Entecavir

Class: Nucleosides and Nucleotides
VA Class: AM800
Chemical Name: 6H-purin-6-one, 2- amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-monohydrate.
Molecular Formula: C12H15N5O3•H2O
CAS Number: 209216-23-9
Brands: Baraclude

Warning(s)

  • Severe acute exacerbations of hepatitis reported in patients who have discontinued anti-hepatitis B virus (HBV) therapy, including entecavir.1 (See Exacerbations of Hepatitis under Cautions.) Closely monitor hepatic function in patients who discontinue anti-HBV therapy; if appropriate, resumption of therapy may be warranted.1

  • Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported in patients receiving nucleoside analogs alone or in conjunction with antiretroviral agents.1 (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  • Because of possible risk of emergence of HIV resistant to nucleoside reverse transcriptase inhibitors (NRTIs), entecavir should not be used for treatment of HBV in HIV-infected patients who are not receiving antiretroviral therapy.1 29 31 (See Individuals Coinfected with HBV and HIV under Cautions.)

Introduction

Antiviral; purine nucleoside analog derived from guanine.1 2 3 4 5 6 13 15

Uses for Entecavir

Chronic Hepatitis B Virus (HBV) Infection

Management of chronic HBV infection in adults and adolescents ≥16 years of age with evidence of active HBV replication and either persistent elevations in serum aminotransaminases (ALT or AST) or histologic evidence of active disease.1 3 5 18 25 26 27 Relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis not known.1

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Has been effective for HBeAg-positive or -negative chronic HBV infection with compensated liver disease in patients who were nucleoside-naive (had not previously received treatment with nucleoside antivirals) or had lamivudine-refractory HBV (history of HBV viremia while receiving lamivudine or HBV strains known to have mutations associated with lamivudine resistance).1 5 25 26 27

Has been effective for treatment of chronic HBV infection in patients coinfected with both HBV and HIV who had recurrence of HBV viremia while receiving a lamivudine-containing antiretroviral regimen.1 2

Should not be used for treatment of HBV infection in HIV-infected patients who are not receiving antiretroviral therapy.1 29 30 31 33 Limited clinical experience in such patients suggests a potential for development of HIV resistance.1 29 30 31 33 (See Individuals Coinfected with HBV and HIV under Cautions.)

Safety and efficacy not established for treatment of chronic HBV infection in liver transplant patients.1 (See Liver Transplant Recipients under Cautions.)

Treatment of chronic HBV infection is complex and rapidly evolving and should be directed by clinicians familiar with the disease; consult a specialist to obtain the most up-to-date information.5 13 14 22

Entecavir Dosage and Administration

Administration

Oral Administration

Administer orally, on an empty stomach at least 2 hours before or 2 hours after meals.1

Administer oral solution using oral dosing spoon according to manufacturer’s instructions.1

Oral solution should not be diluted or mixed with water or any other liquid.1

Dosage

Optimal duration of treatment for chronic HBV infection unknown.1

Pediatric Patients

Chronic Hepatitis B Virus (HBV) Infection
Nucleoside-naive Individuals
Oral

Adolescents ≥16 years of age: 0.5 mg once daily.1

Lamivudine-refractory HBV or known lamivudine- or telbivudine-associated resistance mutations
Oral

Adolescents ≥16 years of age: 1 mg once daily.1

Adults

Chronic Hepatitis B Virus (HBV) Infection
Nucleoside-naive Individuals
Oral

0.5 mg once daily.1

Lamivudine-refractory HBV or known lamivudine- or telbivudine-associated resistance mutations
Oral

1 mg once daily.1

Special Populations

Hepatic Impairment

Dosage adjustment not required.1

Renal Impairment

Decrease dosage in those with Clcr <50 mL/minute, including those undergoing hemodialysis or CAPD.1 Manufacturer states once-daily regimen is preferred.1

Dosage for Treatment of Chronic HBV Infection in Patients with Renal Impairment

Clcr(mL/min)

Nucleoside-naive Individuals

Lamivudine-refractory HBV

30–<50

0.25 mg once daily or 0.5 mg every 48 hours1

0.5 mg once daily or 1 mg every 48 hours1

10–<30

0.15 mg once daily or 0.5 mg every 72 hours1

0.3 mg once daily or 1 mg every 72 hours1

<10

0.05 mg once daily or 0.5 mg every 7 days1

0.1 mg once daily or 1 mg every 7 days1

Hemodialysis or CAPD Patients

0.05 mg once daily or 0.5 mg every 7 days;1 10 give dose after hemodialysis1 10

0.1 mg once daily or 1 mg every 7 days;1 10 give dose after hemodialysis1 10

Cautions for Entecavir

Contraindications

  • None known.1

Warnings/Precautions

Warnings

Exacerbations of Hepatitis

Clinical and laboratory evidence of severe acute exacerbations of hepatitis may occur following discontinuance of HBV therapy, including entecavir.1 Exacerbations of hepatitis or ALT flare (e.g. ALT elevations ≥10 times ULN and ≥2 times baseline) reported in 2, 8, or 12% of nucleoside-naive HBeAg-positive patients, nucleoside-naive HBeAg-negative patients, or lamivudine-refractory patients, respectively, following discontinuance of entecavir.1 The median time to exacerbations of hepatitis was 23 weeks.1

Exacerbations of hepatitis also reported during entecavir treatment, but generally resolved with continued therapy.1

Closely monitor hepatic function clinically and with laboratory studies at repeated intervals for at least several months after entecavir discontinued.1 If appropriate, resumption of anti-HBV therapy may be warranted.1

Individuals Coinfected with HBV and HIV

Use of entecavir for treatment of chronic HBV infection in patients with unrecognized or untreated HIV infection may result in emergence of HIV isolates resistant to NRTIs.1 23 30 31 32 33 HIV testing should be offered to all patients prior to entecavir therapy.1

Entecavir has some activity against HIV and has suppressed HIV-1 RNA levels in at least 3 patients coinfected with HBV and HIV who were receiving entecavir for treatment of HBV infection but were not receiving antiretroviral therapy.23 30 HIV-1 resistance (M184V mutation) was reported in at least 1 of these patients following 6 months of entecavir therapy; this mutation was not present at baseline.23 30

Has not been systematically evaluated in HIV-infected patients with HBV who were not receiving concomitant antiretroviral therapy.23

Because of possible risk of emergence of NRTI-resistant HIV, entecavir should not be used for treatment of HBV in HIV-infected patients who are not receiving antiretroviral therapy.1 29 31 33

Has not been systematically evaluated for treatment of HIV infection and such use is not recommended.1

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported in patients receiving nucleoside analogs alone or in conjunction with antiretrovirals.1 Most reported cases have involved women; obesity and long-term therapy with nucleoside reverse transcriptase inhibitors (NRTIs) also may be risk factors.1

Nucleoside analogs should be used with particular caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors.1

Discontinue entecavir in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).1

General Precautions

Liver Transplant Recipients

Safety and efficacy in liver transplant recipients not evaluated.1 If entecavir considered necessary in liver transplant recipients who have received or are receiving an immunosuppressive agent that may affect renal function (e.g., cyclosporine, tacrolimus), monitor renal function prior to and during entecavir treatment.1 (See Interactions.)

Specific Populations

Pregnancy

Category C.1

Pregnancy registry at 800-258-4263.1 Data not available regarding effect of entecavir therapy on transmission of HBV to the infant; infants born to HBV-infected women should receive HBV vaccine according to the recommended childhood immunization schedule to prevent neonatal acquisition of HBV.1 8 9

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug, taking into account the importance of the drug to the women.1

Pediatric Use

Safety and efficacy not established in children <16 years of age.1

Geriatric Use

Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger adults.1

Use with caution.1 Because of age-related decreases in renal function, select dosage based on degree of renal impairment; monitor renal function in such patients.1 (See Renal Impairment under Dosage and Administration.)

Renal Impairment

Dosage adjustment recommended in patients with Clcr <50 mL/minute, including those undergoing hemodialysis or CAPD.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Headache, fatigue, dizziness, nausea.1 10 Elevated ALT concentrations, hyperbilirubinemia, elevated lipase concentrations, hematuria, glycosuria, hyperglycemia, elevated creatinine concentrations.1 10

Interactions for Entecavir

Entecavir is not a substrate for CYP isoenzymes.1 It does not inhibit or induce CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 3A4, or 2B6 and does not inhibit 3A5 or induce 2E1.1

Pharmacokinetic interactions with drugs metabolized by CYP isoenzymes unlikely.1

Drugs Affecting or Eliminated by Renal Excretion

Concomitant use with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of entecavir and/or the other drug.1 Monitor closely for adverse effects if used concomitantly with drugs excreted renally or with drugs known to affect renal function.1

Specific Drugs

Drug

Interaction

Comments

Adefovir

No evidence of pharmacokinetic interaction1

Immunosuppressive agents (cyclosporine, tacrolimus)

Possible increased entecavir concentrations due to altered renal function1

Monitor renal function prior to and during entecavir treatment in patients receiving immunosuppressive agents that may affect renal function1

Nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zidovudine)

No in vitro evidence of reduced antiviral efficacy of entecavir against HBV or reduced antiretroviral activity of NRTIs 1

Lamivudine: No evidence of pharmacokinetic interaction1

Tenofovir

No evidence of pharmacokinetic interaction 1

No in vitro evidence of reduced antiviral efficacy of entecavir against HBV or reduced antiretroviral activity of tenofovir 1

Entecavir Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.1

Peak plasma concentrations attained within 0.5–1.5 hours after a dose.1 Steady-state concentrations achieved after 6–10 days of once-daily administration with approximately 2-fold accumulation.1

Commercially available tablets and oral solution are bioequivalent.1

Food

Food delays absorption, decreases peak plasma concentrations, and decreases AUC.1

Distribution

Extent

Extensively distributed into tissues.1

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 13% in vitro.1

Elimination

Metabolism

Undergoes phosphorylation by cellular enzymes to form active metabolite, entecavir triphosphate.1 3 4 5 6

Partially metabolized to glucuronide and sulfate conjugates.1

Elimination Route

Excreted principally in urine by both glomerular filtration and tubular secretion.1 5 Approximately 62–73% of an oral dose eliminated unchanged in urine.1

Hemodialysis removes approximately 13% of a dose in 4 hours;1 CAPD removes approximately 0.3% of a dose over 7 days.1

Half-life

Biphasic; terminal half-life approximately 128–149 hours.1

Special Populations

Impaired hepatic function: Pharmacokinetics not affected.1

Impaired renal function: Decreased clearance and increased plasma concentrations and AUC.1

Geriatric adults: Increased AUC compared with younger adults, possibly as the result of age-related changes in renal function.1

Stability

Storage

Oral

Solution

Store in outer carton at 25°C (may be exposed to 15–30°C).1 Protect from light.1 After opening, discard by expiration date noted on bottle.1

Tablets

Tight container at 25°C (may be exposed to 15–30°C).1

Actions and Spectrum

  • Synthetic purine nucleoside analog antiviral agent active in vivo and in vitro against HBV, including some strains of lamivudine-resistant HBV.1 2 3 4 5 6 13 15 17 19 20

  • Active metabolite, entecavir triphosphate, inhibits activities of HBV DNA polymerase (reverse transcriptase).1 3 4 5 6 13 15

  • Has some activity against HIV-1.1 17

  • HBV with reduced susceptibility to entecavir can develop slowly in some patients during long-term use.1 22 28 At week 96, viral rebound due to entecavir resistance reported in <1% of patients who were nucleoside-naive prior to entecavir therapy.1 28 Viral rebound due to entecavir resistance reported in 1% of lamivudine-refractory patients after 1 year of entecavir therapy and in 9% during the second year of therapy.28

  • Cross-resistance may occur among some nucleoside analogs active against HBV.1 Lamivudine- and telbivudine-resistant HBV with reduced susceptibility to entecavir has been reported.1 5 20 Adefovir-resistant HBV with changes in susceptibility to entecavir reported; efficacy of entecavir against such HBV not established.1 HBV strains resistant to entecavir and lamivudine may retain susceptibility to adefovir.1 13 15 18

Advice to Patients

  • Importance of providing a copy of the manufacturer’s patient information.1

  • Importance of taking entecavir exactly as prescribed and not discontinuing or interrupting therapy unless instructed by a clinician; importance of regular medical follow-up.1

  • Advise patients that deterioration of liver disease has occurred when entecavir therapy is discontinued and that any change in treatment should be discussed with the clinician.1

  • Importance of taking entecavir once daily on an empty stomach (at least 2 hours before or 2 hours after meals), preferably at the same time each day.1

  • Importance of protecting oral solution from light.1 When using the oral solution, importance of using the calibrated dosing spoon provided, holding the spoon in a vertical position and filling it gradually to the mark corresponding to the prescribed dose, and rinsing it well after each use.1

  • Importance of liver function test monitoring and immediate reporting of potential exacerbations of hepatitis following discontinuance of entecavir therapy.1

  • Importance of immediately reporting to clinicians any signs or symptoms of lactic acidosis (e.g., weakness/fatigue, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting, feeling cold especially in arms and legs, dizziness or feeling light-headed, fast or irregular heart beat) or hepatotoxicity (e.g., jaundice, dark urine, bowel movements light in color, anorexia, nausea, stomach pain) or any other new symptoms.1

  • Importance of HBV therapy compliance.1 Entecavir is not a cure for HBV infection.1 HBV transmission via sexual contact, sharing needles, or blood contamination is not prevented by entecavir therapy.1

  • Patients should be advised of available measures to prevent spread of HBV infection to close contacts.1

  • Importance of testing for HIV prior to initiation of entecavir therapy.1 Advise patients that if they have HIV infection and are not receiving effective HIV treatment, entecavir may increase the risk of HIV resistance.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, and any concomitant illnesses (e.g., renal disease).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Entecavir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

0.05 mg/mL

Baraclude (with parabens; available with calibrated measuring spoon)

Bristol-Myers Squibb

Oral

Tablets, film-coated

0.5 mg

Baraclude (with povidone)

Bristol-Myers Squibb

1 mg

Baraclude (with povidone)

Bristol-Myers Squibb

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Baraclude 0.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$937.00 or 90/$2,629.11

Baraclude 1MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$920.98 or 90/$2,705.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Bristol-Myers Squibb Company. Baraclude (entecavir) tablets and oral solution prescribing information. Princeton, NJ; 2009 Jan.

2. Rivkina A, Rybalov S. Chronic hepatitis B: current and future treatment options. Pharmacotherapy. 2002; 22: 721-37. [IDIS 482368] [PubMed 12066963]

3. Honkoop P, de Man RA. Entecavir: a potent new antiviral drug for hepatitis B. Expert Opin Investig Drugs. 2003; 12:683-8. [PubMed 12665423]

4. Wolters LM, Niesters HG, de Man RA. Nucleoside analogues for chronic hepatitis B. Eur J Gastroenterol Hepatol. 2001; 13:1499-506. [PubMed 11742201]

5. Shaw T, Locarnini S. Entecavir for the treatment of chronic hepatitis B. Expert Rev Anti Infect Ther. 2004; 2:853-71. [PubMed 15566330]

6. Billich A. Entecavir (Bristol-Myers Squibb). Curr Opin Investig Drugs. 2001; 2:617-21. [PubMed 11569933]

7. Gilead Sciences, Inc. Hepsera (adefovir dipivoxil) tablets prescribing information. Foster City, CA; 2004 Aug.

8. Committee on Infectious Diseases, American Academy of Pediatrics. Red book: 2006 report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

9. Centers for Disease Control and Prevention Advisory Committee on Immunization Practices, American Academy of Pediatrics, and American Academy of Family Physicians. Recommended childhood and adolescent immunization schedule—United States, 2005. Pediatrics. 2005; 115.

10. Bristol-Myers Squibb. Princeton, NJ: Personal communication.

11. Peters MG. Managing hepatitis B coinfection in HIV-infected patients. Curr HIV/AIDS Rep. 2005; 2:122-6. [PubMed 16091258]

12. Nunez M, Soriano V. Management of patients co-infected with hepatitis B virus and HIV. Lancet Infect Dis.2005; 5:374-82. [PubMed 15919623]

13. Perrillo RP. Current treatment of chronic hepatitis B: benefits and limitations.Semin Liver Dis. 2005; 25 (Suppl 1):20-8. [PubMed 16103978]

14. Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2001; 34:1225-41. [PubMed 11732013]

15. Gish RG. Clinical trial results of new therapies for HBV: implications for treatment guidelines. Semin Liver Dis. 2005; 25 (Suppl 1):29-39. [PubMed 16103979]

16. Lai CL, Rosmawati M, Lao J, Van Vlierberghe H et al. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology. 2002; 123:1831-8. [IDIS 492287] [PubMed 12454840]

17. Innaimo SF, Seifer M, Bisacchi GS et al. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus.Antimicrob Agents Chemother. 1997; 41:1444-8. [PubMed 9210663]

18. Anon. Entecavir (Baraclude) for chronic hepatitis B. Med Lett Drugs Ther. 2005; 47:47-8.

19. Yamanaka G, Wilson T, Innaimo S, Bisacchi GS et al. Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus. Antimicrob Agents Chemother. 1999; 43:190-3. [PubMed 9869593]

20. Buti M, Esteban R. Drugs in development for hepatitis B. Drugs. 2005; 65:1451-60. [PubMed 16033287]

21. Tenney DJ, Levine SM, Rose RE et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine. Antimicrob Agents Chemother. 2004; 48:3498-507. [PubMed 15328117]

22. Lok ASF, McMahon BJ. Chronic hepatitis B. AASLD practice guidelines. Hepatology. 2007; 45:507-39. [PubMed 17256718]

23. Lewis-Hall FC. Dear health care provider letter pertaining to important information regarding Baraclude (entecavir) in patients co-infected with HIV and HBV. Bristol-Myers Squibb February 2007.

24. Soriano V, Puoti M, Bonacini M et al. Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV-HBV international panel. AIDS. 2005; 19:221-40. [PubMed 15718833]

25. Chang TT, Gish RG, de Man R et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006; 354:1001-10. [PubMed 16525137]

26. Lai CL, Shouval D, Lok AS et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006; 354:1011-20. [PubMed 16525138]

27. Sherman M, Yurdaydin C, Sollano J et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006; 130:2039-49. [PubMed 16762627]

28. Tenney DJ, Rose RE, Baldick CJ et al. Two-year assessment of entecavir resistance in lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob Agents Chemother. 2007; 51:902-11. [PubMed 17178796]

29. Panel on Clinical Practices for Treatment of HIV infection of the Department of Health and Human Services (DHHS). Supplement to the guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (April 30, 2007). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

30. McMahon MA, Jilek BL, Brennan TP et al. The HBV drug entecavir–effects on HIV-1 replication and resistance. N Engl J Med. 2007; 356:2614-21. [PubMed 17582071]

31. Lewis-Hall FC. Dear healthcare professional letter pertaining to important information regarding Baraclude (entecavir) in patients co-infected with HIV and HBV. Bristol-Myers Squibb. August 2007.

32. Lok ASF, McMahon BJ. Corrections to AASLD guidelines on chronic hepatitis B. Hepatology. 2007; 45:1347. Letter.

33. Kaplan JE, Benson C, Holmes KH et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009; 58 (RR-4):1-207.

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