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DRUG RECORD

 

EMTRICITABINE

OVERVIEW
Emtricitabine

 

Introduction

Emtricitabine is a nucleoside analogue and reverse transcriptase inhibitor used in combination with other agents for treatment and prevention of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Emtricitabine does not appear to be a significant cause of drug-induced liver injury, but may cause flares of disease in patients with underlying chronic hepatitis B virus (HBV) infection.

 

Background

Emtricitabine (5-fluorothiocytidine: FTC) is an L-enantiomer and substituted analogue of cytosine and is active against both HIV and HBV, being similar in structure and activity to lamivudine. Emtricitabine is intracellularly phosphorylated to emtricitabine 5’-triphosphate which competes with the naturally occurring deoxycytidine 5’-triphosphate for incorporation in the HIV DNA by the HIV reverse transcriptase resulting in chain termination and inhibition of the polymerase activity. Emtricitabine was approved for use in HIV infection in the United States in 2006. Current indications include treatment of HIV infection, the prophylaxis of HIV infection in cases of occupational exposure, non-occupational exposure, and perinatal transmission. Emtricitabine is also active against HBV and but has not been specifically approved for use in hepatitis B. The combination of emtricitabine with tenofovir is used in many current antiretroviral regimens and is considered the therapy of choice in patients with HBV-HIV coinfection.  Emtricitabine is available as 200 mg capsules and in an oral solution as a single agent under the brand name of Emtriva; in 200 mg tablets in combination with tenofovir (600 mg) as Truvada; and in tablets in combination with tenofovir (600 mg) and efavirenz (300 mg) as Atripla. The recommended dose of emtricitabine in adults is 200 mg orally once daily.  Side effects of emtricitabine are uncommon.

 

Hepatotoxicity

There is little evidence for direct hepatotoxicity of emtricitabine and it has not been specifically implicated in cases of lactic acidosis with steatosis and hepatic failure. However, patients with chronic hepatitis B can experience a flare of the underlying hepatitis during emtricitabine therapy. These flares occur either at the start therapy (treatment flares), with the development of antiviral resistance (breakthrough flares), or when therapy is abruptly stopped (withdrawal flares). Treatment flares occur in 5-10% of patients, are usually transient and asymptomatic, and rarely require dose modification or discontinuation of therapy. In contrast, withdrawal flares occur in 15-30% of patients but can be symptomatic and severe, in rare instances (~1%) leading to acute liver failure, death or requirement for emergency liver transplantation. Patients who develop emtricitabine resistance often have relapse of disease activity after the appearance of the mutant HBV strain and rise in HBV DNA levels; this relapse can initially be severe and associated with symptoms and jaundice.

 

Mechanism of Injury

The apparent absence of significant hepatotoxicity from emtricitabine may be due to its minimal hepatic metabolism (13%) and the fact that it is both an L-enantiomer of cytidine and is blocked at the 3’ position on the deoxyribose component, making it unlikely that emtricitabine would be used by host nuclear or mitochondrial polymerases. The flares of hepatitis B that occur with initiation, antiviral resistance or withdrawal of therapy probably represent activation of immune responses to HBV caused by the sudden change in levels of viral replication.

 

Outcome and Management

ALT elevations have not been associated with emtricitabine use in patients without hepatitis B. Patients with HBV infection who have a flare of disease during emtricitabine can usually be monitored carefully and continued on therapy. Patients with a flare of hepatitis due to development of antiviral resistance, should be switched to or have the addition of another agent with a different profile of resistance. Patients with a withdrawal flare of hepatitis B, should be evaluated rapidly and restarted on antiviral therapy if appropriate. Cases of acute liver failure requiring liver transplantation have been reported in patients with hepatitis B withdrawn from emtricitabine therapy. Due to the correlation between HIV/HBV coinfection and liver dysfunction in a subset of patients who discontinue emtricitabine, all patients with HIV should be tested for HBV before starting therapy with emtricitabine.

[Nucleoside analogues used in the therapy of HIV infection include: abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine; non-nucleoside reverse transcriptase inhibitors include delavirdine, efavirenz, etravirine and nevirapine; protease inhibitors include amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir-ritonavir, nelfinavir, ritonavir, saquinavir and tipranavir; and miscellaneous agents include enfuvirtide and raltegravir.]

 

Drug Class: Antiviral Agents

Other drugs within this class:

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PRODUCT INFORMATION
Emtricitabine

REPRESENTATIVE TRADE NAMES
 Emtricitabine – Emtriva®

DRUG CLASS
 Antiviral Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Emtricitabine 143491-57-0 C8-H10-F-N3-O3-S Emtricitabine Chemical Structure

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REFERENCES
Emtricitabine

 

References Last Updated: 14 December 2011

  1. Spengler U. Hepatic toxicity of antiviral agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007, pp. 567-91.  (Review of hepatotoxicity of antiviral agents published in 2007; emtricitabine is listed as having low hepatotoxic potential).

  2. Flexner C. Antiretroviral agents and treatment of HIV infection. In, Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman.s the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, 2006, pp. 1273-1314. (Textbook of pharmacology and therapeutics).

  3. Hayden FG. Antiviral agents(nonretroviral). In, Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman.s the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, 2006, pp. 1243-72.  (Textbook of pharmacology and therapeutics).

  4. Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nature Med 1995; 1: 417-23. PubMed Citation  (Review of mechanisms for mitochondrial injury by nucleoside analogues including inhibition of mitochondrial DNA polymerase gamma).

  5. Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JAM, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as a common pathway. AIDS 1998; 12: 1735-44. PubMed Citation  (Review of mitochondrial function and role of mitochondrial toxicity or depletion in the adverse side effects of nucleoside analogues).

  6. Kontorinis N, Dieterich D. Hepatotoxicity of antiretroviral therapy. AIDS Rev 2003; 5: 36-43. PubMed Citation  (Review of hepatotoxicity of antiretroviral drugs; definition of hepatotoxicity in antiretroviral studies; grade 1=1.25-2.5 times, grade 2=2.6-5 times, grade 3=5.1-10 times and grade 4=>10 times ULNl or baseline ALT values; abacavir and lamivudine [similar to emtricitabine] have been least commonly linked to hepatotoxicity).

  7. Gish RG, Trinh H, Leung N, Chan FK, Fried MW, Wright TL, Wang C, et al. Safety and antiviral activity of emtricitabine(FTC) for the treatment of chronic hepatitis B infection: a two-year study. J Hepatol 2005; 43: 60-66. PubMed Citation  (Study of 3 doses of emtricitabine given for 2 years in 98 patients with chronic hepatitis B; on-treatment ALT flares [>20 fold-normal] occurred in 6%, withdrawal flares in 19%, but no case of clinical decompensation).

  8. Pozniak AL, Gallant JE, DeJesus E, Arribas JR, Gazzard B, Campo RE, Chen SS, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes.a 96-week analysis. J Acquir Immune Defic Syndr 2006; 43: 535-40. PubMed Citation  (Controlled trial of tenofovir and emtricitabine vs zidovudine and lamivudine combined with efavirenz in 517 patients with HIV infection; elevations in ALT >3 times normal occurred in 8% vs 9% in first 2 years of study).

  9. Lim SG, Ng TM, Kung N, Volfova M, Husa P, Lee SS, Chan S, et al.; Emtricitabine FTCB-301 Study Group. A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B. Arch Intern Med 2006; 166: 49-56. PubMed Citation  (Controlled trial of emtricitabine vs placebo in 248 patients with chronic hepatitis B; therapy was stopped after 48 weeks in 145 patients, of whom 33 [23%] had a biochemical flare of disease and 1 developed acute liver failure and required emergency liver transplantation).

  10. Lim SG, Krastev Z, Ng TM, Mechkov G, Kotzev IA, Chan S, Mondou E, et al. Randomized, double-blind study of emtricitabine(FTC) plus clevudine versus FTC alone in treatment of chronic hepatitis B. Antimicrob Agents Chemother 2006; 50: 1642-8. PubMed Citation  (Among 81 patients with a 24-week course of emtricitabine, 16% had ALT elevations >3 times normal on treatment and 15% had a withdrawal flare one of which resulted in clinical decompensation).

  11. Jain MK. Drug-induced liver injury associated with HIV medications. Clin Liver Dis 2007; 11: 615-39, vii-viii. PubMed Citation  (Review of hepatotoxicity of antiretroviral medications; ALT elevations occur in 2% to 18% of patients, but often resolve spontaneously even without dose modification; classes of injury include hypersensitivity [nevirapine, efavirenz, abacavir], mitochondrial injury [stavudine, didanosine, zidovudine], flares of hepatitis B [lamivudine, emtricitabine, tenofovir], flares of hepatitis C [any potent regimen], idiosyncratic injury [ritonavir, nevirapine, efavirenz], cholestatic hepatitis [many agents]).

  12. Hammer SM, Eron JJ Jr, Reiss P, Schooley RT, Thompson MA, Walmsley S, Cahn P, et al.; International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008; 300: 555-70. PubMed Citation  (Recent recommendations on use of antiviral therapy in adults with HIV infection including use of recently approved agents: raltegravir, maraviroc and etravirine).

  13. Inductivo-Yu I, Bonacini M. Highly active antiretroviral therapy-induced liver injury. Current Drug Safety 2008; 3: 4-13. PubMed Citation  (Review of drug-induced liver injury due to antiretroviral agents; no discussion of emtricitabinel).

  14. Soriano V, Puoti M, Garcia-Gascó Rockstroh JK, Benhamou Y, Barreiro P, McGovern B. Antiretroviral drugs and liver injury. AIDS 2008; 22: 1-13. PubMed Citation  (Review of hepatotoxicity of antiretroviral drugs with recommendations on management, stopping therapy if symptoms arise, with overt jaundice [direct bilirubin], evidence of mitochondrial toxicity, ALT >10 times ULN, ALT at lower levels if newly marketed agent; important to rule out other causes: problematic agents include didanosine, stavudine and zidovudine; nevirapine and efavirenz, full dose ritonavir and tipranavir).

  15. Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology 2009; 49(5 Suppl): S185-95. PubMed Citation  (Review of side effects of nucleoside analogues used to treat chronic hepatitis B).

 

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OTHER REFERENCE LINKS
Emtricitabine

 

  1. PubMed logoRecent References on Emtricitabine

  2. Clinical Trials logoTrials on Emtricitabine

  3. TOXLINE logoTOXLINE Citations on Emtricitabine

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