Ledipasvir/Sofosbuvir (Harvoni®1)

UTILIZATION MANAGEMENT CRITERIA

DRUG CLASS: NS5A inhibitor and Nucleotide analog NS5B polymerase inhibitor

BRAND (generic) NAME: Harvoni (ledipasvir/sofosbuvir) 90mg/400mg tablet

FDA-APPROVED INDICATIONS: HARVONI is a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and is indicated for the treatment of chronic hepatitis C (CHC) genotype 1, 4, 5, or 6 infection.

COVERAGE AUTHORIZATION CRITERIA Ledipasvir/sofosbuvir may be eligible for coverage when the following criteria are met:

1. The patient has a diagnosis of chronic hepatitis C (CHC) infection with confirmed genotype 1; AND a. The patient is treatment-naïve without cirrhosis and has a pre-treatment HCV RNA <6 million IU/mL;OR b. The patient is treatment naïve and has a pre-treatment HCV RNA >6 million IU/mL; OR c. The patient is treatment naïve with cirrhosis secondary to CHC [Metavir F4 or radiographic evidence of portal hypertension, esophageal varices, ascites] (medical record documentation required); OR d. The patient is treatment experienced i.e. previously been treated with either PEG/RBV or PEG/RBV and a protease inhibitor in the past; OR e. The patient has compensated cirrhosis secondary to CHC [Metavir F4 or radiographic evidence of portal hypertension, esophageal varices, ascites] (medical record documentation required); OR f. The patient has decompensated cirrhosis secondary to CHC and will be using Harvoni with ribavirin; AND 2. Patients with genotype 1 who are treatment-experienced with compensated cirrhosis (Child Pugh A) have a documented FDA labeled contraindication(s) to treatment with Epclusa®1 (medical record documentation required). Please refer to Epclusa utilization management criteria. OR 3. The patient has a diagnosis of chronic hepatitis C (CHC) infection with confirmed genotype 4, 5 or 6; a. The patient does not have decompensated (Child-Pugh B or C) cirrhosis AND 4. Medical record documentation including genotype, fibrosis score, Child-Pugh score, and HCV RNA (within the last 6 months), and as specified within the criteria is provided; AND

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5. The patient has not attempted a previous course of therapy with a NS5A or NS5B inhibitor containing regimen (i.e. Sovaldi®1, Harvoni, ViekiraTM, or TechnivieTM); AND 6. Ledipasvir/sofosbuvir is prescribed by or in consultation with a physician with expertise and experience in the management of infectious hepatitis; AND 7. Ledipasvir/sofosbuvir will not be used in combination with other protease inhibitors used to treat CHC (i.e. boceprevir, simeprevir, or telaprevir); AND 8. The prescribed dosing does not exceed FDA labeling

DURATION OF APPROVAL Table 1 Genotype 1

Treatment Naïve with 8 weeks Pre-treatment HCV RNA <6 million IU/mL* Treatment naïve with 12 weeks Pre-treatment HCV RNA >6 million IU/mL Treatment naïve or experienced with decompensated 12 weeks + ribavirin cirrhosis Treatment experienced without cirrhosis 12 weeks Genotype 4, 5 or 6

Treatment naïve, treatment experienced, with or without 12 weeks compensated cirrhosis *12 week durations will be approved for African Americans or individuals co-infected with HIV.

**Please see coverage authorization criteria for additional details**

DOSAGE AND ADMINISTRATION The recommended dose of ledipasvir/sofosbuvir is one tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or without food.  HCV/HIV-1 co-infection: For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in the Table 1.  A dosage recommendation cannot be made for patients with severe renal impairment or end stage renal disease.

The recommended regimen and treatment duration for ledipasvir/sofosbuvir is provided in Table 1.

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WARNINGS, PRECAUTIONS, AND CONTRAINDICATIONS  Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with Harvoni is not recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended.  Use with other drugs containing sofosbuvir is not recommended  If used in combination with ribavirin, all contraindications to ribavirin also apply to Harvoni combination therapy

**See package labeling for complete information on warnings, precautions, and contraindications**

DRUG-DRUG INTERACTIONS

Drugs that are potent P-gp inducers (e.g., rifampin or St. John’s wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of ledipasvir/sofosbuvir. The use with P-gp inducers is not recommended with ledipasvir/sofosbuvir.

Table 2: Potentially Significant Drug Interactions Drug Class Drugs Within Class Clinical Comments Antacids Aluminum hydroxide and Ledipasvir solubility decreases as pH increases. magnesium hydroxide Drugs that increase gastric pH are expected to decrease concentration of ledipasvir. It is recommended to separate antacid and ledipasvir and sofosbuvir administration by 4 hours. Antiarrythmics Amiodarone Coadministration of amiodarone with ledipasvir and sofosbuvir may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with ledipasvir and sofosbuvir is not recommended; if coadministration is required, cardiac monitoring is recommended Anticonvulsants Carbamazepine, oxcarbazepine, Decrease concentration of sofosbuvir leading to phenobarbital, phenytoin reduced therapeutic effect; coadministration is not recommended. Antimycobacterials Rifampin, rifabutin, rifapentine Decrease concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect; coadministration is not recommended.

Ledipasvir and sofosbuvir should not be used with rifampin, a potent intestinal P-gp inducer. Herbal St. John’s wort Ledipasvir and sofosbuvir should not be used with Supplements St. John’s wort, a potent intestinal P-gp inducer. HIV protease Tipranavir/ritonavir Decrease concentration of ledipasvir and inhibitors sofosbuvir leading to reduced therapeutic effect; coadministration is not recommended.

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**See package labeling for complete information on Drug Interactions** POLICY IMPLEMENTATION/UPDATE INFORMATION

[June 2016] Updated criteria to reflect FDA-labeling

[Dec 2015] Updated current criteria language for consistency, added criteria for genotypes 4, 5, and 6. Updated Warning and Precautions, DRUG-DRUG interactions, and Duration of approval sections.

REFERENCES American Association for the Study of Liver Diseases and Infectious Disease Society of America. Recommendations for Testing, Managing, and Treating Hepatitis C. When and in Whom to Initiate HCV Therapy 2015.

Harvoni (ledipasvir/sofosbuvir) product labeling. Gilead Sciences, Inc. Foster City, CA. November 2015.

Non-Discrimination and Accessibility Notice

Discrimination is Against the Law • Blue Cross and Blue Shield of North Carolina (“BCBSNC”) complies with applicable Federal civil rights laws and does not discriminate on the basis of race, color, national origin, age, disability, or sex. • BCBSNC does not exclude people or treat them differently because of race, color, national origin, age, disability, or sex. BCBSNC: . Provides free aids and services to people with disabilities to communicate effectively with us, such as: - Qualified interpreters - Written information in other formats (large print, audio, accessible electronic formats, other formats) . Provides free language services to people whose primary language is not English, such as: - Qualified interpreters - Information written in other languages • If you need these services, contact Customer Service 1-888-206-4697, TTY and TDD, call 1-800-442-7028.

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• If you believe that BCBSNC has failed to provide these services or discriminated in another way on the basis of race, color, national origin, age, disability, or sex, you can file a grievance with:  BCBSNC, PO Box 2291, Durham, NC 27702, Attention: Civil Rights Coordinator- Privacy, Ethics & Corporate Policy Office, Telephone 919-765- 1663, Fax 919-287-5613, TTY 1-888-291-1783 [email protected] • You can file a grievance in person or by mail, fax, or email. If you need help filing a grievance, Civil Rights Coordinator - Privacy, Ethics & Corporate Policy Office is available to help you.

• You can also file a civil rights complaint with the U.S. Department of Health and Human Services, Office for Civil Rights, electronically through the Office for Civil Rights Complaint Portal, available at https://ocrportal.hhs.gov/ocr/portal/lobby.jsf, or by mail or phone at: U.S. Department of Health and Human Services 200 Independence Avenue, SW Room 509F, HHH Building Washington, D.C. 20201 1- 800-368-1019, 800-537-7697 (TDD). Complaint forms are available at http://www.hhs.gov/ocr/office/file/index.html.

• This Notice and/or attachments may have important information about your application or coverage through BCBSNC. Look for key dates. You may need to take action by certain deadlines to keep your health coverage or help with costs. You have the right to get this information and help in your language at no cost. Call Customer Service 1-888-206-4697.

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LUS CEEV: Yog tias koj hais lus Hmoob, cov kev pab txog lus, muaj kev pab dawb rau koj. Hu rau 1-888-206-4697 (TTY: 1-800-442-7028). ВНИМАНИЕ: Если вы говорите на русском языке, то вам доступны бесплатные услуги перевода. Звоните 1-888-206-4697 (телетайп: 1-800-442-7028). PAUNAWA: Kung nagsasalita ka ng Tagalog, maaari kang gumamit ng mga serbisyo ng tulong sa wika nang walang bayad. Tumawag sa 1-888-206-4697 (TTY: 1-800-442-7028).

સચુ ના: જો તમે ગજુ રાતી બોલતા હો, તો નન:સ쫍ુ કુ ભાષા સહાય સેવાઓ તમારા માટે ઉપલ닍ધ છે. ફોન કરો 1-888-206-4697 (TTY: 1-800-442-7028).

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