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APO-Ciproflox  


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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 2764
DrugBank APRD00424
ChemSpider 2662
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(AU) C(US)
Legal status

Prescription Only (S4)(AU) POM(UK)
Routes Oral, intravenous, topical (ear drops, eye drops)
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Ciprofloxacin (INN) is a drug used to treat bacterial infections. 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 DNA and protein synthesis.

Ciprofloxacin is marketed worldwide with over three hundred different brand names. In the United States, Canada and the UK, it is marketed as Ciloxan, Cipro, Cipro XR, Cipro XL Ciproxin and, most recently, Proquin. In Mexico it is available over the counter and marketed under the names Ciproflox or Ciprofloxacino. In Ecuador it is available and marketed under the name Cidrax. In Nigeria it is sold as Ciprotab while in Bangladesh it is marketed as Tablets and Microcapsules for Suspension by numerous companies, one of which is by Edruc Limited as Cipron. Additionally, 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 F.D.A.-approved human uses and other veterinary uses, but it is often used for non-approved uses (off-label).

Ciprofloxacin interacts with other drugs, herbal and natural supplements, and thyroid medications.[2]

Contents

History

Bayer introduced the first broad-spectrum oral fluoroquinolone, ciprofloxacin, in 1987. In 1991 the intravenous formulation was introduced. Ciprofloxacin is available in more than 100 countries. Under the trade name Cipro HC, it is distributed by Alcon. Ciprofloxacin appears to have been first patented Jan 21, 1986, in Germany, and was later approved by the U.S. Food and Drug Administration on October 22, 1987 for use in the United States to treat specific bacterial infections. The current United States patent appears to be held by Bayer being the assignee.[3] The patent was applied for Jan., 1987 but not approved until 1996 according to its patent history, although the patent history makes reference to a 1982 European Patent (patent number 0049355), as well.

In 2004 ciprofloxacin and levofloxacin together command 65% ($3.3 billion) of the global sales of the fluoroquinolone class.[4] The first nine months of 2008 sales for Ciprofloxacin were $242 million, as compared to $324 million for Bayer Aspirin.[5]

Licensed uses

Ciprofloxacin as sold over the counter in Mexico. Ciprofloxacino is the generic name in that country.

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

Oral and I.V. fluoroquinolones are not licensed by the FDA for use in children due to the risk of permanent injury to the musculoskeletal system, with two exceptions as outlined below. Within the studies submitted in response to a Pediatric Written Request (Ciprofloxacin, circa 2004) the rate of atrophy was reported to be 9.3% at one month and 13.6% at one year.[6] As such the pediatric use of ciprofloxacin is restricted to proven complicated urinary tract infections and pyelonephritis due to E. coli and inhalation anthrax.[7] Although alleged to be effective, ciprofloxacin is not to be considered a first line agent for inhalation anthrax in the pediatric population.[6][8][9][10] 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).[11] However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

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

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)

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

Ciprofloxacin is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae. As such ciprofloxacin is not recommended for community acquired pneumonia and other such chest infections.[17] Antibiotics may not improve the long-term clinical outcome for sinusitis.[18] 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.[19] Nor does antibiotic treatment help sore throats.[20] 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.[21] Additionally ciprofloxacin and other fluoroquinolones have no effect upon viral infections such as the common head cold.

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

Availability

Ciprofloxacin is available as:

  • tablets (250 mg, 500 mg or 750 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.[22]

Mode of action

Ciprofloxacin 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,[23] 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),[24] 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.[25] 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.).[26]

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.[27][28][29][30] As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.[31][32][33][34][35][36]

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 adverse reactions experienced by some patients following fluoroquinolone therapy.[37][38][25]

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.[39]

There are only four contraindications found within the 2009 package insert:[22]

  • 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 which 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 who have been to southeast Asia is increasingly being contraindicated.[40]

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 barrier, 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 mothers 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.[41][42]

  • Pediatric population

Fluoroquinolones are not licensed by the FDA for use in children due to the risk of fatalities[43] 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 (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.

Within the studies submitted in response to a Pediatric Written Request (Ciprofloxacin, circa 2004) the rate of atrophy was reported to be 9.3%.[44] Within the BPCA Pediatric Studies Summary for ciprofloxacin[44] 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[45] 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 that it is their intention to pursue the licensing of the fluoroquinolones for pediatric use in spite of the evidence presented at that 62 Meeting of the Anti-Infective Drugs Advisory Committee that the fluoroquinolones cause irreversible joint damage in the pediatric population.[46]

Adverse effects

See also: Adverse effects of fluoroquinolones

Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes.[47][48] There has been a number of regulatory actions taken as a result of such adverse reactions, which included published warnings,[49][50] additional warnings and safety information added to the package inserts[51] together with the issuance of "Dear Doctor Letters" [52] concerning the recent addition of Black Box Warnings. In 2004 the 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 wasting), Steven Johnson Syndrome, as well as concurrent usage of NSAIDs contributing to the severity of these reactions.

Subsequent to this, on June 25, 2007, the FDA required the manufacturer to add an additional warning to the package inserts that stated that 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.[53] It was not until 2008, (four years later) that the label revisions for ciprofloxacin included any warnings concerning Heart Problems (prolonged QT Interval / Torsades de pointes). Warnings concerning Rhabdomyolysis (muscle wasting) and Steven 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,[54][55] spontaneous tendon rupture and tendonitis,[56][57][58][59] acute liver failure or serious liver injury (Hepatitis),[60][61] QTc prolongation/torsades de pointes,[7] toxic epidermal necrolysis (TEN),[62][63][64] and Stevens-Johnson syndrome, severe central nervous system disorders (CNS)[65] and clostridium difficile associated disease (CDAD: Pseudomembranous colitis),[66][67] as well as photosensitivity/phototoxicity reactions.

Psychotic reactions, and confusional states, acute pancreatitis,[68] bone marrow depression, interstitial nephritis and hemolytic anemia may also occur during ciprofloxacin therapy.[69][70] Additional serious adverse reactions include temporary as well as permanent loss of vision,[71][72] irreversible double vision,[73] drug induced psychosis[74][75] and chorea (involuntary muscle movements),[76] impaired color vision, exanthema, abdominal pain, malaise, drug fever, dysaesthesia and eosinophilia.[77][78] 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.[79]

Children and the elderly are at a much greater risk of experiencing such adverse reactions.[48][80] Such reactions may manifest during, as well as long after fluoroquinolone therapy had been discontinued.[81]

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.[82][83] As noted previously permanent double vision (diplopia) has also been reported.[73] An unusual case of seizures has also been reported with ciprofloxacin ear drops in an elderly patient.[84]

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.[85] Partly as a result of the efforts of The State of Illinois and Public Citizen the FDA ordered a black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.[86]

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 coumadin 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 non-steroidal anti-inflammatory drugs.[87] Quercetin, a flavonoid 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.[88] Ciprofloxacin can reduce phenytoin plasma levels which may in some cases result in seizures.[89] Ciprofloxacin may interfere with the levels of thyroid medications resulting in hypothyroidism.[90] On November 9, 2005, the 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 that 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.[91]

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.[92]

Significant drug interactions

Some drug interactions are associated with molecular structural modifications of the quinolone ring, specifically interactions involving NSAIDS and theophylline. The fluoroquinolones have also been shown to interfere with the metabolism of caffeine[93] and the absorption of levothyroxine. The interference with the metabolism of caffeine may lead to the reduced clearance of caffeine and a prolongation of its serum half-life, resulting in a caffeine overdose. Ciprofloxacin has been shown to interact with thyroid medications (levothyroxine) resulting in unexplained hypothyroidism.[94]

The use of NSAIDs (Non Steroid Anti Inflammatory Drugs) while undergoing fluoroquinolone therapy is contra-indicated due to the risk of severe CNS adverse reactions, including but not limited to seizure disorders. Fluoroquinolones with an unsubstituted piperazinyl moiety at position 7 have the potential to interact with NSAIDs and/or their metabolites, resulting in antagonism of GABA neurotransmission.[95]

Some quinolones exert an inhibitory effect on the cytochrome P-450 system, thereby reducing theophylline clearance and increasing theophylline blood levels. Coadministration of certain fluoroquinolones and other drugs primarily metabolized by CYP1A2 (e.g. theophylline, methylxanthines, tizanidine) results in increased plasma concentrations and could lead to clinically significant side effects of the coadministered drug. Additionally other fluoroquinolones, especially enoxacin, and to a lesser extent ciprofloxacin and pefloxacin, also inhibit the metabolic clearance of theophylline.[96]

Such drug interactions appear to be related to the structural changes of the quinolone ring and the inhibitory effect on the cytochrome P-450 system. As such, these drug interactions involving the fluoroquinolones appear to be drug specific rather than a class effect.

The use of Ciprofloxacin concomitantly has also been associated with transient elevations in serum creatinine in patients receiving cyclosporine, on rare occasions, resulted in severe hypoglycemia with sulfonylurea. Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate toxic reactions. Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin. Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in serum. The fluroquinolones have also been reported to enhance the effects of the warfarin or its derivatives.[97]

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.[98]

Overdose

Overdose of ciprofloxaciin 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.[92]

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.[92]

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 C17H18FN3O3HClH2O.[92]

Pharmacokinetics

"The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q 12 h regimen indicates no evidence of drug accumulation. The absolute bioavailability of oral ciprofloxacin is within a range of 7080% with no substantial loss by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V. dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours." Quoting from the 2009 package insert for Ciprofloxacin.[92]

Biotransformation is hepatic. The half life is 4 hours.[97]

Dosing

The status of the patients renal function and hepatic function must also be taken into consideration to avoid an accumulation that may lead to a fatal drug overdose. Ciprofloxacin is eliminated primarily by renal excretion. 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 substantially excreted by the kidneys, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. The duration of treatment depends upon the severity of infection and the usual duration is 7 to 14 days.[7]

Current litigation

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, miniscal 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 plaintiffs.[99][100][101] 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.[102][103][104][105]

Additional regulatory history

Ciprofloxacin was first patented in 1983 by Bayer A.G. and subsequently approved by the U.S. Food and Drug Administration (FDA) for use in the United States in 1987.

October 1987:

  • FDA approval. The NDA (New Drug Application) documents are no longer available on the FDA site.

October 1987 - September 1998.

  • There is a regulatory gap between 1987 and 1997, resulting in ten years worth of regulatory documentation missing on the FDA site concerning the regulatory history of ciprofloxacin. Hence this section begins with the data available as of 1998 rather than 1987.

September 1998:

  • Addition of taste loss as an ADR. Additional study added that showed 22% of the pediatric cystic fibrosis patients treated with ciprofloxacin experienced musculoskeletal adverse reactions to ciprofloxacin, some of which persisted for a length greater than eight months.[106]

April 17, 2002:

  • Removal of the warning that stated prolonged use of ciprofloxacin may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patients condition and microbial susceptibility testing is essential.
  • Removal of the warning that stated There are, however, no adequate and well-controlled studies in pregnant women. Ciprofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • Removal of the warning that stated Adverse events that were considered likely to be drug related occurred in 7.3% of patients treated, possibly related in 9.2% (total of 16.5% thought to be possibly or probably related to drug therapy), and remotely related in 3.0%. Ciprofloxacin was discontinued because of an adverse event in 3.5% of patients treated." Replaced with the statement Most of the adverse events reported were described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment.[107]
  • Removal of the warning that Allergic reactions ranging from urticaria to anaphylactic reactions have been reported. "Sweating" added as an ADR in its place.[15]

January 18, 2008

  • Phototoxicy warnings reduced significantly.[108]

October 3, 2008

  • Addition of the Black Box Warnings regarding tendon ruptures.[109]

April 6, 2009

  • Addition of warning that ciprofloxacin should not be administered through feeding or NG (nasogastric) tubes.[110]

April 27, 2009

  • Issuance of a Medication Guide and revisions to include new safety information. The FDA has determined that Ciprofloxacin poses a serious and significant public health concern, requiring the distribution of a Medication Guide.[111][112]

June 24, 2009

  • Updating of the carton and container labels to include a statement to let dispensers know that a Medication Guide must be dispensed with the product.[113]

Note: Although the FDA had requested that the revised labeling (which were to include the Black Box Warnings) accompany the package inserts for any newly shipped products (effective January 2009) there are continuing reports that as of September 2009, that the products continue to contain the older labels, and not the revised labels, and that the Medication Guides (absent of the Black Box Warnings) were not being made available for distribution. [109][111]

History of the black box warnings

See also: Quinolone#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.[114] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.[115] 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."[116]

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.[117] 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.[56]

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.[118] 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.[118][119] When the FDA failed to respond to these two petitions as required by law Public Citizen, in January of 2008, filed suit to compel the FDA to respond to their 2006 petition.[120][121] 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.[122] 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.[123] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes.[124] Ortho-McNeil, the manufacturers of Levaquin, issued a similar letter in November.[125] 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.[126][127]

Overprescribing and bacterial resistance

See also: Antibiotic abuse and Antibiotic resistance

Ciprofloxacin is commonly used for urinary tract and intestinal infections (traveler's diarrhea) and was once considered a powerful antibiotic of last resort,[128][129][130] 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.[131][132]

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.[133] Widespread veterinary usage of the fluoroquinolones, particularly in Europe, has been implicated.[134]

As with other fluoroquinolones their use as first line agents is not generally recommended. They are usually reserved for use in patients who are seriously ill and may soon require immediate hospitalization.[135] Though considered to be a very important and necessary drug required to treat severe and life threatening bacterial infections, the associated overprescribing of ciprofloxacin remains unchecked, which has contributed to the problem of bacterial resistance.[136] 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.[137] Fluoroquinolone resistance is an increasing problem not only in the U.S. but also worldwide, potentially due to the widespread misuse of this class of antimicrobials.[138] 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.[139][140]

Fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002.[140] 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.[141][140] 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.

Social and economic impact

See also: Quinolone#Social and economic impact

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."[142] The sale of ciprofloxacin increased dramatically following the anthrax scare of 2001. On October 24, 2002 the Bush Administration (20002008) 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.[143]

  • Generic equivalents:

On October 24, 2001, The Prescription Access Litigation (PAL), filed suit to dissolve an agreement between Bayer, Barr Laboratories, and two other generic drug companies 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 three of its competitorsBarr Laboratories, Rugby, and Hoechst-Marion Roussela total of $200 million to prevent cheaper, (generic versions) of ciprofloxacin being brought to the market, as well as manipulating the price and supply of ciprofloxacin. Numerous other consumer advocacy groups joined this lawsuit. On October 15, 2008, five years after Bayers patent had expired, the United States District Court for the Eastern District of New York granted Bayers and the generic defendants motion for summary judgment, holding that any anti-competitive effects caused by the settlement agreements between Bayer and the generic defendants were within the exclusionary zone of the patent, and thus could not be redressed by federal antitrust law.[144] In effect upholding Bayers agreement to payBarr Laboratories, Rugby, and Hoechst-Marion Roussela total of $200 million to prevent the marketing a generic equivalent of ciprofloxacin.

Risk-benefit ratio

See also: Quinolone#Risk-benefit ratio

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

  • Respiratory infections:

For the most part ciprofloxacin is not usually considered to be a first-line treatment for respiratory infections.[145] In spite of this caveat, the use of the fluoroquinolone to treat community acquired pnuemonia (CAP) increased by >50%, from 25% to 39% of all prescriptions. This increase was at the expense of the macrolide class of antimicrobial drugs, the use of which declined 20% during the study period.[139] Regardless, the use of ciprofloxacin as a first-line therapy is not endorsed in the treatment of acute bacterial sinusitis; as the newer fluoroquinolones have shown to confer no benefit over beta-lactam antibiotics.[146] Nevertheless, for severe forms of community-acquired pneumonia the fluoroquinolones seem to be associated with improved treatment rates, but with no differences found in mortality between antibiotic regimens.[147]

  • Chronic bacterial prostatitis:

A 2004 randomized, double-blind trial involving ciprofloxacin, it was found that ciprofloxacin did not substantially reduce symptoms in men with long-standing CP/CPPS who had at least moderate symptoms.[148] Chronic pelvic pain (category IIIB) is often misdiagnosed as chronic prostatitis and needlessly treated with ciprofloxacin. Within a Bulgarian study, where by definition all patients had negative microbiological results, a 65% adverse drug reaction rate was found for patients treated with ciprofloxacin in comparison to a 9% rate for the placebo patients. This was combined with a higher cure rate (69% v 53%) found within the placebo group. The authors stated that The results of our study show that antibiotics have an unacceptably high rate of adverse side effects as well as a statistically insignificant improvement over placebo...[149]

  • Infectious diarrhea:

A Clostridium difficile infection is the principal cause of ciprofloxacin-associated diarrhea and pseudomembranous colitis.[150][151] In June 2007 the FDA changed the package insert for ciprofloxacin to include the warning that that Clostridium difficile associated diarrhea (CDAD) is associated with the use of ciprofloxacin.[152]

  • Uncomplicated cervical and urethra gonorrhea:

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

Current recommendations by the American Academy of Pediatrics note that the systemic use of ciprofloxacin in children should be restricted to infections caused by multidrug resistant pathogens with no safe or effective alternatives. As such ciprofloxacin should not be considered a first line agent within the pediatric population. [153] Nor should Ciprofloxacin be used as a first-line agent within the elderly population.[153] For example there are limited indications for ciprofloxacin as a first-line therapy within Long Term Care Facilities.[154] Within a 1994 study it was found that 75% of the prescription issued within a long term care setting were judged to be inappropriate by the authors. In more than fifty percent of the cases reviewed ciprofloxacin was not considered to be a first line agent.[155] Additionally ciprofloxacin is not recommended as a first line agent for community acquired pneumonia and other such chest infections as noted above.[146][156] Nor is it to be considered a first line agent for the treatment of STDs,[157] prostatitis,[153] tuberculosis[158] and uncomplicated UTIs. The Infectious Disease Society of America recommends SMX/TMP (trimethoprim and sulfamethoxazole) as a first line agent in uncomplicated UTIs rather than ciprofloxacin.[159]

See also

Package insert links

References

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  104. ^ 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... http://www.zimbio.com/Shocking+Sports+Injuries/articles/W6tlqlrajER/Levaquin+Litigation+Moving+Ahead
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  106. ^ CPY Document Title
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v  d  e
Antibacterials: nucleic acid inhibitors (J01E, J01M)
Antifolates
(inhibits
purine metabolism,
thereby inhibiting
DNA and RNA synthesis)
Other/ungrouped
Combinations
Topoisomerase
inhibitors/
quinolones/
(inhibits
DNA replication)
Ciprofloxacin#  · Enoxacin · Fleroxacin · Lomefloxacin · Nadifloxacin · Ofloxacin · Norfloxacin · Pefloxacin · Rufloxacin
Related agents (DG)
Anaerobic DNA
inhibitors
Nitro- imidazole derivatives
Nitrofuran derivatives
RNA synthesis
#WHO-EM. Withdrawn from market. CLINICAL TRIALS: Phase III. §Never to phase III
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Piperazines

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drug_details.asp Last Updated November 9 2009

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