Norfloxacin is a first generation fluoroquinolone that is typically used to treated urinary tract infections and prostatitis. Norfloxacin has been linked to rare instances of acute hepatocellular injury.
Norfloxacin (nor flox' a sin) is a first generation fluoroquinolone that has been available for treatment of bacterial infections for many years, but which now has limited indications and is not commonly used. Like other fluoroquinolones, norfloxacin 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. Norfloxacin was first approved for use in the United States in 1986. Current indications are for urinary tract infections, sexually transmitted diseases and prostatitis due to sensitive organisms. Norfloxacin has also been used off-label as prophylaxis against spontaneous bacterial peritonitis in patients with cirrhosis and ascites. Norfloxacin is available as 400 mg tablets under the trade name Noroxin. Typical doses are 400 mg every 12 hours for 3 to 10 days, but chronic therapy has been used for antibacterial prophylaxis. Common side effects include gastrointestinal upset, headaches, skin rash and allergic reactions. Less common, but more severe side effects of norfloxacin include prolongation of the QT interval, seizures, hallucinations, tendon rupture angioedema, hypersensitivity reactions, photosensitivity and peripheral neuropathy.
Norfloxacin like other fluoroquinolones is associated with a low rate (1% to 3%) of serum enzyme elevations during therapy. These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy. Norfloxacin has also been linked to rare but occasionally severe and even fatal cases of acute liver injury. While the numbers of cases have been few, the clinical pattern has been consistent with short latency period of 1 day to 3 weeks and abrupt onset of hepatocellular injury. 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. Many (but not all) cases have had allergic manifestations with fever, rash and eosinophilia. Autoantibodies are usually not present.
Cholestatic and mixed patterns of injury have also been described particularly with delayed recognition of the liver injury. These features are typical of all fluoroquinolone associated hepatotoxicity and the injury is believed to be class specific.
Mechanism of Injury
The cause of hepatic injury is unknown, but appears to be hypersensitivity.
Outcome and Management
The severity of liver injury caused by norfloxacin ranges from mild and transient serum enzyme elevations to self-limited but severe hepatitis, to acute liver failure and death. Complete recovery is expected after stopping the drug and recovery is usually rapid (2 to 8 weeks). Cross reactivity of the hepatic injury between different fluoroquinolones has not been well documented, 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.
Case 1. Cholestatic hepatitis in a patient with cirrhosis due to norfloxacin.
[Modified from: Romero-Gómez M, Suárez García E, Fernández MC. Norfloxacin-induced acute cholestatic hepatitis in a patient with alcoholic liver cirrhosis. Am J Gastroenterol. 1999; 94: 2324-5. PubMed Citation]
A 58 year old man with alcoholic cirrhosis and acute variceal hemorrage was treated with intravenous norfloxacin as prophylaxis against spontaneous bacterial peritonitis. After 4 days, he was switched to oral norfloxacin (400 mg twice daily). Five days later, he was noted to be jaundiced and laboratory testing showed increased levels of serum bilirubin (19.1 mg/dL), ALT (214 U/L), and alkaline phosphatase (1921 U/L) as compared to baseline (Table). Tests for hepatitis A, B, C and E were negative as were autoantibodies. Abdominal ultrasound showed no evidence of biliary obstruction. Norfloxacin was stopped and he improved without further intervention over the next several weeks. Six weeks later his blood test results had returned to baseline levels. He was later treated with intravenous ofloxacin without adverse events.
||Norfloxacin, 500 mg daily for 6 days
||3+ (jaundice and hospitalization prolonged)
||Approximately 6 weeks
||Propofol, somatostatin, propranolol, lactitol.
|Time After Starting
||Time After Stopping
||Alk P (U/L)
The abrupt and rapid onset after starting and the rapid resolution on stopping the agent are typical of fluoroquinolone hepatotoxicity. Cases that are cholestatic are less likely to be severe and result in fatalities, but even cholestatic hepatitis has serious implications in patients with cirrhosis. The lack of recurrence with subsequent use of ofloxacin is striking, but it is probably prudent to avoid use of fluoroquinolones in patients with clinically apparent liver injury caused by any agent in that class.
REPRESENTATIVE TRADE NAMES
Norfloxacin – Noroxin®
Product labeling at DailyMed, National Library of Medicine, NIH
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||CAS REGISTRY NO
References updated: 07 January 2014
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Corrado ML, Struble WE, Peter C, Hoagland V, Sabbaj J. Norfloxacin: a review of safety studies. Am J Med 1987; 82 (Suppl 6B): 22-6. PubMed Citation (Early report on safety of norfloxacin from the sponsor; states that adverse events are uncommon and usually mild and that ALT elevations are rare [0.1%]).
López-Navidad A, Domingo P, Cadafalch J, Farrerons J. Norfloxacin-induced hepatotoxicity. J Hepatol 1990; 11: 277-8. PubMed Citation (72 year old woman developed abdominal pain 7 days after starting norfloxacin [peak bilirubin 1.0 mg/dL, ALT 310 U/L, Alk P 271 U/L], resolving within a few weeks upon stopping).
Davoren P, Mainstone K. Norfloxacin-induced hepatitis. Med J Aust 1993; 159: 423, 426. PubMed Citation (25 year old woman developed abdominal pain, fever and jaundice within 2 days of starting norfloxacin [bilirubin 3.7 mg/dL, ALT 2726 U/L, Alk P 168 U/L], resolving within 3 weeks of stopping).
Lucena MI, Andrade RJ, Sanchez-Martinez H, Perez-Serrano JM, Gomez-Outes A. Norfloxacin-induced cholestatic jaundice. Am J Gastroenterol 1998; 93: 2309-11. PubMed Citation (70 year old man developed jaundice and pruritus 12 days after starting norfloxacin [bilirubin 10 mg/dL, ALT 178 U/L, Alk P 443 U/L], resolving within 4 weeks of stopping).
Romero-Gómez M, Suárez García E, Fernández MC. Norfloxacin-induced acute cholestatic hepatitis in a patient with alcoholic liver cirrhosis. Am J Gastroenterol 1999; 94: 2324-5. PubMed Citation (58 year old man with alcoholic cirrhosis but normal liver tests developed jaundice 5 days after starting oral norfloxacin for prophylaxis against spontaneous bacterial peritonitis [bilirubin 14.9 mg/dL, ALT 214 U/L, AST 121 U/L, Alk P 1921 U/L], with return to baseline within 1 month of stopping).
Björnsson E, Olsson R, Remotti H. Norfloxacin-induced eosinophilic necrotizing granulomatous hepatitis. Am J Gastroenterol 2000; 95: 3662-4. PubMed Citation (71 year old woman developed fever and eosinophilia [61%] after a week of therapy with norfloxacin and at 2 weeks had liver test abnormalities [bilirubin normal, ALT 69 Alk P 960 U/L], which returned to normal with stopping; recurrence of fever, eosinophilia [55%] and ALT elevations [102 U/L] within a day of reexposure).
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 gati-floxacin, but not from norfloxacin; average time to onset was 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).
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, including one due to ciprofloxacin, but none to norfloxacin).
Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence,
presentation and outcomes in patients with drug-induced liver injury in the
general population of Iceland. Gastroenterology 2013; 114: 1419-25. PubMed Citation (In a population
based study of drug induced liver injury from Iceland, 96 cases were identified
over a 2 year period, none of which were attributed to a fluoroquinolone).
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