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DRUG RECORD

 

GEMIFLOXACIN

OVERVIEW
Gemifloxacin

 

Introduction

Gemifloxacin is a fourth generation, oral fluoroquinolone antibiotic used in the therapy of mild-to-moderate respiratory tract infections caused by susceptible organisms.  Gemifloxacin has been linked to rare instances of acute liver injury.

 

Background

Gemifloxacin is an oral, fourth generation fluoroquinolone that is used to treat mild-to-moderate respiratory tract infections.  Like other fluoroquinolones, gemifloxacin is active against a wide range of aerobic gram-positive and gram-negative organisms and is believed to act by inhibition of type II DNA topoisomerases (gyrases) that are required for synthesis of bacterial mRNAs (transcription) and DNA replication.  Gemifloxacin was approved for use in the United States in 2003 and has not been as commonly used as other fluoroquinolones such as ciprofloxacin and levofloxacin.  Current indications are limited to acute exacerbations of chronic bronchitis and community acquired pneumonia.  Gemifloxacin is available under the commercial name Factive in 320 mg tablets.  The recommended dose is 320 mg once daily for 5 to 7 days.  Common side effects include diarrhea, nausea, abdominal pain, headaches, skin rash and allergic reactions.  The less common but more severe side effects of the fluoroquinolones include prolongation of the QT interval, seizures, hallucinations, tendon rupture, angioedema and photosensitivity.

 

Hepatotoxicity

Gemifloxacin (jem" i flox' a sin), like other fluoroquinolones, is associated with a low rate (1% to 7%) of serum enzyme elevations during therapy, although this rate may be slightly higher than occurs with placebo or comparative agents.  These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy.  Too few cases of hepatotoxicity due to gemifloxacin have been reported to provide a reliable description of its clinical features and course.  However, the liver injury due to the fluoroquinolones appears to be a class effect, and gemifloxacin injury appears to share these characteristics.  Fluoroquinone hepatotoxicity is marked by a short time to onset (a few days to 3 weeks) and often presents with abrupt onset of nausea, fatigue, abdominal pain and jaundice.  The pattern of serum enzyme elevations can be either hepatocellular or cholestatic; cases with the shorter times to onset are usually more hepatocellular with markedly elevated ALT levels, and occasionally with rapid worsening of prothrombin time and signs of hepatic failure.  The onset of illness may occur a few days after the medication is stopped.  Many (but not all) cases have had allergic manifestations with fever, rash and eosinophilia.  Autoantibodies are usually not present.

 

Mechanism of Injury

The mechanism of fluoroquinolone hepatotoxicity is suspected to be hypersensitivity.  Rechallenge leads to recurrence and should be avoided.

 

Outcome and Management

While few cases of clinically apparent liver injury due to gemifloxacin have been reported, such injury does occur with other fluoroquinolones, even with brief periods of treatment (2 to 5 days).  The severity of injury ranges from mild, asymptomatic and transient serum enzyme elevations to a mild, prolonged cholestatic hepatitis, to self-limited acute hepatocellular jaundice and even to acute liver failure.  Cross reactivity of the hepatic injury between different fluoroquinolones has been demonstrated in a small number of cases, but should be assumed based upon the similarity of clinical patterns of injury and latency.

 

Drug Class:  Antiinfective Agents

 

Other Drugs in the Subclass, Fluoroquinolones:  Ciprofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin

 

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PRODUCT INFORMATION
Gemifloxacin


REPRESENTATIVE TRADE NAMES
Gemifloxacin – Factive®


DRUG CLASS
Antiinfective Agents


COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH


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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Gemifloxacin 175463-14-6 C18-H20-F-N5-O4 Gemifloxacin Chemical Structure

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REFERENCES
Gemifloxacin

 

References updated: 17 March 2014

  1. Zimmerman HJ. Quinolones. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 603.  (Expert review of hepatotoxicity published in 1999, before the availability of gemifloxacin, mentions that cinoxacin, nalidixic acid, ciprofloxacin, norfloxacin, enoxacin, and ofloxacin are associated with minor serum enzyme elevations during therapy and with rare instances of clinically apparent liver injury; gemifloxacin is not discussed).

  2. Moseley RH. Fluoroquinolones.  Hepatotoxicity of antimicrobials and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 468.  (Review of hepatotoxicity of fluoroquinolones mentions that, although rare, hepatocellular and cholestatic forms of fluoroquinolone associated clinically apparent liver injury have been reported including cases of ductopenia, acute liver failure and death; gemifloxacin is not specifically discussed).

  3. Petri WA Jr. The quinolones. Sulfonamides, trimethoprim-sulfamethoxazole, quinolones, and agents for urinary tract infections. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1470-6.  (Textbook of pharmacology and therapeutics).

  4. Bertino J Jr, Fish D. The safety profile of the fluoroquinolones. Clin Ther 2000; 22: 798-817. PubMed Citation  (Systematic review of literature on safety of fluoroquinolones; most common side effects are gastrointestinal complaints [1-8%]; rare side effects include anaphylaxis, prolongation of QTc interval, tendon rupture and CNS toxicity; trovafloxacin has been linked to several cases of acute liver failure; no discussion of gemifloxacin).

  5. File TM Jr, Schlemmer B, Garau J, Cupo M, Young C; 049 Clinical Study Group. Efficacy and safety of gemifloxacin in the treatment of community-acquired pneumonia: a randomized, double-blind comparison with trovafloxacin. J Antimicrob Chemother 2001; 48: 67-74. PubMed Citation  (Controlled trial comparing oral gemifloxacin vs trovafloxacin in 571 patients with community acquired pneumonia found similar rates of response and side effects; ALT or AST elevations occurred in 2.1% of trovafloxacin treated [peak ALT 184 U/L] vs 0.3% of gemifloxacin treated [peak ALT 139 U/L], all of which resolved once therapy was stopped).

  6. Lode H, File TM Jr, Mandell L, Ball P, Pypstra R, Thomas M; 185 Gemifloxacin Study Group. Oral gemifloxacin versus sequential therapy with intravenous ceftriaxone/oral cefuroxime with or without a macrolide in the treatment of patients hospitalized with community-acquired pneumonia: a randomized, open-label, multicenter study of clinical efficacy and tolerability. Clin Ther 2002; 24:1915-36. PubMed Citation  (Controlled trial of oral gemifloxacin vs iv followed by oral ceftriaxone for 7-14 days in 341 patients with community acquired pneumonia; liver test elevations occurred in 7 [4.1%] gemifloxacin vs 12 [7%] ceftriaxone treated subjects, but no mention of clinically apparent liver injury).

  7. Ball P, Mandell L, Patou G, Dankner W, Tillotson G. A new respiratory fluoroquinolone, oral gemifloxacin: a safety profile in context. Int J Antimicrob Agents 2004; 23: 421-9. PubMed Citation  (Review of safety data from 6775 patients treated with gemifloxacin in clinical trials; frequency of adverse events was similar to that in comparator arms using other antibiotics, ALT elevations in 1.5% with gemifloxacin and 0.9% with comparators and "no significant drug-related liver reactions were observed").

  8. Bhavnani SM, Andes DR. Gemifloxacin for the treatment of respiratory tract infections: in vitro susceptibility, pharmacokinetics and pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy 2005; 25: 717-40. PubMed Citation  (Review of pharmacokinetics, efficacy and safety of gemifloxacin; most common side effects are diarrhea, rash, nausea and headache; increased AST values occurred in 0.3% of treated patients in one study).

  9. File TM Jr, Mandell LA, Tillotson G, Kostov K, Georgiev O. Gemifloxacin once daily for 5 days versus 7 days for the treatment of community-acquired pneumonia: a randomized, multicentre, double-blind study. J Antimicrob Chemother 2007; 60: 112-20. PubMed Citation  (Controlled trial comparing 5 and 7 days of oral gemifloxacin in 469 patients with community acquired pneumonia found similar rates of response and tolerance; ALT elevations occurred in 6.1% of patients, but no patient developed clinically apparent liver injury).

  10. Lode HM, Schmidt-Ionas M, Stahlmann R. Gemifloxacin for community-acquired pneumonia. Expert Opin Investig Drugs 2008; 17: 779-86. PubMed Citation  (Systematic review of safety and efficacy of gemifloxacin; rates of common side effects with gemifloxacin are similar to those of comparator fluoroquinolones; ALT elevations occur in 4.7-7.4% with 5 to 7 day course of oral therapy).

  11. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury but only one to a fluoroquinolone, ciprofloxacin).

  12. Orman ES, Conjeevaram HS, Vuppalanchi R, Freston JW, Rochon J, Kleiner DE, Hayashi PH; DILIN Research Group. Clinical and histopathologic features of fluoroquinolone-induced liver injury. Clin Gastroenterol Hepatol 2011; 9: 517-23. PubMed Citation  (Among 679 cases of drug induced liver injury presenting between 2004 and 2010 at 8 US medical centers, 12 [1.8%] were attributed to fluoroquinolones including 6 cipro-, 4 moxi-, 1 levo-, and 1 gatifloxacin; average time to onset 4 days [range 1-39], with both hepatocellular and cholestatic enzyme patterns, seven with rash or fever, mortality limited to those with hepatocellular injury and jaundice; hepatic injury appeared to be class specific; no cases were attributed to gemifloxacin).

  13. Kilincalp S, Deveci M, Coban S, Basar O, Yuksel O. A new cause of acute hepatitis: gemifloxacin. Acta Gastroenterol Belg 2012; 75: 460-1. PubMed Citation  (45 year old woman who was known to be HBsAg positive developed jaundice and pruritus on day 7 of a 10 day course of gemifloxacin [bilirubin 8.2 mg/dL, ALT 361 U/L, Alk P 276 U/L, HBV DNA negative], resolving within 4 weeks of stopping).

  14. Amitabh V, Singhal A, Kumar S, Patel N, Rizvi YS, Mishra P. Efficacy and safety of oral gemifloxacin for the empirical treatment of pneumonia. Lung India 2012; 29: 248-53. PubMed Citation  (Open label study of 105 patients with pneumonia treated with gemifloxacin for 5-7 days found no overall change in ALT, AST or Alk P levels; one patient developed elevated Alk P levels, but it was considered unrelated to the drug).

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OTHER REFERENCE LINKS
Gemifloxacin
  1. PubMed logoRecent References on Gemifloxacin

  2. Clinical Trials logoTrials on Gemifloxacin

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