Hepatitis C Sovaldi and Daklinza

Hepatitis C Sovaldi® and DaklinzaTM Prior Authorization – Through Preferred Agent(s) Criteria Program Summary

This criteria applies to Commerical, GenPlus, and Health Insurance Marketplace formularies.

Medication Indications Dose and Interval HCV genotype 1, 2, 3 or 4 infection, including those with 400 mg tablet taken once daily with or without food for up to 48 hepatocellular carcinoma meeting Sovaldi (sofosbuvir) weeks (hepatocellular carcinoma). Most patients will be on Milan criteria (awaiting liver therapy for 12 to 24 weeks. transplantation) and those with HCV/HIV-1 co-infection 60 mg tablet taken orally once daily with or without food in Treatment of chronic hepatitis C combination with sofosbuvir with or without ribavirin genotype 1 or 3 in combination

Daklinza (daclatasvir) with sofosbuvir with or without Dose modification: Reduce dosage to 30 mg once daily with ribavirin strong CYP3A inhibitors and increase dosage to 90 mg once

daily with moderate CCYP3A inducers

Sofosbuvir18 Efficacy and safety for sofosbuvir has been evaluated in clinical trials. Refer to labeling for details on the clinical trial efficacy. Treatment guidelines as outlined below support the use of sofosbuvir with or without PEG-IFN and ribavirin in certain patient populations. The combination use of sofosbuvir plus simeprevir is supported in the guidelines at a lower level of evidence as compared to the combination regimens of ledipasvir/sofosbuvir and ombitasvir/paritaprevir/ritonavir + dasabvir for primarily genotype 1 patients. The aforementioned regimens have similar efficacy and tolerability to the combination of simeprevir plus sofosbuvir but have a significantly reduced financial obligation. There is not currently evidence to support the use of Sovaldi in patients that have failed ombitasvir/paritaprevir/ritonavir + dasabuvir. Guidelines recommend that patients with advanced fibrosis that have failed a sofosbuvir containing regimen received ledipasvir/sofosbuvir + ribavirin (if able to tolerate ribavirin).8

Daclatasvir19 Efficacy of daclatasvir in combination with sofosbuvir with or without ribavirin for patients with HCV genotype 1 was evaluated in the ALLY-1 and ALLY-2 trials. ALLY-1, an open-label trial, included patients with cirrhosis, recurrent infection, and/or history of liver transplantation. All subjects in the ALLY-1 trial received daclatasvir in combination with sofosbuvir and ribavirin for 12 weeks. The primary outcome was sustained virologic response at 12 weeks following treatment (SVR12) which ranged from 76% to 100% as outlined in Table 1 below.

Table 1: ALLY-1 SVR12 in Genotype 1 Subjects

AL_PS_HepC_Sovaldi_Daklinza_PA_ProgSum_AR0715_r0416 Page 1 of 8

ALLY-2 trial was an open-label trial evaluating the efficacy of daclatasvir in combination with sofosbuvir in patients with chronic HCV genotype 1, 2, 3, 4, 5, or 6. Although this trial included patients with HCV genotype 1 to 6, this combination is FDA approved only for treatment of HCV genotype 1 and 3 therefore, clinical trial data for other genotypes will not be discussed here. Subjects with genotype 1 enrolled in the ALLY-2 trial received daclatasvir plus sofosbuvir for 12 weeks. The primary outcome, overall SVR12, was 97% in genotype 1 patients. Patients with HCV genotype 1 and cirrhosis had a lower SVR12 (91%) as compared to those without cirrhosis (98%). SVR12 in genotype 3 patients was 100%.

Efficacy and safety of daclatasvir in combination with sofosbuvir for HCV genotype 3 was also evaluated in the ALLY-3 trial. The study enrolled 152 subjects with chronic hepatitis C genotype 3 infection and compensated liver disease. 101 subjects were treatment naïve, 7 subjects had been previously treated with a sofosbuvir regimen, and 2 subjects had previously received treatment with an investigational cyclophilin inhibitor. Subjects with previous exposure to an NS5A inhibitor (e.g. daclatasvir, ledipasvir, or ombitasvir) were excluded from the trial. The primary end point, SVR 12, was 92% to 98% and 58% to 69% for patients without cirrhosis and for those with cirrhosis respectively. Relapse rates following completion of treatment were 9% to 14%.

Hepatitis C Hepatitis C is an infection of the liver caused by the Hepatitis C virus (HCV); a blood borne virus. An acute HCV infection is defined as presenting within 6 months following exposure to the virus.18 The infection is defined as chronic if the virus is present beyond six months following exposure. Persons at high risk for contracting HCV infection include intravenous drug user, recipients of donated blood, blood products, and organs (now rare in the United States due to stringent blood screening), babies born to HCV infected mothers, and persons with HIV infection. HCV infection is asymptomatic in the early stages of the disease. However, with disease progression, patients may develop mild to severe chronic liver disease including cirrhosis and liver cancer. Disease progression should be monitored by evaluating liver fibrosis.

The diagram below correlates METAVIR scores with fibrosis stages. METAVIR scores, which describe liver damage, are determined by liver biopsy. Liver biopsy is an invasive procedure and the current standard in viral hepatitis for staging the degree of injury and not for achieving a diagnosis.11 Biopsy scoring systems for liver fibrosis including Metavir, Scheuer, Ishak and histological activity index give a number to a pattern of fibrosis. Fibroscan measures liver stiffness in kPa which correlates with increased fibrosis. Diagnosis of significant fibrosis (F>1) and cirrhosis measurements were 7.65 kPa and 13.01 kPa, respectively.11 Study data shows that Ishak fibrosis stages of ≥3 represent clinically progressive liver disease. Data from the HALT-C study showed that patients with Ishak fibrosis stage 2 had no clinical outcomes until nearly 5 years after randomization and closer to 6 years after the baseline biopsy.12

AL_PS_HepC_Sovaldi_Daklinza_PA_ProgSum_AR0715_r0416 Page 2 of 8

AASLD guidelines on when and in whom to treat:4 The goal of therapy is to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure as evidenced by an SVR. According to the AASLD/IDSA guidelines, treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Treatment should be initiated early because delaying therapy may decrease the benefits of eradicating the hepatitis C viral infection.

AASLD guidelines on management of acute hepatitis C infection17 Hepatitis C infection is considered acute during the 6 month period following exposure. Patients diagnosed with acute HCV infection should be monitored regularly to determine if the infection has cleared or progressed into chronic HCV infection. If a decision is made to treat, AASLD guidelines recommend the same regimens recommended for treatment of chronic HCV. Treatment with antiviral therapy is not recommended for pre-exposure or post-exposure prophylaxis or for those in whom the acute infection clears spontaneously.

Guidelines define IFN ineligible as one or more of the following:  Intolerance* to IFN  Autoimmune hepatitis and other autoimmune disorders  Hypersensitivity to PEG or any of its components  Decompensated hepatic disease  Major uncontrolled depressive illness  A baseline neutrophil count below 1500/µL, a baseline platelet count below 90,000/µL or baseline hemoglobin below 10 g/dL  A history of preexisting cardiac disease *Intolerance is defined by Prime as intolerance to the drug and/or excipients, not the route of administration including patients who have previously discontinued therapy with IFN due to adverse events (e.g. hypersensitivity, anaphylaxis, severe rash, severe anemia, etc.).

References (note not all references have been used in this version): 1. Afdal N, Zeuzem S, Kwo P et al. Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection. New England Journal of Medicine 2014;370:1889-98.

AL_PS_HepC_Sovaldi_Daklinza_PA_ProgSum_AR0715_r0416 Page 3 of 8

© Copyright Prime Therapeutics LLC. 04/2016 All Rights Reserved 2. Afdal N, Reddy KR, Nelson DR et al. Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1 Infection. New England Journal of Medicine 2014;370:1483-93. 3. Kowdley K, Gordon S, Reddy KR et al. Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis. New England Journal of Medicine 2014;370:1879-88. 4. AASLD Treatment Guidelines. When and In Whom to Initiate HCV Therapy. Available at: http://www.hcvguidelines.org/full-report/when-and-whom-initiate-hcv-therapy. Accessed 10/6/2015. 5. (paritaprevir/ritonavir/ombitasvir and dasabuvir) prescribing information. Available at: http://www.rxabbvie.com/pdf/viekirapak_pi.pdf . Accessed 10/6/2015. 6. Harvoni (Ledipasvir-sofosbuvir) prescribing information. Available at: http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf. Accessed 10/6/2015. 7. AASLD Treatment Guidelines, Treatment Naïve or who have experienced relapse after prior PEG/RBV therapy. Available at: http://www.hcvguidelines.org/node/72. Accessed 7/2/2015. 8. AASLD Treatment Guidelines, Retreatment of person in whom prior therapy has failed. Available at: http://www.hcvguidelines.org/full-report/retreatment-persons-whom-prior-therapy-has-failed. . Accessed 8/12/2015. 9. AASLD Treatment Guidelines, Unique Populations. Available at: http://www.hcvguidelines.org/full- report/unique-patient-populations. Accessed 10/6/2015. 10. Photo - epgonline.org. Hepatology. Accessed: February 2014. 11. Scott DR, Levy MT. Liver transient elastography (Fibroscan®): a place in the management algorithms of chronic viral hepatitis. Antiviral Therapy 2010;15:1-11 (doi: 10.3851/IMP1474). 12. Everhart JE, Wright EC, Goodman ZD et al. Prognostic Value of Ishak Fribrosis Stage: Findings from the HALT-C Trial. Hepatology 2010 February:51(2): doi: 10.1002/hep.23315. 13. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-Ombitasvir and Dasabuvir with Ribavirin. N Engl J Med 2014;370:1594-603. 14. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-Ombitasvir and Dasabuvir with Ribavirin for Hepatitis C with Cirrhosis. N Engl J Med 2014;370:1973-82. 15. Ferenci P, Bernstein D, Lalezari J et al. ABT-450/r-Ombitasvir and Dasabuvir with or without Ribavirin for HCV. N Engl J Med 2014;370:1983-92. 16. Viekira Pak prescribing information. Abbvie, Inc. North Chicago, IL. March 2015. 17. AASLD Treatment Guidelines, Management of Acute Hepatitis C Infection. Available at: http://www.hcvguidelines.org/full-report/management-acute-hcv-infection Accessed 10/6/2015. 18. Sofosbuvir prescribing information. Available at: http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf. Accessed 2/11/16. 19. Daklinza prescribing information. Available at: http://packageinserts.bms.com/pi/pi_daklinza.pdf. Accessed 2/11/16.

AL_PS_HepC_Sovaldi_Daklinza_PA_ProgSum_AR0715_r0416 Page 4 of 8

OBJECTIVE The intent of the Hepatitis C Sovaldi and Daklinza Prior Authorization (PA) program is to appropriately select patients for therapy according to the Food and Drug Administration (FDA) approved product labeling and/or clinical guidelines and/or clinical studies. The PA process will evaluate the use of these agents when there is supporting clinical evidence for their use. If the client has preferred agent(s), a preferred agent may be approved for use once criteria has been met; a non-preferred agent may be approved if the patient is currently treated with the non-preferred agent or the prescriber has documented failure of, intolerance to, FDA labeled contraindication to, or hypersensitivity to the preferred agent(s). This criteria includes the use of Sovaldi (sofosbuvir), combination use with Olysio (simeprevir) which is not an approved regimen. For the use of Olysio in combination with peginterferon and ribavirin, see Hepatitis C First Generation criteria. For the use of Harvoni (ledipasvir/sofosbuvir), Viekira Pak (ombitasvir/paritaprevir/ritonavir + dasabuvir), Technivie (ombitasvir/paritaprevir/ritonavir), or Zepatier (elbasvir/grazoprevir) see Hepatitis C Second Generation criteria. Hepatocellular carcinoma patients will be allowed therapy with Sovaldi (sofosbuvir) plus ribavirin.

TARGET DRUGS Sovaldi® (sofosbuvir)* DaklinzaTM (daclatasvir)*

Peginterferons Pegasys® (peg-interferon alfa-2a) PegIntron® (peg-interferon alfa-2b)

*Requested agent/regimen Genotype Preferred agent(s) 1, 4, 5, or 6 without Sovaldi hepatocellular carcinoma Harvoni

Sovaldi 1 or 4 with hepatocellular Sovaldi carcinoma Sovaldi 2 Sovaldi Sovaldi + ribavirin ± peg- 3 Sovaldi + ribavirin ± peg- interferon interferon OR OR Sovaldi + Daklinza Sovaldi + Daklinza Peg-interferon Any genotype Pegasys

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL Initial Evaluation –Sovaldi® (sofosbuvir) ± Pegylated Interferon and DaklinzaTM (daclatasvir)

1. The patient has a diagnosis of chronic hepatitis C infection or hepatocellular carcinoma secondary to chronic hepatitis C infection AND 2. The hepatitis C infection has been confirmed by serological markers AND 3. The patient will NOT be receiving Harvoni (sofosbuvir/ledipasvir), Incivek (telaprevir), Olysio (simeprevir), Technivie (ombitasvir/paritaprevir/ritonavir), Victrelis (boceprevir), Viekira (ombitasvir/paritaprevir/ritonavir + dasabuvir) or Zepatier (elbasvir/grazoprevir) concomitantly with sofosbuvir AND 4. The patient has NOT been previously treated with Daklinza (daclatasvir), Harvoni (sofosbuvir/ledipasvir), Sovaldi (sofosbuvir), Viekira (ombitasvir/paritaprevir/ritonavir +

AL_PS_HepC_Sovaldi_Daklinza_PA_ProgSum_AR0715_r0416 Page 5 of 8

© Copyright Prime Therapeutics LLC. 04/2016 All Rights Reserved dasabuvir), Technivie (ombitasvir/paritaprevir/ritonavir), or Zepatier (elbasvir/grazoprevir as a component of any treatment regimen AND 5. If requesting Sovaldi in combination with Daklinza, the patient has chronic hepatitis C genotype 3 infection AND 6. The agent is being prescribed by a specialist or in consultation with a specialist (i.e. gastroenterologist, hepatologist, infectious disease). If able, the prescriber will provide an SVR post treatment week 12 AND Sofosbuvir will be used in a combination antiviral treatment regimen and length of therapy supported by FDA approved labeling and/or the AASLD guidelines AND 7. The patient does NOT have any FDA labeled contraindications to sofosbuvir or the other agents used in the combination therapy AND 8. The patient is not co-infected with chronic hepatitis B AND 9. If the patient has hepatocellular carcinoma the following are met: a. The patient has either a single tumor 5 cm or less in diameter OR The patient has up to 3 tumors with each being 3 cm or less in diameter AND b. The patient has NO extrahepatic manifestations of cancer or evidence of vascular invasion of tumor AND 10. The dose of Sovaldi is within the FDA labeled dosage (400 mg daily) AND 11. If requesting Daklinza (daclatasvir) ONE of the following: a. The requested dose is less than or equal to 60 mg (one tablet) daily OR b. BOTH of the following: i. The requested dose is 90 mg daily (three 30 mg tablets) AND ii. The patient is concurrently treated with a moderate CYP3A4 inducer

Length of Approval: Up to the duration as determined in Table 3, 4, or 5 below based on regimen and genotype.

Initial Evaluation *Requested agent/regimen Genotype Preferred agent(s) 1, 4, 5, or 6 without Sovaldi hepatocellular carcinoma Harvoni

Non-preferred agent(s) (oral agent(s) and/or peg-interferon, PegIntron) will be approved when the criteria above are met AND ONE of the following is met: 1. The patient is currently being treated with the non-preferred oral agent(s) and/or peg-interferon, PegIntron OR 2. BOTH of the following: a. If requesting a non-preferred peg-interferon PegIntron, ONE of the following: i. The patient has a history of a trial of the preferred peg-interferon, Pegasys OR

AL_PS_HepC_Sovaldi_Daklinza_PA_ProgSum_AR0715_r0416 Page 6 of 8

© Copyright Prime Therapeutics LLC. 04/2016 All Rights Reserved ii. The patient has an FDA labeled contraindication, documented intolerance, or hypersensitivity to the preferred peg-interferon agent, Pegasys AND b. If requesting a non-preferred oral agent, the patient has an FDA labeled contraindication, documented intolerance, or hypersensitivity to the preferred oral agent (see table) OR 3. The prescriber has submitted documentation in support of the use of the non-preferred oral agent and/or no-preferred peg-interferon, for the intended diagnosis which has been reviewed and approved by the Clinical Review pharmacist

Length of Approval: Up to the duration as determined in Table 3, 4, or 5 below based on regimen and genotype.

Table 3: FDA Approved Sovaldi plus ribavirin with or without peginterferon antiviral regimens Patient population* Treatment Duration of therapy Genotype 1 or 4 Sovaldi + Peg-interferon + 12 weeks ribavirin Genotype 1 (interferon Sovaldi + ribavirin 24 weeks ineligible±)

Genotype 2 Sovaldi + ribavirin 12 weeks

Genotype 3 Sovaldi + ribavirin 24 weeks 1-4 with hepatocellular carcinoma Sovaldi + ribavirin Up to 48 weeks awaiting liver transplantation

Table 4: FDA approved Sovaldi plus Daklinza antiviral regimens Genotype Patient population* Treatment Duration of therapy Without cirrhosis Daklinza + Sovaldi 12 weeks Compensated (Child-Pugh A) Daklinza + Sovaldi 12 weeks cirrhosis 1 Decompensated (Child-Pugh B or Daklinza + Sovaldi + 12 weeks C) cirrhosis ribavirin Post-transplant Daklinza + Sovaldi + 12 weeks ribavirin Without cirrhosis Daklinza + Sovaldi 12 weeks Compensated (Child-Pugh A) Daklinza + Sovaldi + 12 weeks cirrhosis ribavirin 3 Decompensated (Child-Pugh B or Daklinza + Sovaldi + 12 weeks C) cirrhosis ribavirin Post-transplant Daklinza + Sovaldi + 12 weeks ribavirin

Table 5: AASLD/IDSA recommended Sovaldi based antiviral regimens Genotype* Treatment Duration of therapy 16 weeks (naïve; with cirrhosis) 2 Sovaldi + ribavirin 12 – 16 weeks (PEG-IFN + RBV failure) 5 Sovaldi + peg-interferon + ribavirin 12 weeks 6 Sovaldi + peg-interferon + ribavirin 12 weeks

*IFN ineligible is defined as one or more of the following:  Intolerance* to IFN  Autoimmune hepatitis and other autoimmune disorders  Hypersensitivity to PEG or any of its components  Decompensated hepatic disease AL_PS_HepC_Sovaldi_Daklinza_PA_ProgSum_AR0715_r0416 Page 7 of 8

© Copyright Prime Therapeutics LLC. 04/2016 All Rights Reserved  Major uncontrolled depressive illness.  A baseline neutrophil count below 1500/µL, a baseline platelet count below 90,000/µL or baseline hemoglobin below 10 g/dL  A history of preexisting cardiac disease *Intolerance is defined by Prime as intolerance to the drug and/or excipients, not the route of administration including patients who have previously discontinued therapy with IFN due to adverse events (e.g. hypersensitivity, anaphylaxis, severe rash, severe anemia, etc.).

Agent(s) Contraindication(s) Contraindicated medications Daklinza Use in combination with drugs that strongly Strong CPY3A (daclatasvir) induce CPY3A due to decreased or loss of efficacy inducers e.g. with Daklinza phenytoin, carbamazepine, rifampin, St. John’s wort Hypersensitivity reactions, autoimmune hepatitis, hepatic decompensation (Child-Pugh score >6), Pegasys neonates and infants, pregnancy, men whose (peginterferon alfa partner is pregnant, hemoglobinopathies (e.g. None -2a) thalassemia major, sickle-cell anemia), coadministration with didanosine Hypersensitivity reactions, autoimmune hepatitis, hepatic decompensation (Child-Pugh score >6), PegIntron neonates and infants, pregnancy, men whose (peginterferon alfa partner is pregnant, hemoglobinopathies (e.g. -2b) None thalassemia major, sickle-cell anemia), creatinine clearance <50 mL/min Pregnancy and for men whose partners are Sovaldi pregnant (ribavirin) and any contraindications (sofosbuvir) that apply to peginterferon if agent will be used in None combination with peginterferon

AL_PS_HepC_Sovaldi_Daklinza_PA_ProgSum_AR0715_r0416 Page 8 of 8