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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 Mexicomarker it is available over the counter and marketed under the names Ciproflox or Ciprofloxacino. In Ecuadormarker 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.

History

The patent history for Ciprofloxacin makes reference to a 1982 European Patent (patent number 0049355), as well a German patent dated Jan 21, 1986. Bayer introduced ciprofloxacin in 1987 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. In 1991 the intravenous formulation was introduced. The current United States patent appears to be held by Bayer; being the assignee. The United States patent was applied for Jan., 1987 but was not approved until 1996 according to the patent history.

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

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:

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)
  • Acute uncomplicated cystitis in females
  • Chronic bacterial prostatitis (not recommended as a first line antibiotic choice)
  • Lower respiratory tract infections (not recommended as a first line antibiotic choice)
  • Acute sinusitis (not recommended as a first line antibiotic choice)
  • 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 (i.e. Asian Countries, United States, Canada and Hawaii) and Scotland due to bacterial resistance. Fluoroquinolones are no longer recommended in the USA for this indication.


Ciprofloxacin is not recommended for the treatment of tuberculosis.

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 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. As such the pediatric use of ciprofloxacin is restricted to proven complicated urinary tract infections and pyelonephritis due to E. coli and inhalation anthrax. Although claimed to be effective, ciprofloxacin is not to be considered a first line agent for inhalation anthrax in the pediatric population. 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). 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 that the systemic use of ciprofloxacin in children should be restricted to infections caused by multidrug resistant pathogens or when no safe or effective alternatives. Indications include:

  • Complicated urinary tract infections and pyelonephritis due to Escherichia coli


  • Inhalational anthrax (post-exposure)


Ciprofloxacin is not recommended to treat CAP (community acquired pneumonia) as a stand alone first line agent. The current guidelines (Infectious Diseases Society of America 2007) state that in very limited circumstances ciprofloxacin or levofloxacin should be combined with other drugs such as a b-lactam drug to treat specific CAP infections, but neither drug is recommended to be used separately as a stand alone first line agent. Additionally the current guidelines state that: “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...”

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...”
does not appear to have changed within these current guidelines.


Antibiotics may not improve the long-term clinical outcome for sinusitis.When prescribed for chronic bronchitis and acute bacterial sinusitis, the use of the fluoroquinolone class offers no compelling advantages over established treatment. Nor does antibiotic treatment help sore throats. 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. 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 (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.

Mode of action

Ciprofloxacin is a broad-spectrum antibiotic that is active against bothGram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV, 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), display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models.Although 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.).

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.

There 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.

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.

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

  • 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.

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 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.

  • Pediatric population
Fluoroquinolones are not licensed by the FDA for use in children due to the risk of fatalities 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%.Within the BPCA Pediatric Studies Summary for ciprofloxacin 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 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.

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 intestine. 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 the usual duration is 7 to 14 days.

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. There has been a number of regulatory actions taken as a result of such adverse reactions, which included published warnings, additional warnings and safety information added to the package inserts together with the issuance of "Dear Doctor Letters"
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.” 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, spontaneous tendon rupture and tendonitis, acute liver failure or serious liver injury (Hepatitis), QTc prolongation/torsades de pointes, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome, severe central nervous system disorders (CNS) and clostridium difficile associated disease (CDAD: Pseudomembranous colitis), as well as photosensitivity/phototoxicity reactions.

Psychotic reactions, and confusional states, acute pancreatitis, bone marrow depression, interstitial nephritis and hemolytic anemia may also occur during ciprofloxacin therapy. Additional serious adverse reactions include temporary as well as permanent loss of vision, irreversible double vision, drug induced psychosis and chorea (involuntary muscle movements), impaired color vision, exanthema, abdominal pain, malaise, drug fever, dysaesthesia and eosinophilia.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.

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

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

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. 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.

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. 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. Ciprofloxacin can reduce phenytoin plasma levels which may in some cases result in seizures. Ciprofloxacin may interfere with the levels of thyroid medications resulting in hypothyroidism.

On 9 November 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:
"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."


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.

Significant drug interactions

Significant and potentially serious interactions with ciprofloxacin and NSAIDS and theophylline may occur. Ciprofloxacin can also interfere with the metabolism of caffeine 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.

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. This potentially serious interaction is the result of increased antagonism of GABA neurotransmission.

Some quinolones, including ciprofloxacin 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.

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.

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.

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.

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.

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.

Pharmacokinetics

The effects of 200–400 mg of ciprofloxacin given intravenously are linear; drug accumulation does not occur when administered 12 hourly. 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. Biotransformation is hepatic. The half life is 4 hours.

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.


April 17, 2002:
  • Removal of the warning that stated “prolonged use of ciprofloxacin may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient’s 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.”


  • Removal of the warning that “Allergic reactions ranging from urticaria to anaphylactic reactions have been reported.” "Sweating" added as an ADR in its place.


January 18, 2008
  • Phototoxicy warnings reduced significantly.


October 3, 2008
  • Addition of the Black Box Warnings regarding tendon ruptures.


April 6, 2009
  • Addition of warning that ciprofloxacin should not be administered through feeding or NG (nasogastric) tubes.


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.


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.


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.

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. Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later. 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."

By August 1996, the FDA had not taken action, and the consumer advocacy group Public Citizen filed a petition with the FDA prompting the agency to act. Two months later, the FDA published an alert in the FDA Medical Bulletin and requested that fluoroquinolone package inserts be amended to include information on this risk.

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. 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. 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. 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. The package inserts for Ciprofloxacin, Avelox (moxifloxacin), Proquin XR, Factive (gemifloxacin), Floxin (ofloxacin), Noroxin (norfloxacin) and Levaquin (levofloxacin) were amended on September 8, 2008 to include these new warnings. Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes. Ortho-McNeil, the manufacturers of Levaquin, issued a similar letter in November. 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.

Overprescribing and bacterial resistance

Ciprofloxacin is commonly used for urinary tract and intestinal infections (traveler's diarrhea) andwas once considered a powerful antibiotic of last resort, 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.

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. Widespread veterinary usage of the fluoroquinolones, particularly in Europe, has been implicated.

Fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002. Nearly half (42%) of these prescriptions were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study that was supported in part by the Agency for Healthcare Research and Quality. Additionally they are commonly prescribed for medical conditions that are not even bacterial to begin with, such as viral infections, or those to which no proven benefit exist.

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." The sale of ciprofloxacin increased dramatically following the anthrax scare of 2001. On October 24, 2002 the Bush Administration (2000–2008) 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.

  • 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 competitors—Barr Laboratories, Rugby, and Hoechst-Marion Roussel—a 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 Bayer’s patent had expired, the United States District Court for the Eastern District of New York granted Bayer’s 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. In effect upholding Bayer’s agreement to pay—Barr Laboratories, Rugby, and Hoechst-Marion Roussel—a total of $200 million to prevent the marketing a generic equivalent of ciprofloxacin.

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.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.

See also



Package insert links



References

  1. (World Health Organization (WHO) Western Pacific Region Gonococcal Antimicrobial Susceptibility Programme (GASP) Report- 2000. Commun Dis Intell 2001; 25:274-277).
  2. 62 Meeting of the Anti-Infective Drugs Advisory Committee
  3. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2000/20780S08ltr.pdf
  4. Mandell LA, et al. Clinical Infectious Dis 2007; 44 (suppl 2):s27-s72 http://www.thoracic.org/sections/publications/statements/resources/idsaats-cap.pdf
  5. Ciprofloxacin in general practice. P. M. Donaldson, A. P. Pallett, and M. P. Carroll http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2540361/pdf/bmj00442-0061a.pdf
  6. Komer RJ, Reeves DS, MacGowan AP. Dangers of oral fluoroquinolone treatment in community acquired upper respiratory tract infections. BMJ 1994;308:191-2. (15 January.) http://www.bmj.com/cgi/content/extract/308/6922/191
  7. BAY 0 9867 Cipro Pediatric Use Study (QUIP) - Study Results - ClinicalTrials.gov
  8. 62 Meeting of the Anti-Infective Drugs Advisory Committee http://fqresearch.org/pdf_files/62nd_fda_meeting.pdf
  9. http://www.fqresearch.org/text_documents/FDA_Medical_Bulletin_1996.doc
  10. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19537s049,19857s031,19847s027,20780s013ltr.pdf
  11. CPY Document Title
  12. Apriloralappletter.PDF
  13. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/019537s067,020780s025ltr.pdf
  14. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/019537s068,019847s042ltr.pdf
  15. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/019537s073,020780s030ltr.pdf
  16. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/019537s070,019847s044ltr.pdf
  17. label
  18. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/019537s071,019847s045,019857s052,020780s029,021473s026ltr.pdf
  19. Retrieved on December 27, 2008.
  20. Full text of the 2005 petition and FDA response available from the Fluoroquinolone Toxicity Research Foundation, a U.S. consumer advocacy group.
  21. The complete labeling history of each drug is available from Drugs@FDA. Medication Guides are available from the FDA's MedWatch system.
  22. Biosecurity requires drug reform. Jan 1, 2002 World Watch ISSN: 0896-0615
  23. M Jacobs, Worldwide Overview of Antimicrobial Resistance. International Symposium on Antimicrobial Agents and Resistance 2005.
  24. K08 HS14563 and HS11313
  25. LegalView Reveals Details of the FDA Mandated Black Box Warning For Fluoroquinolone Antibiotics
  26. 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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