authorised [50:<0.5 mg, entecavir oral solution should be used. When a dose is indicated on a hemodialysis day, give dose after the hemodialysis session. Table 2: Dosage of Entecavir for Adults with Renal Impairment135 Cl cr (mL/min) Nucleoside-naive Individuals Lamivudine-refractory HBV or Decompensated Liver Disease 30 to> <50 0.25 mg once daily or 0.5 mg once every 48 hours 0.5 mg once daily or 1 mg once every 48 hours 10 to> <30 0.15 mg once daily or 0.5 mg once every 72 hours 0.3 mg once daily or 1 mg once every 72 hours> <10, undergoing hemodialysis or CAPD 0.05 mg once daily or 0.5 mg once every 7 days 0.1 mg once daily or 1 mg once every 7 days Pediatric patients ≥2 years of age with renal impairment: Manufacturer states data insufficient to recommend specific dosage adjustments; 1 consider reducing dose or increased dosing intervals similar to recommendations for adults with renal impairment. 1 Geriatric Patients Select dosage with caution because of possible age-related decreases in renal impairment; 1 35 monitor closely. 1 35 (See Geriatric Use under Cautions.) Cautions for Entecavir Contraindications Manufacturers state none known. 1 35 Warnings/Precautions Warnings Exacerbation of Hepatitis Severe acute exacerbations of hepatitis reported following discontinuance of HBV therapy, including entecavir. 1 35 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 35 Median time to exacerbations of hepatitis was 23 weeks. 1 35 Exacerbations of hepatitis also reported during entecavir treatment, but generally resolved with continued therapy. 1 35 Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months after entecavir discontinued. 1 35 If appropriate, resumption of HBV therapy may be warranted. 1 35 HBV-infected Individuals Coinfected with 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 HIV NRTIs. 1 23 30 31 Offer HIV testing to all patients prior to entecavir therapy. 1 35 Has not been systematically evaluated in HBV-infected patients coinfected with HIV who were not receiving concomitant antiretroviral therapy. 23 35 Because of possible risk of emergence of NRTI-resistant HIV, do not use entecavir for treatment of HBV in HIV-infected patients not receiving antiretroviral therapy. 1 31 35 200 Has not been systematically evaluated for treatment of HIV infection and such use not recommended. 1 35 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 35 Most reported cases have involved women; obesity and long-term therapy with NRTIs also may be risk factors. 1 35 Use nucleoside analogs 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 35 Lactic acidosis in patients receiving entecavir often is reported in association with hepatic decompensation, other serious medical conditions, or drug exposures. 1 35 Patients with decompensated liver disease may be at higher risk of lactic acidosis. 1 35 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 aminotransferase elevations). 1 35 Liver Transplant Recipients Only limited data on safety and efficacy in liver transplant recipients. 1 In a small, open-label post-liver transplant trial, frequency and nature of adverse events were consistent with those expected in liver transplant recipients and the known safety profile of entecavir. 1 If 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 Specific Drugs under Interactions.) Specific Populations Pregnancy Category C. 1 Pregnancy registry at 800-258-4263. 1 No adequate, well-controlled studies in pregnant women. 1 35 Use during pregnancy only if potential benefits justify potential risks to fetus. 1 35 Data not available regarding effect of entecavir therapy during pregnancy on transmission of HBV to the infant. 1 Routine screening for HBV infection recommended for all pregnant women. 105 For prevention of perinatal transmission of HBV, US Public Health Service Advisory Committee on Immunization Practices (ACIP), AAP, and others state that infants born to hepatitis B surface antigen (HBsAg)-positive women should receive first dose of hepatitis B vaccine and a dose of hepatitis B immune globulin (HBIG) within 12 hours of birth. 9 105 Lactation Distributed into milk in rats; 1 35 not known whether distributed into human milk. 1 35 Discontinue nursing or the drug, taking into account the importance of the drug to the women. 1 35 Pediatric Use Safety and efficacy not established in children> <2 years of age. 1 Only limited data available on use in lamivudine-experienced pediatric patients; 1 use in such patients only if potential benefits justify potential risks. 1 Since some pediatric patients may require long-term or lifetime management of chronic active HBV infection, consider impact of entecavir use on future treatment options. 1 Geriatric Use Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger adults. 1 35 Use with caution. 1 35 Because of age-related decreases in renal function, select dosage based on degree of renal impairment; monitor renal function in such patients. 1 35 (See Renal Impairment under Dosage and Administration.) Renal Impairment Dosage adjustments recommended in patients with Cl cr> <50 mL/minute, including those undergoing hemodialysis or CAPD. 1 35 (See Renal Impairment under Dosage and Administration.) Hispanic Patients Manufacturers state safety and efficacy not established in the US Hispanic population because of low enrollment of such patients in clinical trials. 1 35 Race No substantial race-related differences in entecavir pharmacokinetics. 1 35 Common Adverse Effects Compensated liver disease: Headache, fatigue, dizziness, nausea. 1 10 Elevated ALT concentrations, hyperbilirubinemia, elevated lipase concentrations, hematuria, glycosuria, hyperglycemia, elevated creatinine concentrations. 1 10 Decompensated liver disease: Peripheral edema, ascites, pyrexia, hepatic encephalopathy, upper respiratory infection. 1 Interactions for Entecavir Entecavir is not a substrate for CYP isoenzymes. 1 35 It does not inhibit or induce CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 3A4, or 2B6 and does not inhibit 2E1 or induce 3A5. 1 35 Pharmacokinetic interactions with drugs metabolized by CYP isoenzymes unlikely. 1 35 Nephrotoxic Drugs or Drugs 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 35 Monitor closely for adverse effects if used concomitantly with drugs excreted renally or with drugs known to affect renal function. 1 35 (See Specific Drugs under Interactions) Specific Drugs Drug Interaction Comments Adefovir No clinically important pharmacokinetic interactions 1 35 HIV nucleoside and nucleotide antiretroviral agents (HIV NRTIs) Lamivudine, tenofovir disoproxil fumarate (tenofovir DF): No pharmacokinetic interactions 1 35 Abacavir, didanosine, lamivudine, stavudine, tenofovir, zidovudine: No in vitro evidence of reduced antiretroviral activity of these drugs against HIV 1 35 Abacavir, didanosine, lamivudine, stavudine, tenofovir, zidovudine: No in vitro evidence of reduced or antagonistic antiviral effects of entecavir against HBV 1 35 36 Immunosuppressive agents (cyclosporine, tacrolimus) Possible increased entecavir concentrations due to altered renal function 1 35 HBV-infected liver transplant recipients receiving cyclosporine or tacrolimus: Increased entecavir exposures; 1 35 potential for pharmacokinetic interactions was not formally evaluated 1 35 Monitor renal function prior to and during entecavir treatment in patients receiving immunosuppressive agents that may affect renal function 1 35 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; 1 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 Pediatric patients 2 years to> <18 years of age with compensated liver disease: Exposures in those who are nucleoside-naive receiving oral solution in a dosage of 0.015 mg/kg (up to 0.5 mg) once daily similar to exposures observed in adults receiving 0.5-mg tablet once daily. 1 Exposures in those who are lamivudine-experienced receiving oral solution in a dosage of 0.03 mg/kg (up to 1 mg) once daily similar to exposures observed in adults receiving 1-mg tablet once daily. 1 35 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 35 Actions and Spectrum Purine nucleoside analog antiviral agent active in vitro and in vivo against HBV, including some strains of lamivudine-resistant HBV. 1 2 3 4 5 6 13 15 17 19 20 Undergoes phosphorylation by cellular enzymes to form the active metabolite, entecavir triphosphate. 1 3 4 5 6 Inhibits activities of HBV DNA polymerase (reverse transcriptase). 1 3 4 5 6 13 15 Has some limited in vitro activity against HIV-1 and HSV-2, varicella zoster virus, and cytomegalovirus, 2 5 6 17 but has not been shown to be effective in clinical infections caused by these viruses. 2 HBV with reduced susceptibility to entecavir can develop slowly in some patients during long-term use. 1 28 97 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 can occur among the nucleoside and nucleotide antivirals used for treatment of HBV. 1 5 20 Lamivudine- and telbivudine-resistant HBV with reduced susceptibility to entecavir reported. 1 5 20 36 Adefovir-resistant HBV with changes in susceptibility to entecavir reported; efficacy of entecavir against such HBV not established. 1 HBV 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 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 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. Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations. * available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name Entecavir Routes Dosage Forms Strengths Brand Names Manufacturer Oral Solution 0.05 mg/mL Baraclude Bristol-Myers Squibb Oral Tablets, film-coated 0.5 mg* Baraclude Bristol-Myers Squibb Entecavir Tablets 1 mg* Baraclude Bristol-Myers Squibb Entecavir Tablets AHFS DI Essentials. Copyright 2017, Selected Revisions October 23, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814. References 1. Bristol-Myers Squibb Company. Baraclude (entecavir) tablets and oral solution prescribing information. Princeton, NJ; 2015 Aug. 2. Rivkina A, Rybalov S. Chronic hepatitis B: current and future treatment options. Pharmacotherapy . 2002; 22: 721-37. [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] 9. Centers for Disease Control and Prevention. Recommended immunization schedule for children and adolescents aged 18 years or younger United States, 2017. Updates may be available at CDC website. 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. 13. Perrillo RP. Current treatment of chronic hepatitis B: benefits and limitations. Semin Liver Dis . 2005; 25 (Suppl 1):20-8. [PubMed 16103978] 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. [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] 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] 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. 34. Jonas MM, Chang MH, Sokal E et al. Randomized, controlled trial of entecavir versus placebo in children with hepatitis B envelope antigen-positive chronic hepatitis B. Hepatology . 2016; 63:377-87. [PubMed 26223345] 35. Teva Pharmaceuticals. Entecavir tablets prescribing information. North Wales, PA; 2017 Apr. 36. Gilead Sciences. Vemlidy (tenofovir alafenamide fumarate) tablets prescribing information. Foster City, CA; 2017 Apr. 37. Committee for Medicinal Products for Human Use, European Medicines Agency. Assessment report: Baraclude, Procedure No. EMEA/H/C/000623/II/0041. 2014 Jul 24. 97. Terrault NA, Bzowej NH, Chang KM et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology . 2016; 63:261-83. [PubMed 26566064] 98. World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. March 2015. Geneva: World Health Organization; 2015. 105. American Academy of Pediatrics. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015. 200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (July 14, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. Next Interactions Print this page Add to My Med List More about entecavir Side Effects During Pregnancy or Breastfeeding Dosage Information Drug Images Drug Interactions Support Group Pricing & Coupons En Español 1 Review Add your own review/rating Drug class: nucleoside reverse transcriptase inhibitors (NRTIs) Consumer resources Entecavir ... +3 more Professional resources Entecavir (FDA) Entecavir (Wolters Kluwer) Other brands: Baraclude Related treatment guides Hepatitis B> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only C Pregnancy Category Risk cannot be ruled out N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Manufacturers Amneal Pharmaceuticals LLC Par Pharmaceutical, Inc. Teva Pharmaceuticals USA, Inc. Zydus Pharmaceuticals (USA) Inc. Aurobindo Pharma Limited Camber Pharmaceuticals, Inc. AvKare, Inc. More... Drug Class Nucleoside reverse transcriptase inhibitors (NRTIs) Related Drugs Hepatitis B Viread , lamivudine , tenofovir , Baraclude , Epivir , Vemlidy , Pegasys , Intron A , adefovir , Hepsera , PegIntron , interferon alfa-2b , Epivir-HBV , Tyzeka , peginterferon alfa-2b , telbivudine , More... Entecavir Rating 1 User Review 10 /10 1 User Review 10 Rate it! Entecavir Images Entecavir systemic 0.5 mg (TEVA 5786) View all images} } a petroleum
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