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Prior Authorization Protocol

EPIVIR HBV TM(lamivudine)

HNMC

Coverage of drugs is first determined by the memberís pharmacy or medical benefit. Please consult with or refer to the Evidence of Coverage document.
  1. FDA Approved Indications:
    • Treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation.
  2. Health Net Approved Indications and Usage Guidelines:
    • Diagnosis of chronic hepatitis B virus (HBV) infection
    AND
    • Failure or clinically significant adverse effects to Viread and Baraclude (new starts only)
    • Combination low-dose IM HBIG (Hepatitis B Immune Globulin) plus lamivudine therapy has been shown to be effective for prophylaxis against hepatitis B recurrence during the liver post transplantation period
  3. Coverage is Not Authorized For:
    • Non-FDA approved indications, which are not listed in the Health Net Approved Indications and Usage Guidelines section, unless there is sufficient documentation of efficacy and safety in the published literature.
  4. General Information:
    • Patient co-infected with HIV should be evaluated by an HIV specialist to see if he/she needs to be treated with a HAART (highly active antiretroviral therapy) regimen that includes a component with activity against HBV (e.g. VireadR-tenofovir, EpivirR-lamivudine, or EmtrivaR-emtricitabine).
    • According to the American Gastroenterological Association (AGA), recommendations on the treatment of chronic hepatitis B (CHB) are as follows:
      • HBV DNA results should be reported in IU/mL (1 IU/mL = 5.6 copies/mL)
      • The upper limit of normal for serum ALT concentrations for men and women are 30 IU/L and 19 IU/L, respectively.
      • Epivir-HBV is not recommended for first line use EXCEPT in the following:
        • in patients receiving short-term antiviral prophylaxis during chemotherapy or in pregnancy, or
        • as part of an HIV regimen in patient with HBV/HIV co-infection, or
        • in combination with adefovir in patients with hepatic decompensation.
      • According to American Association for the Study of Liver Diseases (AASLD), recommendations on the treatment of CHB are as follows:
        • In view of the high rate of drug resistance during long-term treatment, Epivir HBV and or Tyzeka monotherapy are not preferred except wherewith only a short course of treatment is planned.
        • Since Hepsera is less potent than other nucleos(t)ide analogue (NA) and is associated with increasing rate of antiviral resistance after the first year of therapy, it is best utilized as a second line drug in treatment-naive patients.
        • Hepatitis B treatment is recommended if HBV DNA level or ALT becomes higher from baseline in HBeAg-negative CHB patients with initial HBV DNA levels of < 2,000 IU/mL and normal ALT.
        • Management of anti-viral resistant HBV should include monitoring of serum HBV DNA every 3-6 months during treatment.
    • Grading and staging a liver biopsy for patients with hepatitis B are as follows:
      • The grade is given a number based on the amount of inflammation (Knodell Scoring System).
        • 0 = no inflammation
        • 1-4 = minimal inflammation
        • 5-8 = mild inflammation
        • 9-12 = moderate inflammation
        • 13-18 = marked inflammation
      • The stage is scored based on the amount of fibrosis or scarring (Metavir Scoring System).
        • 0 = no scarring
        • 1 = minimal scarring
        • 2 = scarring has occurred and is outside the areas of the liver which include blood vessels
        • 3 = bridging fibrosis
        • 4 = cirrhosis or advanced scarring of the liver
    • Nonresponders may require to switch treatment if the patient still has HBV DNA level more than 2,000 IU for HBeAg(-) and 20,000 for HBeAg(+) after one year of treatment. If the lack of response is due to drug resistance, pre-existing Tyzeka-resistant or Epivir-HBV-resistant mutations predispose to Baraclude resistance.
    • Cumulative rates of antiviral resistance in nucleos(t)ide-naive CHB patients are as follows:

    NucleoSIDE Analog
    NucleoTIDE Analog
    Epivir HBVR
    TyzekaR
    BaracludeR
    HepseraR
    VireadR
    Drug Resistance
    (** Baraclude resistance reported within year 1 in patients with prior lamivudine resistance)
    ~20%, year 1
    ~70%, year 5
    ~25% up to year 2
    ~1% up to year 5 **
    None, year 1
    29%, year 5
    None, year 1
    na beyond 1 year

    • Prophylactic antiviral therapy is recommended for HBV carriers several weeks before or at the onset of cancer chemotherapy or a finite course of immunosuppressive therapy and maintained for 6 months afterwards. Antiviral prophylaxis is also considered for patients with HBsAg(+) undergoing therapy with anti-TNF agents (e.g. Remicade, Enbrel) for rheumatoid arthritis or inflammatory bowel disease. Epivir or Tyzeka can be used if the treatment is short (<12 months). Baraclude or Viread is preferred if longer duration of treatment is anticipated. Hepsera is a less suitable choice in the renal transplantation setting because of its risk of nephrotoxicity.
    • In vitro studies showed that Baraclude-resistant mutations are susceptible to Hepsera and Viread, but there are very little clinical data on the efficacy of Hepsera in patients with Baraclude-resistant HBV.
    • Tyzeka resistant mutations are cross-resistant with Epivir.
    • Hepsera resistant mutations showed reductions in susceptibility to Viread.
    • For lamuvidine-refractory patients, combination therapy of Epivir HBV and Hepsera or Viread has been shown effective in terms of virologic and biologic improvement. Adding Baraclude to Epivir lacks supporting data. Adding Tyzeka to Epivir is not more effective than Tyzeka alone.
    • Prevention of resistance may be a greater benefit of combination therapy than enhanced potency; however, large well-designed studies are needed to confirm this concept. There are insufficient robust data to approve coverage of combination use. Additional phase III studies evaluating Baraclude+Hepsera are ongoing. The phase III study of Baraclude+Viread concluded May 2011 but results are not published.
    • Micromedex class IIa- In a retrospective, long-term study of 147 patients who received liver transplants for hepatitis B virus infection, the post transplantation use of lamivudine plus low doses of hepatitis B immunoglobulin was safe and effective long-term prophylaxis against recurrent HBV infection
  5. Therapeutic Alternatives:
    Drug Dosing Regimen Dose Limit/ Maximum Dose

    HepseraR (adefovir dipivoxil)

    10 mg PO daily

    Dosage should be reduced in patients with renal impairment.
    Creatinine Clearance (mL/min): Dosing
    ≥ 50: 10 mg once daily
    30-49: 10 mg every 48 hrs
    10-29: 10 mg every 72 hrs
    Hemodialysis:
    10 mg every 7 days following dialysis


    10 mg/day

    BaracludeTM (Entecavir)

    Epivir-HBV -naive patients
    0.5 mg PO daily

    Dosage should be reduced in patients with renal impairment.
    Creatinine Clearance (mL/min): Dosing
    ≥ 50: 0.5 mg once daily
    30-49: 0.25 mg once daily or 0.5 mg every 48 hrs
    10-29: 0.15 mg once daily or 0.5 mg every 72 hrs
    <10, hemodialysis, continuous ambulatory peritoneal dialysis (CAPD):
    0.05 mg once daily following hemodialysis or 0.5 mg every 7 days

    Patients with prior Epivir-HBV treatment or decompensated liver disease
    1 mg PO daily

    Dosage should be reduced in patients with renal impairment.

    Creatinine Clearance (mL/min): Dosing
    ≥ 50: 1 mg once daily or 1 mg every 48 hrs
    30-49: 0.5 mg once daily or 1 mg every 72 hrs
    10-29: 0.3 mg once daily or 1 mg every 7 days
    <10, hemodialysis, CAPD:
    0.1 mg once daily


    0.5 mg/day

    PegasysR (peginterferon alfa 2a)*

    180 mcg SQ q week as monotherapy

    180 mcg q weekly for 48 weeks

    TyzekaTM (Telbivudine)*

    600 mg PO daily

    Dosage should be reduced in patients with renal impairment
    Creatinine Clearance (mL/min): Dosing
    ≥ 50: 600 mg once daily
    30-49: 600 mg every 48 hrs or 400 mg once daily
    <30 (not on dialysis):
    600 mg every 72 hrs or 200 mg once daily
    ESRD:
    600 mg every 96 hrs after hemodialysis or 120 mg once daily after hemodialysis


    600 mg/day

    VireadR (tenofovir)*

    300 mg PO daily
    Dosage should be reduced in patients with renal impairment.
    Creatinine Clearance (mL/min): Dosing
    ≥ 50: 300 mg once daily
    30-49: 300 mg every 48 hrs
    10-29: 300 mg every 72 to 96 hrs
    Hemodialysis:
    300 mg every 7 days or after 12 hours of dialysis
    300 mg/day
    * Requires Prior Authorization
  6. Recommended Dosing Regimen and Authorization Limit:
    Drug Dosing Regimen Authorization Limit

    lamivudine (Epivir HBVR)

    100 mg PO daily
    Dose in HIV co-infected patients will be 150 mg BID or
    300 mg QD in combination with other anti-retroviral therapy.
    Length of Benefit
  7. Product Availability:
    Tablet: 100 mg
    Oral Solution: 5 mg/ml
  8. References:
    1. Epivir HBV [Prescribing Information] Research Triangle Park, NC: GlaxoSmithKline; December 2013.
    2. Viread[Prescribing Information] Foster City, CA: Gilead Sciences; October, 2013.
    3. Baraclude [Prescribing Information] Princeton, NJ: Bristol Myers Squibb Company; March 2014.
    4. Hepsera [Prescribing Information] Foster City, CA: Gilead Sciences; November 2012.
    5. Tyzeka [Prescribing Information] East Hanover, NJ: Novartis Pharmaceuticals Corp; January 2013.
    6. Pegasys [Prescribing Information] Hutley, NJ: Hoffmann-La Roche Inc; July 2013.
    7. Keeffe EB, Dieterich DT, Han SB, et al. A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: An Update. Clin Gastroenterol and Hepatol. 2006;4:936-962.
    8. Lok ASF, McMahon BJ. AASLD Practice Guidelines-Chronic Hepatitis B: Update 2009. Hepatology 2009; Vol. 50, No.3, 1-36.
    9. Dore GJ. The impact of HIV therapy on co-infection with hepatitis B and hepatitis C viruses. Curr Opin Infect Dis. 2001;14(6):749-755.
    10. Ristig MB, Crippin J, Aberg JA, et al. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alfa and lamivudine therapy have failed. J Inf Dis. 2002;186:1844-1847.
    11. Chang TT, Shiffman M. Durability of HbeAg Seroconversion after Adefovir Dipivoxil (ADV) Treatment for Chronic Hepatitis B 2004, EASL.
    12. Liaw YF. Management of YMDD mutations during lamivudine therapy in patients with chronic Hepatitis B. J Gastroenterol and Hepatol. 2002;17, S333-S337.
    13. Gish R, Chang TT, Hadziyannis S, et al. Sustained viral load and ALT reduction following 48 weeks of entecavir treatment in HBeAg-negative and positive patients with chronic hepatitis B who have failed prior lamivudine therapy [abstract]. J Hepatol. 2003;38(suppl 2):32.
    14. Lai CL, Rosmawati M, Lao J, et al. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology. 2002;123:1831-1838.
    15. US National Institutes of Health. Entecavir plus tenofovir combination therapy versus entacavir monotherapy in naive subjects with chronic hepatitis B. Available at: http://clinicaltrials.gov/ct/show/NCT00410072?order=1 Accessed June 9, 2014.
    16. US National Institutes of Health. Entecavir plus adefovir combination therapy versus entacavir monotherapy and adefovir monotherapy for chronic hepatitis B infected subjects. Available at: http://clinicaltrials.gov/ct/show/NCT00410202?order=1 Accessed July 2, 2013.
    17. MicromedexR Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed June 9, 2014.
    18. Clinical Pharmacology Web site. Available at:http://www.clinicalpharmacology-ip.com/Default.aspx. Accessed June 9, 2014.
    19. American Hospital Formulary Service Drug Information Web site. Available at: http://www.medicinescomplete.com/mc/ahfs/current/. Accessed June 9, 2014.
The material provided to you are guidelines used by this plan to authorize, modify or determine coverage for persons with similar illnesses or conditions. Specific care and treatment may vary depending on individual need and the benefits covered under your contract.