Pefloxacin: Wikis

  

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Pefloxacin
Systematic (IUPAC) name
1-ethyl-6-fluoro-7- (4-methylpiperazin-1-yl)- 4-oxo-quinoline-3-carboxylic acid
Identifiers
CAS number 70458-92-3
ATC code J01MA03
PubChem 51081
DrugBank APRD00108
Chemical data
Formula C 17H20FN3O3  
Mol. mass 333.358 g/mol
Pharmacokinetic data
Bioavailability 100%
Protein binding 20–30%
Metabolism Hepatic
Half life 8.6 hours
Excretion Mostly renal, also biliary
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?
 Yes check.svgY(what is this?)  (verify)

Pefloxacin is a synthetic chemotherapeutic agent used to treat severe and life threatening bacterial infections. Pefloxacin is commonly referred to as a fluoroquinolone (or quinolone) drug and is a member of the fluoroquinolone class of antibacterials. It is an analog of norfloxacin. It is a synthetic fluoroquinolone, belonging to the 3rd generation of quinolones. Pefloxacin is extensively prescribed in France.[1] Pefloxacin has not been approved for use in the United States.

There are no licensed uses for Pefloxacin in the United States, as the FDA has not approved this drug. The licensed use varies in other countries and is quite limited as Pefloxacin is to be considered a drug of last resort when all other antibiotics have failed. There appears to be eight common uses in the adult population and no approved uses in the pediatric population, as well as a variety of veterinary uses (as documented within the package inserts). Pefloxacin interacts with a number of other drugs, a number of herbal and natural supplements, and certain thyroid medications.

Contents

History

Pefloxacin was developed in 1979 (German Patent Roger Bellon/Dainippon). It was approved in France for human use in 1985.[2]

Licensed uses

Oral and I.V. fluoroquinolones are not licensed for use in children due to the risk of permanent injury to the musculoskeletal system. At least ten cases of arthropathy occurred in pediatric patients receiving fluoroquinolones; seven of these cases involved pefloxacin.[3] Clinical features included joint swelling or pain in one or more joints. Usually the knees were most oftentimes reported. One patient had evidence of significant joint damage to the right hip and both knees.[3][4] One study that calculated the risk of such injury had stated that such injury occurred more often with Pefloxacin.[5]

However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK. Prescribing a fluoroquinolone to treat an unapproved use within the pediatric (as well as the adult population) exposes the treating physician to the risk of being sued for malpractice should the treating physician fail to both warn the patient of this fact, as well as the risks of any adverse drug reactions the patient may experience.[6][7]

Note: Not recommended for the treatment of infections which can be treated by simple and established antibiotics.[8]

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

  • Uncomplicated gonococcal urethritis in males.[9]
  • Bacterial infections in the gastrointestinal system.[9]
  • Genitourinary tract infections.[9]
  • Lower respiratory tract
  • Bone and joint infections
  • Renal and abdominal infections
  • Infections of skin and soft tissues
  • Gonorrhoeae. however this indication is no longer effective due to bacterial resistance.[10]

Pefloxacin has been increasingly used as a veterinary medicine to treat microbial infections.[11]

Antibiotics such as Pefloxacin do not improve sinusitis symptoms.[12] When prescribed for Community Acquired Pneumonia, Chronic Bronchitis, and Acute Bacterial Sinusitis the use of the fluoroquinolone class offers no compelling advantages over established treatment [13] Nor does antibiotic treatment help sore throats.[14] The use of antibiotics such as Pefloxacin to treat bronchitis is to be considered unnecessary and as such exposes the patient to an unacceptable risk of suffering a severe adverse reaction.[15] Antibiotics' futility against bronchitis had been confirmed in 2002.[16] Since Streptococci and Pneumococci show only intermediate susceptibility to pefloxacin, the drug should not be prescribed as 1st-line treatment in respiratory tract infections, when bacteriological examination has not been carried out.[17]

Additionally Pefloxacin and other fluoroquinolones have no effect upon viral infections such as the common head cold.

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

Availability

Pefloxacin is available as:

  • Tablet; Oral Multiple Strengths Prescription
  • Injectable; Injection Multiple Strengths Prescription
  • Solution; Oral Prescription

See the latest package insert for pefloxacin for additional details.

Trade names

Trade names are being redirected to this article.

Mode of action

Pefloxacin 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,[18] which is an enzyme necessary to separate, replicated DNA, thereby inhibiting cell division.

  • Mechanism of action:

The bactericidal action of pefloxacin results from interference with the activity of the bacterial enzymes DNA gyrase and topoisomerase IV, which are needed for the transcription and replication of bacterial DNA. DNA gyrase appears to be the primary quinolone target for gram-negative bacteria. Topoisomerase IV appears to be the preferential target in gram-positive organisms. Interference with these two topoisomerases results in strand breakage of the bacterial chromosome, supercoiling, and resealing. As a result DNA replication and transcription is inhibited.[19]

The fluoroquinolones interfere with DNA replication by inhibiting an enzyme complex called DNA gyrase. This can also affect mammalian cell replication. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models. Although the quinolone is highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986 (Hussy et al.) [20]

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.[21][22][23] [24] As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.[25][26][27][28][29] [30]

There continues to be considerable debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe and non abating adverse reactions experienced by some patients following fluoroquinolone therapy.[31] [32]

Contraindications

  • Hypersensitivity (allergy) to pefloxacin or to one of its components or to another member of the quinolones.
  • Known deficiency in glucose-6 phosphate dehydogenase (a blood red cells enzyme).
  • Due to growing prevalence of antibiotic resistance to the fluoroquinolones in Southeast Asia, the use of pefloxacin in patients who have been to Southeast Asia is increasingly being contraindicated.[33]
  • Pefloxacin is also considered to be contraindicated within the pediatric population (due to the risk of arthropathies), pregnancy, nursing mothers, and in patients with epilepsy or other seizure disorders.
  • Precautions:
Coadministration of Pefloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug.
Patients should be warned to avoid exposure to direct sunlight or UV light during treatment and until 36 hours after the discontinuation of treatment, because of the risk of phototoxicity reactions (allergic skin rashes).
Tendinitis (inflammation of tendon) may occur and can lead to tendon rupture, particularly in the Achilles tendon and more frequently in elderly patients. Age, past history of tendinitis, vigorous physical exercise and long-term corticoid treatment may predispose a patient to tendinitis and tendon rupture. Therefore, as soon as the treatment with pefloxacin is initiated, it is recommended to look for pain or edema at the level of Achilles tendon, particularly in patients at risk. If such signs are identified therapy should be discontinued immediately.
In patients with a past history of convulsions or with risk factors of convulsions pefloxacin should be used with caution.
In case of myasthenia pefloxacin should be used with caution in these patients.
  • Pregnancy

The fluoroquinolones rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. For this reason the Fluroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The 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.[34][35]

  • Pediatric population

Fluoroquinolones are not licensed for use in children due to the risk of fatalities[36] as well as permanent injury to the musculoskeletal system, with two exceptions. Ciprofloxacin is being licensed in the United States for the treatment of Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli and Inhalational Anthrax (post-exposure) and Levofloxacin was recently licensed for the treatment of Inhalational Anthrax (post-exposure). However, the Fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

At least ten cases of arthropathy occurred in pediatric patients receiving fluoroquinolones; seven of these cases involved pefloxacin.[3] Clinical features included joint swelling or pain in one or more joints. Usually the knees were most oftentimes reported. One patient had evidence of significant joint damage to the right hip and both knees.[3][4] One study that calculated the risk of such injury had stated that such injury occurred more often with Pefloxacin.[5] Within another study it was stated that the pediatric patient has a 3.8% chance of experiencing a serious musculoskeletal adverse event.[37] Within the studies submitted in response to a Pediatric Written Request (Ciprofloxacin, circa 2004) the rate of athropy was reported to be 9.3%.[38]

Pefloxacin is well known to be associated with high incidence of arthropathy in humans because the drug affects articular cartilage and the epiphyseal growth plate. The importance of this toxicity is that it is irreversible and manifest later after the drug is discontinued.[39] Musculoskeletal events tended to be more frequent with pefloxacin.[40][41]

Adverse effects

Fluoroquinolones are generally well tolerated with most side effects being mild and serious adverse effects occurring rarely.[42][43] Some of the serious adverse effects, which occur more commonly with fluoroquinolones than with other antibiotic drug classes, include CNS and tendon toxicity.[42] Unusual adverse reactions include psychosis and chorea (involuntary muscle movements).[44][45] [46] The currently marketed quinolones have safety profiles similar to that of other antimicrobial classes.[42] Phototoxicity, neurological symptoms, impaired colour vision, exanthema, abdominal pain, malaise, drug fever, peripheral neuropathy, dysaesthesia and eosinophilia have been observed as adverse effects of Pefloxacin.[47] [48][49] [50] [41][51]

The serious events may occur with therapeutic or with acute overdose. At therapeutic doses they include central nervous system toxicity, cardiovascular toxicity, tendon/ articular toxicity, and rarely hepatic toxicity.[52] Events that may occur in acute overdose are rare and include renal failure and seizure.[52] Children and the elderly are at greater risk.[42][53] Adverse reactions may manifest during, as well as after fluoroquinolone therapy.[54]

Some groups refer to these adverse events as "fluoroquinolone toxicity". These groups of people claim to have suffered serious long-term harm to their health from using fluoroquinolones. This has led to a class action lawsuit by people harmed by the use of fluoroquinolones as well as legal action by the consumer advocate group Public Citizen.[55][56] Partly as a result of the efforts of The State of Illinois (United States) and Public Citizen the FDA ordered a black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.[57]

  • Irreversible peripheral neuropathy has been associated with Pefloxacin.[49][50]
  • Pefloxacin has associated with the highest reporting rate in regards to adverse reactions.[41]
  • Severe phototoxic adverse events are also noted for pefloxacin.[58]

[59] Pefloxacin is also reported to be the most potent inducer of photosensitivity in the ultraviolet A(UVA) range, with a higher incidence of skin rash and photosensitization than other quinolones.[60][61]

  • Pefloxacin has also associated with ocular damage when given to animals in high dosages. Manifestations included cataracts, multiple punctate lenticular opacities, retinal morphologic changes, and altered visual acuity.[63]

Tendinitis and rupture, usually of the Achilles tendon, are a class-effects of the fluoroquinolones, most frequently reported with pefloxacin.[43][64] The estimated risk of tendon damage during pefloxacin therapy has been estimated by the French authorities in 2000 to be 1 case per 23,130 treatment days as compared to ciprofloxacin where it has been estimated to be 1 case per 779,600.[65] As early as 1996 E, Voisin MC et al.[4] report upon the destructive polyarthropathy in a 17-year-old male after administration of Pefloxacin, which resulted in total bilateral knee and right hip replacements.

Interactions

Pefloxacin absorption is influenced by antacid containing aluminium or magnesium hydroxide. Fluoroquinolones, especially enoxacin, and to a lesser extent ciprofloxacin and pefloxacin, inhibit the metabolic clearance of theophylline and caffeine.[66]

Significant drug interactions

Given concomitantly, Pefloxacin with theophylline may increase theophylline plasma concentrations. It is recommended to monitor theophylline plasma levels, if necessary, the dose of theophylline should be reduced.[8]

Cimetidine reduces the metabolic clearance of pefloxacin. [66]

Overdose

In the event of acute overdosage, the patient should be kept under close medical supervision and given supportive treatment. Hemodialysis is not effective.

Pharmacology

  • Chemical name:

1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid Formula: C17H20FN3O3 Pharmacology: Pefloxacin is a fluoroquinolone antibiotic. Flouroquinolones such as pefloxacin possess excellent activity against gram-negative aerobic bacteria such as E.coli and Neisseria gonorrhoea as well as gram-positive bacteria including S. pneumoniae and Staphylococcus aureus. They also possess effective activity against shigella, salmonella, campylobacter, gonococcal organisms, and multi drug resistant pseudomonas and enterobacter. Half life: 8.6 hours Unchanged pefloxacin and its metabolites may be identified in the urine 84 hours after the intake of the product. In elderly, in comparison with younger patients, the plasma clearance and the apparent volume of distribution are decreased approximately by 50%[19]

  • Elimination half life is 11–12 hours mainly through metabolites
  • Pefloxacin is metabolized in the liver (85%-90%)
  • Major route of elimination is renal – 9-16% of the drugs is eliminated unchanged. Limited excretion via bile
  • Major metabolites constitute up to 84% of drugs recovered in urine

Pharmacokinetics

  • Biotransformation:

Cytochrome P450 1A2 (CYP1A2) Hepatic metabolism is considerable. The main metabolites are demethylated pefloxacin, norfloxacin and pefloxacin N-oxide.[19]

  • There are marked changes in pharmacokinetics in patients with hepatic impairment. Careful monitoring of plasma levels together with appropriate dosage adjustment will be necessary.

Dosing

Pefloxacin 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. Pefloxacin is eliminated partially through renal excretion.[67] However, the drug is also metabolized and partially cleared through the liver and the intestine. Modification of the dosage is recommended 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 partially excreted by the kidneys, the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Recommended Doseage: 400 mg p.o. BID or QD Injectable; Injection; Pefloxacin Mesylate Dihydrate 400 mg / 5 ml Tablet, Film-Coated; Oral; Pefloxacin Mesylate Dihydrate 400 mg Oral Tablets: 400 mg Twice daily Injection: Administer by slow I.V. at a dosage of 400 mg diluted in 100 or 250 ml of 5% isotonic solution (Over a period of 1 hr) Twice daily.[68]

Susceptible bacteria

Current litigation

There are a significant number of cases currently pending before the United States District Court, District of Minnesota, involving one of the drugs found within the fluoroquinolone class; Levaquin (levofloxacin). 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.[56] As a result of this order, product liability attorneys are currently aggressively seeking additional plaintiffs who may have been damaged by this class. Several class action lawsuits had been filed in regards to the adverse reactions suffered by those exposed to ciprofloxacin, another fluoroquinolone drug, during the Anthrax scare of 2001[69][70] as well as most recently, a class action lawsuit involving a third fluoroquinolone; Tequin (gatifloxacin).[71] Currently there does not appear to be any class action lawsuits pending that involve pefloxacin, but there are a significant number of law firms aggressively seeking to represent patients who have suffered a spontaneous tendon rupture, or liver injury, following fluoroquinolone therapy.

Regulatory history

Pefloxacin has not been approved for use in the United States, hence there is no FDA regulator history to refer to. However pefloxacin is categorized under the following by the FDA: Anti-Infectives; ATC:J01MA03. In 2008 the FDA manadated a Black Box Warning be added to all fluoroquinolone drugs in reference to the potential for severe adverse reactions resulting in spontaneous tendon ruptures.

In 2008 the National Pharmaceutical Control Bureau, Ministry of Health Malaysia required the addition of stronger warnings concerning the tendon issues. The DCA had decided that all drugs found within the fluoroquinolone class must have the following statement in the section “Special Warnings and Precautions for Use” of the package inserts:

Musculo-skeletal system: “The risk of developing fluoroquinolone-associated tendonitis and tendon rupture is further increased in people older than 60, in those taking corticosteroid drugs, and in kidney, heart, and lung transplant recipients. Patients experiencing pain, swelling, inflammation of a tendon or tendon rupture should be advised to stop taking their fluoroquinolone medication (to specify the active ingredient) and to contact their healthcare professional promptly about changing their antimicrobial therapy. Patients should also avoid exercise and using the affected area at the first sign of tendon pain, swelling, or inflammation[72]

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.[73] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.[74] 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."[75]

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.[76] 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.[77]

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.[78] In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for a black box warning.[78][79] In January 2008, Public Citizen filed suit to compel the FDA to respond to their 2006 petition.[80][81] On July 7, the FDA ordered the makers of systemic-use fluoroquinolones to add a boxed warning regarding tendon rupture, and to develop a Medication Guide for patients.[82] The package inserts for Cipro (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.[83] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes.[84] Ortho-McNeil, the manufacturers of Levaquin, issued a similar letter in November.[85] through the Health Care Notification Network, a registration-only website that distributes drug alerts 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 April 2009. And there are numerous reports that this information has not been dessiminated to the pharmacist, the 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.

Antibiotic misuse and bacterial resistance

Resistance to pefloxacin 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.[86] Widespread veterinary usage of the fluoroquinolones, in particular over in Europe, has been implicated.[87] The ever increasing bacterial resistance to pefloxacin, (which is a major concern) together with an unacceptable safety profile, may very well threaten its future viability to treat serious and life threatening bacterial infections. Years ago the FDA had added warnings regarding the proper use of the fluoroquinolones drugs within the package inserts to combat such scripting abuse. Advising physicians that fluoroquinolones: "...should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria..."(See the monographs for this class)

Normally pefloxacin 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.[88] Though considered to be a very important and necessary drug required to treat severe and life threatening bacterial infections, the associated scripting abuse of pefloxacin remains unchecked, which has contributed to the problem of bacterial resistance. The overuse of antibiotics such as happens with children suffering from otitis media has given rise to a breed of super bacteria which are resistant to antibiotics entirely.[89]

For example the use of the fuoroquinolones 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.[90][91]

Within a recent study concerning the proper use of this class 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.[92]

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 regulatory agencies, 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.[91][93]. Additionally they are commonly prescribed for medical conditions that are not even bacterial to begin, with such as viral infections, or those to which no proven benefit exist.

There are three known mechanisms of resistance.[94] Some types of efflux pumps can act to decrease intracellular quinolone concentration. In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or Topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug's effectiveness.

Social and economic impact

Any number of adverse drug reaction forums related to pefloxacin, as well as the fluoroquinolone class, may be found on the Internet. The various manufacturers and the members of the medical community’s reaction to these forums have been one of disbelief and denial. Claiming that “Some of the personal stories {of these members} on the Internet are truly wacky...” [95]

Increased hospitalizations attributed to adverse drug reactions alone account for billions of dollars each year within the US healthcare system. Severe reactions do occur with the fluoroquinolone class and can add significantly to the cost of care. Antibacterial adverse effects account for nearly 25% of all adverse drug reactions amongst hospitalized patients. “Indirect costs as a result of reduced quality of life or loss of productivity are certainly not reflected in the acquisition costs of antimicrobials.”[96]

  • Economic impact: adverse reactions:

The adverse drug reaction profile of levofloxacin and other fluoroquinolone drugs has spawned a grass root movement of those so effected to lobby for Black Box Warnings and Dear Doctor Letters as well as the petitioning of the FDA for the removal of some fluoroquinolone drugs from clinical practice.[97][98][99][100][101][102][103][104]

A number of class action lawsuits as well as malpractice litigation has been spawned by this unacceptable safety profile. The various manufacturers have countered these allegations stating that they believe that these drugs are both safe and effective antibiotics, well tolerated with a minimum of side effects, such reactions are “rare” (contrary to the literature) and the benefits of such therapy outweigh the perceived risks.

See also

Package insert links

Package insert information

References

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  79. ^ "Public Citizen Petitions the FDA to Include a Black Box Warning on Fluoroquinolone Antibiotics (HRG Publication #1781)". Public Citizen. August 29, 2006. http://www.citizen.org/publications/release.cfm?ID=7453. Retrieved 2008-12-27.  
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  97. ^ In The United States District Court For The District Of Columbia Public Citizen, Inc. VS. Food And Drug Administration January 3, 2008
  98. ^ Office Of The Attorney General State Of Illinois Lisa Madigan Citizen Petition to Include a Black Box Warning on Fluoroquinolone Antibiotics May 18, 2005
  99. ^ Public Citizen’s Petition to Include a Black Box Warning on Fluoroquinolone Antibiotics (HRG Publication #1781) August 29, 2006
  100. ^ Public Citizen's Petition to Require a Warning on All Fluoroquinolone Antibiotics (HRG Publication #1399) August 1, 1996
  101. ^ Public Citizen's Petition to Ban the Antibiotic Gatifloxacin (Tequin) (HRG Publication #1768)
  102. ^ Public Citizen's Petition to immediately ban the antibiotic Trovafloxacin (Trovan). (HRG Publication #1485) Date: June 3, 1999
  103. ^ Public Citizen's Petition to immediately stop the distribution of dangerous, misleading prescription drug information to the public. HRG Publication #1442 Date: June 9, 1998
  104. ^ June 2004, A petition To the United States Congress to immediately take action to protect consumers from the reckless and negligent abuses of the FDA and the following Pharmaceutical Companies: Bayer, Ortho-McNeill, Pfizer, Merck, Bristol-Myers Squibb, Sanofi Winthrop, Bertek Pharmaceuticals – Rhone-Poulenc Rorer and Barr. These companies manufacture and distribute fluoroquinolone antibiotics in the United States in a manner that fails to warn of serious adverse event risks, and downplays and fails to warn physicians of the serious risks associated with fluoroquinolone therapy.

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