Entecavir

Last updated
Entecavir
Entecavir structure.svg
Entecavir ball-and-stick model.png
Clinical data
Pronunciation /ɛnˈtɛkəvɪər/ en-TEK-ə-veer
Trade names Baraclude, others
Other namesBMS-200475-01
AHFS/Drugs.com Monograph
MedlinePlus a605028
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: WARNING [2] Rx-only [3]
  • EU:Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability n/a (≥70) [3]
Protein binding 13% (in vitro)
Metabolism negligible/nil
Elimination half-life 128–149 hours
Excretion Kidney 62–73%
Identifiers
  • 2-Amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-1H-purin-6-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.111.234 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H15N5O3
Molar mass 277.284 g·mol−1
3D model (JSmol)
Melting point 220 °C (428 °F) value applies to entecavir monohydrate and is a minimum value [4]
  • C=C1C(CC(C1CO)O)N2C=NC3=C2N=C(NC3=O)N
  • InChI=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 X mark.svgN
  • Key:QDGZDCVAUDNJFG-FXQIFTODSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Entecavir (ETV), sold under the brand name Baraclude, is an antiviral medication used in the treatment of hepatitis B virus (HBV) infection. [5] In those with both HIV/AIDS and HBV antiretroviral medication should also be used. [5] Entecavir is taken by mouth as a tablet or solution. [5]

Contents

Common side effects include headache, nausea, high blood sugar, and decreased kidney function. [5] Severe side effects include enlargement of the liver, high blood lactate levels, and liver inflammation if the medication is stopped. [5] While there appears to be no harm from use during pregnancy, this use has not been well studied. [1] Entecavir is in the nucleoside reverse transcriptase inhibitors (NRTIs) family of medications. [5] [6] It prevents the hepatitis B virus from multiplying by blocking reverse transcriptase. [5]

Entecavir was approved for medical use in 2005. [5] It is on the World Health Organization's List of Essential Medicines. [7] Available as a generic medication in the United States.

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. [3] It is also used to prevent HBV reinfection after liver transplant [8] and to treat HIV patients infected with HBV. 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 [9] as it may select for resistance to lamivudine and emtricitabine in HIV. [10]

The efficacy of entecavir has been studied in several randomized, double-blind, multicentre trials. Entecavir by mouth is effective and generally well tolerated treatment. [11]

Pregnancy and breastfeeding

No adequate and well-controlled studies exist in pregnant women. [1]

Side effects

The majority of people who use entecavir have little to no side effects. [12] The most common side effects include headache, fatigue, dizziness, and nausea. [3] Less common effects include trouble sleeping and gastrointestinal symptoms such as sour stomach, diarrhea, and vomiting. [13]

Serious side effects from entecavir include lactic acidosis, liver problems, liver enlargement, and fat in the liver. [3]

Laboratory tests may show an increase in alanine transaminase (ALT), hematuria, glycosuria, and an increase in lipase. [3] Periodic monitoring of hepatic function and hematology are recommended. [3]

Mechanism of action

Entecavir is a nucleoside analog, [14] 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 HBV in the blood by reducing its ability to multiply and infect new cells. [15]

Administration

Entecavir is taken by mouth as a tablet or solution. Doses are based on a person's weight. [3] 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. [3]

History

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. [27] [28] 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 on 12 June 2014, by the US Court of Appeals for the Federal Circuit (752 F.32d 967).

On August 26, 2014, Teva Pharmaceuticals USA gained FDA approval for generic equivalents of Baraclude 0.5 mg and 1 mg tablets; [29] Hetero Labs received such approval on August 21, 2015; [30] and Aurobindo Pharma on August 26, 2015. [31]

Related Research Articles

<span class="mw-page-title-main">Hepatitis</span> Inflammation of the liver

Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain, and diarrhea. Hepatitis is acute if it resolves within six months, and chronic if it lasts longer than six months. Acute hepatitis can resolve on its own, progress to chronic hepatitis, or (rarely) result in acute liver failure. Chronic hepatitis may progress to scarring of the liver (cirrhosis), liver failure, and liver cancer.

<span class="mw-page-title-main">Viral hepatitis</span> Liver inflammation from a viral infection

Viral hepatitis is liver inflammation due to a viral infection. It may present in acute form as a recent infection with relatively rapid onset, or in chronic form, typically progressing from a long-lasting asymptomatic condition up to a decompensated hepatic disease and hepatocellular carcinoma (HCC).

Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.

<span class="mw-page-title-main">Lamivudine</span> Chemical compound

Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as zidovudine, dolutegravir, and abacavir. Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. Lamivudine is taken by mouth as a liquid or tablet.

<span class="mw-page-title-main">Emtricitabine</span> Antiretroviral drug used to treat HIV infection

Emtricitabine, with trade name Emtriva, is a nucleoside reverse-transcriptase inhibitor (NRTI) for the prevention and treatment of HIV infection in adults and children. In 2019, it was the 494th most commonly prescribed medication in the United States, with more than 3 thousand prescriptions.

<span class="mw-page-title-main">Tenofovir disoproxil</span> Antiviral drug used to treat or prevent HIV and hepatitis infections

Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention of HIV/AIDS among those at high risk before exposure, and after a needlestick injury or other potential exposure. It is sold both by itself and together in combinations such as emtricitabine/tenofovir, efavirenz/emtricitabine/tenofovir, and elvitegravir/cobicistat/emtricitabine/tenofovir. It does not cure HIV/AIDS or hepatitis B. It is available by mouth as a tablet or powder.

<span class="mw-page-title-main">Adefovir</span> Chemical compound

Adefovir is a prescription medicine used to treat (chronic) infections with hepatitis B virus. A prodrug form of adefovir was previously called bis-POM PMEA, with trade names Preveon and Hepsera. It is an orally administered nucleotide analog reverse-transcriptase inhibitor (ntRTI). It can be formulated as the pivoxil prodrug adefovir dipivoxil.

<span class="mw-page-title-main">Nucleoside analogue</span> Biochemical compound

Nucleoside analogues are structural analogues of a nucleoside, which normally contain a nucleobase and a sugar. Nucleotide analogues are analogues of a nucleotide, which normally has one to three phosphates linked to a nucleoside. Both types of compounds can deviate from what they mimick in a number of ways, as changes can be made to any of the constituent parts. They are related to nucleic acid analogues.

<span class="mw-page-title-main">Lamivudine/zidovudine</span> Combination drug for HIV

Lamivudine/zidovudine, sold under the brand name Combivir among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains two antiretroviral medications, lamivudine and zidovudine. It is used together with other antiretrovirals. It is taken by mouth twice a day.

Hepatitis B is endemic in China. Of the 350 million individuals worldwide infected with the hepatitis B virus (HBV), one-third reside in China. As of 2006 China has immunized 11.1 million children in its poorest provinces as part of several programs initiated by the Chinese government and as part of the Global Alliance for Vaccines and Immunization (GAVI). However, the effects of these programs have yet to reach levels of immunization that would limit the spread of hepatitis B effectively.

<span class="mw-page-title-main">Nitazoxanide</span> Broad-spectrum antiparasitic and antiviral medication

Nitazoxanide, sold under the brand name Alinia among others, is a broad-spectrum antiparasitic and broad-spectrum antiviral medication that is used in medicine for the treatment of various helminthic, protozoal, and viral infections. It is indicated for the treatment of infection by Cryptosporidium parvum and Giardia lamblia in immunocompetent individuals and has been repurposed for the treatment of influenza. Nitazoxanide has also been shown to have in vitro antiparasitic activity and clinical treatment efficacy for infections caused by other protozoa and helminths; evidence as of 2014 suggested that it possesses efficacy in treating a number of viral infections as well.

<span class="mw-page-title-main">Telbivudine</span> Chemical compound

Telbivudine is an antiviral drug used in the treatment of hepatitis B infection. It is marketed by Swiss pharmaceutical company Novartis under the trade names Sebivo and Tyzeka. Clinical trials have shown it to be significantly more effective than lamivudine or adefovir, and less likely to cause resistance. However, HBV signature resistance mutation M204I or L180M+M204V have been associated with Telbivudine resistance.

<span class="mw-page-title-main">Elvucitabine</span> Medication

Elvucitabine is an experimental nucleoside reverse transcriptase inhibitor (NRTI), developed by Achillion Pharmaceuticals, Inc. for the treatment of HIV infection.

<span class="mw-page-title-main">Hepatitis B</span> Human viral infection

Hepatitis B is an infectious disease caused by the Hepatitis B virus (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.

<i>Hepatitis B virus</i> Species of the genus Orthohepadnavirus

Hepatitis B virus (HBV) is a partially double-stranded DNA virus, a species of the genus Orthohepadnavirus and a member of the Hepadnaviridae family of viruses. This virus causes the disease hepatitis B.

Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.

<span class="mw-page-title-main">Hepatitis B virus precore mutant</span>

A precore mutant is a variety of hepatitis B virus that does not produce hepatitis B virus e antigen (HBeAg). These mutants are important because infections caused by these viruses are difficult to treat, and can cause infections of prolonged duration and with a higher risk of liver cirrhosis. The mutations are changes in DNA bases from guanine to adenine at base position 1896 (G1896A), and from cytosine to thymine at position 1858 (C1858T) in the precore region of the viral genome.

<span class="mw-page-title-main">Carbocyclic nucleoside</span> Class of chemical compounds

Carbocyclic nucleosides are nucleoside analogues in which a methylene group has replaced the oxygen atom of the furanose ring. These analogues have the nucleobase attached at a simple alkyl carbon rather than being part of a hemiaminal ether linkage. As a result, they have increased chemical stability. They also have increased metabolic stability because they are unaffected by phosphorylases and hydrolases that cleave the glycosidic bond between the nucleobase and furanose ring of nucleosides. They retain many of the biological properties of the original nucleosides with respect to recognition by various enzymes and receptors.

<span class="mw-page-title-main">NS5B inhibitor</span> Class of pharmaceutical drugs

Non-structural protein 5B (NS5B) inhibitors are a class of direct-acting antivirals widely used in the treatment of chronic hepatitis C. Depending on site of action and chemical composition, NS5B inhibitors may be categorized into three classes—nucleoside active site inhibitors (NIs), non-nucleoside allosteric inhibitors, and pyrophosphate analogues. Subsequently, all three classes are then subclassified. All inhibit RNA synthesis by NS5B but at different stages/sites resulting in inability of viral RNA replication. Expression of direct-acting NS5B inhibitors does not take place in cells that are not infected by hepatitis C virus, which seems to be beneficial for this class of drugs.

<span class="mw-page-title-main">Lobucavir</span> Chemical compound

Lobucavir is an antiviral drug that shows broad-spectrum activity against herpesviruses, hepatitis B and other hepadnaviruses, HIV/AIDS and cytomegalovirus. It initially demonstrated positive results in human clinical trials against hepatitis B with minimal adverse effects but was discontinued from further development following the discovery of increased risk of cancer associated with long-term use in mice. Although this carcinogenic risk is present in other antiviral drugs, such as zidovudine and ganciclovir that have been approved for clinical use, development was halted by Bristol-Myers Squibb, its manufacturer.

References

  1. 1 2 3 "Entecavir (Baraclude) Use During Pregnancy". Drugs.com. 3 December 2019. Retrieved 24 January 2021.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  3. 1 2 3 4 5 6 7 8 9 "Baraclude- entecavir tablet, film coated Baraclude- entecavir solution". DailyMed. Retrieved 24 January 2021.
  4. ↑ O'Neil MJ (2006). "The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals". The Merck Index (14th ed.). p. 613. ISBN   978-0-911910-00-1.
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  6. ↑ Shetty K, Wu GY (2009). Chronic Viral Hepatitis: Diagnosis and Therapeutics. Springer Science & Business Media. p. 34. ISBN   9781597455657.
  7. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ↑ 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 (October 2011). "Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation". Gastroenterology. 141 (4): 1212–1219. doi: 10.1053/j.gastro.2011.06.083 . PMID   21762659.
  9. ↑ "Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents" (PDF). Panel on Antiretroviral Guidelines for Adults and Adolescents. Archived (PDF) from the original on 1 November 2016. Retrieved 15 March 2015.
  10. ↑ 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 (June 2007). "The HBV drug entecavir - effects on HIV-1 replication and resistance". The New England Journal of Medicine. 356 (25): 2614–2621. doi:10.1056/NEJMoa067710. PMC   3069686 . PMID   17582071.
  11. ↑ Scott LJ, Keating GM (May 2009). "Entecavir: a review of its use in chronic hepatitis B". Drugs. 69 (8): 1003–1033. doi:10.2165/00003495-200969080-00005. PMID   19496629. S2CID   115493805. Archived from the original on 2011-10-08. Retrieved 2010-03-29.
  12. ↑ "Entecavir: Indications, Side Effects, Warnings - Drugs.com". www.drugs.com. Archived from the original on 2016-11-07. Retrieved 2016-11-10.
  13. ↑ "Entecavir Side Effects in Detail - Drugs.com". www.drugs.com. Archived from the original on 2016-11-10. Retrieved 2016-11-10.
  14. ↑ Sims KA, Woodland AM (December 2006). "Entecavir: a new nucleoside analog for the treatment of chronic hepatitis B infection". Pharmacotherapy. 26 (12): 1745–1757. doi: 10.1592/phco.26.12.1745 . PMID   17125436. S2CID   13149070.
  15. ↑ "Entecavir: Indications, Side Effects, Warnings - Drugs.com". www.drugs.com. Archived from the original on 2016-11-07. Retrieved 2016-11-07.
  16. ↑ Slusarchyk, WA, Field AK, Greytok JA, Taunk P, Tooumari AV, Young MG, Zahler R (1992). "4-Hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl purines and pyrimidines, a new class of anti-herpesvirus agents". Antiviral Research. 17: 98. doi:10.1016/0166-3542(92)90200-o.
  17. 1 2 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 (1997). "BMS-200475, a novel carbocyclic 29-deoxyguanosine analog with potent and selective antihepatitis B virus activity in vitro". Bioorganic & Medicinal Chemistry Letters. 7 (2): 127–132. doi:10.1016/s0960-894x(96)00594-x.
  18. ↑ Innaimo SF, Seifer M, Bisacchi GS, Standring DN, Zahler R, Colonno RJ (July 1997). "Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus". Antimicrobial Agents and Chemotherapy. 41 (7): 1444–1448. doi:10.1128/AAC.41.7.1444. PMC   163937 . PMID   9210663.
  19. ↑ Seifer M, Hamatake RK, Colonno RJ, Standring DN (December 1998). "In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS-200475 and lobucavir". Antimicrobial Agents and Chemotherapy. 42 (12): 3200–3208. doi:10.1128/AAC.42.12.3200. PMC   106023 . PMID   9835515.
  20. ↑ Yamanaka G, Wilson T, Innaimo S, Bisacchi GS, Egli P, Rinehart JK, Zahler R, Colonno RJ (January 1999). "Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus". Antimicrobial Agents and Chemotherapy. 43 (1): 190–193. doi: 10.1128/AAC.43.1.190 . PMC   89048 . PMID   9869593.
  21. ↑ Colonno RJ, Genovesi EV, Medina I, Lamb L, Durham SK, Huang ML, Corey L, Littlejohn M, Locarnini S, Tennant BC, Rose B, Clark JM (November 2001). "Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection". The Journal of Infectious Diseases. 184 (10): 1236–1245. doi: 10.1086/324003 . PMID   11679911.
  22. ↑ Levine S, Hernandez D, Yamanaka G, Zhang S, Rose R, Weinheimer S, Colonno RJ (August 2002). "Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro". Antimicrobial Agents and Chemotherapy. 46 (8): 2525–2532. doi:10.1128/aac.46.8.2525-2532.2002. PMC   127388 . PMID   12121928.
  23. ↑ 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 (March 2006). "A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B". The New England Journal of Medicine. 354 (10): 1001–1010. doi: 10.1056/nejmoa051285 . PMID   16525137.
  24. ↑ Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L (March 2006). "Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B". The New England Journal of Medicine. 354 (10): 1011–1020. doi: 10.1056/NEJMoa051287 . hdl: 10722/45018 . PMID   16525138.
  25. ↑ 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 (June 2006). "Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B". Gastroenterology. 130 (7): 2039–2049. doi: 10.1053/j.gastro.2006.04.007 . PMID   16762627.
  26. ↑ "Drug Approval Package: Baraclude (Entecavir) NDA #021797 & 021798". U.S. Food and Drug Administration (FDA). 28 December 2011. Retrieved 24 January 2021.
  27. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". U.S. Food and Drug Administration (FDA). Archived from the original on 4 March 2016. Retrieved 2015-08-29.
  28. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". U.S. Food and Drug Administration (FDA). Archived from the original on 15 November 2016. Retrieved 14 November 2016.{{cite web}}: CS1 maint: unfit URL (link)
  29. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". U.S. Food and Drug Administration (FDA). Search results from the "OB_Rx" table for query on "202122.". Archived from the original on 22 December 2015. Retrieved 2015-08-29.
  30. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". U.S. Food and Drug Administration (FDA). Search results from the "OB_Rx" table for query on "205740.". Archived from the original on 4 March 2016. Retrieved 2015-08-29.
  31. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". U.S. Food and Drug Administration (FDA). Search results from the "OB_Rx" table for query on "206217.". Archived from the original on 4 March 2016. Retrieved 2015-08-29.
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