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DRUG RECORD

 

OFLOXACIN

OVERVIEW
Ofloxacin

 

Introduction

Ofloxacin is a second generation fluoroquinolone that was previously used widely for therapy of mild-to-moderate bacterial infections, but which has been replaced by more potent and less toxic fluoroquinolones and is now used largely topically as eye and ear drops.  Ofloxacin has been linked to rare instances of acute hepatocellular injury.

 

Background

Ofloxacin (oh flox' a sin) is an oral, second generation fluoroquinolone that was previously widely used to treat mild-to-moderate urinary and respiratory tract infections caused by susceptible organisms.  Ofloxacin is a semisynthetic antibiotic and a racemic mixture; its l-enantiomer is available as levofloxacin which continues to be a widely used antibiotic.  Like other fluoroquinolones, ofloxacin 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 toposiomerases (gyrases) that are required for synthesis of bacterial mRNAs (transcription) and DNA replication.  Ofloxacin was approved for use in the United States in 1990, but was discontinued by its initial sponsor in 2009, partially because of the frequency of adverse side effects.  Nevertheless, ofloxacin remains available several in generic forms as 200, 300 and 400 mg tablets.  Current indications are acute bronchitis, community acquired pneumonia, skin, infections, cystitis, pelvic inflammatory disease, prostatitis, urethritis and gonorrhea.  Typical doses are 200 to 400 mg every 12 hours for 3 to 10 days, but longer courses are sometimes used for complicated or recurrent infections.  Common side effects include gastrointestinal upset, headaches, skin rash and allergic reactions.  Less common but more severe side effects of fluoroquinolones include prolongation of the QT interval, seizures, hallucinations, tendon rupture, hypersensitivity reactions and photosensitivity.

 

Hepatotoxicity

Mild elevations in ALT and alkaline phosphatase levels occur in 1 to 2% of patients on ofloxacin.  These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy.  Ofloxacin has also been linked to rare but occasionally severe and even fatal cases of acute liver injury.  The time to onset is typically short (2 days to 2 weeks) and the presentation is often abrupt with 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 usually being 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.  Cases with a cholestatic pattern of enzymes may run a prolonged course but are usually self-limiting.  Many (but not all) cases have had allergic manifestations with fever, rash and eosinophilia.  Autoantibodies are usually not present.  The hepatotoxicity of ofloxacin is similar to that of other fluoroquinolones and appears to represent a class effect.

 

Mechanism of Injury

The cause of hepatic injury is unknown, but appears to be hypersensitivity.

 

Outcome and Management

The severity of ofloxacin induced liver injury ranges from mild and transient serum enzyme elevations to self-limited jaundice to acute liver failure.  Recovery is usually rapid (2 to 8 weeks) after stopping the medication.  Cross reactivity of the hepatic injury between different fluoroquinolones has not been well defined, but is suspected based upon the similarity of clinical patterns of injury and latency.  Thus, patients should be advised to avoid further exposure to the fluoroquinolones, particularly levofloxacin which is the levorotatory isomer of ofloxacin.

 

Drug Class:  Antiinfective Agents

 

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

 

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PRODUCT INFORMATION
Ofloxacin

 

REPRESENTATIVE TRADE NAMES
Ofloxacin – Generic, Floxin®


DRUG CLASS
Antiinfective Agents


COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH


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DRUG CAS REGISTRY NO MOLECULAR FORMULA STRUCTURE
Ofloxacin 82419-36-1 C18-H20-F-N3-O4 Ofloxacin  chemical structure

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REFERENCES
Ofloxacin

 

References updated: 26 January 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. p 603.  (Expert review of hepatotoxicity published in 1999; 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).

  2. Moseley RH. Fluoroquinolones. Hepatotoxicity of antimicrobial and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd Edition. Amsterdam:  Elsevier, 2013. p. 468-9.  (Review of hepatotoxicity of antibiotics mentions that hepatocellular and cholestatic forms of injury have been reported due to the quinolones including cases of ductopenia, acute liver failure and death).

  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. 1463-76.  (Textbook of pharmacology and therapeutics).

  4. Jüngst G, Mohr R. Side effects of ofloxacin in clinical trials and in postmarketing surveillance. Drugs 1987; 34 (Suppl 1): 144-9. PubMed Citation  (In postmarketing surveillance of 1.5 million patients treated with ofloxacin in Germany, 18 liver-related adverse events were reported, 15 serum enzyme elevations and 3 cases of "cholestasis")

  5. Blum A. Ofloxacin-induced acute severe hepatitis. South Med J 1991; 84: 1158. PubMed Citation  (86 year old woman with heart disease developed nausea and vomiting 10 days after completing a 14 day course of ofoxacin [bilirubin not mentioned, ALT 4160 U/L, LDH 5510 U/L, Alk P 403 U/L], with accompanying renal failure and rapid resolution; suggestive of ischemic liver injury).

  6. Hautekeete ML, Kockx MM, Naegels S, Holvoet JK, Hubens H, Kloppel G. Cholestatic hepatitis related to quinolones: a report of two cases. J Hepatol 1995; 23: 759-60. PubMed Citation  (82 year old woman developed jaundice after 12 days of oral ofloxacin [bilirubin 4.5 rising to 6.5 mg/dL, ALT 65 U/L, Alk P 352 U/L, eosinophils 11%], jaundice lasting 4 weeks and then resolving; a second case was due to ciprofloxacin).

  7. Jones SF, Smith RH. Quinolones may induce hepatitis. BMJ 1997; 314: 869. PubMed Citation  (21 year old man developed jaundice 5 days after starting ofloxacin and 1 day after starting ciprofloxacin [peak bilirubin 8.2 mg/dL, AST 557 U/L, Alk P 530 U/L], resolving within 4 weeks of stopping).

  8. González Carro P, Huidobro ML, Zabala AP, Vicente EM. Fatal subfulminant hepatic failure with ofloxacin. Am J Gastroenterol 2000; 95: 1606. PubMed Citation  (70 year old man developed jaundice 5 weeks after a 5 day course of ofloxacin [bilirubin 13.5 mg/dL, ALT 1382 U/L, Alk P 392 U/L], with gradual worsening and hepatic failure resulting in death 16 weeks after onset).

  9. Stahlmann R. Clinical toxicological aspects of fluoroquinolones. Toxicol Lett 2002; 127: 269-77. PubMed Citation  (Review of the serious toxicities of the fluoroquinolones, their frequency and possible mechanisms; the hepatotoxicity of trovafloxacin became evident only after appproval and over 2.5 milllion prescriptions worldwide with 140 reported cases of "severe hepatic reactions" despite no serious hepatotoxicity in clinical trials in several thousand patients).

  10. 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: 517-523. 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 gati-floxacin, but none to ofloxacin; 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).

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OTHER REFERENCE LINKS
Ofloxacin
  1. PubMed logoRecent References on Ofloxacin

  2. Clinical Trials logoTrials on Ofloxacin

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