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 85% - 95%

Protein binding 32%

Metabolism ?

Half life 8–9 hours

Excretion ?

Therapeutic considerations

C(US)
Pregnancy cat.

Legal status ℞-only(US)

Routes Oral, IV, topical (eye drops and ear drops)

(what is this?) (verify)

Ofloxacin is a fluoroquinolone antibiotic 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.[1] 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.[2]
[3]
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.
[4]
Ofloxacin has also been associated with severe psychiatric adverse reactions.

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.[5][7][8][9]

Contents
[hide]

• 1 History
• 2 Licensed use
• 3 Available forms
• 4 Mode of action
• 5 Contraindications
o 5.1 Pregnancy
o 5.2 Pediatric use
• 6 Adverse effects
o 6.1 Tendon damage
• 7 Interactions
• 8 Overdose
• 9 Pharmacology
• 10 Pharmacokinetics
• 11 Dosage
• 12 Susceptible bacteria
• 13 Additional regulatory history
o 13.1 History of the black box warnings
• 14 Antibiotic abuse and bacterial resistance
• 15 Current litigation
• 16 Package insert links
• 17 See also
• 18 References

• 19 External links

[edit] History
Ofloxacin (floxin – floxacin) was developed as a broader-spectrum analog of norfloxacin,
the first fluoroquinolone antibiotic,[10] 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.[11][12] This reaction was detailed within Stephen
Fried’s 1999 book: “Bitter Pills”[13]

In the United States name branded ofloxacin is rarely used anymore, having been
discontinued by the manufacturer (Ortho McNeil Janssen).[14] 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.[15][16] 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.
[17][18]

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.[17][18]

[edit] 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.[19][20] Ofloxacin (and its derivatives) has also been
associated with a few isolated reports of unexplained pediatric fatalities.[21][22] Children
(those under 18) are also at an increased risk of bone, joint, or tendon toxicities.[23]

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.[23]

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

• Community-acquired Pneumonia

• Uncomplicated skin and skin structure infections

• Nongonococcal urethritis and cervicitis

• Mixed Infections of the urethra and cervix

• Acute pelvic inflammatory disease

• Uncomplicated cystitis

• Complicated urinary tract infections

• Prostatitis

• Acute, uncomplicated urethral and cervical gonorrhea.

Note: Ofloxacin has not been shown to be effective in the treatment of syphilis.[23] Floxin
is now considered to be contraindicated for the treatment of certain sexually transmitted
diseases by some experts due to bacterial resistance.[24]

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,[25] 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.[26]

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of

the quinolones and the induction of micronuclei.[27][28][29] As such some fluoroquinolones
may cause injury to the chromosome of eukaryotic cells.[30][31][32][33][34]

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.[35][36][37]

[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.[24]

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.[23]

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.[38]

Caution in patients with liver disease.[39] 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. [40][41]
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.[42][43]
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.[44][45] 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,[45] but if safer antibiotics such as penicillin,
cephalosporins or erythromycin are an option they should be used instead due to their
clearer safety profile.[44]

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.[46] 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,[47]
Pefloxacin,[48] Norfloxacin[49] and Nalidixic acid.[50] It is generally accepted that the
fluoroquinolone class should not be used to treat women who are pregnant due to such
risks.[51][52][53]

[edit] 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.[54]

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[2] which showed and ADR rate in excess of 40%, as well as a number of
reported fatalities. Within the first study[55] 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[56] 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.[57]

[edit] 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.[58][59] There has been a number of regulatory actions taken as a
result of such adverse reactions associated with ofloxacin therapy, which included
published warnings,[60][61] additional warnings and safety information added to the
package inserts.[62] 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. To date no such letters have been issued.

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,[63] and additional warnings concerning
irreversible peripheral neuropathy and Torsades de pointes being associated with floxin
therapy were added.[64] In 2007 warnings regarding fatal Clostridium difficile associated
diarrhea (CDAD: reported to occur over two months after the administration),[65] severe
photosensitivity/phototoxicity reactions and hepatic failure (including fatal cases) and
Toxic Epidermal Necrolysis (TEN) were added to the package inserts.[66]

The psychiatric adverse events,[67][68][69][70] as well as CNS (Central Nervous System)[71][72]

[73]
and PNS (Peripheral Nervous System)[73] associated with ofloxacin has been well
documented within the literature.

Adverse reactions may manifest during, as well as after fluoroquinolone therapy.[74]

Liver damage and dysglycemia has been associated with ofloxacin.[75][76][77][77]

Additionally in 2005 acute rhabdomyolysis had been associated with
ofloxacin/levofloxacin therapy.[78]

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.[79][80] 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.[81]

• 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.[82][83] 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.[23] 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.[23]

[edit] Tendon damage

As with all fluoroquinolones, there is a possibility of spontaneous tendon rupture.[84] 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.[84] The
risk of tendon damage is greater in people taking corticosteroids and in the elderly.[85]
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.[85]

[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.[86] 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.[87] 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.[86] 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.[88]

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.[89]

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.[23]

[edit] 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.[23] Overdose may
result in central nervous system toxicity, cardiovascular toxicity, tendon/articular toxicity,
and hepatic toxicity[90] as well as renal failure and seizure.[90] Seizures have however, been
reported to occur at therapeutic dosage as well as severe psychiatric reactions.[11][12][13]

[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 elimination half-
life is approximately 4 to 5 hours in patients and approximately 6.4 to 7.4 hours in elderly
patients.[23]
[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."[23][91]

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.[23]

[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.[23]

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] Additional regulatory history

See also Levaquin regulator history

Floxin:

• 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.[92] As
such the regulatory history begins fourteen years after initial approval beginning
with the 2004 changes:

• 09/15/2004[64] 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.

• 06/14/2006[93]

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.”

• 06/19/2007[66]

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.

• 10/03/2008[94]
Addition of Black Box Warning.

• 2/12/2009[95]

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.[94]

• 4/30/2009[96][97]

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.[98] Rheumatic
disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.
[99]
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."[100]

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.[101] 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.[102]

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.[103] In 2006, Public Citizen, supported by the Illinois
Attorney General, renewed its demand of ten years prior for a Black Box Warning.[103][104]
In January 2008, Public Citizen filed suit in Federal Court to compel the FDA to respond
to their 2006 petition.[105][106] 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.[85] 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.[62][107] Bayer, which manufactures Cipro, Avelox and Proquin
XR, issued a Dear Healthcare Professional letter on October 22, 2008 concerning these
changes.[108] Ortho-McNeil, the manufacturers of Levaquin and Floxin, issued a similar
letter in November.[109] 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)[94] 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.

[edit] 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.[110]

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....".[23]

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.[111]

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.[112][113]

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.[114]

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.[113][115] 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.

[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.[80] Such ruptures have also been
associated with ofloxacin, as well as other drugs found within this class.[116][117][118][119][120]
[121]

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.[122]

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.[123]

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.[124][125][126]