Norfloxacin

The initial approval by the U.S. Food and Drug Administration (FDA) in 1986 encompassed the following indications:

• Uncomplicated urinary tract infections (including cystitis)
• Complicated urinary tract infections (restricted use)
• Uncomplicated urethral and cervical gonorrhea (however this indication is no longer considered to be effective by some experts due to bacterial resistance) {{cite web |url=http://prod.hopkins-abxguide.org/literature_review/09-2007/update_to_cdc_s_sexually_transmitted_diseases_treatment.html?contentInstanceId=254789&siteId=153 |title=Hopkins ABX Guide |author= |website=ABXguide.org }}{{cite web | vauthors = Blank S, Schillinger J |title=DOHMH ALERT #8:Fluoroquinolone-resistant gonorrhea, NYC |url=http://www.nycms.org/article_view.php3?view=947&part=1 |publisher=New York County Medical Society |location=USA |date=May 14, 2004 |access-date=July 22, 2009 |url-status=dead |archive-url=https://web.archive.org/web/20110722022617/http://www.nycms.org/article_view.php3?view=947&part=1 |archive-date=July 22, 2011 }}
• Prostatitis due to Escherichia coli.{{cite journal | vauthors = Naber KG | title = The role of quinolones in the treatment of chronic bacterial prostatitis | journal = Infection | volume = 19 | issue = Suppl 3 | pages = S170–S177 | year = 1991 | pmid = 1647371 | doi = 10.1007/bf01643692 | s2cid = 40584185 }}
• Syphilis treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis.{{cite web | title = Label Update to NOROXINTM (norfloxacin) Tablets, 400 mg| url = http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19384s040,042,043ltr.pdf | archive-url = https://web.archive.org/web/20121016175452/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19384s040,042,043ltr.pdf | url-status = dead | archive-date = October 16, 2012 | publisher = U.S. Food and Drug Administration | date = July 23, 2004 }}

Although fluoroquinolones are sometimes used to treat typhoid and paratyphoid fever, norfloxacin had more clinical failures than the other fluoroquinolones (417 participants, 5 trials).{{cite journal | vauthors = Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA | title = Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever) | journal = The Cochrane Database of Systematic Reviews | volume = 2011 | issue = 10 | pages = CD004530 | date = October 2011 | pmid = 21975746 | pmc = 6532575 | doi = 10.1002/14651858.CD004530.pub4 | veditors = Bhutta ZA }}

In ophthalmology, Norfloxacin licensed use is limited to the treatment of conjunctival infections caused by susceptible bacteria.

Norfloxacin has been restricted in the Republic of Ireland due to the risks of C. difficile super infections and permanent nerve as well as tendon injuries. Its licensed use in acute and chronic complicated kidney infections has been withdrawn as a result.{{cite web |author=Clodagh Sheehy |title=Warning over two types of antibiotic |url=http://www.herald.ie/national-news/warning-over-two-types-of-antibiotic-1445498.html |location=Republic of Ireland |date=August 2, 2008 |access-date=July 17, 2009}}

The European Medicines Agency, also in 2008, had recommended restricting the use of oral norfloxacin to treat urinary infections. CHMP had concluded that the marketing authorizations for norfloxacin, when used in the treatment of acute or chronic complicated pyelonephritis, should be withdrawn because the benefits do not outweigh their risks in this indication. CHMP stated that doctors should not prescribe oral norfloxacin for complicated pyelonephritis and should consider switching patients already taking oral norfloxacin for this type of infection to an alternative antibiotic.{{Cite web |url=http://www.docguide.com/news/content.nsf/news/852571020057CCF68525749000687709 |title=EMEA Restricts Use of Oral Norfloxacin Drugs in UTIs |publisher=DGNews |location=UK |date=July 24, 2008 }}

Norfloxacin is used for prevention of spontaneous bacterial peritonitis in cirrhotic patients who have a low ascites fluid protein level, impaired renal function, severe liver disease, have had a prior episode of spontaneous bacterial peritonitis, or esophageal variceal bleeding.{{cite journal | vauthors = Runyon BA | title = Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis | journal = Gastroenterology | volume = 91 | issue = 6 | pages = 1343–1346 | date = December 1986 | pmid = 3770358 | doi = 10.1016/0016-5085(86)90185-X }}{{cite journal | vauthors = Fernández J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, Vila C, Pardo A, Quintero E, Vargas V, Such J, Ginès P, Arroyo V | display-authors = 6 | title = Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis | journal = Gastroenterology | volume = 133 | issue = 3 | pages = 818–824 | date = September 2007 | pmid = 17854593 | doi = 10.1053/j.gastro.2007.06.065 | doi-access = free }}{{cite journal | vauthors = Grangé JD, Roulot D, Pelletier G, Pariente EA, Denis J, Ink O, Blanc P, Richardet JP, Vinel JP, Delisle F, Fischer D, Flahault A, Amiot X | display-authors = 6 | title = Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites: a double-blind randomized trial | journal = Journal of Hepatology | volume = 29 | issue = 3 | pages = 430–436 | date = September 1998 | pmid = 9764990 | doi = 10.1016/S0168-8278(98)80061-5 }}{{cite journal | vauthors = Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila FI, Soares-Weiser K, Uribe M | title = Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding | journal = The Cochrane Database of Systematic Reviews | volume = 2010 | issue = 9 | pages = CD002907 | date = September 2010 | pmid = 20824832 | pmc = 7138054 | doi = 10.1002/14651858.CD002907.pub2 }}

Note: Norfloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.

As noted above, under licensed use, norfloxacin is also now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.

Norfloxacin is contraindicated in those with a history of tendonitis, tendon rupture and those with a hypersensitivity to fluoroquinolones.{{Cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/019384_S027_NOROXIN.pdf |archive-url=https://web.archive.org/web/20121016180249/http://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/019384_S027_NOROXIN.pdf |url-status=dead |archive-date=October 16, 2012 |title=19-384/S027 |publisher=FDA |location=USA |year=1995 }}

There are three contraindications found within the 2008 package insert:

• "Noroxin (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents."
• "Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored."
• "Concomitant administration with tizanidine is contraindicated"

Norfloxacin is also considered to be contraindicated within the pediatric population.

• Pregnancy

Norfloxacin has been reported to rapidly cross the blood-placenta and blood-milk barrier, and is extensively distributed into the fetal tissues. For this reason norfloxacin and other fluoroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The fluoroquinolones have also been reported as being present in the mother's milk and are passed on to the nursing child, which may increases the risk of the child having an adverse reaction even though the child had never been prescribed or taken any of the drugs found within this class.{{cite journal | vauthors = Shin HC, Kim JC, Chung MK, Jung YH, Kim JS, Lee MK, Amidon GL | title = Fetal and maternal tissue distribution of the new fluoroquinolone DW-116 in pregnant rats | journal = Comparative Biochemistry and Physiology. Toxicology & Pharmacology | volume = 136 | issue = 1 | pages = 95–102 | date = September 2003 | pmid = 14522602 | doi = 10.1016/j.cca.2003.08.004 }}{{cite journal | vauthors = Dan M, Weidekamm E, Sagiv R, Portmann R, Zakut H | title = Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women | journal = Antimicrobial Agents and Chemotherapy | volume = 37 | issue = 2 | pages = 293–296 | date = February 1993 | pmid = 8452360 | pmc = 187655 | doi = 10.1128/AAC.37.2.293 }} As safer alternatives are generally available norfloxacin is contraindicated during pregnancy, especially during the first trimester. The manufacturer only recommends use of norfloxacin during pregnancy when benefit outweighs risk.{{Cite web | url=https://www.drugs.com/pregnancy/norfloxacin.html | title=Norfloxacin (Noroxin) Use During Pregnancy | work = Drugs.com }}

• Children

A 1998 retrospective survey found that numerous side effects have been recorded in reference to the unapproved use of norfloxacin in the pediatric population.{{cite journal | vauthors = Pariente-Khayat A, Vauzelle-Kervroedan F, d'Athis P, Bréart G, Gendrel D, Aujard Y, Olive G, Pons G | display-authors = 6 | title = [Retrospective survey of fluoroquinolone use in children] | journal = Archives de Pédiatrie | volume = 5 | issue = 5 | pages = 484–488 | date = May 1998 | pmid = 9759180 | doi = 10.1016/S0929-693X(99)80311-X }}

Fluoroquinolones are not licensed by the FDA for use in children due to the risk of fatalities{{cite journal | vauthors = Karande SC, Kshirsagar NA | title = Adverse drug reaction monitoring of ciprofloxacin in pediatric practice | journal = Indian Pediatrics | volume = 29 | issue = 2 | pages = 181–188 | date = February 1992 | pmid = 1592498 }} as well as permanent injury to the musculoskeletal system, with two exceptions. Ciprofloxacin is being licensed for the treatment of Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli and Inhalational Anthrax (post-exposure) and levofloxacin was recently licensed for the treatment of Inhalational Anthrax (post-exposure). However, the Fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

In general, fluoroquinolones are well tolerated, with most side-effects being mild to moderate.{{cite journal | vauthors = Owens RC, Ambrose PG | title = Antimicrobial safety: focus on fluoroquinolones | journal = Clinical Infectious Diseases | volume = 41 | issue = Suppl 2 | pages = S144–S157 | date = July 2005 | pmid = 15942881 | doi = 10.1086/428055 | doi-access = free }} On occasion, serious adverse effects occur.{{cite journal | vauthors = De Sarro A, De Sarro G | title = Adverse reactions to fluoroquinolones. an overview on mechanistic aspects | journal = Current Medicinal Chemistry | volume = 8 | issue = 4 | pages = 371–384 | date = March 2001 | pmid = 11172695 | doi = 10.2174/0929867013373435 }} Common side-effects include gastrointestinal effects such as nausea, vomiting, and diarrhea, as well as headache and insomnia.

The overall rate of adverse events in patients treated with fluoroquinolones is roughly similar to that seen in patients treated with other antibiotic classes.{{cite web | vauthors = Levine GJ, Szarfman A | title = Data Mining Analysis of Multiple Antibiotics in AERS | work = Anti-Infective Drugs Advisory Committee Meeting | date = December 15, 2006 |url= https://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4266s1-01-06-FDA-Levine.ppt | archive-url = https://web.archive.org/web/20091105141536/https://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4266s1-01-06-FDA-Levine.ppt | archive-date = November 5, 2009 | publisher = Food and Drug Administration }}{{cite journal | vauthors = Skalsky K, Yahav D, Lador A, Eliakim-Raz N, Leibovici L, Paul M | title = Macrolides vs. quinolones for community-acquired pneumonia: meta-analysis of randomized controlled trials | journal = Clinical Microbiology and Infection | volume = 19 | issue = 4 | pages = 370–378 | date = April 2013 | pmid = 22489673 | doi = 10.1111/j.1469-0691.2012.03838.x | doi-access = free }}{{cite journal | vauthors = Falagas ME, Matthaiou DK, Vardakas KZ | title = Fluoroquinolones vs beta-lactams for empirical treatment of immunocompetent patients with skin and soft tissue infections: a meta-analysis of randomized controlled trials | journal = Mayo Clinic Proceedings | volume = 81 | issue = 12 | pages = 1553–1566 | date = December 2006 | pmid = 17165634 | doi = 10.4065/81.12.1553 }}{{cite journal | vauthors = Van Bambeke F, Tulkens PM | title = Safety profile of the respiratory fluoroquinolone moxifloxacin: comparison with other fluoroquinolones and other antibacterial classes | journal = Drug Safety | volume = 32 | issue = 5 | pages = 359–378 | year = 2009 | pmid = 19419232 | doi = 10.2165/00002018-200932050-00001 | s2cid = 19026852 }} A U.S. Centers for Disease Control study found patients treated with fluoroquinolones experienced adverse events severe enough to lead to an emergency department visit more frequently than those treated with cephalosporins or macrolides, but less frequently than those treated with penicillins, clindamycin, sulfonamides, or vancomycin.{{cite journal | vauthors = Shehab N, Patel PR, Srinivasan A, Budnitz DS | title = Emergency department visits for antibiotic-associated adverse events | journal = Clinical Infectious Diseases | volume = 47 | issue = 6 | pages = 735–743 | date = September 2008 | pmid = 18694344 | doi = 10.1086/591126 | doi-access = free }}

Post-marketing surveillance has revealed a variety of relatively rare but serious adverse effects that are associated with all members of the fluoroquinolone antibacterial class. Among these, tendon problems and exacerbation of the symptoms of the neurological disorder myasthenia gravis are the subject of "black box" warnings in the United States. The most severe form of tendonopathy associated with fluoroquinolone administration is tendon rupture, which in the great majority of cases involves the Achilles tendon. Younger people typically experience good recovery, but permanent disability is possible, and is more likely in older patients.{{cite journal | vauthors = Kim GK | title = The Risk of Fluoroquinolone-induced Tendinopathy and Tendon Rupture: What Does The Clinician Need To Know? | journal = The Journal of Clinical and Aesthetic Dermatology | volume = 3 | issue = 4 | pages = 49–54 | date = April 2010 | pmid = 20725547 | pmc = 2921747 }} The overall frequency of fluoroquinolone-associated Achilles tendon rupture in patients treated with ciprofloxacin or levofloxacin has been estimated at 17 per 100,000 treatments.{{cite journal | vauthors = Sode J, Obel N, Hallas J, Lassen A | title = Use of fluroquinolone and risk of Achilles tendon rupture: a population-based cohort study | journal = European Journal of Clinical Pharmacology | volume = 63 | issue = 5 | pages = 499–503 | date = May 2007 | pmid = 17334751 | doi = 10.1007/s00228-007-0265-9 | s2cid = 3330687 }}{{cite journal | vauthors = Owens RC, Ambrose PG | title = Antimicrobial safety: focus on fluoroquinolones | journal = Clinical Infectious Diseases | volume = 41 | issue = Suppl 2 | pages = S144–S157 | date = July 2005 | pmid = 15942881 | doi = 10.1086/428055 | doi-access = free }} Risk is substantially elevated in the elderly and in those with recent exposure to topical or systemic corticosteroid therapy. Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture.{{cite journal | vauthors = Khaliq Y, Zhanel GG | title = Musculoskeletal injury associated with fluoroquinolone antibiotics | journal = Clinics in Plastic Surgery | volume = 32 | issue = 4 | pages = 495–502, vi | date = October 2005 | pmid = 16139623 | doi = 10.1016/j.cps.2005.05.004 }} Tendon damage may manifest during, as well as up to a year after fluoroquinolone therapy has been completed.{{cite journal | vauthors = Saint F, Gueguen G, Biserte J, Fontaine C, Mazeman E | title = [Rupture of the patellar ligament one month after treatment with fluoroquinolone] | language = fr | journal = Revue de Chirurgie Orthopedique et Reparatrice de l'Appareil Moteur | volume = 86 | issue = 5 | pages = 495–497 | date = September 2000 | pmid = 10970974 | url = http://www.masson.fr/masson/MDOI-RCO-09-2000-86-5-0035-1040-101019-ART7 }}

FQs prolong the QT interval by blocking voltage-gated potassium channels.{{cite journal | vauthors = Heidelbaugh JJ, Holmstrom H | title = The perils of prescribing fluoroquinolones | journal = The Journal of Family Practice | volume = 62 | issue = 4 | pages = 191–197 | date = April 2013 | pmid = 23570031 }} Prolongation of the QT interval can lead to torsades de pointes, a life-threatening arrhythmia, but in practice, this appears relatively uncommon in part because the most widely prescribed fluoroquinolones (ciprofloxacin and levofloxacin) only minimally prolong the QT interval.{{cite journal | vauthors = Rubinstein E, Camm J | title = Cardiotoxicity of fluoroquinolones | journal = The Journal of Antimicrobial Chemotherapy | volume = 49 | issue = 4 | pages = 593–596 | date = April 2002 | pmid = 11909831 | doi = 10.1093/jac/49.4.593 | doi-access = free }}

Clostridioides difficile-associated diarrhea may occur in connection with the use of any antibacterial drug, especially those with a broad spectrum of activity such as clindamycin, cephalosporins, and fluoroquinolones. Fluoroquinoline treatment is associated with risk that is similar to{{cite journal | vauthors = Deshpande A, Pasupuleti V, Thota P, Pant C, Rolston DD, Sferra TJ, Hernandez AV, Donskey CJ | display-authors = 6 | title = Community-associated Clostridium difficile infection and antibiotics: a meta-analysis | journal = The Journal of Antimicrobial Chemotherapy | volume = 68 | issue = 9 | pages = 1951–1961 | date = September 2013 | pmid = 23620467 | doi = 10.1093/jac/dkt129 | doi-access = free }} or less {{cite journal | vauthors = Slimings C, Riley TV | title = Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis | journal = The Journal of Antimicrobial Chemotherapy | volume = 69 | issue = 4 | pages = 881–891 | date = April 2014 | pmid = 24324224 | doi = 10.1093/jac/dkt477 | doi-access = free }} than that associated with broad spectrum cephalosporins. Fluoroquinolone administration may be associated with the acquisition and outgrowth of a particularly virulent Clostridioides strain.{{cite journal | vauthors = Vardakas KZ, Konstantelias AA, Loizidis G, Rafailidis PI, Falagas ME | title = Risk factors for development of Clostridium difficile infection due to BI/NAP1/027 strain: a meta-analysis | journal = International Journal of Infectious Diseases | volume = 16 | issue = 11 | pages = e768–e773 | date = November 2012 | pmid = 22921930 | doi = 10.1016/j.ijid.2012.07.010 | doi-access = free }}

The U.S. prescribing information contains a warning regarding uncommon cases of peripheral neuropathy, which can be permanent.{{cite web |url=https://www.fda.gov/Drugs/DrugSafety/ucm365050.htm | archive-url = https://web.archive.org/web/20140102192621/https://www.fda.gov/Drugs/DrugSafety/ucm365050.htm | archive-date = January 2, 2014 | work = FDA Drug Safety Communication | title = FDA requires label changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or by injection | date = August 15, 2013 | publisher = Food and Drug Administration }} Other nervous system effects include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis{{cite journal | vauthors = Galatti L, Giustini SE, Sessa A, Polimeni G, Salvo F, Spina E, Caputi AP | title = Neuropsychiatric reactions to drugs: an analysis of spontaneous reports from general practitioners in Italy | journal = Pharmacological Research | volume = 51 | issue = 3 | pages = 211–216 | date = March 2005 | pmid = 15661570 | doi = 10.1016/j.phrs.2004.08.003 }} Other rare and serious adverse events have been observed with varying degrees of evidence for causation.{{cite journal | vauthors = Babar SM | title = SIADH associated with ciprofloxacin | journal = The Annals of Pharmacotherapy | volume = 47 | issue = 10 | pages = 1359–1363 | date = October 2013 | pmid = 24259701 | doi = 10.1177/1060028013502457 | s2cid = 36759747 }}{{cite journal | vauthors = Rouveix B | title = [Clinically significant toxicity and tolerance of the main antibiotics used in lower respiratory tract infections] | journal = Médecine et Maladies Infectieuses | volume = 36 | issue = 11–12 | pages = 697–705 | date = Nov–Dec 2006 | pmid = 16876974 | doi = 10.1016/j.medmal.2006.05.012 | doi-access = }}{{cite journal | vauthors = Mehlhorn AJ, Brown DA | title = Safety concerns with fluoroquinolones | journal = The Annals of Pharmacotherapy | volume = 41 | issue = 11 | pages = 1859–1866 | date = November 2007 | pmid = 17911203 | doi = 10.1345/aph.1K347 | s2cid = 26411679 }}{{cite journal | vauthors = Jones SE, Smith RH | title = Quinolones may induce hepatitis | journal = BMJ | volume = 314 | issue = 7084 | pages = 869 | date = March 1997 | pmid = 9093098 | pmc = 2126221 | doi = 10.1136/bmj.314.7084.869 }}

Events that may occur in acute overdose are rare, and include kidney failure and seizure.{{Cite book| vauthors = Nelson LH, Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA |title=Goldfrank's toxicologic emergencies |publisher=McGraw-Hill, Medical Pub. Division |location=New York |year=2006 |isbn=978-0-07-143763-9 |url=https://books.google.com/books?id=cvJuLqBxGUcC&q=goldfranks+Fluoroquinolone+toxicity&pg=PA849 }} Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.{{cite journal | vauthors = Iannini PB | title = The safety profile of moxifloxacin and other fluoroquinolones in special patient populations | journal = Current Medical Research and Opinion | volume = 23 | issue = 6 | pages = 1403–1413 | date = June 2007 | pmid = 17559736 | doi = 10.1185/030079907X188099 | s2cid = 34091286 }}{{Cite web| vauthors = Farinas ER | work = Public Health Service Food and Drug Administration Center for Drug Evaluation and Research |title=Consult: One-Year Post Pediatric Exclusivity Postmarketing Adverse Events Review |url=https://www.fda.gov/OHRMS/DOCKETS/AC/05/briefing/2005-4152b1_03_01_Cipro%20AE.pdf |archive-url=https://web.archive.org/web/20090710194429/http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4152b1_03_01_Cipro%20AE.pdf |url-status=dead |archive-date=July 10, 2009 |publisher=FDA |location=USA |date=March 1, 2005 |access-date=August 31, 2009}}

The toxicity of drugs that are metabolised by the cytochrome P450 system is enhanced by concomitant use of some quinolones. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. Coadministration may dangerously increase coumadin warfarin activity; INR should be monitored closely.

They may also interact with the GABA A receptor and cause neurological symptoms; this effect is augmented by certain non-steroidal anti-inflammatory drugs.{{cite journal | vauthors = Brouwers JR | title = Drug interactions with quinolone antibacterials | journal = Drug Safety | volume = 7 | issue = 4 | pages = 268–281 | date = July 1992 | pmid = 1524699 | doi = 10.2165/00002018-199207040-00003 | s2cid = 6701544 }}

The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, norfloxacin should be used with caution in individuals receiving NSAIDS concomitantly.{{cite web | title = Update to label: NOROXINTM (norfloxacin) Tablets, 400 mg | url = http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/019384s045LTR.pdf | archive-url = https://web.archive.org/web/20121016175457/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/019384s045LTR.pdf | url-status = dead | archive-date = October 16, 2012 | publisher = U.S. Food and Drug Administration | date = May 16, 2006 }}

Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly.

The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered.

Some quinolones exert an inhibitory effect on the cytochrome P-450 system, thereby reducing theophylline clearance and increasing theophylline blood levels. Coadministration of certain fluoroquinolones and other drugs primarily metabolized by CYP1A2 (e.g. theophylline, methylxanthines, tizanidine) results in increased plasma concentrations and could lead to clinically significant side effects of the coadministered drug. Additionally other fluoroquinolones, especially enoxacin, and to a lesser extent ciprofloxacin and pefloxacin, also inhibit the metabolic clearance of theophylline.{{cite journal | vauthors = Janknegt R | title = Drug interactions with quinolones | journal = The Journal of Antimicrobial Chemotherapy | volume = 26 | issue = Suppl D | pages = 7–29 | date = November 1990 | pmid = 2286594 | doi = 10.1093/jac/26.suppl_D.7 }}

Such drug interactions are associated with the molecular structural modifications of the quinolone ring, specifically interactions involving NSAIDS and theophylline. As such, these drug interactions involving the fluoroquinolones appear to be drug specific rather than a class effect. The fluoroquinolones have also been shown to interfere with the metabolism of caffeine{{cite journal | vauthors = Harder S, Fuhr U, Staib AH, Wolff T | title = Ciprofloxacin-caffeine: a drug interaction established using in vivo and in vitro investigations | journal = The American Journal of Medicine | volume = 87 | issue = 5A | pages = 89S–91S | date = November 1989 | pmid = 2589393 | doi = 10.1016/0002-9343(89)90031-4 | doi-access = }} and the absorption of levothyroxine. The interference with the metabolism of caffeine may lead to the reduced clearance of caffeine and a prolongation of its serum half-life, resulting in a caffeine overdose. This may lead to reduced clearance of caffeine and a prolongation of the plasma's half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin.

The use of NSAIDs (Non Steroid Anti Inflammatory Drugs) while undergoing fluoroquinolone therapy is contra-indicated due to the risk of severe CNS adverse reactions, including but not limited to seizure disorders. Fluoroquinolones with an unsubstituted piperazinyl moiety at position 7 have the potential to interact with NSAIDs and/or their metabolites, resulting in antagonism of GABA neurotransmission.{{cite journal | vauthors = Domagala JM | title = Structure-activity and structure-side-effect relationships for the quinolone antibacterials | journal = The Journal of Antimicrobial Chemotherapy | volume = 33 | issue = 4 | pages = 685–706 | date = April 1994 | pmid = 8056688 | doi = 10.1093/jac/33.4.685 }}

The use of norfloxacin concomitantly has also been associated with transient elevations in serum creatinine in patients receiving cyclosporine, on rare occasions, resulted in severe hypoglycemia with sulfonylurea. Renal tubular transport of methotrexate may be inhibited by concomitant administration of norfloxacin, potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate toxic reactions.

Current or past treatment with oral corticosteroids is associated with an increased risk of Achilles tendon rupture, especially in elderly patients who are also taking the fluoroquinolones.{{cite journal | vauthors = van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH | title = Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids | journal = Archives of Internal Medicine | volume = 163 | issue = 15 | pages = 1801–1807 | date = August 2003 | pmid = 12912715 | doi = 10.1001/archinte.163.15.1801 | doi-access = }}

Treatment of overdose includes emptying of the stomach via induced vomiting or by gastric lavage. Careful monitoring and supportive treatment, monitoring of renal and liver function, and maintaining adequate hydration is recommended by the manufacturer. Administration of magnesium, aluminum, or calcium containing antacids can reduce the absorption of norfloxacin.

Norfloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV,{{cite journal | vauthors = Drlica K, Zhao X | title = DNA gyrase, topoisomerase IV, and the 4-quinolones | journal = Microbiology and Molecular Biology Reviews | volume = 61 | issue = 3 | pages = 377–392 | date = September 1997 | pmid = 9293187 | pmc = 232616 | doi = 10.1128/mmbr.61.3.377-392.1997 }} enzymes necessary to separate bacterial DNA, thereby inhibiting cell division. Norfloxacin does not bind to DNA gyrase but does bind to the substrate DNA.{{cite journal | vauthors = Shen LL, Pernet AG | title = Mechanism of inhibition of DNA gyrase by analogues of nalidixic acid: the target of the drugs is DNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 2 | pages = 307–311 | date = January 1985 | pmid = 2982149 | pmc = 397026 | doi = 10.1073/pnas.82.2.307 | doi-access = free | bibcode = 1985PNAS...82..307S }} A review in 2001 suggests that cytotoxicity of fluoroquinolones is likely a 2-step process involving (1) conversion of the topoisomerase-quinolone-DNA complex to an irreversible form and (2) generation of a double-strand break by denaturation of the topoisomerase.{{cite journal | vauthors = Hooper DC | title = Mechanisms of action of antimicrobials: focus on fluoroquinolones | journal = Clinical Infectious Diseases | volume = 32 | issue = Suppl 1 | pages = S9–S15 | date = March 2001 | pmid = 11249823 | doi = 10.1086/319370 | doi-access = free }}

"Absorption of norfloxacin is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately one hour after dosing. The effective half-life of norfloxacin in serum and plasma is 3–4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. Two to three hours after a single 400-mg dose, urinary concentrations of 200 μg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 μg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%." Quoting from the 2009 package insert for Noroxin.

Biotransformation is via the liver and kidneys, with a half-life of 3–4 hours.{{cite web | url=http://www.drugbank.ca/drugs/DB01059 | title=Norfloxacin | date=June 10, 2013 | access-date=January 5, 2014 | work = Drugs.com }}

The first members of the quinolone antibacterial class were relatively low potency drugs such as nalidixic acid, used mainly in the treatment of urinary tract infections owing to their renal excretion and propensity to be concentrated in urine.{{cite web |url= http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19757S10lbl.pdf |archive-url= https://web.archive.org/web/20121016140628/http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19757S10lbl.pdf |url-status= dead |archive-date= October 16, 2012 |title=Chibroxin (Norfloxacin) Ophthalmic solution | work = Merck Sharp & Dohme |date=September 2000 |publisher=FDA |location=USA }}{{cite journal | vauthors = Mayrer AR, Andriole VT | title = Urinary tract antiseptics | journal = The Medical Clinics of North America | volume = 66 | issue = 1 | pages = 199–208 | date = January 1982 | pmid = 7038329 | doi = 10.1016/s0025-7125(16)31453-5 }} In 1979 the publication of a patent{{cite patent |url=https://www.google.com/patents/US4146719| country = US | number = 4146719 | title = Piperazinyl derivatives of quinoline carboxylic acids | inventor = Irikura T | assign1 = Kyorin Pharmaceutical Co Ltd. | gdate = March 27, 1979 }} filed by the pharmaceutical arm of Kyorin Seiyaku Kabushiki Kaisha disclosed the discovery of norfloxacin, and the demonstration that certain structural modifications including the attachment of a fluorine atom to the quinolone ring leads to dramatically enhanced antibacterial potency.{{cite journal | vauthors = Khan MY, Gruninger RP, Nelson SM, Klicker RE | title = Comparative in vitro activity of norfloxacin (MK-0366) and ten other oral antimicrobial agents against urinary bacterial isolates | journal = Antimicrobial Agents and Chemotherapy | volume = 21 | issue = 5 | pages = 848–51 | date = May 1982 | pmid = 6213200 | pmc = 182027 | doi = 10.1128/AAC.21.5.848 }}

In spite of the substantial increase in antibacterial activity of norfloxacin relative to early fluoroquinolones, it did not become a widely used antibiotic. Other companies initiated fluoroquinolone discovery programs in the aftermath of the publication of the norfloxacin patent. Bayer Pharmaceuticals discovered that the addition of a single carbon atom to the norfloxacin structure provided another 4 to 10-fold improvement in activity.{{cite journal | vauthors = Wise R, Andrews JM, Edwards LJ | title = In vitro activity of Bay 09867, a new quinoline derivative, compared with those of other antimicrobial agents | journal = Antimicrobial Agents and Chemotherapy | volume = 23 | issue = 4 | pages = 559–564 | date = April 1983 | pmid = 6222695 | pmc = 184701 | doi = 10.1128/aac.23.4.559 }} Ciprofloxacin reached the market just one year after norfloxacin and achieved sales of 1.5 billion Euros at its peak.{{cite web |url=https://www.sec.gov/Archives/edgar/data/1144145/000115697302000306/f00360e20vf.txt |title= Bayer Corporation Annual Report | date = June 24, 2002 | work = www.sec.gov }}{{cite web |title=Cipro |url=http://www.prescriptionaccess.org/lawsuitssettlements/past_lawsuits?id=0010 |publisher=Prescription Access |location=USA |access-date=September 4, 2009}}

Kyorin granted Merck & Company, Inc., an exclusive license (in certain countries, including the United States), to import and distribute Norfloxacin under the brand name Noroxin. The U.S. Food and Drug Administration (FDA) approved Noroxin for distribution in the United States on October 31, 1986.{{Cite news|url=https://www.federalregister.gov/documents/2017/12/12/2017-26693/determination-that-noroxin-norfloxacin-tablets-400-milligrams-was-not-withdrawn-from-sale-for|title=Determination That NOROXIN (Norfloxacin) Tablets, 400 Milligrams, Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness|date=December 12, 2017|work=Federal Register|access-date=November 7, 2018}}

In most countries, all formulations require a prescription. In Colombia (South America) it is marketed under Ambigram from Laboratorios Bussié.

Noroxin was discontinued in the US as of April 2014

See the latest package insert for norfloxacin (Noroxin) for additional details.

{{Reflist}}

{{QuinoloneAntiBiotics}}

Category:CYP3A4 inhibitors

Category:Fluoroquinolone antibiotics

Category:1,4-di-hydro-7-(1-piperazinyl)-4-oxo-3-quinolinecarboxylic acids

Category:Drugs developed by AstraZeneca

Category:1-Piperazinyl compounds