Entecavir

{{Short description|Chemical compound}} {{Distinguish|Emtricitabine}} {{Use dmy dates|date=July 2024}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 464189683 | image = Entecavir structure.svg | image_class = skin-invert-image | width = 240 | alt = | image2 = Entecavir ball-and-stick model.png | image_class2 = bg-transparent | alt2 = | caption =

| pronounce = {{IPAc-en|ɛ|n|ˈ|t|ɛ|k|ə|v|ɪər}} {{respell|en|TEK|ə|veer}} | tradename = Baraclude, others | Drugs.com = {{drugs.com|monograph|entecavir}} | MedlinePlus = a605028 | DailyMedID = Entecavir | pregnancy_AU = B3 | pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Entecavir (Baraclude) Use During Pregnancy | website=Drugs.com | date=3 December 2019 | url=https://www.drugs.com/pregnancy/entecavir.html | access-date=24 January 2021 | archive-date=7 November 2016 | archive-url=https://web.archive.org/web/20161107162421/https://www.drugs.com/pregnancy/entecavir.html | url-status=live }}</ref> | pregnancy_category= | routes_of_administration = By mouth | class = | ATC_prefix = J05 | ATC_suffix = AF10 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Baraclude FDA label" /> | legal_EU = Rx-only | legal_EU_comment = <ref>{{cite web | website=European Medicines Agency | title=Baraclude EPAR | date=26 June 2006 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/baraclude | access-date=5 July 2024 | archive-date=6 March 2024 | archive-url=https://web.archive.org/web/20240306150057/https://www.ema.europa.eu/en/medicines/human/EPAR/baraclude | url-status=live }}</ref> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| CAS_number_Ref = {{cascite|changed|CAS}} | CAS_number = 142217-69-4 | CAS_supplemental = | PubChem = 135398508 | IUPHAR_ligand = | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00442 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 135679 | UNII_Ref = {{fdacite|changed|FDA}} | UNII = NNU2O4609D | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D04008 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 473990 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 713 | NIAID_ChemDB = | PDB_ligand = | synonyms = ETV, BMS-200475-01

| IUPAC_name = 2-Amino-9-[(1''S'',3''R'',4''S'')-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-1''H''-purin-6-one | C=12 | H=15 | N=5 | O=3 | SMILES = C=C1C(CC(C1CO)O)N2C=NC3=C2N=C(NC3=O)N | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 1S/C12H15N5O3/c1-5-6(3-18)8(19)2-7(5)17-4-14-9-10(17)15-12(13)16-11(9)20/h4,6-8,18-19H,1-3H2,(H3,13,15,16,20)/t6-,7-,8-/m0/s1 | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = QDGZDCVAUDNJFG-FXQIFTODSA-N | density = | density_notes = | melting_point = 220 | melting_high = | melting_notes = value applies to entecavir monohydrate and is a minimum value<ref>{{cite encyclopedia |encyclopedia=The Merck Index |edition=14th |year=2006 |page=613 |isbn=978-0-911910-00-1 |title=The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals | vauthors = O'Neil MJ }}</ref> | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Entecavir''', sold under the brand name '''Baraclude''', is an antiviral medication used in the treatment of hepatitis B virus infection.<ref name=AHFS2016/> In those with both HIV/AIDS and hepatitis B virus antiretroviral medication should also be used.<ref name=AHFS2016/> Entecavir is taken by mouth as a tablet or solution.<ref name=AHFS2016/>

Common side effects include headache, nausea, high blood sugar, and decreased kidney function.<ref name=AHFS2016/> Severe side effects include enlargement of the liver, high blood lactate levels, and liver inflammation if the medication is stopped.<ref name=AHFS2016/> While there appears to be no harm from use during pregnancy, this use has not been well studied.<ref name="Drugs.com pregnancy" /> Entecavir is in the nucleoside reverse transcriptase inhibitors (NRTIs) family of medications.<ref name=AHFS2016/><ref>{{cite book| vauthors = Shetty K, Wu GY |title=Chronic Viral Hepatitis: Diagnosis and Therapeutics|date=2009|publisher=Springer Science & Business Media|isbn=978-1-59745-565-7|page=34|url=https://books.google.com/books?id=o67J8smzgHEC&pg=PA34|language=en}}</ref> It prevents the hepatitis B virus from multiplying by blocking reverse transcriptase.<ref name=AHFS2016/>

Entecavir was approved for medical use in 2005.<ref name=AHFS2016>{{cite web|title=Entecavir|url=https://www.drugs.com/monograph/entecavir.html|publisher=The American Society of Health-System Pharmacists|access-date=28 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161220224057/https://www.drugs.com/monograph/entecavir.html|archive-date=20 December 2016}}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">{{cite book | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> It is available as a generic medication.

==Medical uses== Entecavir is mainly used to treat chronic hepatitis B infection in adults and children two years and older with active viral replication and evidence of active disease with elevations in liver enzymes.<ref name="Baraclude FDA label">{{cite web | title=Baraclude- entecavir tablet, film coated Baraclude- entecavir solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=046e61c9-9298-4b2e-b76e-b26b81fecd20 | access-date=24 January 2021 | archive-date=8 November 2016 | archive-url=https://web.archive.org/web/20161108140245/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=046e61c9-9298-4b2e-b76e-b26b81fecd20 | url-status=live }}</ref> It is also used to prevent hepatitis B virus reinfection after liver transplant<ref>{{cite journal | vauthors = Fung J, Cheung C, Chan SC, Yuen MF, Chok KS, Sharr W, Dai WC, Chan AC, Cheung TT, Tsang S, Lam B, Lai CL, Lo CM | title = Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation | journal = Gastroenterology | volume = 141 | issue = 4 | pages = 1212–1219 | date = October 2011 | pmid = 21762659 | doi = 10.1053/j.gastro.2011.06.083 | doi-access = free }}</ref> and to treat HIV patients infected with hepatitis B virus. Entecavir is weakly active against HIV, but is not recommended for use in HIV-HBV co-infected patients without a fully suppressive anti-HIV regimen<ref>{{cite web|title=Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents|url=http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf|publisher=Panel on Antiretroviral Guidelines for Adults and Adolescents|access-date=15 March 2015|archive-url=https://web.archive.org/web/20161101202407/https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf|archive-date=1 November 2016}}</ref> as it may select for resistance to lamivudine and emtricitabine in HIV.<ref>{{cite journal | vauthors = McMahon MA, Jilek BL, Brennan TP, Shen L, Zhou Y, Wind-Rotolo M, Xing S, Bhat S, Hale B, Hegarty R, Chong CR, Liu JO, Siliciano RF, Thio CL | title = The HBV drug entecavir - effects on HIV-1 replication and resistance | journal = The New England Journal of Medicine | volume = 356 | issue = 25 | pages = 2614–2621 | date = June 2007 | pmid = 17582071 | pmc = 3069686 | doi = 10.1056/NEJMoa067710 }}</ref>

The efficacy of entecavir has been studied in several randomized, double-blind, multicentre trials. Entecavir by mouth is effective and generally well tolerated treatment.<ref name="enteca">{{cite journal | vauthors = Scott LJ, Keating GM | title = Entecavir: a review of its use in chronic hepatitis B | journal = Drugs | volume = 69 | issue = 8 | pages = 1003–1033 | date = May 2009 | pmid = 19496629 | doi = 10.2165/00003495-200969080-00005 | s2cid = 115493805 | url = http://adisonline.com/drugs/abstract/2009/69080/Entecavir__A_Review_of_its_Use_in_Chronic.5.aspx | access-date = 29 March 2010 | archive-url = https://web.archive.org/web/20111008153846/http://adisonline.com/drugs/abstract/2009/69080/Entecavir__A_Review_of_its_Use_in_Chronic.5.aspx | archive-date = 8 October 2011 | url-access = subscription }}</ref>

=== Pregnancy and breastfeeding === No adequate and well-controlled studies exist in pregnant women.<ref name="Drugs.com pregnancy" />

==Side effects== The majority of people who use entecavir have little to no side effects.<ref>{{cite web|url=https://www.drugs.com/cdi/entecavir.html|title=Entecavir: Indications, Side Effects, Warnings - Drugs.com|website=www.drugs.com|access-date=10 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161107161241/https://www.drugs.com/cdi/entecavir.html|archive-date=7 November 2016}}</ref> The most common side effects include headache, fatigue, dizziness, and nausea.<ref name="Baraclude FDA label"/> Less common effects include trouble sleeping and gastrointestinal symptoms such as sour stomach, diarrhea, and vomiting.<ref>{{cite web|url=https://www.drugs.com/sfx/entecavir-side-effects.html|title=Entecavir Side Effects in Detail - Drugs.com|website=www.drugs.com|access-date=10 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161110172702/https://www.drugs.com/sfx/entecavir-side-effects.html|archive-date=10 November 2016}}</ref>

Serious side effects from entecavir include lactic acidosis, liver problems, liver enlargement, and fat in the liver.<ref name="Baraclude FDA label" />

Laboratory tests may show an increase in alanine transaminase (ALT), hematuria, glycosuria, and an increase in lipase.<ref name="Baraclude FDA label" /> Periodic monitoring of hepatic function and hematology are recommended.<ref name="Baraclude FDA label" />

==Mechanism of action== Entecavir is a nucleoside analog,<ref name="pmid17125436">{{cite journal | vauthors = Sims KA, Woodland AM | title = Entecavir: a new nucleoside analog for the treatment of chronic hepatitis B infection | journal = Pharmacotherapy | volume = 26 | issue = 12 | pages = 1745–1757 | date = December 2006 | pmid = 17125436 | doi = 10.1592/phco.26.12.1745 | s2cid = 13149070 | doi-access = free }}</ref> or more specifically, a deoxyguanosine analogue that belongs to a class of carbocyclic nucleosides and inhibits reverse transcription, DNA replication and transcription in the viral replication process. Other nucleoside and nucleotide analogues include lamivudine, telbivudine, adefovir dipivoxil, and tenofovir.

Entecavir reduces the amount of hepatitis B virus in the blood by reducing its ability to multiply and infect new cells.<ref>{{cite web|url=https://www.drugs.com/cdi/entecavir.html|title=Entecavir: Indications, Side Effects, Warnings - Drugs.com|website=www.drugs.com|access-date=7 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161107161241/https://www.drugs.com/cdi/entecavir.html|archive-date=7 November 2016}}</ref>

==Administration== Entecavir is taken by mouth as a tablet or solution. Doses are based on a person's weight.<ref name="Baraclude FDA label" /> The solution is recommended for children more than 2 years old who weigh up to 30 kg. Entecavir is recommended on an empty stomach at least 2 hours before or after a meal, generally at the same time every day. It is not used in children less than 2 years old. Dose adjustments are also recommended for people with decreased kidney function.<ref name="Baraclude FDA label" />

==History== * 1992: SQ-34676 at Squibb as part of anti-herpes virus program<ref>{{cite journal | vauthors=Slusarchyk, WA, Field AK, Greytok JA, Taunk P, Tooumari AV, Young MG, Zahler R | title=4-Hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl purines and pyrimidines, a new class of anti-herpesvirus agents | journal=Antiviral Research | volume=17 | year=1992 | doi=10.1016/0166-3542(92)90200-o | page=98}}</ref> * 1997: BMS 200475 developed at BMS pharmaceutical research institute as antiviral nucleoside analogue à Activity demonstrated against hepatitis B virus, HSV-1, HCMV, VZV in cell lines & no or little activity against HIV or influenza<ref name="Bisacch_1997">{{cite journal | vauthors = Bisacchi GS, Chao ST, Bachard C, Daris JP, Innaimo SF, Jacobs JA, Kocy O, Lapointe P, Martel A, Merchant Z, Slusarchyk WA, Sundeen JE, Young MG, Colonno R, Zahler R | year = 1997 | title = BMS-200475, a novel carbocyclic 29-deoxyguanosine analog with potent and selective antihepatitis B virus activity in vitro | journal = Bioorganic & Medicinal Chemistry Letters | volume = 7 | issue = 2| pages = 127–132 | doi=10.1016/s0960-894x(96)00594-x }}</ref> * Superior activity observed against hepatitis B virus pushed research towards BMS 200475, its base analogues and its enantiomer against hepatitis B virus in HepG2.2.15 cell line<ref name="Bisacch_1997" /> * Comparison to other NAs, proven more selective potent inhibitor of hepatitis B virus by virtue of being Guanine NA<ref>{{cite journal | vauthors = Innaimo SF, Seifer M, Bisacchi GS, Standring DN, Zahler R, Colonno RJ | title = Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus | journal = Antimicrobial Agents and Chemotherapy | volume = 41 | issue = 7 | pages = 1444–1448 | date = July 1997 | pmid = 9210663 | pmc = 163937 | doi = 10.1128/AAC.41.7.1444 }}</ref> * 1998: Inhibition of hepadnaviral polymerases was demonstrated in vitro in comparison to a number of NAs-TP<ref>{{cite journal | vauthors = Seifer M, Hamatake RK, Colonno RJ, Standring DN | title = In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS-200475 and lobucavir | journal = Antimicrobial Agents and Chemotherapy | volume = 42 | issue = 12 | pages = 3200–3208 | date = December 1998 | pmid = 9835515 | pmc = 106023 | doi = 10.1128/AAC.42.12.3200 }}</ref> * Metabolic studies showed more efficient phosphorylation to triphosphate active form<ref>{{cite journal | vauthors = Yamanaka G, Wilson T, Innaimo S, Bisacchi GS, Egli P, Rinehart JK, Zahler R, Colonno RJ | title = Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus | journal = Antimicrobial Agents and Chemotherapy | volume = 43 | issue = 1 | pages = 190–193 | date = January 1999 | pmid = 9869593 | pmc = 89048 | doi = 10.1128/AAC.43.1.190 | doi-access = free }}</ref> * 3-year treatment of woodchuck model of CHB à sustained antiviral efficacy and prolonged life spans without detectable emergence of resistance<ref>{{cite journal | vauthors = Colonno RJ, Genovesi EV, Medina I, Lamb L, Durham SK, Huang ML, Corey L, Littlejohn M, Locarnini S, Tennant BC, Rose B, Clark JM | title = Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection | journal = The Journal of Infectious Diseases | volume = 184 | issue = 10 | pages = 1236–1245 | date = November 2001 | pmid = 11679911 | doi = 10.1086/324003 | doi-access = free }}</ref> * Efficacy # LVD resistant hepatitis B virus replication in vitro<ref>{{cite journal | vauthors = Levine S, Hernandez D, Yamanaka G, Zhang S, Rose R, Weinheimer S, Colonno RJ | title = Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro | journal = Antimicrobial Agents and Chemotherapy | volume = 46 | issue = 8 | pages = 2525–2532 | date = August 2002 | pmid = 12121928 | pmc = 127388 | doi = 10.1128/aac.46.8.2525-2532.2002 }}</ref> * Superior activity compared to LVD in vivo for both HBeAg+ & HBeAg− patients<ref>{{cite journal | vauthors = Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D | title = A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B | journal = The New England Journal of Medicine | volume = 354 | issue = 10 | pages = 1001–1010 | date = March 2006 | pmid = 16525137 | doi = 10.1056/nejmoa051285 | doi-access = free | hdl = 1765/71057 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L | title = Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B | journal = The New England Journal of Medicine | volume = 354 | issue = 10 | pages = 1011–1020 | date = March 2006 | pmid = 16525138 | doi = 10.1056/NEJMoa051287 | doi-access = free | hdl = 10722/45018 | hdl-access = free }}</ref> * Efficacy in LVD refractory CHB patients<ref>{{cite journal | vauthors = Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, Boron-Kaczmarska A, Martin P, Goodman Z, Colonno R, Cross A, Denisky G, Kreter B, Hindes R | title = Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B | journal = Gastroenterology | volume = 130 | issue = 7 | pages = 2039–2049 | date = June 2006 | pmid = 16762627 | doi = 10.1053/j.gastro.2006.04.007 | doi-access = free }}</ref> * Entecavir was approved by the U.S. Food and Drug Administration (FDA) in March 2005.<ref>{{cite web | title=Drug Approval Package: Baraclude (Entecavir) NDA #021797 & 021798 | website=U.S. Food and Drug Administration (FDA) | date=28 December 2011 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21797_21798_BaracludeTOC.cfm | access-date=24 January 2021 | archive-date=24 March 2013 | archive-url=https://web.archive.org/web/20130324094415/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21797_21798_BaracludeTOC.cfm | url-status=live }}</ref>

===Patent information=== Bristol-Myers Squibb was the original patent holder for Baraclude, the brand name of entecavir in the US and Canada. The drug patent expiration for Baraclude was in 2015.<ref>{{cite web|url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021797&Product_No=001&table1=OB_Rx|title=Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations|website=U.S. Food and Drug Administration (FDA)|archive-url=https://web.archive.org/web/20160304084741/http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021797&Product_No=001&table1=OB_Rx|archive-date=4 March 2016|access-date=29 August 2015}}</ref><ref>{{cite web|url=https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=001&Appl_No=021798&Appl_type=N|title=Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations|website=U.S. Food and Drug Administration (FDA)|access-date=14 November 2016|url-status=unfit|archive-url=https://web.archive.org/web/20161115140215/http://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=001&Appl_No=021798&Appl_type=N|archive-date=15 November 2016}}</ref> Entecavir patents were a subject of litigation in the US between Bristol Myers Squibb (the patent owner) and Teva Pharmaceuticals USA (a generic manufacturer). The lawsuit resulted in a relatively rare in the pharmaceutical field patent invalidation for obviousness, which was affirmed in June 2014, by the US Court of Appeals for the Federal Circuit (752 F.32d 967).

In August 2014, Teva Pharmaceuticals USA gained FDA approval for generic equivalents of Baraclude 0.5 mg and 1 mg tablets;<ref>{{cite web|url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=202122&TABLE1=OB_Rx|title=Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations|website=U.S. Food and Drug Administration (FDA)|at=Search results from the "OB_Rx" table for query on "202122."|archive-url=https://web.archive.org/web/20151222125427/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=202122&TABLE1=OB_Rx|archive-date=22 December 2015|access-date=29 August 2015}}</ref> Hetero Labs received such approval on 21 August 2015;<ref>{{cite web|url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=205740&TABLE1=OB_Rx|title=Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations|website=U.S. Food and Drug Administration (FDA)|at=Search results from the "OB_Rx" table for query on "205740."|archive-url=https://web.archive.org/web/20160304060955/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=205740&TABLE1=OB_Rx|archive-date=4 March 2016|access-date=29 August 2015}}</ref> and Aurobindo Pharma on 26 August 2015.<ref>{{cite web|url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=206217&TABLE1=OB_Rx|title=Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations|website=U.S. Food and Drug Administration (FDA)|at=Search results from the "OB_Rx" table for query on "206217."|archive-url=https://web.archive.org/web/20160304053459/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=206217&TABLE1=OB_Rx|archive-date=4 March 2016|access-date=29 August 2015}}</ref>

== References == {{reflist}}

Category:Drugs developed by Bristol Myers Squibb Category:Nucleoside analog reverse transcriptase inhibitors Category:Purines Category:Hepatotoxins Category:World Health Organization essential medicines Category:Wikipedia medicine articles ready to translate Category:Cyclopentanes Category:Alkene derivatives Category:Hydroxymethyl compounds