Ciprofloxacin

From Wikipedia, the free encyclopedia
  (Redirected from Ciproflex)
Jump to: navigation, search
Ciprofloxacin
Systematic (IUPAC) name
1-cyclopropyl- 6-fluoro- 4-oxo- 7-piperazin- 1-yl- quinoline- 3-carboxylic acid
Identifiers
CAS number 85721-33-1
ATC code J01MA02 S01AX13 S02AA15 S03AA07
PubChem CID 2764
DrugBank DB00537
ChemSpider 2662 YesY
UNII 5E8K9I0O4U YesY
KEGG D00186 YesY
ChEMBL CHEMBL8 YesY
Chemical data
Formula C17H18FN3O3 
Mol. mass 331.346
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 69%[1]
Metabolism Hepatic, including CYP1A2
Half-life 4 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat. B3
Legal status Prescription Only (S4)
Routes Oral, intravenous, topical (ear drops, eye drops)
 YesY(what is this?)  (verify)

Ciprofloxacin (INN) is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.[2][3] 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 protein.

Ciprofloxacin is marketed worldwide with over three hundred different brand names. In the United States, Canada, and the UK, it is marketed as Baycip, Ciloxan, Ciflox, Cipro, Cipro XR, Cipro XL, Ciproxin, Prociflor, and most recently, Proquin. In addition, ciprofloxacin is available as a generic drug under a variety of different brand names and is also available for limited use in veterinary medicine.

Ciprofloxacin was first patented in 1983 by Bayer A.G. and subsequently approved by the United States Food and Drug Administration (FDA) in 1987. Ciprofloxacin has 12 FDA-approved human uses and other veterinary uses, but it is often used for unapproved uses (off-label). Ciprofloxacin interacts with other drugs, herbal and natural supplements, and thyroid medications.[4]

Contents

History

Ciprofloxacin 250mg tablets from Ukraine

The patent history for ciprofloxacin makes reference to a 1982 European Patent (patent number 0049355), as well a German patent dated 21 January 1986. Bayer introduced ciprofloxacin in 1987 and was later approved by the U.S. FDA on 22 October 1987 for use in the United States to treat specific bacterial infections. In 1991, the intravenous formulation was introduced. The current United States patent appears to be held by Bayer, being the assignee.[5] The United States patent was applied for in January 1987, but was not approved until 1996 according to the patent history.

In 2004, ciprofloxacin and levofloxacin together commanded 65% ($3.3 billion) of the global sales of the fluoroquinolone class.[6] The first nine months of 2008 sales for ciprofloxacin were $242 million, as compared to $324 million for Bayer aspirin.[7] Ciprofloxacin has proven to be a blockbuster drug for Bayer A. G., generating billions of dollars in additional revenue. "In 1999, Cipro was the eleventh most prescribed drug in the United States based on new prescriptions, and ranked twentieth in total United States sales. In 1999, Bayer's gross sales of Cipro in the United States were approximately $1.04 billion."[8] The sale of ciprofloxacin increased dramatically following the anthrax scare of 2001. On 24 October 2002, the Bush Administration (2001–2009) announced a deal between the government and Bayer Pharmaceuticals to purchase 100 million tablets of ciprofloxacin at a reduced price of $0.95 per pill. A full course of ciprofloxacin for postexposure prophylaxis (60 days) resulting from this arrangement costs the government $204 per person treated, compared with $12 per person treated with doxycycline, the drug normally used to treat anthrax, a difference of $192.[9]

Generic equivalents

On 24 October 2001, The Prescription Access Litigation (PAL), filed suit to dissolve an agreement between Bayer and three of its competitors which produced generic versions of drugs (Barr Laboratories, Rugby Laboratories, and Hoechst-Marion-Roussel) that it claimed was blocking access to adequate supplies and cheaper, generic versions of ciprofloxacin. The plaintiffs charged that Bayer Corporation, a unit of Bayer AG, had unlawfully paid the three competing companies a total of $200 million to prevent cheaper, generic versions of ciprofloxacin from being brought to the market, as well as manipulating the price and supply of ciprofloxacin. Numerous other consumer advocacy groups joined the lawsuit. On 15 October 2008, five years after Bayer’s patent had expired, the United States District Court for the Eastern District of New York granted Bayer’s and the other defendants’ motion for summary judgment, holding that any anticompetitive effects caused by the settlement agreements between Bayer and its codefendants were within the exclusionary zone of the patent and thus could not be redressed by federal antitrust law,[10] in effect upholding Bayer’s agreement with its competitors.

Licensed uses

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

In the adult population, ciprofloxacin is limited to the treatment of proven bacterial infections such as:

  • Urinary tract infections (not recommended as a first-line antibiotic)[11]
  • Acute uncomplicated cystitis in females
  • Chronic bacterial prostatitis (not recommended as a first-line antibiotic choice)[12][13]
  • Lower respiratory tract infections (not recommended as a first-line antibiotic choice)[14][15][16]
  • Acute sinusitis (not recommended as a first-line antibiotic choice)[17]
  • Skin and skin structure infections
  • Bone and joint infections
  • Infectious diarrhea
  • Typhoid fever (enteric fever) caused by Salmonella typhi
  • Uncomplicated cervical and urethra gonorrhea (due to N. gonorrhoeae) – however, this indication is no longer effective in some areas (e.g., Asian countries,[18] United States (including Hawaii), Canada ,[19] and Scotland)[20] due to bacterial resistance. Fluoroquinolones are no longer recommended in the USA for this indication.[21]

Ciprofloxacin is not recommended for the treatment of tuberculosis.[22]

As well as in combination with other specific drugs:

  • Complicated intra-abdominal infections (in combination with metronidazole);
  • Empirical therapy for febrile neutropenic patients (in combination with piperacillin)

Oral and intravenous fluoroquinolones are not licensed by the U.S. FDA for use in children due to the risk of permanent injury to the musculoskeletal system, with two exceptions as outlined below. Within the studies submitted in response to a Pediatric Written Request (ciprofloxacin, circa 2004) the rate of arthropathy was reported to be 9.3% at one month and 13.6% at one year.[23] As such the pediatric use of ciprofloxacin is restricted to proven complicated urinary tract infections and pyelonephritis due to E. coli and inhalation anthrax.[24] Although claimed to be effective, ciprofloxacin is not to be considered a first line agent for inhalation anthrax in the pediatric population.[23][25][26][27] The CDC revoked its recommendation regarding the use of ciprofloxacin as a first line agent in treating anthrax due to the unacceptable risk documented within the Antimicrobial Postexposure Prophylaxis for Anthrax study (aka Cipro 60 day study).[28] However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

Current recommendations by the American Academy of Pediatrics note the systemic use of ciprofloxacin in children should be restricted to infections caused by multidrug resistant pathogens or when no safe or effective alternatives are available.[29]

Indications include:

Ciprofloxacin is not recommended to treat community acquired pneumonia (CAP) as a stand-alone first-line agent. The current guidelines (Infectious Diseases Society of America 2007) state, in very limited circumstances, ciprofloxacin or levofloxacin should be combined with other drugs such as a beta-lactam drug to treat specific CAP infections, but neither drug is recommended to be used separately as a stand-alone first-line agent. In addition, the current guidelines state: “Data exist suggesting that resistance to macrolides and older fluoroquinolones (ciprofloxacin and levofloxacin) results in clinical failure. Other studies have shown that repeated use of fluoroquinolones predicts an increased risk of infection with fluoroquinolone-resistant pneumococci....”[32]

As such, the general opinion stated in 1994 that ciprofloxacin “is not to be considered a suitable agent for use in general practice for the blind initial treatment of chest infections....”[33][34] does not appear to have changed within these current guidelines.

Antibiotics may not improve the long-term clinical outcome for sinusitis.[35] When prescribed for chronic bronchitis and acute bacterial sinusitis, the use of the fluoroquinolone class offers no compelling advantages over established treatment.[36] Nor does antibiotic treatment help sore throats.[37] The use of antibiotics such as ciprofloxacin to treat bronchitis is to be considered unnecessary and as such exposes the patient to an unacceptable risk of suffering a severe adverse reaction.[38] Additionally, antibiotics have no effect upon viral infections, such as the common head cold or viral respiratory infections.

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

Availability

Ciprofloxacin is available as:

  • tablets (100 mg, 250 mg, 500 mg, 750 mg or 1000 mg)
  • intravenous solutions (5% and 10%, 100 mL)
  • eye and ear drops

In most countries, all formulations require a prescription.

See the latest package insert for ciprofloxacin (Cipro) for additional details.[39]

Mode of action

Ciprofloxacin is a broad-spectrum antibiotic active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV,[40] enzymes necessary to separate bacterial DNA, thereby inhibiting cell division.

This mechanism can also affect mammalian cell replication. In particular, some congeners of this drug family (for example those that contain the C-8 fluorine)[41] 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.[42] Although quinolones are 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.).[43]

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.[44][45][46][47] As such, some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.[48][49][50][51][52][53]

There continues to be debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe adverse reactions experienced by some patients following fluoroquinolone therapy.[42][54][55]

Contraindications

As noted above, under licensed use, ciprofloxacin is also now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.[56]

There are only four contraindications found within the 2009 package insert:[39]

  • “Coadministration of ciprofloxacin 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.”
  • “Concomitant administration with tizanidine is contraindicated.”
  • “Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components.”
  • “Local I.V. site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin reactions that resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen.”

Due to growing prevalence of antibiotic resistance to the fluoroquinolones in southeast Asia, the use of ciprofloxacin in patients having been to southeast Asia is increasingly being discouraged.[57]

Ciprofloxacin is also considered to be contraindicated within the pediatric population (except for the indications outlined under licensed use above), pregnancy, nursing mothers, and in patients with epilepsy or other seizure disorders.

  • Pregnancy

The fluoroquinolones rapidly cross the blood-placenta and blood-milk barriers, and are extensively distributed into the fetal tissues. For this reason, the fluoroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The fluoroquinolones 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.[58][59]

  • Pediatric population

Fluoroquinolones are not licensed by the U.S. FDA for use in children due to the risk of fatalities[60] as well as permanent injury to the musculoskeletal system, with two exceptions. Ciprofloxacin is being licensed for the treatment of complicated urinary tract infections and pyelonephritis due to Escherichia coli, and inhalational anthrax (postexposure), and levofloxacin was recently licensed for the treatment of inhalational anthrax (postexposure). However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

Within the studies submitted in response to a Pediatric Written Request (ciprofloxacin, circa 2004), the rate of atrophy was reported to be 9.3%.[61] Within the BPCA Pediatric Studies Summary for ciprofloxacin,[61] it was stated that the overall incidence of adverse events at six weeks was 41%. This would be consistent with the safety profile found with the other fluoroquinolones studied in the pediatric population. As such, the current ban on the use of the fluoroquinolones in the pediatric population is both reasonable and supported by various clinical studies. The most recent long term study, BAY 0 9867 Cipro Pediatric Use Study (QUIP), which followed pediatric patients from 1999–2008,[62] supports the current expert opinion that the risk of permanent injury continues to outweigh the potential benefits of ciprofloxacin therapy in the pediatric population.

Within the United States, the FDA has stated it is their intention to pursue the licensing of the fluoroquinolones for pediatric use in spite of the evidence presented at that 62 Meeting of the Anti-Infective Drugs Advisory Committee that the fluoroquinolones cause irreversible joint damage in the pediatric population.[63]

Special precautions

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 an overdose and the development of toxicity. Ciprofloxacin is eliminated primarily by renal excretion. However, the drug is also metabolized and partially cleared through the liver and the intestines. Modification of the dosage is recommended using the table found within the package insert for those with impaired liver or kidney function. 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 is usually 7 to 14 days.[24]

Adverse effects

Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes. In most, adverse reactions are mild to moderate; however, occasionally serious adverse effects occur.[64][65] There have been a number of regulatory actions taken as a result of such adverse reactions, which included published warnings,[66][67] additional warnings and safety information added to the package inserts[68] together with the issuance of "Dear Doctor Letters"[69] concerning the recent addition of Black Box Warnings. In 2004, the U.S. FDA requested new warning labels to be added to all of the fluoroquinolones, including ciprofloxacin, regarding peripheral neuropathy (irreversible nerve damage), tendon damage, heart problems (prolonged QT Interval / torsades de pointes), pseudomembranous colitis, rhabdomyolysis (muscle breakdown), Stevens-Johnson syndrome, as well as concurrent usage of NSAIDs contributing to the severity of these reactions.

Subsequent to this, on 25 June 2007, the U.S. FDA required the manufacturer to add an additional warning to the package inserts that stated “Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including ciprofloxacin.”[70] It was not until 2008, (four years later) that the label revisions for ciprofloxacin included any warnings concerning heart problems (prolonged QT interval / torsade de pointes). Warnings concerning rhabdomyolysis and Stevens-Johnson syndrome are still conspicuously absent from the package inserts as of September 2009.

The serious adverse effects that may occur as a result of ciprofloxacin therapy include irreversible peripheral neuropathy,[71][72] spontaneous tendon rupture and tendonitis,[73][74][75][76] acute liver failure or serious liver injury (hepatitis),[77][78] QTc prolongation/torsades de pointes,[24] toxic epidermal necrolysis (TEN),[79][80][81] and Stevens-Johnson syndrome, severe central nervous system disorders (CNS)[30] and Clostridium difficile associated disease (CDAD: pseudomembranous colitis),[82][83] as well as photosensitivity/phototoxicity reactions.

Psychotic reactions and confusional states, acute pancreatitis,[84] bone marrow depression, interstitial nephritis and hemolytic anemia may also occur during ciprofloxacin therapy.[85][86] Additional serious adverse reactions include temporary, as well as permanent, loss of vision,[87][88] irreversible double vision,[89] drug induced psychosis[90][91] and chorea (involuntary muscle movements),[92] impaired color vision, exanthema, abdominal pain, malaise, drug fever, dysaesthesia and eosinophilia.[93][94] Pseudotumor cerebri, commonly known as idiopathic intracranial hypertension (IIH), (also referred to as increased intracranial pressure), has been reported to occur as a serious adverse reaction to ciprofloxacin.[95]

Children and the elderly are at a much greater risk of experiencing such adverse reactions.[96][97] Such reactions may manifest during fluoroquinolone therapy, and long after it had been discontinued.[98]

Serious visual complications have also been reported to occur with ophthalmic fluoroquinolone therapy, which may also occur with ciprofloxacin eye drops, especially corneal perforation, but also evisceration and enucleation. This increased incidents of corneal perforation may be due to fluoroquinolones causing alterations in stromal collagen, leading to a reduction in tectonic strength.[99][100] As noted previously permanent double vision (diplopia) has also been reported.[89] An unusual case of seizures has also been reported with ciprofloxacin ear drops in an elderly patient.[101]

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.[102] Partly as a result of the efforts of the State of Illinois and Public Citizen, the FDA ordered black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.[103]

Interactions

The toxicity of drugs that are metabolised by the cytochrome P450 system is enhanced by concomitant use of some quinolones. Coadministration may dangerously increase coumarin (warfarin) activity; INR should be monitored closely. They may also interact with the GABA A receptor and cause neurological symptoms; this effect is augmented by certain nonsteroidal anti-inflammatory drugs.[104] Quercetin, a flavonol, occasionally used as a dietary supplement, may interact with fluoroquinolones, as quercetin competitively binds to bacterial DNA gyrase. Some foods, such as garlic and apples, contain high levels of quercetin; whether this inhibits or enhances the effect of fluoroquinolones is not entirely clear.[105] Ciprofloxacin can reduce phenytoin plasma levels, which may, in some cases, result in seizures.[106] Ciprofloxacin may interfere with the levels of thyroid medications resulting in hypothyroidism.[107]

On 9 November 2005, the U.S. FDA required the manufacturers to provide additional warnings within the package inserts concerning ciprofloxacin being an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. The new warning stated:

"Coadministration of ciprofloxacin 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."[108]

Concurrent administration of ciprofloxacin with magnesium or aluminum antacids, sucralfate or products containing calcium, iron, or zinc (including multivitamins or other dietary supplements) may substantially decrease the absorption of ciprofloxacin, resulting in serum and urine levels considerably lower than desired.[109]

Significant drug interactions

Ciprofloxacin can alter and be altered by the metabolism and effects of other drugs, resulting in some significant drug-drug interactions that may affect the musculoskeletal, central nervous, renal, and other systems.

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.[110] This is the subject of Black box warnings in FDA and BNF labeling for quinolones.

The Committee on the Safety of Medicines and the FDA warn that central nervous system adverse effects, including seizure risk, may be increased when NSAIDs are combined with quinolones.[24][111] The interaction between quinolones and NSAIDs is important, because it has the potential for considerable CNS toxicity. The mechanism for this interaction is believed to be due to a synergistic increased antagonism of GABA neurotransmission.[65]

Ciprofloxacin's renal clearance may affect other drugs subject to renal clearance or otherwise affecting the kidney. The use of ciprofloxacin concomitantly with cyclosporine has also been associated with transient elevations in serum creatinine. Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate and risk of methotrexate toxicity. Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in serum.[24]

Some quinolones, including ciprofloxacin, exert an inhibitory effect on the cytochrome P-450 enzyme CYP1A2, thereby reducing clearance, and thus increasing blood levels of tizanidine and methylxanthines (e.g., theophylline and caffeine).[112][113] The quinolones have also been reported to enhance the effects of warfarin or its derivatives.[24] Such interactions can augment the effects of the co-administered drug, including adverse effects. Ciprofloxacin can reduce effects of other drugs; for example, it has been shown to interact with thyroid medications (levothyroxine), resulting in unexplained hypothyroidism.[114] Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.[24]

Overdose

Overdose of ciprofloxacin may result in reversible renal toxicity. Treatment of overdose includes emptying of the stomach via induced vomiting or by gastric lavage. Careful monitoring and supportive treatment, monitoring of renal function and maintaining adequate hydration is recommended by the manufacturer. Administration of magnesium, aluminum, or calcium containing antacids can reduce the absorption of ciprofloxacin. Hemodialysis or peritoneal dialysis removes only less than 10 percent of ciprofloxacin.[109] Ciprofloxacin may be quantitated in plasma or serum to monitor for drug accumulation in patients with hepatic dysfunction or to confirm a diagnosis of poisoning in acute overdose victims.[115]

Chemistry

Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4 g/mol. It is a faintly yellowish to light yellow crystalline substance.[109]

Ciprofloxacin hydrochloride (USP) is the monohydrochloride monohydrate salt of ciprofloxacin. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8 g/mol. Its empirical formula is C17H18FN3O3HCl•H2O.[109]

Pharmacokinetics

The effects of 200–400 mg of ciprofloxacin given intravenously are linear; drug accumulation does not occur when administered at 12 hour intervals. Bioavailability is approximately 70-80%, with no significant first pass effect. IV administration produces a similar serum levels as those achieved with administration of 500 mg administered orally. IV administration over 60 minutes given every 8 hours produces similar serum levels of the drug as 750 mg administered orally every 12 hours.[109] Biotransformation is hepatic. The elimination half life is 4 hours.[24]

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.[116] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.[117] In response to 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."[118]

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.[119] 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.[73]

Nine years later, in 2005, the Illinois Attorney General filed a second petition with the FDA again 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.[120] In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for Black Box Warnings by filing a third petition requesting such changes be made.[120][121] When the FDA failed to respond to these two petitions as required by law Public Citizen, in January 2008, filed suit to compel the FDA to respond to their 2006 petition.[122][123] On July 7, 2008 the FDA requested that the makers of systemic-use fluoroquinolones add a boxed warning regarding spontaneous tendon ruptures, and to develop a Medication Guide for patients.[124] 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.[125] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes.[126] Ortho-McNeil, the manufacturers of Levaquin, issued a similar letter in November.[127] 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 majority of the generic versions of the fluoroquinolones have not been updated to include this Black Box Warning as of September 2009. Additionally there are numerous reports that this information has not been dessiminated to the pharmacist, the name brand 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.

FDA warning letters

Additionally the manufacturers of ciprofloxacin (Bayer A.G.) received numerous warning letters from the United States Food and Drug Administration regarding false advertising and failure to provide adequate warnings within their promotional materials.[128][129]

Overprescribing and bacterial resistance

Ciprofloxacin is commonly used for urinary tract and intestinal infections (traveler's diarrhea) and was once considered a powerful antibiotic of last resort,[130][131][132] used to treat especially tenacious infections. Not all physicians agreed with this assessment, as evidenced by its wide spread use to treat minor infections as well as non-approved uses. As a result in recent years many bacteria have developed resistance to this drug, leaving it significantly less effective than it would have been otherwise.[133][134]

Resistance to ciprofloxacin 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.[135] Widespread veterinary usage of the fluoroquinolones, particularly in Europe, has been implicated.[136]

Fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002.[137] 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.[137][138] 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.

Current litigation

Bayer AG A class action had been filed against Bayer AG on behalf of employees of the Brentwood Post Office in Washington, D.C., and workers at the U.S. Capitol, along with employees of American Media, Inc. in Florida and postal workers in general who allege that they have suffered serious adverse effects from taking the antibiotic ciprofloxacin (Cipro) in the aftermath of the anthrax attacks in 2001. The adverse effects included; tendon rupture, seizures, intestinal problems, tendonitis, anxiety, insomnia, muscle aches, depression and meniscus tears. The action alleged that Bayer failed to warn class members of the potential side effects of the drug, thereby violating the Pennsylvania Unfair Trade Practices and Consumer Protection Laws. According to the allegations within the complaint, exposed individuals were not informed of the true safety profile of ciprofloxacin, the high rate of adverse events associated with its use, or the availability of safer and equally effective alternative drugs. The complaint further alleged that, as a result of taking Cipro, many individuals suffered severe and debilitating injuries. The action sought funding for a medical monitoring program and compensatory damages for those workers who have suffered side effects. In 2004, the law firm of Goodell, DeVries, Leech & Dann, LLP were retained as national counsel in this litigation. The class action was defeated and the litigation abandoned by the plaintiffs.[139][140][141] A similar action had been filed in New Jersey that covers New Jersey postal workers. Final disposition of that lawsuit is unknown. Following the addition of the Black Box Warning in 2008, regarding tendon damage, a significant number of product liability law firms began soliciting clients who have suffered a spontaneous tendon rupture following fluoroquinolone therapy.[142][143][144]

See also

Package insert links

References

  1. ^ Drusano GL, Standiford HC, Plaisance K, Forrest A, Leslie J, Caldwell J, GL (September 1986). "Absolute oral bioavailability of ciprofloxacin". Antimicrob Agents Chemother. 30 (3): 444–6. doi:10.1128/AAC.. ISSN 0066-4804. PMID 3777908. PMC 180577. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=3777908. 
  2. ^ Nelson, JM.; Chiller, TM.; Powers, JH.; Angulo, FJ. (Apr 2007). "Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story.". Clin Infect Dis 44 (7): 977–80. doi:10.1086/512369. PMID 17342653. 
  3. ^ Kawahara, S. (Dec 1998). "[Chemotherapeutic agents under study]". Nippon Rinsho 56 (12): 3096–9. PMID 9883617. 
  4. ^ Cooper JG, Harboe K, Frost SK, Skadberg Ø, JG (April 2005). "Ciprofloxacin interacts with thyroid replacement therapy". BMJ 330 (7498): 1002. doi:10.1136/bmj.330.7498.1002. ISSN 0959-8138. PMID 15860826. 
  5. ^ Streuff, et al (15 February 1994). "United States Patent 5,286,754". USA: uspto.gov. http://patft.uspto.gov/netacgi/nph-Parser?u=%2Fnetahtml%2Fsrchnum.htm&Sect1=PTO1&Sect2=HITOFF&p=1&r=1&l=50&f=G&d=PALL&s1=5286754.PN.&OS=PN/5286754&RS=PN/5286754. Retrieved 30 August 2009. 
  6. ^ "Commercial Perspectives: Fluoroquinolones - Established Products Drive Market Growth". 28 January 2004. https://www.leaddiscovery.co.uk/reports/843/Commercial_Perspectives_Fluoroquinolones_Established_Products_Drive_Market_Growth. Retrieved 30 August 2009. 
  7. ^ Dr. Katrin Schneider (29 October 2008). "Stockholders’ Newsletter" (PDF). Bayer AG. http://www.stockholders-newsletter-q3-08.bayer.com/en/bayer_stockholders_newsletter_3Q_08.pdfx. Retrieved 30 August 2009. 
  8. ^ "Cipro". USA: Prescription Access. http://www.prescriptionaccess.org/lawsuitssettlements/past_lawsuits?id=0010. Retrieved 4 September 2009. 
  9. ^ Bayer Corporation (24 October 2001). "HHS, BAYER AGREE TO CIPRO PURCHASE". USA: U.S. Department of Health & Human Services. http://www.hhs.gov/news/press/2001pres/20011024.html. Retrieved 4 September 2009. [dead link]
  10. ^ United States Court of Appeals for the Federal Circuit (2008). "United States Court of Appeals for the Federal Circuit" (PDF). USA. http://www.cafc.uscourts.gov/opinions/08-1097.pdf. Retrieved 4 September 2009. [dead link]
  11. ^ "Fluroquinolone Drug Class Review". Oregon State University College of Pharmacy. 2002. http://pharmacy.oregonstate.edu/drug_policy/pages/dur_board/reviews/articles/fluroquinolone-lit.html. Retrieved 4 September 2009. 
  12. ^ Litwin, RB; Chronic Prostatitis Collaborative Research, KJ; Nadler, AJ; Zeitlin, JR; Nickel, J. Curtis, JC; O'Leary, Michael P, MP; Pontari, Michel A, MA; McNaughton-collins, Mary, M et al. (October 19, 2004). "Ciprofloxacin or Tamsulosin in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Randomized, Double-Blind Trial". Annals of Internal Medicine 141 (8): 581. ISSN 0003-4819. PMID 15492337. http://www.annals.org/cgi/content/full/141/8/581. "did not substantially reduce symptoms in men with long-standing CP/CPPS who had at least moderate symptoms.". 
  13. ^ J. Dimitrakov; J. Tchitalov, T. Zlatanov, D. Dikov. "A Prospective, Randomized, Double-Blind, Placebo-Controlled Study Of Antibiotics For The Treatment Of Category Iiib Chronic Pelvic Pain Syndrome In Men". Third International Chronic Prostatitis Network. http://www.prostatitis.org/a92000.html. Retrieved 4 September 2009. 
  14. ^ A Zuger (3 November 1998). "Ciprofloxacin for Acute Exacerbations of Chronic Bronchitis". Journal Watch (General) 1998 (1103): 4. http://general-medicine.jwatch.org/cgi/content/citation/1998/1103/4. "Because of its unpredictable activity against the pneumococcus, ciprofloxacin is not usually considered a first-line treatment for respiratory infections...". 
  15. ^ Vardakas, KZ.; Siempos, II.; Grammatikos, A.; Athanassa, Z.; Korbila, IP.; Falagas, ME. (December 2008). "Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials.". CMAJ 179 (12): 1269–77. doi:10.1503/cmaj.080358. PMID 19047608. PMC 2585120. http://www.ecmaj.com/cgi/reprint/179/12/1269. 
  16. ^ Donaldson, Pm, PM; Pallett, Ap, AP; Carroll, Mp, MP (May 1994). "Ciprofloxacin in general practice." (PDF). BMJ (Clinical research ed.) 308 (6941): 1437. ISSN 0959-8138. PMID 8019264. PMC 2540361. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2540361&blobtype=pdf. 
  17. ^ Karageorgopoulos, DE.; Giannopoulou, KP.; Grammatikos, AP.; Dimopoulos, G.; Falagas, ME. (March 2008). "Fluoroquinolones compared with beta-lactam antibiotics for the treatment of acute bacterial sinusitis: a meta-analysis of randomized controlled trials.". CMAJ 178 (7): 845–54. doi:10.1503/cmaj.071157. PMID 18362380. PMC 2267830. http://www.cmaj.ca/cgi/content/full/178/7/845. 
  18. ^ (World Health Organization (WHO) Western Pacific Region Gonococcal Antimicrobial Susceptibility Programme (GASP) Report- 2000. Commun Dis Intell 2001; 25:274-277).
  19. ^ DEPARTMENT OF HEALTH AND HUMAN SERVICES; Centers for Disease Control and Prevention (November 2004). "Gonococcal Isolate Surveillance Project (GISP) Annual Report - 2003" (PDF). USA: Center for Disease Controlo. http://www.cdc.gov/STD/gisp2003/GISP2003.pdf. Retrieved 31 August 2009. 
  20. ^ Hugh Young (22 July 2003). "Ciprofloxacin resistant gonorrhoea: the situation in Scotland and implications for therapy" (PDF). SCIEH Weekly Report - SCOTTISH CENTRE FOR INFECTION AND ENVIRONMENTAL HEALTH (Scotland: National Health Service) 37. ISSN 1357-4493. http://www.documents.hps.scot.nhs.uk/ewr/pdf2003/0329.pdf. 
  21. ^ Centers for Disease Control and Prevention (CDC) (13 April 2007). [Center for Disease Control "Update to CDC's sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections."] (PDF). Morbidity and Mortality Weekly Report (USA: Center for Disease Control) 56 (14): 332–336. PMID 17431378. Center for Disease Control. Retrieved 31 August 2009. 
  22. ^ Ziganshina, LE; Vizel, AA; Squire, SB; Ziganshina, Lilia (July 2005). "Fluoroquinolones for treating tuberculosis.". Cochrane database of systematic reviews (Online) (3): CD004795. doi:10.1002/14651858.CD004795.pub2. PMID 16034951. 
  23. ^ a b Meyer, Joette (16 March 2004). "Division of Special Pathogen and Immunologic Drug Products - Summary of Clinical Review of Studies Submitted in Response to a Pediatric Written Request" (PDF). USA: FDA. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4152b1_03_03_Cipro%20medical.pdf. Retrieved 31 August 2009. 
  24. ^ a b c d e f g h Bayer HealthCare Pharmaceuticals Inc (September 2008). "CIPRO (ciprofloxacin hydrochloride) TABLETS CIPRO,(ciprofloxacin*) ORAL SUSPENSION" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019537s68,19847s42,19857s49,20780s26,21473s24lbl.pdf. Retrieved 31 August 2009. 
  25. ^ Chalumeau, M., M; Tonnelier, S; D'athis, P; Tréluyer, JM; Gendrel, D; Bréart, G; Pons, G; Pediatric Fluoroquinolone Safety Study Investigators, Investigators (June 2003). "Fluoroquinolone Safety in Pediatric Patients: A Prospective, Multicenter, Comparative Cohort Study in France" (PDF). Pediatrics 111 (6 Pt 1): e714. doi:10.1542/peds.111.6.e714. ISSN 0031-4005. PMID 12777590. http://pediatrics.aappublications.org/cgi/reprint/111/6/e714. 
  26. ^ 62 Meeting of the Anti-Infective Drugs Advisory Committee
  27. ^ Farinas, Evelyn R; DEPARTMENT OF HEALTH AND HUMAN (1 March 2005). "Consult: One-Year Post Pediatric Exclusivity Postmarketing Adverse Events Review" (PDF). USA: FDA. http://www.fda.gov/OHRMS/DOCKETS/AC/05/briefing/2005-4152b1_03_01_Cipro%20AE.pdf. Retrieved 31 August 2009. 
  28. ^ Shepard, Cw, CW; Cdc Adverse Events Working, M; Zell, Er, ER; Hayslett, J, J; Lukacs, S, S; Goldstein, S, S; Factor, S, S; Jones, J, J et al. (October 2002). "Antimicrobial postexposure prophylaxis for anthrax: adverse events and adherence.". Emerging infectious diseases (USA: Center for Disease Control) 8 (10): 1124–32. ISSN 1080-6040. PMID 12396927. http://www.cdc.gov/ncidod/EID/vol8no10/02-0349.htm. 
  29. ^ Lexi-Comp (February 2009). "Ciprofloxacin". Merk. http://www.merck.com/mmpe/lexicomp/ciprofloxacin.html. Retrieved 4 September 2009. 
  30. ^ a b Renata Albrecht (25 March 2004). "NDA 19-537/S-049, NDA 19-857/S-031, NDA 19-847/S-027, NDA 20-780/S-013" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19537s049,19857s031,19847s027,20780s013ltr.pdf. Retrieved 7 September 2009. 
  31. ^ Dianne Murphy. "NDA 19-537/S-038, NDA 19-847/S-024, NDA 19-857/S-027, NDA 19-858/S-021, NDA 20-780/S-008" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2000/20780S08ltr.pdf. 
  32. ^ Mandell, LA.; Wunderink, RG.; Anzueto, A.; Bartlett, JG.; Campbell, GD.; Dean, NC.; Dowell, SF.; File, TM. et al. (Mar 2007). "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults." (PDF). Clin Infect Dis 44 Suppl 2: S27–72. doi:10.1086/511159. PMID 17278083. http://www.thoracic.org/sections/publications/statements/resources/idsaats-cap.pdf. 
  33. ^ Donaldson, PM.; Pallett, AP.; Carroll, MP. (May 1994). "Ciprofloxacin in general practice." (PDF). BMJ 308 (6941): 1437. PMID 8019264. PMC 2540361. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2540361/pdf/bmj00442-0061a.pdf. 
  34. ^ Körner, RJ.; Reeves, DS.; MacGowan, AP. (Jan 1994). "Dangers of oral fluoroquinolone treatment in community acquired upper respiratory tract infections.". BMJ 308 (6922): 191–2. PMID 8312775. PMC 2542530. http://www.bmj.com/cgi/content/extract/308/6922/191. 
  35. ^ van Buchem, F. L. (March 8, 1997). "Primary-care-based randomised placebo-controlled trial of antibiotic treatment in acute maxillary sinusitis". The Lancet 349 (9053): 683–687. doi:10.1016/S0140-6736(96)07585-X. PMID 9078199. 
  36. ^ "Moxifloxacin - a new fluoroquinolone antibacterial". Drug and Therapeutics Bulletin 42 (8): 61. August 2004. doi:10.1136/dtb.2004.42861. ISSN 0012-6543. PMID 15310155. http://dtb.bmj.com/cgi/content/abstract/42/8/61. 
  37. ^ Majeed, A, A; Harris, T, T (August 1997). "Acute otitis media in children.". BMJ (Clinical research ed.) 315 (7104): 321–2. ISSN 0959-8138. PMID 9270442. PMC 2127258. http://www.bmj.com/archive/7104/7104e1.htm. 
  38. ^ Hueston, Wj, WJ (March 1997). "Antibiotics: neither cost effective nor 'cough' effective." (Free full text). The Journal of family practice 44 (3): 261–5. ISSN 0094-3509. PMID 9071245. http://www.nlm.nih.gov/medlineplus/antibiotics.html. 
  39. ^ a b Bayer HealthCare Pharmaceuticals (12 February 2009). "CIPRO (ciprofloxacin hydrochloride) TABLETS CIPRO (ciprofloxacin*) ORAL SUSPENSION" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019537s69,19847s43,19857s50,20780s27lbl.pdf. Retrieved 1 September 2009. 
  40. ^ Drlica K, Zhao X, K (September 1, 1997). "DNA gyrase, topoisomerase IV, and the 4-quinolones". Microbiol Mol Biol Rev. 61 (3): 377–92. ISSN 1092-2172. PMID 9293187. PMC 232616. http://mmbr.asm.org/cgi/pmidlookup?view=long&pmid=9293187. 
  41. ^ Robinson MJ, Martin BA, Gootz TD, McGuirk PR, Osheroff N, MJ (April 1992). "Effects of novel fluoroquinolones on the catalytic activities of eukaryotic topoisomerase II: Influence of the C-8 fluorine group" (PDF). Antimicrob. Agents Chemother. 36 (4): 751–6. ISSN 0066-4804. PMID 1323952. PMC 189387. http://aac.asm.org/cgi/reprint/36/4/751.pdf. 
  42. ^ a b Sissi C, Palumbo M, C (November 2003). "The quinolone family: from antibacterial to anticancer agents". Curr Med Chem Anticancer Agents 3 (6): 439–50. doi:10.2174/1568011033482279. ISSN 1568-0118. PMID 14529452. http://openurl.ingenta.com/content/nlm?genre=article&issn=1568-0118&volume=3&issue=6&spage=439&aulast=Sissi. "The present review focuses on the structural modifications responsible for the transformation of an antibacterial into an anticancer agent. Indeed, a distinctive feature of drugs based on the quinolone structure is their remarkable ability to target different type II topoisomerase enzymes. 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.". 
  43. ^ Hussy P, Maass G, Tümmler B, Grosse F, Schomburg U, P (June 1986). "Effect of 4-quinolones and novobiocin on calf thymus DNA polymerase alpha primase complex, topoisomerases I and II, and growth of mammalian lymphoblasts" (PDF). Antimicrob. Agents Chemother. 29 (6): 1073–8. ISSN 0066-4804. PMID 3015015. PMC 180502. http://aac.asm.org/cgi/reprint/29/6/1073.pdf. 
  44. ^ "Mutagenicity of norfloxacin and AM-833 in bacteria and mammalian cells". Rev. Infect. 1 (jstor.org) 10: S148–S149. 1988. http://www.jstor.org/pss/4454399. 
  45. ^ Forsgren A, Bredberg A, Pardee AB, Schlossman SF, Tedder TF, A (May 1987). "Effects of ciprofloxacin on eucaryotic pyrimidine nucleotide biosynthesis and cell growth" (PDF). Antimicrob. Agents Chemother. 31 (5): 774–9. ISSN 0066-4804. PMID 3606077. PMC 174831. http://aac.asm.org/cgi/reprint/31/5/774.pdf. 
  46. ^ Gootz TD, Barrett JF, Sutcliffe JA, TD (January 1990). "Inhibitory effects of quinolone antibacterial agents on eucaryotic topoisomerases and related test systems". Antimicrob. Agents Chemother. 34 (1): 8–12. ISSN 0066-4804. PMID 2158274. PMC 171510. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=171510&blobtype=pdf. 
  47. ^ Lawrence JW, Darkin-Rattray S, Xie F, Neims AH, Rowe TC, JW (February 1993). "4-Quinolones cause a selective loss of mitochondrial DNA from mouse L1210 leukemia cells" (Free full text). J. Cell. Biochem. 51 (2): 165–74. doi:10.1002/jcb.240510208. ISSN 0730-2312. PMID 8440750. 
  48. ^ Elsea SH, Osheroff N, Nitiss JL, SH (July 1992). "Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast". J. Biol. Chem. 267 (19): 13150–3. ISSN 0021-9258. PMID 1320012. http://www.jbc.org/cgi/reprint/267/19/13150. 
  49. ^ Suto MJ, Domagala JM, Roland GE, Mailloux GB, Cohen MA, MJ (December 1992). "Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity". J. Med. Chem. 35 (25): 4745–50. doi:10.1021/jm00103a013. ISSN 0022-2623. PMID 1469702. 
  50. ^ Enzmann H, Wiemann C, Ahr HJ, Schlüter G, H (April 1999). "Damage to mitochondrial DNA induced by the quinolone Bay y 3118 in embryonic turkey liver". Mutat. Res. 425 (2): 213–24. doi:10.1016/S0027-5107(99)00044-5. ISSN 0027-5107. PMID 10216214. 
  51. ^ Kashida Y, Sasaki YF, Ohsawa K, Y (October 2002). "Mechanistic study on flumequine hepatocarcinogenicity focusing on DNA damage in mice". Toxicol. Sci. 69 (2): 317–21. doi:10.1093/toxsci/69.2.317. ISSN 1096-6080. PMID 12377980. http://toxsci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12377980. 
  52. ^ Thomas A, Tocher J, Edwards DI, A (May 1990). "Electrochemical characteristics of five quinolone drugs and their effect on DNA damage and repair in Escherichia coli". J. Antimicrob. Chemother. 25 (5): 733–44. doi:10.1093/jac/25.5.733. ISSN 0305-7453. PMID 2165050. http://jac.oxfordjournals.org/cgi/reprint/25/5/733. 
  53. ^ "Fluoroquinolones and Quinolones". The American Academy of Optometry (British Chapter). http://www.academy.org.uk/pharmacy/fluoroq.htm. Retrieved 29 January 2009. 
  54. ^ Al-Soud, Yaseen A.; Al-masoudi, Najim A (2003). "A new class of dihaloquinolones bearing N'-aldehydoglycosylhydrazides, mercapto-1,2,4-triazole, oxadiazoline and a-amino ester precursors: synthesis and antimicrobial activity". J. Braz. Chem. Soc 14 (5). doi:10.1590/S0103-50532003000500014. http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532003000500014&lng=es&nrm=iso&tlng=es. "Nevertheless, some quinolones cause injury to the chromosome of eukaryotic cells.21,22 These findings prompted us to optimize the substituent at C-3, by...". 
  55. ^ Yaseen A. Al-Soud a and Najim A. Al-Masoudi (2003). "A New Class of Dihaloquinolones Bearing N’-Aldehydoglycosylhydrazides, Mercapto-1,2,4-triazole, Oxadiazoline and α-Amino Ester Precursors: Synthesis and Antimicrobial Activity" (PDF). J. Braz. Chem. Soc 14 (5): 790–796. http://jbcs.sbq.org.br/jbcs/2003/v14_n5/13-048-02.pdf. "Although the current quinolones are not considered to be potent inhibitors of eucaryotic topoisomerases, some effects on these and other enzymes involved with DNA replication have been observed". 
  56. ^ Susan Blank; Julia Schillinger (14 May 2004). "DOHMH ALERT #8:Fluoroquinolone-resistant gonorrhea, NYC". USA: New York County Medical Society. http://www.nycms.org/article_view.php3?view=947&part=1. Retrieved 22 July 2009. 
  57. ^ Centers for Disease Control and Prevention (CDC) (October 1995). "Fluoroquinolone resistance in Neisseria gonorrhoeae—Colorado and Washington, 1995". MMWR Morb Mortal Wkly Rep. 44 (41): 761–4. ISSN 0149-2195. PMID 7565558. http://www.cdc.gov/mmwr/preview/mmwrhtml/00039305.htm. 
  58. ^ Shin HC, Kim JC, Chung MK, HC (September 2003). "Fetal and maternal tissue distribution of the new fluoroquinolone DW-116 in pregnant rats". Comp. Biochem. Physiol. C Toxicol. Pharmacol. 136 (1): 95–102. doi:10.1016/j.cca.2003.08.004. ISSN 1532-0456. PMID 14522602. 
  59. ^ Dan M, Weidekamm E, Sagiv R, Portmann R, Zakut H, M (February 1993). "Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women". Antimicrob. Agents Chemother. 37 (2): 293–6. ISSN 0066-4804. PMID 8452360. PMC 187655. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=8452360. 
  60. ^ Karande SC, Kshirsagar NA, SC (February 1992). "Adverse drug reaction monitoring of ciprofloxacin in pediatric practice" (Free full text). Indian Pediatr 29 (2): 181–8. ISSN 0019-6061. PMID 1592498. 
  61. ^ a b Joette Meyer; Renata Albrecht (16 March 2004). "Division of Special Pathogen and Immunologic Drug Products Summary of Clinical Review of Studies Submitted in Response to a Pediatric Written Request" (PDF). USA: FDA. http://www.fda.gov/ohrms/dockets/AC/05/briefing/2005-4152b1_03_03_Cipro%20medical.pdf. Retrieved 22 July 2009. 
  62. ^ BAY 0 9867 Cipro Pediatric Use Study (QUIP) - Study Results - ClinicalTrials.gov
  63. ^ 62 Meeting of the Anti-Infective Drugs Advisory Committee FQresearch.org
  64. ^ Owens Rc, Jr; Ambrose, PG (July 2005). "Antimicrobial safety: focus on fluoroquinolones.". Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 41 Suppl 2: S144–57. doi:10.1086/428055. ISSN 1058-4838. PMID 15942881. 
  65. ^ a b De Sarro A, De Sarro G (March 2001). "Adverse reactions to fluoroquinolones. an overview on mechanistic aspects" (PDF). Curr. Med. Chem. 8 (4): 371–84. PMID 11172695. http://www.fqresearch.org/pdf_files/cmc.pdf. 
  66. ^ U S Food and Drug Administration (8 July 2008). "FDA Requests Boxed Warnings on Fluoroquinolone Antimicrobial Drugs" (PDF). USA: FDA. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116919.htm. Retrieved 5 September 2009. 
  67. ^ US Food and Drug Administration (2008). "Fluoroquinolone Antimicrobial Drugs [ciprofloxacin (marketed as Cipro and generic ciprofloxacin), ciprofloxacin extended release (marketed as Cipro XR and Proquin XR), gemifloxacin (marketed as Factive), levofloxacin (marketed as Levaquin), moxifloxacin (marketed as Avelox), norfloxacin (marketed as Noroxin), and ofloxacin (marketed as Floxin and generic ofloxacin)"]. USA. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm084316.htm. Retrieved 5 September 2009. [dead link]
  68. ^ US Food and Drug Administration. "Drugs at FDA: FDA Approved Drug Products". USA: FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist. Retrieved 5 September 2009. 
  69. ^ Paul MacCarthy (22 October 2008). "Important Change in the Avelox (moxifloxacin hydrochloride) and Cipro (ciprofloxacin) Complete Prescribing Information – Addition of Boxed Warning and Medication Guide Regarding Tendinitis and Tendon Rupture" (PDF). Bayer healthcare pharmaceuticals. http://www.avelox.com/html/pdf/dhpl.pdf. Retrieved 5 September 2009. 
  70. ^ Renata Albrecht (19 June 2006). "NDA 19-537/S-062, NDA 20-780/S-023, NDA 19-847/S-037, NDA 19-857/S-042, NDA 21-473/S-016" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/019537s62,020780s23,019847s37,019857s42,021473s16LTR.pdf. Retrieved 5 September 2009. 
  71. ^ Renata Albrecht (14 July 2004). "NDA 19-537/S-053, S-054, NDA 20-780/S-017, S-018" (PDF). USA. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19537s053,054,20780s017,018ltr.pdf. Retrieved 5 September 2009. 
  72. ^ Zehnder, D; Hoigné, R; Neftel, KA; Sieber, R (November 1995). "Painful dysaesthesia with ciprofloxacin.". BMJ (Clinical research ed.) 311 (7014): 1204. ISSN 0959-8138. PMID 7488901. PMC 2551120. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2551120&blobtype=pdf. "One case of peripheral neuropathy has been reported. We report two cases of generalised painful dysaesthesia due to ciprofloxacin, a reaction not previously associated with this particular fluoroquinolone". 
  73. ^ a b "Reports of adverse events with fluoroquinolones" (Doc). FDA Medical Bulletin 26 (3). October 1996. http://www.fqresearch.org/text_documents/FDA_Medical_Bulletin_1996.doc. 
  74. ^ Renata Albrecht (15 March 2004). "NDA 19-537/S-048, S-050, S-051, NDA 20-780/S-012, S-014, S-015" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19537slr048,050,051,20780slr012,014,015ltr.pdf. Retrieved 5 September 2009. 
  75. ^ FQresearch.org
  76. ^ Renata Albrecht (3 October 2008). "NDA 19-537/S-068, NDA 19-847/S-042, NDA 19-857/S-049, NDA 20-780/S-026, NDA 21-473/S-024" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/019537s068,019847s042ltr.pdf. Retrieved 5 September 2009. 
  77. ^ Sherman, O; Beizer, JL (October 1994). "Possible ciprofloxacin-induced acute cholestatic jaundice." (Free full text). The Annals of pharmacotherapy 28 (10): 1162–4. ISSN 1060-0280. PMID 7841570. http://www.nlm.nih.gov/medlineplus/bileductdiseases.html. 
  78. ^ Zimpfer, A; Propst, A; Mikuz, G; Vogel, W; Terracciano, L; Stadlmann, S (January 2004). "Ciprofloxacin-induced acute liver injury: case report and review of literature.". Virchows Archiv : an international journal of pathology 444 (1): 87–9. doi:10.1007/s00428-003-0917-9. ISSN 0945-6317. PMID 14994731. 
  79. ^ Jongen-Lavrencic, M; Schneeberger; Van Der Hoeven (December 2003). "Ciprofloxacin-induced toxic epidermal necrolysis in a patient with systemic lupus erythematosus.". Infection 31 (6): 428–9. doi:10.1007/s15010-003-2128-3. ISSN 0300-8126. PMID 14735388. 
  80. ^ Moshfeghi, M; Mandler (December 1993). "Ciprofloxacin-induced toxic epidermal necrolysis.". The Annals of pharmacotherapy 27 (12): 1467–9. ISSN 1060-0280. PMID 8305780. 
  81. ^ Moshfeghi, M; Mandler (December 1993). "Ciprofloxacin-induced toxic epidermal necrolysis.". The Annals of pharmacotherapy 27 (12): 1467–9. ISSN 1060-0280. PMID 8305780. 
  82. ^ Deshpande, A; Pant; Jain; Fraser; Rolston (February 2008). "Do fluoroquinolones predispose patients to Clostridium difficile associated disease? A review of the evidence.". Current medical research and opinion 24 (2): 329–33. doi:10.1185/030079908X253735. ISSN 0300-7995. PMID 18067688. 
  83. ^ Renata Albrecht (25 June 2007). "NDA 19-537/S-065, NDA 19-847/S-039, NDA 19-857/S-046, NDA 20-780/S-024, NDA 21-473/S-022" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/019537s65,19847s39,19857s46,20780s24,21473s22ltr.pdf. Retrieved 4 September 2009. 
  84. ^ Mann, S; Thillainayagam (December 2000). "Is ciprofloxacin a new cause of acute pancreatitis?". Journal of Clinical Gastroenterology 31 (4): 336. doi:10.1097/00004836-200012000-00014. ISSN 0192-0790. PMID 11129278. 
  85. ^ Dutta, TK; Badhe (September 1999). "Ciprofloxacin-induced bone marrow depression.". Postgraduate medical journal 75 (887): 571–3. ISSN 0032-5473. PMID 10616701. 
  86. ^ Lim, S; Alam (July 2003). "Ciprofloxacin-induced acute interstitial nephritis and autoimmune hemolytic anemia.". Renal failure 25 (4): 647–51. doi:10.1081/JDI-120022557. ISSN 0886-022X. PMID 12911170. 
  87. ^ Vrabec, TR; Sergott; Jaeger; Savino; Bosley (June 1990). "Reversible visual loss in a patient receiving high-dose ciprofloxacin hydrochloride (Cipro)". Ophthalmology 97 (6): 707–10. ISSN 0161-6420. PMID 2374675. 
  88. ^ Samarakoon, N; Harrisberg; Ell (January 2007). "Ciprofloxacin-induced toxic optic neuropathy.". Clinical & experimental ophthalmology 35 (1): 102–4. doi:10.1111/j.1442-9071.2007.01427.x. ISSN 1442-6404. PMID 17300586. 
  89. ^ a b Fraunfelder, FW; Fraunfelder (September 2009). "Diplopia and fluoroquinolones". Ophthalmology 116 (9): 1814–7. doi:10.1016/j.ophtha.2009.06.027. ISSN 0161-6420. PMID 19643481. 
  90. ^ Mulhall, JP; Bergmann (July 1995). "Ciprofloxacin-induced acute psychosis.". Urology 46 (1): 102–3. doi:10.1016/S0090-4295(99)80171-X. ISSN 0090-4295. PMID 7604468. 
  91. ^ Reeves, RR (July 1992). "Ciprofloxacin-induced psychosis.". The Annals of pharmacotherapy 26 (7-8): 930–1. ISSN 1060-0280. PMID 1504404. 
  92. ^ Azar, S; Ramjiani; Van Gerpen (April 2005). "Ciprofloxacin-induced chorea.". Movement disorders : official journal of the Movement Disorder Society 20 (4): 513–4; author reply 514. doi:10.1002/mds.20425. ISSN 0885-3185. PMID 15739219. 
  93. ^ "Therapy of acute and chronic gram-negative osteomyelitis with ciprofloxacin. Report from a Swedish Study Group.". The Journal of antimicrobial chemotherapy 22 (2): 221–8. August 1988. doi:10.1093/jac/22.2.221. ISSN 0305-7453. PMID 3053554. 
  94. ^ Zehnder, D; Hoigné; Neftel; Sieber (November 1995). "Painful dysaesthesia with ciprofloxacin.". BMJ (Clinical research ed.) 311 (7014): 1204. ISSN 0959-8138. PMID 7488901. "One case of peripheral neuropathy has been reported. We report two cases of generalised painful dysaesthesia due to ciprofloxacin, a reaction not previously associated with this particular fluoroquinolone.". 
  95. ^ Winrow, AP; Supramaniam (October 1990). "Benign intracranial hypertension after ciprofloxacin administration." (PDF). Archives of disease in childhood 65 (10): 1165–6. doi:10.1136/adc.65.10.1165. ISSN 0003-9888. PMID 2248512. PMC 1792342. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1792342&blobtype=pdf. 
  96. ^ Iannini, PB (June 2007). "The safety profile of moxifloxacin and other fluoroquinolones in special patient populations.". Current medical research and opinion 23 (6): 1403–13. doi:10.1185/030079907X188099. ISSN 0300-7995. PMID 17559736. 
  97. ^ Owens Rc, Jr; Ambrose (July 2005). "Antimicrobial safety: focus on fluoroquinolones.". Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 41 Suppl 2: S144–57. doi:10.1086/428055. ISSN 1058-4838. PMID 15942881. 
  98. ^ Saint, F; Gueguen; Biserte; Fontaine; Mazeman (September 2000). "Rupture of the patellar ligament one month after treatment with fluoroquinolone". Revue de chirurgie orthopedique et reparatrice de l'appareil moteur 86 (5): 495–7. ISSN 0035-1040. PMID 10970974. 
  99. ^ Gangopadhyay, N; Daniell; Weih; Taylor (April 2000). "Fluoroquinolone and fortified antibiotics for treating bacterial corneal ulcers." (PDF). The British journal of ophthalmology 84 (4): 378–84. doi:10.1136/bjo.84.4.378. ISSN 0007-1161. PMID 10729294. PMC 1723447. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1723447&blobtype=pdf. 
  100. ^ Walter, K; Tyler (August 2006). "Severe corneal toxicity after topical fluoroquinolone therapy: report of two cases.". Cornea 25 (7): 855–7. doi:10.1097/01.ico.0000224642.43601.14. ISSN 0277-3740. PMID 17068466. 
  101. ^ Orr, Cf; Rowe, Db (April 2003). "Eardrop attacks: seizures triggered by ciprofloxacin eardrops.". The Medical journal of Australia 178 (7): 343. ISSN 0025-729X. PMID 12670280. http://www.mja.com.au/public/issues/178_07_070403/orr10717_fm.html. 
  102. ^ "Public Citizen Warns of Cipro Dangers". USA: Consumer affairs. 30 August 2006. http://www.consumeraffairs.com/news04/2006/08/pubcit_cipro.html. Retrieved 7 September 2009. 
  103. ^ "FDA orders 'black box' label on some antibiotics". CNN. 8 July 2008. http://www.cnn.com/2008/HEALTH/07/08/antibiotics.risk/index.html. Retrieved 2008-07-08. 
  104. ^ Brouwers JR, JR (July 1992). "Drug interactions with quinolone antibacterials". Drug Saf 7 (4): 268–81. doi:10.2165/00002018-199207040-00003. ISSN 0114-5916. PMID 1524699. 
  105. ^ Hilliard JJ, Krause HM, Bernstein JI, JJ (1995). "A comparison of active site binding of 4-quinolones and novel flavone gyrase inhibitors to DNA gyrase". Adv Exp Med Biol. 390: 59–69. ISSN 0065-2598. PMID 8718602. 
  106. ^ Carol Langlois; Pascale Springuel (January 1998). "Risk of seizures from concomitant use of ciprofloxacin and phenytoin in patients with epilepsy" (PDF). Canada: Canadian Adverse Drug Reaction Newsletter. http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/carn-bcei_v8n1-eng.pdf. Retrieved 2009-01-30. 
  107. ^ Cooper JG, Harboe K, Frost SK, Skadberg Ø, JG (April 2005). "Ciprofloxacin interacts with thyroid replacement therapy". BMJ 330 (7498): 1002. doi:10.1136/bmj.330.7498.1002. ISSN 0959-8138. PMID 15860826. PMC 557149. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15860826. 
  108. ^ Renata Albrecht (2005-11-09). "NDA 19-537/S-060, NDA 19-847/S-036, NDA 19-857/S-041, NDA 20-780/S-020, NDA 21-473/S-013" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/019537s60,019847s36,019857s41,020780s20,021473s13ltr.pdf. Retrieved 2009-09-08. 
  109. ^ a b c d e Bayer HealthCare Pharmaceutucals (12 February 2009). "CIPRO (ciprofloxacin hydrochloride) TABLETS CIPRO (ciprofloxacin*) ORAL SUSPENSION" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019537s073,020780s030lbl.pdf. Retrieved 8 September 2009. 
  110. ^ van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH, PD (August 2003). "Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids". Arch. Intern. Med. 163 (15): 1801–7. doi:10.1001/archinte.163.15.1801. ISSN 0003-9926. PMID 12912715. http://archinte.ama-assn.org/cgi/content/full/163/15/1801. 
  111. ^ Royal Pharmaceutical Society of Great Britain (2009). "5 Infections". British National Formulary (BNF 57). BMJ Group and RPS Publishing. ISBN 9780853698456. 
  112. ^ Harder S, Fuhr U, Staib AH, Wolff T, S (November 1989). "Ciprofloxacin-caffeine: a drug interaction established using in vivo and in vitro investigations" (Free full text). Am. J. Med. 87 (5A): 89S–91S. doi:10.1016/0002-9343(89)90031-4. ISSN 0002-9343. PMID 2589393. 
  113. ^ Janknegt R, R (November 1990). "Drug interactions with quinolones". J. Antimicrob. Chemother. 26 Suppl D: 7–29. ISSN 0305-7453. PMID 2286594. 
  114. ^ Cooper JG, Harboe K, Frost SK, Skadberg Ø, JG (2005-04). "Ciprofloxacin interacts with thyroid replacement therapy". BMJ 330 (7498): 1002. doi:10.1136/bmj.330.7498.1002. ISSN 0959-8138. PMID 15860826. PMC 557149. http://www.bmj.com/cgi/content/full/330/7498/1002. 
  115. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 313-315.
  116. ^ Bailey RR, Natale R, Linton AL, RR (October 1972). "Nalidixic acid arthralgia". Can Med Assoc J 107 (7): 604 passim. ISSN 0008-4409. PMID 4541768. 
  117. ^ Bailey RR, Kirk JA, Peddie BA, RR (July 1983). "Norfloxacin-induced rheumatic disease". N Z Med J 96 (736): 590. ISSN 0028-8446. PMID 6223241. 
  118. ^ Szarfman A, Chen M, Blum MD, A (January 1995). "More on fluoroquinolone antibiotics and tendon rupture" (letter). N Engl J Med 332 (3): 193. doi:10.1056/NEJM199501193320319. ISSN 0028-4793. PMID 7800023. 
  119. ^ "Petition to Require a Warning on All Fluoroquinolone Antibiotics (HRG Publication #1399)". Public Citizen. August 1, 1996. http://www.citizen.org/publications/release.cfm?ID=6595.  Retrieved on December 27, 2008.
  120. ^ a b Office of the Illinois Attorney General (August 29, 2006). "Madigan, Public Citizen, petition FDA for "Black Box" warning regarding potential adverse effects of certain popular antibiotics". Press release. http://www.illinoisattorneygeneral.gov/pressroom/2006_08/20060829.html. Retrieved 2008-12-27.  Full text of the 2005 petition and FDA response available from the Fluoroquinolone Toxicity Research Foundation, a U.S. consumer advocacy group.
  121. ^ "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. 
  122. ^ "Public Citizen v. Food and Drug Administration (FDA) (Fluoroquinolone)". Public Citizen. January 3, 2008. http://www.citizen.org/litigation/forms/cases/CaseDetails.cfm?cID=444. Retrieved 2008-12-27. 
  123. ^ Ravn, Karen (August 18, 2008). "Behind the FDA’s ‘black box’ warnings". Los Angeles Times. http://articles.latimes.com/2008/aug/18/health/he-closer18. Retrieved 2008-12-27. 
  124. ^ U.S. Food and Drug Administration (2008-07-08). "FDA Requests Boxed Warnings on Fluoroquinolone Antimicrobial Drugs". Press release. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01858.html. Retrieved 2008-10-11. 
  125. ^ The complete labeling history of each drug is available from Drugs@FDA. Medication Guides are available from the FDA's MedWatch system.
  126. ^ MacCarthy, Paul (October 22, 2008). "Important Change in the Avelox (moxifloxacin hydrochloride) and Cipro (ciprofloxacin) Complete Prescribing Information – Addition of Boxed Warning and Medication Guide Regarding Tendinitis and Tendon Rupture" (PDF). Bayer HealthCare Pharmaceuticals. http://www.cipro.com/html/pdf/dhpl.pdf. Retrieved 2008-12-27. 
  127. ^ Rosenthal, Norman (November 2008). "Important Change in the LEVAQUIN (Ievofloxacin) Complete Prescribing Information -Addition of Boxed Warning and Medication Guide Regarding Tendinitis and Tendon Rupture" (PDF). Ortho-McNeil Janssen Scientific Affairs, LLC. http://www.fqresearch.org/pdf_files/Levaquin_11_2008_ortho_mcneil_dear_dr_letter.pdf. Retrieved 2008-12-27. 
  128. ^ FDA (2 April 1999). "NDA #19-537 Cipro (ciprofloxacin) Tablets Macmis ID #7451" (PDF). USA: Food and Drug Administration. http://www.fqresearch.org/pdf_files/040299_bayer.pdf. Retrieved 30 January 2009. 
  129. ^ FDA (18 July 2003). "RE: Cipro HC Otic Suspension (Ciprofloxacin Hydrochloride and Hydrocortisone Otic Suspension) NDA 20-805 Ciloxan (ciprofloxacin ophthalmic) Solution NDA 19-992 MACMIS ID# 11015" (PDF). USA: Food and Drug Administration. http://www.fqresearch.org/pdf_files/11015.pdf. Retrieved 30 January 2009. 
  130. ^ Biosecurity requires drug reform. Jan 1, 2002 World Watch ISSN: 0896-0615
  131. ^ Nawaz, H.; Rauf, S.; Akhtar, K.; Khalid, AM. (July 2006). "Electrochemical DNA biosensor for the study of ciprofloxacin-DNA interaction.". Anal Biochem 354 (1): 28–34. doi:10.1016/j.ab.2006.04.004. PMID 16707087. 
  132. ^ Stacey L. Knobler ... (2003). The Resistance Phenomenon in Microbes and Infectious Disease Vectors: Implications for Human Health and Strategies for Containment, Workshop Summary. National Academies Press. p. 34. ISBN 978-0309088541. http://books.google.com/?id=90F3Q6MnkcAC. 
  133. ^ A.C. Vatopoulos; V. Kalapothaki (1997). "Bacterial Resistance to Ciprofloxacin in Greece: Results from the National Electronic Surveillance System" (PDF). http://www.cdc.gov/ncidod/eid/vol5no3/pdf/vatopoulos.pdf. 
  134. ^ "Bacterial resistance prompts concern among health officials". 26 February 2009. http://www.health.state.mn.us/news/pressrel/2009/bacterial022609.html. 
  135. ^ M Jacobs, Worldwide Overview of Antimicrobial Resistance. International Symposium on Antimicrobial Agents and Resistance 2005.
  136. ^ FDA (16 July 1999). "Update On Extra-Label Use Of Fluoroquinolones". USA: FDA. http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm127657.htm. Retrieved 12 August 2009. 
  137. ^ a b Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS (March 2005). "Fluoroquinolone prescribing in the United States: 1995 to 2002". Am. J. Med. 118 (3): 259–68. doi:10.1016/j.amjmed.2004.09.015. PMID 15745724. http://linkinghub.elsevier.com/retrieve/pii/S0002-9343(04)00711-9. 
  138. ^ K08 HS14563 and HS11313
  139. ^ "Anthrax Scare Leaves Trail of Cipro Victims - Class Actions filed in Two States". USA: Sheller Ludwig & Sheller. 17 October 2003. http://www.sheller.com/NewsDetails.asp?NewsID=72. Retrieved 9 September 2009. [dead link]
  140. ^ "Legal Brief of Postal Employees Cases (EEOC, MSPB, District Courts)". USA: Postal Reporter. Archived from the original on 2007-10-21. http://web.archive.org/web/20071021073109/http://www.lunewsviews.com/legal_briefs_archives.htm#cipro. Retrieved 9 September 2009. 
  141. ^ Charles P. Goodell, Jr. "Profile". USA: Goodell, DeVries, Leech & Dann, LLP. http://www.gdldlaw.com/content/bio_goodell.htm. Retrieved 9 September 2009. 
  142. ^ "LegalView Reveals Details of the FDA Mandated Black Box Warning For Fluoroquinolone Antibiotics". PRlog. 11 July 2008. http://www.prlog.org/10088464-legalview-reveals-details-of-the-fda-mandated-black-box-warning-for-fluoroquinolone-antibiotics.html. 
  143. ^ Cynthia Diaz (6 July 2009). "Levaquin Litigation Moving Ahead". Zimbio. http://www.zimbio.com/Shocking+Sports+Injuries/articles/W6tlqlrajER/Levaquin+Litigation+Moving+Ahead. "In May we wrote that most litigation specialists expected thousands of people to file lawsuits against the makers of Levaquin and similar drugs..." 
  144. ^ Carey and Danis LLC (3 September 2009). "Carey and Danis LLC Announces Four Lawsuits against the Makers of Levaquin". Reuters. http://www.reuters.com/article/pressRelease/idUS199242+03-Sep-2009+BW20090903. 

External links


Previous Next