ weekly • 1.5 mcg/kg subQ weekly – Screen for resistance • Proclick autoinjectors • Redipens Genotype 1a • • Vials for reconstitution • Vials for reconstitution • Avoid with Q80K polymorphism – 50 - 150 mcg vials

Ribavirin (Copegus®) Package Insert Roche Laboratories Inc. 340 Kingsland Street Nutley, New Jersey 07110-1199 39 37 Pefinterferon alfa-2a (Pegasys ®) package insert Hoffmann-La Roche, Inc. c/o Genentech, Inc. South San Francisco, CA 94080-4990 Simeprevir ( Olysio® ) package insert. Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560 Pefinterferon alfa-2b (Pegintron ®) package insert. Merck & CO., INC., Whitehouse Station, NJ 08889, USA

Simeprevir (Olysio®) Ribavirin and Peginterferon

• Dosing: 150 mg tablet by mouth daily with food Adverse effects • Limitations of use: Ribavirin Peginterferon alfa Not recommended as monotherapy – • Anemia • Flu-like symptoms Resistance screening for Q80K strongly recommended – • Hemolytic anemia • Psychiatric symptoms – Sever hepatic impairment • Nausea, vomiting, diarrhea • Depression • Fatal cases have been reported • Teratogenicity • Neutropenia – Patients who have failed treatment with protease inhibitors – Males and Females must use • Thrombocytopenia • Not recommended (i.e. boceprevir, telaprevir) contraception during and 6 • Alopecia – Drug interactions months post-treatment • Injection site reactions Adverse effects • • Cough – Photosensitivity, rash, nausea, myalgia, and dyspnea 38 Ribavirin (Copegus®) Package Insert Roche Laboratories Inc. 340 Kingsland Street Nutley, New Jersey 07110-1199 40 Simeprevir ( Olysio® ) package insert. Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560 Pefinterferon alfa-2a (Pegasys ®) package insert Hoffmann-La Roche, Inc. c/o Genentech, Inc. South San Francisco, CA 94080-4990

10 3/2/2016

Treatment Monitoring Cost • Prior to starting therapy – Barriers to compliance and drug interactions • Wholesaler acquisition (WAC) cost for Harvoni ® – HCV genotype, subtype and HCV RNA viral load – $94,500 - $189,900 – ± resistance testing – Estimated cost is $1,125 per pill • CBC, INR, hepatic function panel, renal function • With exception of mandated rebates, negotiation of – Baseline, week 4, and as indicated drug prices are considered confidential • HCV RNA viral load – Lack of transparency regarding actual prices – Baseline, week 4, and 12 months after treatment end date – Negotiated discount is reported to be 46% off of the WAC • If detectable at week 4, check again at week 6 • Difficult to estimate true cost and cost-effectiveness • If viral load has increased by 10-fold discontinue therapy – Government and pharmaceutical companies collaborating • Thyroid-stimulating hormone (if using ) • To help bring affordability and access to all who need it – Every 12 weeks American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. 41 American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. 43 "Monitoring Patients Who Are Starting HCV Treatment, Are On Treatment, Or Have Completed Therapy." (2015) "OVERVIEW OF COST, REIMBURSEMENT, AND COST-EFFECTIVENESS CONSIDERATIONS FOR HEPATITIS C TREATMENT REGIMENS." (2015)

The Role of the Pharmacist Future Therapies

• Assessing barriers to compliance • Pan-genotypic regimes • Selection of drug regimen • Screening for drug interactions – Package insert or http://hep-druginteractions.org/ • Monitoring for adverse effects • Patient education • If Approved – Would be the first all-oral pan-genotypic single tablet regimen for chronic HCV

42 "Gilead Announces SVR12 Rates from Four Phase 3 Studies Evaluating a Once-Daily, Fixed-Dose Combination of 44 Sofosbuvir (SOF) and (VEL) (GS-5816) for the Treatment of All Six Hepatitis C Genotypes . N.p., 21 Sept. 2015. Web. 29 Feb. 2016.

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Assessment Questions

1. The center for disease control (CDC) recommends that heterosexual monogamous partners use barrier protection such as condoms to prevent the transmission of hepatitis C from an infected partner to a non-infected partner. False

2. Acid reducing agents will decrease the absorption of both sofosbuvir and ledipasvir. False 3. Everyone who contracts hepatitis C must receive treatment. False

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Treatment of Hepatitis C

Jay Hazelcorn, Pharm.D. PGY-1 Pharmacy Resident Broward Health Medical Center

www.fshp.org

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