Ofloxacin
Encyclopedia
Ofloxacin is a synthetic chemotherapeutic antibiotic
of the fluoroquinolone drug class considered to be a second-generation fluoroquinolone. The original brand, Floxin, has been discontinued by the manufacturer in the United States on 18 June 2009, though generic equivalents continue to be available.
Ofloxacin 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 drop
s and ear drop
s (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. When levofloxacin disks were not available in early clinical trials, a 5-pg ofloxacin 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.
Like other quinolone
s, ofloxacin has been associated with a significant number of serious adverse drug reaction
s, 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.
Hepatotoxicity
has also been reported with the use of ofloxacin. Case reports of hepatitis
have been published for the older fluoroquinolones including ciprofloxacin
, ofloxacin, and norfloxacin
.
, the first fluoroquinolone antibiotic
,
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. This reaction was detailed within Stephen Fried’s 1999 book: “Bitter Pills”
In the United States name branded ofloxacin is rarely used anymore, having been discontinued by the manufacturer, Ortho McNeil Janssen, a subsidiary of Johnson & Johnson
. 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. However generic use continues. The FDA website lists 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 levofloxacin 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.
During the 2009 meeting, yet another shareholder who alleges to have been crippled by these drugs, 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
Children (those under 18) are also at an increased risk of bone, joint, or tendon toxicities.
Prescribing ofloxacin 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.
In the adult population ofloxacin is limited to the treatment of proven serious and life threatening bacterial infections such as:
Ofloxacin has not been shown to be effective in the treatment of syphilis
. Floxin is now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.
Ofloxacin is also used in animals. Its veterinary formulation is sold as Marfloxacin (not to be confused with marbofloxacin
, another veterinary-use fluoroquinolone).
that is active against both
Gram-positive
and Gram-negative
bacteria. It functions by inhibiting DNA gyrase
, a type II topoisomerase
, and topoisomerase IV, 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.
Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.
As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.
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.
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.
Caution in patients with liver disease
. 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.
. Breast-feeding mothers who take ofloxacin may expose their infants to severe adverse reactions.
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.
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. 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, but if safer antibiotics such as penicillin, cephalosporins or erythromycin are an option they should be used instead due to their clearer safety profile.
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. 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
, Pefloxacin
, Norfloxacin
and Nalidixic acid
. It is generally accepted that the fluoroquinolone class should not be used to treat women who are pregnant due to such risks.
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 which showed and ADR rate in excess of 40%, as well as a number of reported fatalities. Within the first study 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 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.
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), Stevens–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, and additional warnings concerning irreversible peripheral neuropathy and Torsades de pointes being associated with floxin therapy were added. In 2007 warnings regarding fatal Clostridium difficile
associated diarrhea (CDAD: reported to occur over two months after the administration), severe photosensitivity/phototoxicity reactions and hepatic failure (including fatal cases) and Toxic Epidermal Necrolysis (TEN) were added to the package inserts.
The psychiatric adverse events, as well as central nervous system
and peripheral nervous system
associated with ofloxacin has been well documented within the literature.
Adverse reactions may manifest during, as well as after fluoroquinolone therapy.
Liver damage and dysglycemia has been associated with ofloxacin. Additionally in 2005 acute rhabdomyolysis
had been associated with ofloxacin/levofloxacin therapy.
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
. Partly as a result of the efforts of Public Citizen
the FDA requested a Black Box Warning
s on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.
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.
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
. 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.
, not as eye drop
s or ear drop
s) 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.
and arrhythmias, anticoagulant
effects, the formation of non-absorbable complexes, as well as increasing the risk of toxicity. Concurrent administration of ofloxacin, with magnesium
or aluminium 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. 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. 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.
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.
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.
toxicity, cardiovascular toxicity, tendon/articular
toxicity, and hepatic toxicity as well as renal failure and seizure. Seizures have however, been reported to occur at therapeutic dosage as well as severe psychiatric reactions.
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.
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.
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.
Aerobic Gram-negative microorganisms
Other microorganisms
Referencing the latest package insert for Floxin.
Floxin:
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.
Notice given to the FDA of the discontinuance of Floxacin by the manufacturer effective June 18, 2009.
antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic acid
. Rheumatic disease after use of a fluoroquinolone (norfloxacin
) was first reported eleven years later. 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."
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. 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.
In 2005, the Illinois Attorney General
filed a petition with the FDA seeking black box warning
s 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. In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for a Black Box Warning. In January 2008, Public Citizen filed suit in Federal Court to compel the FDA to respond to their 2006 petition. 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. 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. Bayer
, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22, 2008 concerning these changes. Ortho-McNeil, the manufacturers of Levaquin and Floxin, issued a similar letter in November. 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) 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.
to ofloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogen
s, including Staphylococcus aureus
, enterococci, and Streptococcus pyogenes
now exhibit resistance worldwide.
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....".
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.
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.
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.
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. 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.
(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.
Such ruptures have also been associated with ofloxacin, as well as other drugs found within this class.
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.
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.
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.
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
of the fluoroquinolone drug class considered to be a second-generation fluoroquinolone. The original brand, Floxin, has been discontinued by the manufacturer in the United States on 18 June 2009, though generic equivalents continue to be available.
Ofloxacin 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
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
equivalents, for oral and intravenous administration. Ofloxacin is also available for topical use, as eye drop
Eye drop
Eye drops are saline-containing drops used as a route to administer medication in the eye. Depending on the condition being treated, they may contain steroids, antihistamines, sympathomimetics, beta receptor blockers, parasympathomimetics, parasympatholytics, prostaglandins, non-steroidal...
s and ear drop
Ear drop
Ear drops are a form of medicine used to treat or prevent ear infections, especially infections of the outer ear and ear canal .Bacterial infections are sometimes treated with antibiotics...
s (marketed as Ocuflox and Floxin Otic respectively in the United States).
Ofloxacin is a racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
mixture, which consists of 50% levofloxacin
Levofloxacin
Levofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class and is used to treat severe or life-threatening bacterial infections or bacterial infections that have failed to respond to other antibiotic classes. It is sold under various brand names, such as Levaquin and...
(the biologically active component) and 50% of its “mirror image” or enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
dextrofloxacin. When levofloxacin disks were not available in early clinical trials, a 5-pg ofloxacin 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.
Like other quinolone
Quinolone
The quinolones are a family of synthetic broad-spectrum antibiotics. The term quinolone refers to potent synthetic chemotherapeutic antibacterials....
s, ofloxacin has been associated with a significant number of serious adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s, such as tendon
Tendon
A tendon is a tough band of fibrous connective tissue that usually connects muscle to bone and is capable of withstanding tension. Tendons are similar to ligaments and fasciae as they are all made of collagen except that ligaments join one bone to another bone, and fasciae connect muscles to other...
damage (including spontaneous tendon ruptures) and peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
(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.
Hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
has also been reported with the use of ofloxacin. Case reports of hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
have been published for the older fluoroquinolones including ciprofloxacin
Ciprofloxacin
Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
, ofloxacin, and norfloxacin
Norfloxacin
Norfloxacin is a synthetic chemotherapeutic antibacterial agent occasionally used to treat common as well as complicated urinary tract infections. It is sold under various brand names with the most common being Noroxin. In form of ophthalmic solutions it is known as Chibroxin...
.
History
Ofloxacin was developed as a broader-spectrum analog of norfloxacinNorfloxacin
Norfloxacin is a synthetic chemotherapeutic antibacterial agent occasionally used to treat common as well as complicated urinary tract infections. It is sold under various brand names with the most common being Noroxin. In form of ophthalmic solutions it is known as Chibroxin...
, the first fluoroquinolone antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
,
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. This reaction was detailed within Stephen Fried’s 1999 book: “Bitter Pills”
In the United States name branded ofloxacin is rarely used anymore, having been discontinued by the manufacturer, Ortho McNeil Janssen, a subsidiary of Johnson & Johnson
Johnson & Johnson
Johnson & Johnson is an American multinational pharmaceutical, medical devices and consumer packaged goods manufacturer founded in 1886. Its common stock is a component of the Dow Jones Industrial Average and the company is listed among the Fortune 500....
. 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. However generic use continues. The FDA website lists 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 levofloxacin 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.
During the 2009 meeting, yet another shareholder who alleges to have been crippled by these drugs, 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
Medical uses
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. Ofloxacin (and its derivatives) has also been associated with a few isolated reports of unexplained pediatric fatalities.Children (those under 18) are also at an increased risk of bone, joint, or tendon toxicities.
Prescribing ofloxacin 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.
In the adult population ofloxacin is limited to the treatment of proven serious and life threatening bacterial infections such as:
- Acute bacterial exacerbations of chronic bronchitisChronic bronchitisChronic bronchitis is a chronic inflammation of the bronchi in the lungs. It is generally considered one of the two forms of chronic obstructive pulmonary disease...
- Community-acquired pneumoniaPneumoniaPneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
- Uncomplicated skin and skin structure infections
- Nongonococcal urethritisUrethritisUrethritis is inflammation of the urethra. The most common symptom is painful or difficult urination.-Causes:The disease is classified as either gonococcal urethritis, caused by Neisseria gonorrhoeae, or non-gonococcal urethritis , most commonly caused by Chlamydia trachomatis...
and cervicitisCervicitisCervicitis is inflammation of the uterine cervix. Cervicitis in women has many features in common with urethritis in men and many cases are caused by sexually transmitted infections...
- Mixed Infections of the urethraUrethraIn anatomy, the urethra is a tube that connects the urinary bladder to the genitals for the removal of fluids out of the body. In males, the urethra travels through the penis, and carries semen as well as urine...
and cervixCervixThe cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall...
- Acute pelvic inflammatory diseasePelvic inflammatory diseasePelvic inflammatory disease is a generic term for inflammation of the uterus, fallopian tubes, and/or ovaries as it progresses to scar formation with adhesions to nearby tissues and organs. This may lead to infections. PID is a vague term and can refer to viral, fungal, parasitic, though most...
- Uncomplicated cystitisCystitisCystitis is a term that refers to urinary bladder inflammation that results from any one of a number of distinct syndromes. It is most commonly caused by a bacterial infection in which case it is referred to as a urinary tract infection.-Signs and symptoms:...
- Complicated urinary tract infections
- ProstatitisProstatitisProstatitis is an inflammation of the prostate gland, in men. A prostatitis diagnosis is assigned at 8% of all urologist and 1% of all primary care physician visits in the United States.-Classification:...
- Acute, uncomplicated urethral and cervical gonorrheaGonorrheaGonorrhea is a common sexually transmitted infection caused by the bacterium Neisseria gonorrhoeae. The usual symptoms in men are burning with urination and penile discharge. Women, on the other hand, are asymptomatic half the time or have vaginal discharge and pelvic pain...
.
Ofloxacin has not been shown to be effective in the treatment of syphilis
Syphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...
. Floxin is now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.
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
Marbofloxacin
Marbofloxacin is a potent antibiotic of the fluoroquinolone group. It is used in veterinary medicine under the trade names Marbocyl and Zeniquin...
, another veterinary-use fluoroquinolone).
Mode of action
Ofloxacin is a broad-spectrum antibioticBroad-spectrum antibiotic
The term broad-spectrum antibiotic refers to an antibiotic that acts against a wide range of disease-causing bacteria. A broad-spectrum antibiotic acts against both Gram-positive and Gram-negative bacteria, in contrast to a narrow-spectrum antibiotic, which is effective against specific families of...
that is active against both
Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
and Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria. It functions by inhibiting DNA gyrase
DNA gyrase
DNA gyrase, often referred to simply as gyrase, is an enzyme that relieves strain while double-stranded DNA is being unwound by helicase. This causes negative supercoiling of the DNA...
, a type II topoisomerase
Topoisomerase
Topoisomerases are enzymes that regulate the overwinding or underwinding of DNA. The winding problem of DNA arises due to the intertwined nature of its double helical structure. For example, during DNA replication, DNA becomes overwound ahead of a replication fork...
, and topoisomerase IV, 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
Vivo
-Computer and technology:* Video In Video Out* Vivo Software, streaming format, acquired in 1998 by RealNetworks* VivoActive, Vivo Software's video format* Vivo S.A., a major Brazilian mobile phone company...
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.
Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.
As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.
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.
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.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.
Caution in patients with liver disease
Liver disease
Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...
. 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
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
, nursing mothers, patients with psychiatric illnesses and in patients with epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
or other seizure disorders.
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 plasmaPlasma (physics)
In physics and chemistry, plasma is a state of matter similar to gas in which a certain portion of the particles are ionized. Heating a gas may ionize its molecules or atoms , thus turning it into a plasma, which contains charged particles: positive ions and negative electrons or ions...
. Breast-feeding mothers who take ofloxacin may expose their infants to severe adverse reactions.
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.
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. 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, but if safer antibiotics such as penicillin, cephalosporins or erythromycin are an option they should be used instead due to their clearer safety profile.
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. According to the March of Dimes
March of Dimes
The March of Dimes Foundation is a United States nonprofit organization that works to improve the health of mothers and babies.-Organization:...
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
Ciprofloxacin
Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
, Pefloxacin
Pefloxacin
Pefloxacin is a synthetic chemotherapeutic agent used to treat severe and life threatening bacterial infections. Pefloxacin is commonly referred to as a fluoroquinolone drug and is a member of the fluoroquinolone class of antibacterials. It is an analog of norfloxacin. It is a synthetic...
, Norfloxacin
Norfloxacin
Norfloxacin is a synthetic chemotherapeutic antibacterial agent occasionally used to treat common as well as complicated urinary tract infections. It is sold under various brand names with the most common being Noroxin. In form of ophthalmic solutions it is known as Chibroxin...
and Nalidixic acid
Nalidixic acid
Nalidixic acid is the first of the synthetic quinolone antibiotics...
. It is generally accepted that the fluoroquinolone class should not be used to treat women who are pregnant due to such risks.
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.However the two most recent pediatric studies involving the use of levofloxacin
Levofloxacin
Levofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class and is used to treat severe or life-threatening bacterial infections or bacterial infections that have failed to respond to other antibiotic classes. It is sold under various brand names, such as Levaquin and...
, 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 which showed and ADR rate in excess of 40%, as well as a number of reported fatalities. Within the first study 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 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.
Adverse effects
Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes. There has been a number of regulatory actions taken as a result of such adverse reactions associated with ofloxacin therapy, which included published warnings, 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. 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
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
(irreversible nerve damage), tendon damage, heart problems (prolonged QT interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
/ torsades de pointes
Torsades de pointes
Torsades de pointes, or simply torsades, is a French term that literally means "twisting of the points". It was first described by Dessertenne in 1966 and refers to a specific, rare variety of ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram .- Presentation...
), pseudomembranous colitis
Pseudomembranous colitis
Pseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...
, rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
(muscle wasting), Stevens–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, and additional warnings concerning irreversible peripheral neuropathy and Torsades de pointes being associated with floxin therapy were added. In 2007 warnings regarding fatal Clostridium difficile
Clostridium difficile
Clostridium difficile , also known as "CDF/cdf", or "C...
associated diarrhea (CDAD: reported to occur over two months after the administration), severe photosensitivity/phototoxicity reactions and hepatic failure (including fatal cases) and Toxic Epidermal Necrolysis (TEN) were added to the package inserts.
The psychiatric adverse events, as well as central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
associated with ofloxacin has been well documented within the literature.
Adverse reactions may manifest during, as well as after fluoroquinolone therapy.
Liver damage and dysglycemia has been associated with ofloxacin. Additionally in 2005 acute rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
had been associated with ofloxacin/levofloxacin therapy.
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
Public Citizen
Public Citizen is a non-profit, consumer rights advocacy group based in Washington, D.C., United States, with a branch in Austin, Texas. Public Citizen was founded by Ralph Nader in 1971, headed for 26 years by Joan Claybrook, and is now headed by Robert Weissman.-Lobbying Efforts:Public Citizen...
. Partly as a result of the efforts of Public Citizen
Public Citizen
Public Citizen is a non-profit, consumer rights advocacy group based in Washington, D.C., United States, with a branch in Austin, Texas. Public Citizen was founded by Ralph Nader in 1971, headed for 26 years by Joan Claybrook, and is now headed by Robert Weissman.-Lobbying Efforts:Public Citizen...
the FDA requested a Black Box Warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
s on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.
Severe hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
has been reported as noted above. Reports of hepatic or hypersensitivity vasculitis
Vasculitis
Vasculitis refers to a heterogeneous group of disorders that are characterized by inflammatory destruction of blood vessels. Both arteries and veins are affected. Lymphangitis is sometimes considered a type of vasculitis...
occurring as a result of ofloxacin therapy have also been reported.
Older patients may have an increased risk of tendinopathy
Tendinopathy
Tendinopathy refers to a disease of a tendon. More specifically, it can refer to:* Tendinitis* TendinosisTendon injury arise from a combination of intrinsic and extrinsic factors; acute tendon injuries may be predominantly caused by extrinsic factors, whereas in overuse syndromes as in the case of...
(including rupture), especially with concomitant corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
use and such patients may also be more susceptible to prolongation of the QT interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
. Patients with known prolongation, those with hypokalemia
Hypokalemia
Hypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
, or being treated with other drugs that prolong the QT interval should avoid the use of ofloxacin. Hematologic reactions (including agranulocytosis
Agranulocytosis
Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
, thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
), and renal toxicities may occur after multiple doses.
Tendon damage
As with all fluoroquinolones, there is a possibility of spontaneous tendon rupture. 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. The risk of tendon damage is greater in people taking corticosteroids and in the elderly. Since July 2008, all systemic fluoroquinolones (those taken internallyRoute of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
, not as eye drop
Eye drop
Eye drops are saline-containing drops used as a route to administer medication in the eye. Depending on the condition being treated, they may contain steroids, antihistamines, sympathomimetics, beta receptor blockers, parasympathomimetics, parasympatholytics, prostaglandins, non-steroidal...
s or ear drop
Ear drop
Ear drops are a form of medicine used to treat or prevent ear infections, especially infections of the outer ear and ear canal .Bacterial infections are sometimes treated with antibiotics...
s) available in the United States were requested, by the FDA, to carry a black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
of the risk of tendon damage. However, the addition of this warning was not mandatory.
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 cardiotoxicityCardiotoxicity
Cardiotoxicity is the occurrence of heart electrophysiology dysfunction or/and muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood...
and arrhythmias, anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
effects, the formation of non-absorbable complexes, as well as increasing the risk of toxicity. Concurrent administration of ofloxacin, with magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
or aluminium antacids, sucralfate
Sucralfate
Sucralfate is a cytoprotective agent, an oral gastrointestinal medication primarily indicated for the treatment of active duodenal ulcers. Brand names include Sucramal in Italy; Carafate in U.S.A.; Pepsigard, Sucral, Sucrafil, Hapifate in India; Sutra or Musin in parts of South-East Asia; Sulcrate...
or products containing calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
, iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
or zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
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
Theophylline
Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
and enhance the effects of the warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
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. 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
Acenocoumarol
Acenocoumarol is an anticoagulant that functions as a vitamin K antagonist . It is a derivative of coumarin and is marketed under the brand names Sintrom and Sinthrome.- Dosage :...
, Anisindione
Anisindione
Anisindione is a synthetic anticoagulant and an indanedione derivative. It prevents the formation of active procoagulation factors II, VII, IX, and X, as well as the anticoagulant proteins C and S, in the liver by inhibiting the vitamin K–mediated gamma-carboxylation of precursor proteins....
, and Dicumarol
Dicumarol
Dicoumarol or dicumarol is an anticoagulant that functions as a vitamin K antagonist . It is also used in biochemical experiments as an inhibitor of reductases....
. Additionally there is an increase the risk of cardiotoxicity and arrhythmias when co administered with drugs such as Dihydroquinidine
Dihydroquinidine
Dihydroquinidine is an organic compound and as a cinchona alkaloid closely related to quinine. The specific rotation is +226° in ethanol @ 2g/100 ml. A derivative of this molecule is used as chiral ligand in the AD-mix for Sharpless Dihydroxylation....
barbiturate, Quinidine
Quinidine
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
, and Quinidine barbiturate. 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.
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.
A possible interaction between oral hypoglycemic drugs (e.g., glyburide/glibenclamide
Glibenclamide
Glibenclamide , also known as glyburide , is an antidiabetic drug in a class of medications known as sulfonylureas, closely related to sulfa drugs...
) or with insulin and fluoroquinolone antimicrobial agents have been reported resulting in a potentiation of the hypoglycemic action of these drugs.
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. Overdose may result in central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
toxicity, cardiovascular toxicity, tendon/articular
Articular
The articular bone is part of the lower jaw of most tetrapods, including amphibians, sauropsids and early synapsids. In these animals it is connected to two other lower jaw bones, the suprangular and the angular...
toxicity, and hepatic toxicity as well as renal failure and seizure. Seizures have however, been reported to occur at therapeutic dosage as well as severe psychiatric reactions.
Pharmacology
The bioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
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.
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."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.
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.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 historyFloxin:
- December 28, 1990 The approval of the new drug application (NDA for floxacin).
- December 28, 1990 to March 6, 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. As such the regulatory history begins fourteen years after initial approval beginning with the 2004 changes:
- September 15, 2004 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.
- June 14, 2006
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.”
- June 19, 2007
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.
- October 3, 2008
Addition of Black Box Warning.
- February 12, 2009
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.
- April 30, 2009
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 quinoloneQuinolone
The quinolones are a family of synthetic broad-spectrum antibiotics. The term quinolone refers to potent synthetic chemotherapeutic antibacterials....
antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic acid
Nalidixic acid
Nalidixic acid is the first of the synthetic quinolone antibiotics...
. Rheumatic disease after use of a fluoroquinolone (norfloxacin
Norfloxacin
Norfloxacin is a synthetic chemotherapeutic antibacterial agent occasionally used to treat common as well as complicated urinary tract infections. It is sold under various brand names with the most common being Noroxin. In form of ophthalmic solutions it is known as Chibroxin...
) was first reported eleven years later. In a 1995 letter published in the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
, 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."
By August 1996, the FDA had not taken action, and the consumer advocacy group Public Citizen
Public Citizen
Public Citizen is a non-profit, consumer rights advocacy group based in Washington, D.C., United States, with a branch in Austin, Texas. Public Citizen was founded by Ralph Nader in 1971, headed for 26 years by Joan Claybrook, and is now headed by Robert Weissman.-Lobbying Efforts:Public Citizen...
filed a petition with the FDA prompting the agency to act. 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.
In 2005, the Illinois Attorney General
Illinois Attorney General
The Illinois Attorney General is the highest legal officer of the state of Illinois in the United States. Originally an appointed office, it is now an office filled by election through universal suffrage...
filed a petition with the FDA seeking black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
s 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. In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for a Black Box Warning. In January 2008, Public Citizen filed suit in Federal Court to compel the FDA to respond to their 2006 petition. 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. The package inserts for Ciprofloxacin
Ciprofloxacin
Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
, Avelox (moxifloxacin
Moxifloxacin
Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent developed by Bayer AG . It is marketed worldwide under the brand names Avelox, Avalox, and Avelon for oral treatment. In most countries, the drug is also available in parenteral form for intravenous infusion...
), Proquin XR, Factive (gemifloxacin
Gemifloxacin
Gemifloxacin mesylate is an oral broad-spectrum quinolone antibacterial agent used in the treatment of acute bacterial exacerbation of chronic bronchitis and mild-to-moderate pneumonia....
), Floxin (ofloxacin), Noroxin (norfloxacin
Norfloxacin
Norfloxacin is a synthetic chemotherapeutic antibacterial agent occasionally used to treat common as well as complicated urinary tract infections. It is sold under various brand names with the most common being Noroxin. In form of ophthalmic solutions it is known as Chibroxin...
) and Levaquin (levofloxacin
Levofloxacin
Levofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class and is used to treat severe or life-threatening bacterial infections or bacterial infections that have failed to respond to other antibiotic classes. It is sold under various brand names, such as Levaquin and...
) were amended on September 8, 2008 to include these new warnings. Bayer
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...
, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22, 2008 concerning these changes. Ortho-McNeil, the manufacturers of Levaquin and Floxin, issued a similar letter in November. 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
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
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) 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
ResistanceAntibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
to ofloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s, including Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
, enterococci, and Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...
now exhibit resistance worldwide.
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....".
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.
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.
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.
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. 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 LitigationMultidistrict litigation
In the United States, multidistrict litigation refers to a special federal legal procedure designed to speed the process of handling complex cases such as air disaster litigation or complex product liability suits....
(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.
Such ruptures have also been associated with ofloxacin, as well as other drugs found within this class.
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
New Jersey Supreme Court
The New Jersey Supreme Court is the highest court in the U.S. state of New Jersey. It has existed in three different forms under the three different state constitutions since the independence of the state in 1776...
to accord mass-tort
Tort
A tort, in common law jurisdictions, is a wrong that involves a breach of a civil duty owed to someone else. It is differentiated from a crime, which involves a breach of a duty owed to society in general...
treatment to their suits against the manufacturer, Johnson & Johnson subsidiary Ortho-McNeil Pharmaceutical Inc.
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.
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.
Package insert links
See also
- Adverse effects of fluoroquinolonesAdverse effects of fluoroquinolonesThe adverse effects of fluoroquinolones are the negative and sometimes serious effects that may occur as a result of fluoroquinolone use. The fluoroquinolones are synthetic broad-spectrum antibiotics. In general, the common side-effects are mild to moderate and self-limiting. On occasion, serious...
- Fluoroquinolone
- QuinoloneQuinoloneThe quinolones are a family of synthetic broad-spectrum antibiotics. The term quinolone refers to potent synthetic chemotherapeutic antibacterials....
- LevofloxacinLevofloxacinLevofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class and is used to treat severe or life-threatening bacterial infections or bacterial infections that have failed to respond to other antibiotic classes. It is sold under various brand names, such as Levaquin and...
- Cetraxal
External links
- Ofloxacin: an overview - A site with its chemical properties and alternate brand names.
- U.S. National Library of Medicine: Drug Information Portal - Ofloxacin