Ofloxacin

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Ofloxacin
200px
Systematic (IUPAC) name
(RS)-7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5(13),6,8,11-tetraene-11-carboxylic acid
Clinical data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 Oral, IV, topical (eye drops and ear drops)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 85% - 95%
Protein binding 32%
Biological half-life 8–9 hours
Identifiers
CAS Number 82419-36-1
ATC code J01MA01 (WHO) ,S01AX11, S02AA16
PubChem CID 4583
DrugBank APRD00502
ChemSpider 4422
Synonyms (+)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid
Chemical data
Formula C18H20FN3O4
Molar mass 361.368 g/mol[[Script error: No such module "String".]]
  (verify)
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Ofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class [1][2] considered to be a second-generation fluoroquinolone. Floxin (branded version) had been discontinued by the manufacturer, in the United States, effective June 18, 2009, though generic equivalents continue to be available.

The fluoroquinolone (quinolone) class of chemotherapeutic agents are considered by prudent physicians to be a drug of last resort to treat serious and life threatening bacterial infections. Ofloxacin (floxin – floxacin) was first patented in 1982 (European Patent Daiichi) and received approval from the U.S. Food and Drug Administration (FDA) on December 28, 1990. Ofloxacin is sold under a wide variety of brand names as well as generic drug equivalents, for oral and intravenous administration. Ofloxacin is also available for topical use, as eye drops and ear drops (marketed as Ocuflox and Floxin Otic respectively in the United States).

Ofloxacin is a racemic mixture, which consists of 50% levofloxacin (the biologically active component) and 50% of its “mirror image” or enantiomer dextrofloxacin.[3] When levofloxacin disks were not available in early clinical trials, a 5-pg Floxin (ofloxacin –floxacin) disk was substituted. The U.S. Food and Drug Administration (FDA) medical reviewers considered the two drugs to be one and the same and hence interchangeable.[4][5]

Like other quinolones, ofloxacin has been associated with a significant number of serious adverse drug reactions, such as tendon damage (including spontaneous tendon ruptures) and peripheral neuropathy (which may be irreversible); such reactions may manifest long after therapy had been completed, and, in severe cases, may result in life-long disabilities.[6] Ofloxacin has also been associated with severe psychiatric adverse reactions.

Hepatotoxicity has also been reported with the use of ofloxacin.[7][8] Case reports of hepatitis have been published for the older fluoroquinolones including ciprofloxacin, ofloxacin, and norfloxacin.[7][9][10][11]

History

Ofloxacin (floxin – floxacin) was developed as a broader-spectrum analog of norfloxacin, the first fluoroquinolone antibiotic,[12] Ofloxacin was first patented in 1982 (European Patent Daiichi) and received U.S. Food and Drug Administration (FDA) approval December 28, 1990. One of the first major adverse reactions noted with Ofloxacin were psychiatric in nature. Ofloxacin can cause serious psychiatric side effects with up to 25% of such patients suffering such reactions.[13][14] This reaction was detailed within Stephen Fried’s 1999 book: “Bitter Pills”[15]

In the United States name branded ofloxacin is rarely used anymore, having been discontinued by the manufacturer (Ortho McNeil Janssen).[16] Johnson and Johnson's annual sales of Floxin in 2003 was approximately $30 million, where as their combined sales of Levaquin/Floxin exceeded $ 1.15 billion in the same year.[17][18] However generic use continues. The FDA website list ofloxacin/floxin (Ortho McNeil Jannsen) as being discontinued, with just a few generic equivalents still in use. The otic solution continues to be listed as being available both as an original drug as well as a generic equivalent.

During the 2008 Johnson & Johnson shareholder’s meetings, the safety of both ofloxacin and levafloxacin were called into question. Paul Cahan, a shareholder who had suffered severe and continuing adverse reactions to ofloxacin, publicly challenged Johnson and Johnson’s CEO, William Weldon, to adhere to the company’s credo. This credo states in part “to put the needs and well-being of the people we serve first”. Mr. Cahan requested additional warnings be added to the package inserts for both ofloxacin and levofloxacin.[19][20]

During the 2009 meeting, yet another shareholder who alleges to have been crippled by these drugs, John Fratti, raised these same issues having seen no significant changes in the warnings (regarding the issues raised during the 2008 meeting). Once again a public request for stronger warnings for both ofloxacin and levofloxacin was made. Though the FDA requested additional Black Box Warnings concerning the tendon issues in 2008, these warnings were still not present in the inserts for ofloxacin or levofloxacin that are being dispensed by pharmacists in 2009, prompting this second request by a shareholder for stronger warnings and Dear Doctor Letters.[19][20]

Licensed use

The licensed uses for Floxin in the United States are as follows:

Oral and I.V. Floxin is not licensed by the FDA for use in children due to the risk of serious reversible and irreversible injury to the musculoskeletal system. Other fluoroquinolones do have a limited licensed uses in children but are generally not recommended due to safety concerns.[21][22] Ofloxacin (and its derivatives) has also been associated with a few isolated reports of unexplained pediatric fatalities.[23][24] Children (those under 18) are also at an increased risk of bone, joint, or tendon toxicities.[25]

Prescribing Floxin (ofloxacin tablets) Tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of severe adverse drug reactions.[25]

In the adult population Floxin is limited to the treatment of proven serious and life threatening bacterial infections such as:

  • Uncomplicated skin and skin structure infections
  • Acute, uncomplicated urethral and cervical gonorrhea.

Note: Ofloxacin has not been shown to be effective in the treatment of syphilis.[25] Floxin is now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.[26]

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

Available forms

Ofloxacin for systemic use is available as tablets (multiple strengths), oral solution (250 mg/ml), and injectable solution (multiple strengths). It is also used as eye drops (trade name Exocin, known as Ocuflox in the United States) and ear drops (Floxin Otic and "Cetraxal Otic").

Ofloxacin is also used in animals. Its veterinary formulation is sold as Marfloxacin (not to be confused with marbofloxacin, another veterinary-use fluoroquinolone).

Mode of action

Ofloxacin 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,[27] which is an enzyme necessary to separate replicated DNA, thereby inhibiting cell division.

The fluoroquinolones interfere with DNA replication by inhibiting an enzyme complex called DNA gyrase. This can also affect mammalian cell replication. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models. Although the quinolone is highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986.[28]

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.[29][30][31] As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.[32][33][34][35][36]

There is debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe and non abating adverse reactions experienced by some patients following fluoroquinolone therapy.[37][38][39]

Contraindications

As noted above, under licensed use, ofloxacin is now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.[26]

There is one contraindication now found within the 2008 package insert for Floxin. That being that Floxin is to be avoided in patients with a known hypersensitivity to ofloxacin or other quinolone drugs.[25]

Due to growing prevalence of antibiotic resistance to the fluoroquinolones in southeast Asia, the use of ofloxacin in patients who have been to southeast Asia is increasingly being contraindicated.[40]

Caution in patients with liver disease.[41] The excretion of ofloxacin may be reduced in patients with severe liver function disorders (e.g., cirrhosis with or without ascites).

Ofloxacin is also considered to be contraindicated within the pediatric population, pregnancy, nursing mothers, patients with psychiatric illnesses and in patients with epilepsy or other seizure disorders.iuyiuyiuy

Pregnancy

Research indicates that the fluoroquinolones can rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. Peak concentration in human breast milk is similar to levels attained in plasma. Breast-feeding mothers who take ofloxacin may expose their infants to severe adverse reactions. [42][43] Other flouroquinolones 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 suffering from this syndrome as well, even though the child had never been prescribed or taken any of the drugs found within this class.[44][45]

The data on the safety of the fluoroquinolones in pregnancy contains conflicting reports and is to be considered incomplete due to the lack of adequate studies. But it should be noted that several studies have reported spontaneous abortions following the exposure to the fluoroquinolones during pregnancy, as well as therapeutic/elective abortions due to the perceived, as well as actual, risk of birth defects.[46][47] However, within one study the authors concluded that the use of quinolones during pregnancy may in some cases be necessary; e.g. drug resistant serious infections,[47] but if safer antibiotics such as penicillin, cephalosporins or erythromycin are an option they should be used instead due to their clearer safety profile.[46]

In regards to Floxin, within a prospective follow-up study of 93 women treated with ofloxacin during pregnancy, the authors report that there was a higher than expected (11.9%) malformation rate among the infants.[48] According to the March of Dimes only about 3 to 5 percent of all pregnancies result in children born with birth defects.

For this reason the prescribing of ofloxacin is contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. Such spontaneous abortions and birth defects have also been found with other drugs within this class, i.e. Ciprofloxacin,[49] Pefloxacin,[50] Norfloxacin[51] and Nalidixic acid.[52] It is generally accepted that the fluoroquinolone class should not be used to treat women who are pregnant due to such risks.[53][54][55]

Pediatric use

Oral and IV fluoroquinolones including ofloxacin are not licensed by the FDA for use in children due to the risk of permanent injury to the musculoskeletal system. Within one study it was stated that the pediatric patient has a 3.8% chance of experiencing a serious musculoskeletal adverse event.[56]

However the two most recent pediatric studies involving the use of levofloxacin, the biologically active component of floxin, indicates that the pediatric patient has a greater than 50% chance of experiencing one or more adverse reactions. Which would be consistent with the studies found within the NDA (new drug application) for Levofloxacin[4] which showed and ADR rate in excess of 40%, as well as a number of reported fatalities. Within the first study[57] it is stated that “Of the 712 subjects evaluable for safety, 275 (52%) levofloxacin-treated subjects experienced one or more adverse event.... Serious adverse events were reported in 33 (6%) levofloxacin-treated subjects.... Two serious adverse events in levofloxacin-treated subjects resulted in fatal outcomes.” Within the second study[58] it is stated that “Of the 204 subjects evaluable for safety, 122 experienced one or more adverse events...Twelve subjects (6%) discontinued study drug due to an adverse event.... Seven subjects (3%) experienced 8 serious adverse events.” (circa 2007)

As such the current ban on the use of ofloxacin and other fluoroquinolones in the pediatric population appears to be both reasonable and supported by various clinical studies. The risk of permanent injury may outweigh the potential benefits. Within the United States the FDA has stated that it is their intention to pursue the licensing of the fluoroquinolones for pediatric use in spite of the evidence presented at that 62 Meeting of the Anti-Infective Drugs Advisory Committee (1996) that the fluoroquinolones cause irreversible joint damage in the pediatric population.[59]

Adverse effects

See also: Adverse effects of fluoroquinolones and Levofloxacin#Adverse effects

Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes.[60][61] There has been a number of regulatory actions taken as a result of such adverse reactions associated with ofloxacin therapy, which included published warnings,[62][63][64] additional warnings and safety information added to the package inserts which includes a Black Box Warning concerning spontaneous tendon ruptures and the resultant permanent disability.[65] In 2008 the FDA had also requested that the manufacturers of Floxin (as well as generic ofloxacin) issue a "Dear Doctor Letter" to inform physicians of this Black Box Warning.

In 2004 the FDA requested new warning labels to be added to all of the Fluoroquinolones, including ofloxacin, regarding Peripheral Neuropathy (irreversible nerve damage), Tendon Damage, Heart Problems (prolonged QT Interval / Torsades de pointes), Pseudomembranous colitis, Rhabdomyolysis (muscle wasting), Steven Johnson Syndrome, as well as concurrent usage of NSAIDs contributing to the severity of these reactions. Subsequently changes were made to the package insert for Floxin to state that Floxin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria,[66] and additional warnings concerning irreversible peripheral neuropathy and Torsades de pointes being associated with floxin therapy were added.[67] In 2007 warnings regarding fatal Clostridium difficile associated diarrhea (CDAD: reported to occur over two months after the administration),[68] severe photosensitivity/phototoxicity reactions and hepatic failure (including fatal cases) and Toxic Epidermal Necrolysis (TEN) were added to the package inserts.[69]

The psychiatric adverse events,[70][71][72][73] as well as CNS (Central Nervous System)[74][75][76] and PNS (Peripheral Nervous System)[76] associated with ofloxacin has been well documented within the literature.

Adverse reactions may manifest during, as well as after fluoroquinolone therapy.[77]

Liver damage and dysglycemia has been associated with ofloxacin.[78][79][80][80] Additionally in 2005 acute rhabdomyolysis had been associated with ofloxacin/levofloxacin therapy.[81]

Some groups refer to the presentation of these multiple adverse events as "fluoroquinolone toxicity". These groups of patients claim to have suffered serious long term harm to their health from using fluoroquinolones. This has led to a class action lawsuit being filed by these groups as well as action by the consumer advocate group Public Citizen.[82][83] Partly as a result of the efforts of Public Citizen the FDA requested a Black Box Warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.[84]

  • Precautions

Severe hepatotoxicity has been reported as noted above. Reports of hepatic or hypersensitivity vasculitis occurring as a result of ofloxacin therapy have also been reported.[85][86] Older patients may have an increased risk of tendinopathy (including rupture), especially with concomitant corticosteroid use and such patients may also be more susceptible to prolongation of the QT interval.[25] Patients with known prolongation, those with hypokalemia, or being treated with other drugs that prolong the QT interval should avoid the use of ofloxacin. Hematologic reactions (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses.[25]

Tendon damage

As with all fluoroquinolones, there is a possibility of spontaneous tendon rupture.[87] Such ruptures may occur both during therapy and long after therapy has been discontinued; there are documented cases where rupture has occurred six months after therapy.[87] The risk of tendon damage is greater in people taking corticosteroids and in the elderly.[88] Since July 2008, all systemic fluoroquinolones (those taken internally, not as eye drops or ear drops) available in the United States were requested, by the FDA, to carry a Black Box Warning of the risk of tendon damage. However, the addition of this warning was not mandatory.[88]

Interactions

Ofloxacin has been reported to interact with a significant number of other drugs, as well as a number of herbal and natural supplements. Such interactions increased the risk of cardiotoxicity and arrhythmias, anticoagulant effects, the formation of non-absorbable complexes, as well as increasing the risk of toxicity.[89] Concurrent administration of ofloxacin, with magnesium or aluminum antacids, sucralfate or products containing calcium, iron or zinc may substantially decrease the absorption of ofloxacin, resulting in serum and urine levels considerably lower than desired.

Specific drug interaction studies do not appear to have been conducted with ofloxacin. However, the systemic administration of some fluoroquinolones has been shown to interfere with the metabolism of caffeine, elevate plasma concentrations of theophylline and enhance the effects of the warfarin and its derivatives. Some fluoroquinolones exert an inhibitory effect on the cytochrome P-450 system, thereby reducing theophylline clearance and increasing theophylline blood levels. Co-administration may dangerously increase coumadin warfarin activity, therefore International Normalized Ratio (INR) should be monitored closely. Such drug interactions appear to be related to the structural changes of the quinolone ring and the inhibitory effect on the cytochrome P-450 system. As such, these drug interactions involving the fluoroquinolones appear to be drug specific rather than a class effect.

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.[90] Patients have reported reactions to NSAIDS long after completion of fluoroquinolone therapy, but there does not appear to be any research that would either confirm or deny this association other than these anecdotal reports.

The fluoroquinolones have been shown to increase the anticoagulant effect of Acenocoumarol, Anisindione, and Dicumarol. Additionally there is an increase the risk of cardiotoxicity and arrhythmias when co administered with drugs such as Dihydroquinidine barbiturate, Quinidine, and Quinidine barbiturate.[89] The fluoroquinolones have also been reported to interact with the GABA A receptor and cause neurological symptoms; this effect is augmented by certain non-steroidal anti-inflammatory drugs.[91]

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.[92]

A possible interaction between oral hypoglycemic drugs (e.g., glyburide/glibenclamide) or with insulin and fluoroquinolone antimicrobial agents have been reported resulting in a potentiation of the hypoglycemic action of these drugs.[25]

Overdose

There is only limited information on overdose with ofloxacin. Current advise for the management of an acute overdose of ofloxacin is emptying of the stomach, along with close observation, and making sure that the patient is appropriately hydrated. Hemodialysis or peritoneal dialysis is of only limited effectiveness.[25] Overdose may result in central nervous system toxicity, cardiovascular toxicity, tendon/articular toxicity, and hepatic toxicity[93] as well as renal failure and seizure.[93] Seizures have however, been reported to occur at therapeutic dosage as well as severe psychiatric reactions.[13][14][15]

Pharmacology

The bioavailability of ofloxacin in the tablet form is approximately 98% following oral administration reaching maximum serum concentrations within one to two hours. Between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via the kidneys within 48 hours of dosing. Therefore elimination is mainly by renal excretion. However, four to eight percent of an ofloxacin dose is excreted in the feces. This would indicate a small degree of biliary excretion as well. Plasma elimination half-life is approximately 4 to 5 hours in patients and approximately 6.4 to 7.4 hours in elderly patients.[25]

Pharmacokinetics

"After multiple-dose administration of 200 mg and 300 mg doses, peak serum levels of 2.2 μg/mL and 3.6 μg/mL, respectively, are predicted at steady-state. In vitro, approximately 32% of the drug in plasma is protein bound. Floxin is widely distributed to body tissues. Ofloxacin has been detected in blister fluid, cervix, lung tissue, ovary, prostatic fluid, prostatic tissue, skin, and sputum. Pyridobenzoxazine ring appears to decrease the extent of parent compound metabolism. Less than 5% is eliminated by the kidneys as desmethyl or N-oxide metabolites; 4% to 8% by feces."[25][94]

There are a number of the endogenous compounds that have been reported to be affected by ofloxacin as inhibitors, alteraters and depletors. See the latest package insert for Ofloxacin for additional details.[25]

Dosage

Ofloxacin should only be administered as described within the Dosage Guidelines table found within the most current package insert. The status of the patient’s renal function and hepatic function must also be taken into consideration to avoid an accumulation that may lead to a fatal drug overdose. Ofloxacin is eliminated primarily by renal excretion. However, the drug is also metabolized and partially cleared through the liver. Modification of the dosage is required using the table found within the package insert for those with impaired liver or kidney function (Particularly for patients with severe renal dysfunction). However, since the drug is known to be substantially excreted by the kidneys, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. The duration of treatment depends upon the severity of infection and the usual duration is 7 to 14 days.[25]

NOTE: The patient’s serum levels should be monitored during therapy to avoid a drug overdose. See the most current Package Insert for proper dosing guidelines and relevant warnings/precautions.

Susceptible bacteria

Aerobic Gram-positive microorganisms

  • Staphylococcus aureus (methicillin-susceptible strains)
  • Streptococcus pneumoniae (penicillin-susceptible strains)
  • Streptococcus pyogenes

Aerobic Gram-negative microorganisms

  • Citrobacter (diversus) koseri
  • Enterobacter aerogenes
  • Escherichia coli
  • Haemophilus influenzae
  • Klebsiella pneumoniae
  • Neisseria gonorrhoeae
  • Proteus mirabilis
  • Pseudomonas aeruginosa

Other microorganisms

  • Chlamydia trachomatis

Referencing the latest package insert for Floxin.

Additional regulatory history

See also Levaquin regulator history

Floxin: Cetraxal

  • 12-28-1990 The approval of the new drug application (NDA for floxacin).
  • 12/28/1990 to 03/06/2004 Fourteen years worth of data has been removed from the FDA website. As such, this information is no longer available. The NDA (new drug application) documents have also been removed from the FDA site.[95] As such the regulatory history begins fourteen years after initial approval beginning with the 2004 changes:
  • 09/15/2004[67] The Tendon effects subsection was revised which minimized the warnings concerning that spontaneous tendon ruptures may be increased in patients receiving corticosteroids with Floxin (ofloxacin—floxacin) and other quinolones. The statement that tendon rupture can occur “at any time” was removed.

The Indications and Usage section of the package insert was revised as follows: “Uncomplicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Streptococcus pyogenes, or Proteus mirabilis.”

The Tendon effects subsection was revised to minimize the warnings stating that the risk of serious tendon disorders is higher in those over 65 years of age, especially those on steroids.

Addition of Black Box Warning.

Issuance of a Medication Guide and revisions to include new safety information including the addition of the Black Box Warning to the Medication Guide. The FDA had determined that Ofloxacin poses a serious and significant public health concern, requiring the distribution of a Medication Guide

Note: Although the FDA had requested that the revised labeling (which were to include the Black Box Warnings) accompany the package inserts for any newly shipped products (effective January 2009) there are continuing reports that as of September 2009, that the products continue to contain the older labels, and not the revised labels, and that the Medication Guides (absent of the Black Box Warnings) were not made available for distribution.[97]

Notice given to the FDA of the discontinuance of Floxacin by the manufacturer effective June 18, 2009.

History of the black box warnings

Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic acid.[101] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.[102] In a 1995 letter published in the New England Journal of Medicine, representatives of the U.S. Food and Drug Administration (FDA) stated that the agency would "update the labeling [package insert] for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture."[103]

By August 1996, the FDA had not taken action, and the consumer advocacy group Public Citizen filed a petition with the FDA prompting the agency to act.[104] Two months later, the FDA published an alert in the FDA Medical Bulletin and requested that fluoroquinolone package inserts be amended to include information on this risk.[105]

In 2005, the Illinois Attorney General filed a petition with the FDA seeking black box warnings and "Dear Doctor" letters emphasizing the risk of tendon rupture; the FDA responded that it had not yet been able to reach a decision on the matter, though they had been reviewing this issue since 1995.[106] In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for a Black Box Warning.[106][107] In January 2008, Public Citizen filed suit in Federal Court to compel the FDA to respond to their 2006 petition.[108][109] On July 7, 2008 the FDA requested that the makers of systemic-use fluoroquinolones add a boxed warning regarding tendon rupture, and to develop a Medication Guide for patients.[88] The package inserts for Ciprofloxacin, Avelox (moxifloxacin), Proquin XR, Factive (gemifloxacin), Floxin (ofloxacin), Noroxin (norfloxacin) and Levaquin (levofloxacin) were amended on September 8, 2008 to include these new warnings.[65][110] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22, 2008 concerning these changes.[111] Ortho-McNeil, the manufacturers of Levaquin and Floxin, issued a similar letter in November.[112] through the Health Care Notification Network, a registration-only website that distributes drug alerts only to licensed healthcare professionals.

Review of the FDA website indicates that the generic versions of the fluoroquinolones have not been updated to include this Black Box Warning as of June 2009. And there are numerous reports that this information has not been dessiminated to the pharmacist, the generic products (as well name branded products) continue to contain the previous labels that are absent of this warning, and the Medication Guide has not been made available to the pharmicist or physician for distribution.

Although the FDA had requested that the revised labeling (which included the Black Box Warnings)[97] accompany the package inserts for any newly shipped products (effecticve January 2009) there are continuing reports that as of September 2009, that the products continue to contain the older labels, and not the revised labels, and are absent of the required medication guides.

Antibiotic abuse and bacterial resistance

See also: Antibiotic abuse and Antibiotic resistance

Resistance to ofloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, and Streptococcus pyogenes now exhibit resistance worldwide.[113]

Years ago the FDA had added warnings regarding the proper use of ofloxacin within the package insert to combat such antibiotic abuse, advising physicians that ofloxacin: "...should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria....".[25]

Normally ofloxacin should only be used in patients who have failed at least one prior therapy. Reserved for the use in patients who are seriously ill and may soon require immediate hospitalization.[114]

The use of the ofloxacin and other fluoroquinolones had increased threefold in an emergency room environment in the United States between 1995 and 2002, while the use of safer alternatives such as macrolides declined significantly.[115][116]

Within a recent study concerning the proper use of ofloxacin and other fluoroquinolones in the emergency room it was revealed that 99% of these prescriptions were in error. Out of the one hundred total patients studied, eighty one received a fluoroquinolone for an inappropriate indication. Out of these cases, forty three (53%) were judged to be inappropriate because another agent was considered first line, twenty seven (33%) because there was no evidence of a bacterial infection to begin with (based on the documented evaluation), and eleven (14%) because of the need for such therapy was questionable. Out of the nineteen patients who received a fluoroquinolone for an appropriate indication, only one patient out of one hundred received both the correct dose and duration of therapy.[117]

Ofloxacin and other fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002. Nearly half (42%) of these prescriptions were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study that was supported in part by the Agency for Healthcare Research and Quality.[116][118] Additionally they are commonly prescribed for medical conditions that are not even bacterial to begin with, such as viral infections, or those to which no proven benefit exists.

Current litigation

The manufacturers (Johnson and Johnson/Ortho McNeil) of ofloxacin are currently embroiled in litigation concerning levofloxacin/ofloxacin in regards to spontaneous tendon ruptures. There are a significant number of cases currently pending before the United States District Court, District of Minnesota, involving spontaneous tendon ruptures alleged to be caused by these drugs. On June 13, 2008 a Judicial Panel On Multidistrict Litigation (MDL) granted the Plaintiffs’ motion to centralize individual and class action lawsuits involving levaquin in the District of Minnesota over objection of Defendants, Johnson and Johnson / Ortho McNeil.[83] Such ruptures have also been associated with ofloxacin, as well as other drugs found within this class.[119][120][121][122][123][124]

Douglas & London in New York, who represents more than 200 such plaintiffs from 38 States, expects to file many additional product liability suits involving levofloxacin/ofloxacin. As plaintiffs attorney, lawyer Michael London had recently asked the New Jersey Supreme Court to accord mass-tort treatment to their suits against the manufacturer, Johnson & Johnson subsidiary Ortho-McNeil Pharmaceutical Inc.[125]

The various manufacturers have countered these allegations stating that they believe that these drugs are both safe and effective antibiotics, well tolerated with a minimum of side-effects, that such reactions are “rare” and the benefits of such therapy outweigh the perceived risks.[126]

Several class action lawsuits had been filed in regards to the adverse reactions suffered by those exposed to Ciprofloxacin during the Anthrax scare of 2001 as well.[127][128][129]

Package insert links

See also

References

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External links

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  2. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  3. ↑ http://www.wvnd.uscourts.gov/Opinions/orthoorder.pdf
  4. ↑ 4.0 4.1 R.W. Johnson (24 April 2007). "Levaquin (Levofloxacin) NDA 20634 Approved: 12/20/1996". USA: FDA. Retrieved 22 July 2009. 
  5. ↑ Davis, R., and H. M. Bryson. 1994. Levofloxacin. Drugs 47:677–700.
  6. ↑ Clodagh Sheehy (2 August 2008). "Warning over two types of antibiotic". Republic of Ireland. Retrieved 17 July 2009. 
  7. ↑ 7.0 7.1 Blum, A (1991). "Ofloxacin-induced acute severe hepatitis". Southern medical journal. 84 (9): 1158. doi:10.1097/00007611-199109000-00027. PMID 1891746. 
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  10. ↑ Hautekeete, ML; Kockx; Naegels; Holvoet; Hubens; Kloppel (1995). "Cholestatic hepatitis related to quinolones: a report of two cases". Journal of hepatology. 23 (6): 759–60. doi:10.1016/0168-8278(95)80045-X. PMID 8750178.  More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help); More than one of |author6= and |last6= specified (help)
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  17. ↑ Business Wire (2 September 2003). "Teva Announces Approval of Ofloxacin Tablets, 200 mg, 300 mg, and 400 mg". 
  18. ↑ Johnson and johnson (2003). "Building on a foundation of health" (PDF). Shareholder. 
  19. ↑ 19.0 19.1 http://www.investor.jnj.com/webcasts-presentations.cfm 2009 shareholders meeting; time stamped at 1 hour 42 minutes
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  24. ↑ http://www.fdable.com/aers/advanced_query/1322bfd51750 3431736 00Q1 3452229 DEATH DE LEVOFLOXACIN (01/19/00 R.W. JOHNSON 13 year old male) 3461848 00Q1 SUDDEN DEATH UNEXPLAINED DE LEVOFLOXACIN (01/19/00 R.W. JOHNSON 13 year old male)
  25. ↑ 25.00 25.01 25.02 25.03 25.04 25.05 25.06 25.07 25.08 25.09 25.10 25.11 25.12 Ortho-McNeil-Janssen Pharmaceuticals, Inc (2008). "FLOXIN Tablets (Ofloxacin Tablets)" (PDF). USA: FDA. 
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  37. ↑ Al-Soud, Yaseen A.; Al-masoudi, Najim A (2003). "A new class of dihaloquinolones bearing N'-aldehydoglycosylhydrazides, mercapto-1,2,4-triazole, oxadiazoline and a-amino ester precursors: synthesis and antimicrobial activity". J. Braz. Chem. Soc. 14 (5). doi:10.1590/S0103-50532003000500014. Nevertheless, some quinolones cause injury to the chromosome of eukaryotic cells.21,22 These findings prompted us to optimize the substituent at C-3, by...  More than one of |author1= and |last1= specified (help)
  38. ↑ Yaseen A. Al-Soud a and Najim A. Al-Masoudi (2003). "A New Class of Dihaloquinolones Bearing N'-Aldehydoglycosylhydrazides, Mercapto-1,2,4-triazole, Oxadiazoline and α-Amino Ester Precursors: Synthesis and Antimicrobial Activity" (PDF). J. Braz. Chem. Soc. 14 (5): 790–796. Although the current quinolones are not considered to be potent inhibitors of eucaryotic topoisomerases, some effects on these and other enzymes involved with DNA replication have been observed 
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  54. ↑ Compliance a Key Consideration: Fewer Options in Pregnancy http://www.medscape.com/viewarticle/406494_9 “Tetracyclines (e.g. doxycycline) and fluoroquinolones (e.g. ofloxacin) should not be used to treat women who are pregnant because of associated adverse events in the fetus. “
  55. ↑ http://www.healthline.com/yodocontent/pregnancy/treatment-chlamydial-infection.html “The treatment for gonorrhea in pregnant women is essentially the same as in non-pregnant women. The notable exception is that quinolone antibiotics, like ciprofloxacin and ofloxacin, should not be used since these antibiotics inhibit DNA formation and can cause birth defects.”
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  60. ↑ Owens Rc, Jr; Ambrose (2005). "Antimicrobial safety: focus on fluoroquinolones". Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 41 Suppl 2: S144–57. doi:10.1086/428055. PMID 15942881.  More than one of |author2= and |last2= specified (help)
  61. ↑ Iannini, PB (2007). "The safety profile of moxifloxacin and other fluoroquinolones in special patient populations". Current medical research and opinion. 23 (6): 1403–13. doi:10.1185/030079907X188099. PMID 17559736. 
  62. ↑ http://www.fqresearch.org/text_documents/FDA_Medical_Bulletin_1996.doc
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  64. ↑ US Food and Drug Administration (2008). "Fluoroquinolone Antimicrobial Drugs [ciprofloxacin (marketed as Cipro and generic ciprofloxacin), ciprofloxacin extended release (marketed as Cipro XR and Proquin XR), gemifloxacin (marketed as Factive), levofloxacin (marketed as Levaquin), moxifloxacin (marketed as Avelox), norfloxacin (marketed as Noroxin), and ofloxacin (marketed as Floxin and generic ofloxacin)]". USA. Retrieved 5 September 2009. 
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  66. ↑ Renata Albrecht (2004). "NDA 19-735/S-051" (PDF). USA: FDA. 
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  99. ↑ Douglas C. Throckmorton (19 May 2009). "Novartis Pharmaceuticals Corp. et al.; Withdrawal of Approval of 92 New Drug Applications and 49 Abbreviated New Drug Applications". USA: Trading Markets. 
  100. ↑ see also FDA Notices Vol. 74, No. 095 [Docket No. FDA-2009-N-0211]
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  106. ↑ 106.0 106.1 "Madigan, Public Citizen, petition FDA for "black box" warning regarding potential adverse effects of certain popular antibiotics" (Press release). Office of the Illinois Attorney General. August 29, 2006. http://www.illinoisattorneygeneral.gov/pressroom/2006_08/20060829.html. Retrieved 2008-12-27.  Full text of the 2005 petition and FDA response available from the Fluoroquinolone Toxicity Research Foundation, a U.S. consumer advocacy group.
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  111. ↑ MacCarthy, Paul (October 22, 2008). "Important Change in the Avelox (moxifloxacin hydrochloride) and Cipro (ciprofloxacin) Complete Prescribing Information – Addition of Boxed Warning and Medication Guide Regarding Tendinitis and Tendon Rupture" (PDF). Bayer HealthCare Pharmaceuticals. Retrieved 2008-12-27. 
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  122. ↑ van der Linden, PD.; Sturkenboom, MC.; Herings, RM.; Leufkens, HM.; Rowlands, S.; Stricker, BH. (2003). "Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids". Arch Intern Med. 163 (15): 1801–7. doi:10.1001/archinte.163.15.1801. PMID 12912715.  More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help); More than one of |author6= and |last6= specified (help)
  123. ↑ Aouam, K.; El Aïdli, S.; Daghfous, R.; Kastalli, S.; Lakhal, M.; Loueslati, MH.; Belkahia, C. (2004). "[Ofloxacin-induced achilles tendinitis in the absence of a predisposition]". Therapie. 59 (6): 653–5. PMID 15789832.  More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help); More than one of |author6= and |last6= specified (help); More than one of |author7= and |last7= specified (help)
  124. ↑ Uppsala Monitoring Centre. "NATIONALLY CIRCULATED INFORMATION". World Health Organisation. Tendon ruptures represent 81 cases for 921 reports of tendon disorders which are related in decreasing order to pefloxacin 1/23130 case per days of treatment, ofloxin, norfloxacin and ciprofloxacin 1/779600 case per days of treatment. 
  125. ↑ Charles Toutant (13 May 2009). "Mass-Tort Treatment Sought for Suits Over Ortho-McNeil Antibiotic Levaquin - FDA says Levaquin users are at heightened risk of tendonitis and tendon rupture in the shoulder, biceps, hand and thumb". USA: New Jersey Law Journal. Retrieved May 16, 2009. 
  126. ↑ In The United States District Court District Of Minnesota Levaquin Products Liability Litigation Mdl No. 08-1943 Court File No. 09-Cv-00812 (JRT) Defendant Johnson & Johnson's Answer To Plaintiff's Complaint Filed May 12, 2009 www.fqresearch.org/pdf_files/232-1.pdf
  127. ↑ "Anthrax Scare Leaves Trail of Cipro Victims - Class Actions filed in Two States". USA: Sheller Ludwig & Sheller. 17 October 2003. Retrieved 9 September 2009. 
  128. ↑ "LEGAL BRIEF of Postal Employees Cases (EEOC, MSPB, District Courts)". USA: Postal Reporter. Retrieved 9 September 2009. 
  129. ↑ Charles P. Goodell, Jr. "Profile". USA: Goodell, DeVries, Leech & Dann, LLP. Retrieved 9 September 2009. 
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