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Ofloxacin

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Ofloxacin
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
Identifiers
CAS number 82419-36-1
ATC code J01MA01 J01MA02, J01MA12, S01AX11, S01AX13, S01AX19, S03AA07
PubChem 4583
DrugBank APRD00502
ChemSpider 4422
Chemical data
Formula C18H20FN3O4 
Mol. mass 361.368 g/mol
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
Pharmacokinetic data
Bioavailability  ?
Protein binding 32%
Metabolism  ?
Half life 8- 9 hours
Excretion  ?
Therapeutic considerations
Pregnancy cat.

C(US)
Legal status

℞-only(US)
Routes Oral, IV, topical (eye drops and ear drops)

Ofloxacin is a fluoroquinolone antibiotic considered to be a second-generation fluoroquinolone. The fluoroquinolone (quinolone) class of chemotherapeutic agents are considered to be a drug of last resort to treat life threatening bacterial infections.[1][2] 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, of which levofloxacin is the biologically active component; levofloxacin is a “mirror image” or enantiomer of ofloxacin. 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.[3][4]

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. Ofloxacin has also been associated with severe psychiatric adverse reactions. Recently name branded ofloxacin had been discontinued in the United States, though generic equivalents continue to be available.

Hepatotoxicity has also been reported with the use of ofloxacin.[5][6] Case reports of hepatitis have been published for the older fluoroquinolones including ciprofloxacin, ofloxacin, and norfloxacin. [7][8][9][10]

Contents

[edit] History

Ofloxacin (floxin – floxacin) was developed as a broader-spectrum analog of norfloxacin, the first fluoroquinolone antibiotic, [11] 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.[12][13] This reaction was detailed within Stephen Fried’s 1999 book: “Bitter Pills”[14]

In the United States name branded ofloxacin is rarely used anymore, having been discontinued by the manufacturer (Ortho McNeil Janssen).[15] 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. [16][17] 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.[18][19]

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. [20][21]

[edit] Licensed use

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

Oral and I.V. Floxin and other fluoroquinolones are not licensed by the FDA for use in children due to the risk of fatalities [22] as well as permanent injury to the musculoskeletal system, with two exceptions. Ciprofloxacin has been approved to treat Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli as well as Inhalational Anthrax (post-exposure) and recently levofloxacin received approval to treat Anthrax (post-exposure). Although alleged to be effective, levofloxacin is not to be considered a first line agent for Inhalation Anthrax in the pediatric population due to severe adverse reactions involving the musculoskeletal system and other serious adverse reactions, including fatalities. [23][24][25][26][27] [28]

The Centers for Disease Control and Prevention (CDC) revoked its recommendation regarding the use of fluoroquinolones (ciprofloxacin) as a first line agent in treating anthrax due to the unacceptable risk documented within the Antimicrobial Postexposure Prophylaxis for Anthrax study (aka Cipro 60 day study).[29] However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK. Prescribing a fluoroquinolone to treat an unapproved use within the pediatric (as well as the adult population) exposes the treating physician to the risk of being sued for malpractice should the treating physician fail to both warn the patient of this fact, as well as the risks of any adverse drug reactions the patient may experience. [30][31]

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. Within the current package insert it is stated that:

"FLOXIN (ofloxacin tablets) Tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria."[32]

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.[33] Floxin is now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.[34]

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

[edit] 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).

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

[edit] 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[35], 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 (Hussy et al.)[36].

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.[37][38][39][40] As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.[41] [42] [43] [44] [45] [46]

There continues to be considerable 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.[47] [48] [49]

[edit] 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. [50]

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.[51]

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.[52]

Caution in patients with liver disease.[53] 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.

[edit] 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. [54][55] 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.[56][57]

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 percieved, as well as actual, risk of birth defects.[58][59] However, within one study the authors concluded that the use of quinolones during pregnancy may in some cases be necessary; eg drug resistant serious infections,[60] but if safer antibiotics such as penicillin, cephalosporins or erythromycin are an option they should be used instead due to their clearer safety profile. [61]

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. [62] According to the March of Dimes only about 3 to 5 percent of all pregnancies result in children born with birth defects. [63]

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 [64], Pefloxacin [65], Norfloxacin [66] and Nadilixic acid [67] It is generally accepted that the fluoroquinolone class should not be used to treat women who are pregnant due to such risks. [68] [69] [70]

[edit] Pediatric use

Oral and IV fluoroquinolones are not licensed by the FDA for use in children due to the risk of permanent injury to the musculoskeletal system, with two exceptions. Ciprofloxacin is only licensed for the treatment of Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli and Inhalational Anthrax (post-exposure). Within the studies submitted in response to a Pediatric Written Request (Ciprofloxacin, circa 2004) the rate of athropy was reported to be 9.3%.[71] 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.

Ofloxacin is not licensed for use in the pediatric population due to the risk of serious, life threatening and permanent injury to the pediatric patient. Within one study it was stated that the pediatric patient has a 3.8% chance of experiencing a serious musculoskeletal adverse event.[72]

However the two most recent pediatric studies involving the use of levofloxacin, 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[73] which showed and ADR rate in excess of 40%, as well as a number of reported fatalities. Within the first study[74] 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[75] 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 that the fluoroquinolones cause irreversible joint damage in the pediatric population.[76]

[edit] Adverse effects

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

The psychiatric adverse events [77] [78] [79] [80], as well as CNS (Central Nervous System) [81] [82] [83] and PNS (Peripheral Nervous System) [84] associated with ofloxacin has been well documented within the literature.

The serious events may occur with a therapeutic dose of ofloxacin as well as with acute overdose. At therapeutic doses serious reactions include: central nervous system toxicity, cardiovascular toxicity, tendon/articular toxicity, and rarely hepatic toxicity.[85] Events that may occur in acute overdose are rare and include: renal failure and seizure.[85] Seizures have however, been reported to occur at therapeutic dosage as well as severe psychiatric reactions.[86][87][88] Toxic epidermal necrolysis is a rare, but possible, adverse effect of ofloxacin.[89] Stevens-Johnson syndrome is also a rare, but possible, adverse reaction to ofloxacin as this has also been associated with Norfloxacin [90], of which ofloxacin is an analog, as well as other drugs in this class, particularly ciprofloxacin and moxifloxacin. [91] [92] [93] [94] [95] [96]

Adverse reactions may manifest during, as well as after fluoroquinolone therapy.[97]

Liver damage and dysglycemia has been associated with ofloxacin but this is considered to be a rare, but serious adverse reaction.[98][99][100][101] Another very rare but serious adverse effect is autoimmune hemolytic anemia.[102] Additionally in 2005 acute rhabdomyolysis has been associated with ofloxacin/levofloxacin therapy.[103]

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.[104][105] 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.[106]

  • Precautions

Severe hepatotoxicity has been reported as noted above. Rare reports of hepatic or hypersensitivity vasculitis occurring as a result of ofloxacin therapy have also been reported.[107][108] 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.[109] 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.[110]

[edit] Tendon damage

As with all fluoroquinolones, there is a possibility of spontaneous tendon rupture.[111] 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.[111] The risk of tendon damage is greater in people taking corticosteroids and in the elderly.[112] 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.[112]

[edit] 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.[113] 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. (See package insert)

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.

Some drug interactions are associated with molecular structural modifications of the quinolone ring, specifically interactions involving NSAIDS. 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.[114] Whether or not such reactions occur after completion of therapy is a matter of considerable debate. 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. [115] In patients receiving systemic cyclosporine concomitantly, transient elevations in serum creatinine has been noted.[116] 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.[117]

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.[118] This effect seems to be restricted to people aged 60 or over, and within this group concomitant use of corticosteroids increases this risk substantially. Though technically not to be considered a drug interaction, mention of this is made here due to fact that the etiology of such ruptures remains elusive and further research may confirm such a drug interaction may play a role in this particular reaction.

As noted above the fluoroquinolones have also been shown to interfere with the metabolism of caffeine[119] 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. It should be noted that Ciprofloxacin has been shown to interact with thyroid medications (levothyroxine) resulting in unexplained hypothyroidism.[120] As such it is possible that ofloxacin may interact with thyroid medications as well.

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.[121]

[edit] Overdose

"Information on overdosage with ofloxacin is limited.... In the event of an acute overdose, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Ofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis." Quoting directly from the recent package insert for Floxin[122]

[edit] 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 half-life is approximately 4 to 5 hours in patients and approximately 6.4 to 7.4 hours in elderly patients. [123]

[edit] 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." [124] [125]

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.[126]

[edit] 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.[127]

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.

[edit] 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.

[edit] 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.[128] Such ruptures have also been associated with ofloxacin, as well as other drugs found within this class.[129][130][131][132][133][134]

As a result of this order, product liability attorneys are currently aggressively seeking additional plaintiffs who may have been damaged by ofloxacin as well as levofloxacin. 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. [135]

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.[136][137][138]

[edit] Regulatory history

See also Levaquin regulator history

Floxin:

  • 12-28-1990 The approval of the new drug application (NDA for floxacin).
  • The regulator history beginning 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.[139]

Changes 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...Prescribing FLOXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient.

  • 09/15/2004[141] A peripheral neuropathy subsection was added to warn the physician and patient that irreversible peripheral neuropathy was associated with Floxin.

The Tendon effects subsection was revised to minimize 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.

A warning regarding Torsades de pointes was added including the fact that elderly patients may be more sensitive to drug-associated effects on the QT interval.

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.”

  • 05/16/2007[143] Warnings regarding fatal Clostridium difficile associated diarrhea (CDAD) and that this (CDAD) has been reported to occur over two months after the administration of antibacterial agents.

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.

Warnings added concerning severe photosensitivity/phototoxicity reactions.

Under the Adverse Reactions/Post-Marketing Adverse Reactions subsection, the following events were added: Hepatic Failure (including fatal cases); Torsades de Pointes; Toxic Epidermal Necrolysis (TEN)

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 June 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. [147][148]


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

[edit] 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.[151] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.[152] 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."[153]

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.[154] 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.[155]

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.[156] In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for a Black Box Warning.[156][157] In January 2008, Public Citizen filed suit in Federal Court to compel the FDA to respond to their 2006 petition.[158][159] 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.[112] 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.[160] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22, 2008 concerning these changes.[161] Ortho-McNeil, the manufacturers of Levaquin and Floxin, issued a similar letter in November.[162] 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)[163] accompany the package inserts for any newly shipped products (effecticve January 2009) there are continuing reports that as of June 2009, that the products continue to contain the older labels, and not the revised labels, and are absent of the required medication guides.

[edit] FDA warning letters

In January 1997 R.W. Johnson was cited by the FDA for promoting the use of ofloxacin for unapproved uses as well as failing to disclose that ofloxacin is not approved for use in severe infections. The FDA also cited the manufacturer for promoting the use of ofloxacin in the pediatric population while falsely stating that it was both safe and effective, while failing to provide any information regarding the adverse effects associated with its use, or that such use is contraindicated. [164] We find similar violations with levofloxacin/ofloxacin opthalmic solution as well. [165][166][167]

[edit] Scripting abuse and bacterial 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.[168] Widespread veterinary usage of the fluoroquinolones, in particular in Europe, has been implicated.[169]

Years ago the FDA had added warnings regarding the proper use of ofloxacin within the package insert to combat such scripting 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...." [170]

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. [171] Though considered to be a very important and necessary drug required to treat severe and life threatening bacterial infections, the associated scripting abuse of ofloxacin remains unchecked, which has contributed to the problem of bacterial resistance. The overuse of antibiotics such as happens with children suffering from otitis media for example has given rise to a breed of super bacteria which are resistant to antibiotics entirely.[172]

The use of the ofloxacin and other fluoroquinolones had increased three-fold in an emergency room environment in the United States between 1995 and 2002, while the use of safer alternatives such as macrolides declined significantly.[173][174]

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.[175]

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.[176][177]. 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 exist.

[edit] Social and economic impact

Any number of adverse drug reaction forums related to ofloxacin, as well as the fluoroquinolone class, may be found on the Internet. The various manufacturers and the members of the medical community’s reaction to these forums have been one of disbelief and denial. Claiming that “Some of the personal stories {of these members} on the Internet are truly wacky....” [178]

However increased hospitalizations attributed to adverse drug reactions alone account for billions of dollars each year within the US healthcare system. Severe reactions do occur with ofloxacin and can add significantly to the cost of care. Antibacterial adverse effects account for nearly 25% of all adverse drug reactions amongst hospitalized patients. “Indirect costs as a result of reduced quality of life or loss of productivity are certainly not reflected in the acquisition costs of antimicrobials.”[179]

  • Economic impact: adverse reactions:

The adverse drug reaction profile of ofloxacin and other fluoroquinolone drugs has spawned a grass root movement of those so effected to lobby for Black Box Warnings and Dear Doctor Letters as well as the petitioning of the FDA for the removal of some fluoroquinolone drugs from clinical practice.[180][181][182][183][184][185][186][187]

A number of lawsuits filed against the manufacturers, as well as malpractice litigation, has been spawned by this unacceptable safety profile. 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, such reactions are “rare” (contrary to the literature) and the benefits of such therapy outweigh the perceived risks.[188] [189]

[edit] Risk/benefit assessment

The benefits of ofloxacin therapy have also been disputed. There are discrepancies between the promoted image and the clinically interpreted usefulness of ofloxacin, and what has been reported within the leading medical journals or the results of independent double blind studies.

  • Respiratory infections

In a 1986 issue of the Journal of Antimicrobial Chemotherapy, a leading article on quinolones in chest infections concludes that there is little reason for optimism about the role of fluoroquinolones in chest infections mainly because of problems with resistance, recurrence, and reinfection with Pseudomonas aeruginosa and S pneumoniae.[190] Antibiotics do not improve sinusitis symptoms a number of studies have shown. Primary care physicians (family doctors) commonly prescribe ofloxacin to treat acute maxillary sinusitis (inflamed membranes of the sinuses), although there is no evidence that this approach is effective. A report in the British medical Journal the Lancet found that antibiotics did nothing more than the placebos used as the control.[191] Only about 5-10% of bronchitis cases are caused by a bacterial infection. Most cases of bronchitis are caused by a viral infection and are "self-limited" and resolve themselves in a few weeks.[192] The use of antibiotics such as ofloxacin to treat bronchitis is to be considered unnecessary and as such exposes the patient to an unacceptable risk of suffering a severe adverse reaction.[193]

When prescribed for Community Acquired Pneumonia, Chronic Bronchitis, and Acute Bacterial Sinusitis the use of the fluoroquinolone class offers no compelling advantages over established treatment.[194] Nor does antibiotic treatment help sore throats.[195] Additionally ofloxacin and other fluoroquinolones have no effect upon viral infections such as the common head cold.

  • Chronic bacterial prostatitis

Prostatitis has been termed "the waste basket of clinical ignorance" by prominent Stanford University Urologist Dr. Thomas Stamey. Campbell's Urology, the urologist's most authoritative reference text, identifies only about 5% of all patients with prostatitis as having bacterial prostatitis which can be "cured" at least in the short term by antibiotics. In other words, 95% of men with prostatitis have little hope for a cure with antibiotics alone since they don't actually have any identifiable bacterial infection. Within a 2003 study involving the use of fluoroquinolones to treat Chronic Bacterial Prostatitis it was found that the level of improvement was no different from that associated with placebo. [196]

Chronic pelvic pain (category IIIB) is often misdiagnosed as chronic prostatitis and needlessly treated with a fluoroquinolone drug. Within a Bulgarian study, where by definition all patients had negative microbiological results, we see a 65% adverse drug reaction rate for patients treated with a fluoroquinolone in comparison to a 9% rate for the placebo patients. This was combined with a higher cure rate (69% v 53%) found within the placebo group. The authors stated that “The results of our study show that antibiotics have an unacceptably high rate of adverse side effects as well as a statistically insignificant improvement over placebo...” [197]


  • Infectious diarrhea

A Clostridium difficile infection is the principal cause of ofloxacin-associated diarrhea and pseudomembranous colitis. [198] [199][200]

In May 2007 the FDA changed the package insert for ofloxacin to include the warning that that Clostridium difficile associated diarrhea (CDAD) is associated with the use of ofloxacin. [201][202] [203] As such the efficacy of ofloxacin to treat infectious diarrhea would be called into question.

  • Uncomplicated cervical and urethra gonorrhea

As previously stated the use of ofloxacin to treat this disease has been severely compromised by bacterial resistance.

Most of the approved uses for ofloxacin have shown either lack of reasonable efficacy within some independent studies, or has been severely compromised by growing bacterial resistance. Applying a reasonable risk/benefit assessment to the use of ofloxacin there should be very few cases where the use of a fluoroquinolone drug, such as ofloxacin, would be considered by the treating physician to be a first line agent.[204][205][206] Ofloxacin has been associated with significant adverse reactions during therapy; as such the potential for benefit may not outweigh the proven risk when there is a safer alternative available to the treating physician. A complete risk/benefit assessment should be performed prior to implementing fluoroquinolone therapy, and the patient fully advised concerning possible adverse reactions beforehand.

[edit] Package insert links

[edit] See also

[edit] References

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  128. ^ http://www.mnd.uscourts.gov/MDL-Levaquin/index.shtml
  129. ^ Clinical Infectious Diseases 2003;36:1404-1410 Fluoroquinolone-Associated Tendinopathy: A Critical Review of the Literature Yasmin Khaliq and George G. Zhanel Received 29 November 2002; accepted 6 February 2003; electronically published 20 May 2003. “6 cases (6.1%) were reported in association with ofloxacin....”
  130. ^ Rev Rhum Engl Ed. 1999 Jul-Sep;66(7-9):419-21. Suspected role of ofloxacin in a case of arthalgia, myalgia, and multiple tendinopathy. Schwald N, Debray-Meignan S. Geriatrics Department, Hotel-Dieu, Paris, France.
  131. ^ Long term outcome after Fluoroquinolones tendinopathies 13/01/2004 14:11:07 P-0077 C Guy (1); Y Murat (1); MN Beyens (1); M Ratrema (1); G Mounier (1); M Ollagnier (1); (1) Centre de Pharmacovigilance, Hôpital Bellevue - CHU St-Etienne, Sant-Etienne
  132. ^ Arch Intern Med. 2003;163:1801-1807. Vol. 163 No. 15, August 11, 2003 Increased Risk of Achilles Tendon Rupture With Quinolone Antibacterial Use, Especially in Elderly Patients Taking Oral Corticosteroids Paul D. van der Linden, PharmD; Miriam C. J. M. Sturkenboom, PhD; Ron M. C. Herings, PhD; Hubert M. G. Leufkens, PhD; Sam Rowlands, MD; Bruno H. Ch. Stricker, PhD
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  134. ^ 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. http://www.who-umc.org/DynPage.aspx?id=14335
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  160. ^ The complete labeling history of each drug is available from Drugs@FDA. Medication Guides are available from the FDA's MedWatch system.
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  175. ^ Fluoroquinolone Utilization in the Emergency Departments of Academic Medical Centers Prevalence of, and Risk Factors for, Inappropriate Use Ebbing Lautenbach, MD, MPH; Lori A. Larosa, PharmD; Nishaminy Kasbekar, PharmD; Helen P. Peng, PharmD; Richard J. Maniglia, MD; Neil O. Fishman, MD Arch Intern Med.2003;163:601-605. http://archinte.ama-assn.org/cgi/reprint/163/5/601.pdf
  176. ^ K08 HS14563 and HS11313
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  187. ^ June 2004, A petition To the United States Congress to immediately take action to protect consumers from the reckless and negligent abuses of the FDA and the following Pharmaceutical Companies: Bayer, Ortho-McNeill, Pfizer, Merck, Bristol-Myers Squibb, Sanofi Winthrop, Bertek Pharmaceuticals – Rhone-Poulenc Rorer and Barr. These companies manufacture and distribute fluoroquinolone antibiotics in the United States in a manner that fails to warn of serious adverse event risks, and downplays and fails to warn physicians of the serious risks associated with fluoroquinolone therapy.
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  204. ^ Source: University Of California - San Francisco Date: 2002-10-01 Cipro, Related Antibiotics Over-Prescribed, Fueling Microbe Resistance
  205. ^ Gatifloxacin and moxifloxacin have no proven clinical advantages over other fluoroquinolones, macrolides, or amoxicillin Gatifloxacin (Tequin®) and moxifloxacin (Avelox®) Therapeutics Letter Canadian Family Physician K. Bassett B. Mintzes V. Musini T.L. Perry Jr M. Wong J.M. Wright
  206. ^ From The Cochrane Library, Issue 3, 2006. Chichester, UK: John Wiley & Sons, Ltd. All rights reserved. Fluoroquinolones for treating tuberculosis (Cochrane Review) Ziganshina LE, Vizel AA, Squire SB

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