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Ciprofloxacin
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Ciprofloxacin (INN) is a synthetic chemotherapeutic agent used to treat severe and life threatening bacterial infections. Ciprofloxacin is commonly referred to as a fluoroquinolone (or quinolone) drug and is a member of the fluoroquinolone class of antibacterials. Ciprofloxacin is marketed worldwide; with well over three hundred different brand names. Ciprofloxacin is marketed in the United States, Canada and the UK as: Ciloxan, Cipro, Cipro XR, Cipro XL Ciproxin and most recently, Proquin (Synonyms: Ciprofloxacin Hydrochloride).
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Ciprofloxacin (INN) is a synthetic chemotherapeutic agent used to treat severe and life threatening bacterial infections. Ciprofloxacin is commonly referred to as a fluoroquinolone (or quinolone) drug and is a member of the fluoroquinolone class of antibacterials. Ciprofloxacin is marketed worldwide; with well over three hundred different brand names. Ciprofloxacin is marketed in the United States, Canada and the UK as: Ciloxan, Cipro, Cipro XR, Cipro XL Ciproxin and most recently, Proquin (Synonyms: Ciprofloxacin Hydrochloride). In Mexico it is available over the counter and marketed under the names Ciproflox or Ciprofloxacino. 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 U.S. Food and Drug Administration (FDA) for use in the United States in 1987 to treat severe and life threatening bacterial infections.
The licensed uses for ciprofloxacin in the United States are quite limited as ciprofloxacin is to be considered a drug of last resort when all other antibiotics have failed. These consist of ten approved uses in the adult population and two approved uses in the pediatric population, as well as a variety of veterinary uses (as documented within the package inserts). Any other use is to be considered off label since it has not been approved by the FDA. Ciprofloxacin interacts with a number of other drugs, a number of herbal and natural supplements, and certain thyroid medications.
History
Bayer Pharmaceuticals introduced the first broad-spectrum oral fluoroquinolone, Ciprofloxacin (Cipro, Ciproxin) in 1987. In 1991 the intravenous formulation of Cipro was introduced. Cipro is available in more than 100 countries. Ciprofloxacin is considered by some to be a second-generation fluoroquinolone antibiotic, marketed by Bayer in the United States and Canada under the trade names Cipro, Cipro XR, Cipro HC, Proquin and Ciproxin. Cipro HC is distributed by Alcon. Ciprofloxacin appears to have been first patented Jan 21, 1986 [DE] and was later approved by the U.S. Food and Drug Administration on October 22, 1987 for use in the United States to treat severe and life threatening bacterial infections. The current United States patent appears to be held by Bayer Aktiengesellschaft (Leverkusen, DE) being the assignee.The patent was applied for Jan., 1987 but not approved until 1996 according to it’s patent history. However 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 global sales. The first nine months of 2008 sales for Ciprofloxacin were $242 million, as compared to $324 million for Bayer Aspirin.
Licensed uses
The licensed uses for ciprofloxacin in the United States are as follows:
Fluoroquinolones are not licensed by the FDA for use in children due to the risk of permanent injury to the multiskeletal 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 alleged to be effective, ciprofloxacin is not to be considered a first line agent for inhalation anthrax in the pediatric population due to severe adverse reactions involving the multiskeletal system and other serious adverse reactions, including fatalities. 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. Prescribing a fluoroquinolone to treat an unapproved use within the pediatric (as well as the adult population) exposes the treating physician to the risk of being sued for malpractice should the treating physician fail to both warn the patient of this fact, as well as the risks of any adverse drug reactions the patient may experience.
In the adult population ciprofloxacin is limited to the treatment of proven serious and life threatening bacterial infections such as:
- Urinary Tract Infections
- Acute Uncomplicated Cystitis in females
- Chronic Bacterial Prostatitis
- Lower Respiratory Tract Infections
- Acute Sinusitis
- 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 due to bacterial resistance.
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 serious and life threatening bacterial infections such as:
- Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli
- Inhalational Anthrax (post-exposure)
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. Antibiotics such as ciprofloxacin do not improve sinusitis symptoms. 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. 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. Antibiotics' futility against bronchitis had been confirmed in 2002. 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 in English speaking countries under the following brand names.
- Australia: C-Flox, Ciloquin, Ciloxan, Ciprol, Ciproxin, Profloxin, Proquin
- Canada: Ciloxan, Cipro
- Ireland: Biofloxcin, Cifloxager, Ciproxin, Profloxin, Truoxin
- New Zealand: Ciloxan, Cipflox, Ciproxin, Topistin, Ufexil
- South Africa: Adco-Ciprin, Biocip, Cifloc, Cifran, Ciloxan, Ciploxx, Cipro-Hexal, Ciprobay, Ciprogen, Dynafloc, Orpic, Spec-Topistin
- United Kingdom: Ciloxan, Ciproxin
- United States: Ciloxan, Cipro
It is also available as a multi-drug preparation under the following brand names.
Activity
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, which is an enzyme necessary to separate replicated DNA, thereby inhibiting cell division.
The fluoroquinolones interfere with DNA replication by inhibiting an enzyme complex called DNA gyrase. This can also affect mammalian cell replication. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models. Although the quinolone is highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986 (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 considerable debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe and non abating adverse reactions experienced by some patients following fluoroquinolone therapy.
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 prevalance 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.
The fluoroquinolones rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. For this reason the Fluroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The Flouroquinolones have also been reported as being present in the mother’s milk and are passed on to the nursing child, which may increases the risk of the child suffering from this syndrome as well, even though the child had never been prescribed or taken any of the drugs found within this class.
Fluoroquinolones are not licensed by the FDA for use in children due to the risk of fatalities as well as permanent injury to the multiskeletal 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 one study it was stated that the pediatric patient has a 3.8% chance of experiencing a serious multiskeletal adverse event. Within the studies submitted in response to a Pediatric Written Request (Ciprofloxacin, circa 2004) the rate of athropy was reported to be 9.3%.
Two recent pediatric studies involving the use of levofloxacin indicates that the pediatric patient has a greater than 50% chance of experiencing one or more adverse reactions. Which would be consistent with the studies found within the NDA (new drug application) for Levofloxacin which showed and ADR rate in excess of 40%, as well as a number of reported fatalities. Within the first study it is stated that “Of the 712 subjects evaluable for safety, 275 (52%) levofloxacin-treated subjects experienced one or more adverse event... Serious adverse events were reported in 33 (6%) levofloxacin-treated subjects... Two serious adverse events in levofloxacin-treated subjects resulted in fatal outcomes.” Within the second study it is stated that “Of the 204 subjects evaluable for safety, 122 experienced one or more adverse events...Twelve subjects (6%) discontinued study drug due to an adverse event...Seven subjects (3%) experienced 8 serious adverse events.” (circa 2007)
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 consistant with the safety profile found with the other fluoroquinolones studied in the pediatric population, as noted above with levofloxacin. 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 risk of permanent injury outweighs the potential benefits.
Adverse effects
Fluoroquinolones are generally well tolerated with most side effects being mild and serious adverse effects occuring rarely. Some of the serious adverse effects which occur more commonly with fluoroquinolones than with other antibiotic drug classes include CNS and tendon toxicity. Unusual adverse reactions include psychosis and chorea (involuntary muscle movements). The currently marketed quinolones have safety profiles similar to that of other antimicrobial classes. Phototoxicity, neurological symptoms, impaired colour vision, exanthema, abdominal pain, malaise, drug fever, peripheral neuropathy, dysaesthesia and eosinophilia have been observed as adverse effects of ciprofloxacin.
The serious events may occur with therapeutic or with acute overdose. At therapeutic doses they include: central nervous system toxicity, cardiovascular toxicity, tendon / articular toxicity, and rarely hepatic toxicity. Events that may occur in acute overdose are rare and include: renal failure and seizure. Children and the elderly are at greater risk. Adverse reactions may manifest during, as well as after fluoroquinolone therapy. Unusual but potentially serious adverse reactions occur as a result of ciprofloxacin administration bone marrow depression, interstitial nephritis and hemolytic anemia occur during ciprofloxacin use.
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.
Pseudotumor cerebri, commonly known as idiopathic intracranial hypertension (IIH), also referred to as increased intracranial pressure, has been reported to occur as a serious but isolated adverse reaction to ciprofloxacin. An unusual case of seizures has been reported with ciprofloxacin ear drops in an elderly lady.
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 the levels of thyroid medications resulting in hypothyroidism.
Concurrent administration of ciprofloxacin, with magnesium or aluminum antacids, sucralfate or products containing calcium, iron, or zinc may substantially decrease the absorption of ciprofloxacin, resulting in serum and urine levels considerably lower than desired. (See package insert)
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 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. 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. Whether or not such reactions occur after completion of therapy is a matter of considerable debate. Patients have reported reactions to NSAIDS long after completion of fluoroquinolone therapy, but there does not appear to be any research that would either confirm or deny this association other than these anecdotal reports.
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.
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.
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. This effect seems to be restricted to people aged 60 or over, and within this group concomitant use of corticosteroids increases this risk substantially. Though technically not to be considered a drug interaction, mention of this is made here due to fact that the etiology of such ruptures remains elusive and further research may confirm such a drug interaction may play a role in this particular reaction. However, at the moment, this is to be considered speculatory in nature and additional research to confirm or deny is required.
Overdose
"In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given supportive treatment, including monitoring of renal function and administration of magnesium, aluminum, or calcium containing antacids which can reduce the absorption of ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal dialysis." Qouting from the 2009 package insert for Ciprofloxacin
Pharmacology
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. It is a faintly yellowish to light yellow crystalline substance.
Ciprofloxacin hydrochloride, USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8. Its empirical formula is C17H18FN3O3•HCl•H2O.
There are a number of the endogenous compounds that have been reported to be affected by Ciprofloxacin as inhibitors, alteraters and depletors. See the latest package insert for Ciprofloxacin for additional details.
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 70–80% 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.
Biotransformation is hepatic. The half life is 4 hours.
Dosing
Ciprofloxacin should only be administered as described within the Dosage Guidelines table found within the most current package insert. The status of the patient’s renal function and hepatic function must also be taken into consideration to avoid an accumulation that may lead to a fatal drug overdose. 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.
NOTE: The patient’s serum levels should be monitored during therapy to avoid a drug overdose. See the most current Package Insert for proper dosing guidelines and relevant warnings/precautions.
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 side effects from taking the antibiotic ciprofloxacin (Cipro) in the aftermath of the anthrax attacks in 2001. 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.
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. There is a regulatory gap between 1987 and 1994 as well as between 1994 and 1997, resulting in ten years worth of regulatory documentation missing on the FDA site concerning the regulatory history of ciprofloxacin.
October 1996:
- Within a FDA Medical Bulletin issued October 1996, the FDA gave notice to practicing physicians within the United States regarding spontaneous tendon ruptures and chronic tendonitis being associated with the fluoroquinolones.
September 1997:
- Addition of the CNS adverse reaction warnings.
September 1998:
- Addition of taste loss as an adr. 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.
August 30, 2000:
- Approval of the adult and pediatric use of ciprofloxacin for inhalational anthrax (post-exposure).
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.”
In 2004 new warning labels were supposed to have been added to all of the Fluoroquinolones 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.
A review of the last 2004 label revisions for ciprofloxacin failed to indicate that any warnings concerning Heart Problems (prolonged QT Interval / Torsades de pointes), Rhabdomyolysis (muscle wasting), or Steven Johnson Syndrome were added to the label. It was not until the latest label (2008) that the warnings concerning prolonged QT Interval / Torsades de pointes appear. Warnings concerning Rhabdomyolysis (muscle wasting) and Steven Johnson Syndrome are still conspicuously absent.
March 15, 2004
- Addition of the warning concerning ruptures of the Achilles and other tendons in relation to the
concomitant use of corticosteroids, especially in the elderly.
- Removal of the warning that “Allergic reactions ranging from urticaria to anaphylactic reactions have been reported.” “Sweating” added as an adr in its place.
March 25, 2004
- Approval of the pediatric use to treat Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
July 14, 2004
- Addition of the peripheral neuropathy warning, and concomitant use of NSAIDS warning.
November 9, 2005
- Addition of warnings concerning Ciprofloxacin being an inhibitor of humancytochrome P450 1A2 (CYP1A2) mediated metabolism. “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.”
June 25, 2007
- Addition of the warning that “Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including ciprofloxacin.”
- Addition of the warning that Clostridium difficile associated diarrhea (CDAD) is associated with the use of ciprofloxacin.
January 18, 2008
- Phototoxicy warnings diluted and trivialized.
October 3, 2008
- Addition of the BLACK BOX WARNINGS regarding tendon ruptures.
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 a 1995 letter published in the New England Journal of Medicine, representatives of the U.S. Food and Drug Administration (FDA) stated that the agency would "update the labeling [package insert] for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture."
By August 1996, the FDA had not taken action, and the consumer advocacy group Public Citizen filed a petition with the FDA prompting the agency to act. Two months later, the FDA published an alert in the FDA Medical Bulletin and requested that fluoroquinolone package inserts be amended to include information on this risk.
In 2005, the Illinois Attorney General filed a petition with the FDA seeking black box 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 a black box warning. In January 2008, Public Citizen filed suit to compel the FDA to respond to their 2006 petition. On July 7, the FDA ordered the makers of systemic-use fluoroquinolones to add a boxed warning regarding tendon rupture, and to develop a Medication Guide for patients. 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 generic versions of the fluoroquinolones have not been updated to include this Black Box Warning as of January 2009. And there are numerous reports that this information has not been dessiminated to the pharmacist, the products continue to contain the previous labels that are absent of this warning, and the Medication Guide has not been made available to the pharmicist or physician for distribution.
FDA warning letters
Additionally the manufacturers of ciprofloxacin (Bayer A.G.) received numerous warning letters from the FDA regarding false advertising and failure to provide adequate warnings within their promotional materials:
Bayer
Scripting abuse and bacterial resistance
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.
The ever increasing bacterial resistance to ciprofloxacin, (which is a major concern), may very well threaten its future viability to treat serious and life threatening bacterial infections. Years ago the FDA had added warnings regarding the proper use of these drugs within the package inserts to combat such scripting abuse. Advising physicians that ciprofloxacin: "...should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria..."(See the monographs for this class)
Normally ciprofloxacin should only be used in patients who have failed at least one prior therapy. Reserved for the use in patients who are seriously ill and may soon require immediate hospitalization. Though considered to be a very important and necessary drug required to treat severe and life threatening bacterial infections, the associated scripting abuse of ciprofloxacin remains unchecked, which has contributed to the problem of bacterial resistance. The overuse of antibiotics such as happens with children suffering from otitis media has given rise to a breed of super bacteria which are resistant to antibiotics entirely. “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.”
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.
Within a recent study concerning the proper use of this class in the emergency room it was revealed that 99% of these prescriptions were in error. Out of the one hundred total patients studied, eighty one received a fluoroquinolone for an inappropriate indication. Out of these cases, forty three (53%) were judged to be inappropriate because another agent was considered first line, twenty seven (33%) because there was no evidence of a bacterial infection to begin with (based on the documented evaluation), and eleven (14%) because of the need for such therapy was questionable. Out of the nineteen patients who received a fluoroquinolone for an appropriate indication, only one patient out of one hundred received both the correct dose and duration of therapy.
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.
There are three known mechanisms of resistance. Some types of efflux pumps can act to decrease intracellular quinolone concentration. In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or Topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug's effectiveness.
Social and economic impact
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.
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.
Under the George W. Bush administration (2001-2008) patent extension legislation was signed into law that allowed Bayer A. G., as well as other drug companies, a six month patent extension for testing their products for safety in children. It has been estimated that Bayer A.G.'s revenue increased an extra $358 million due to ciprofloxacin's pediatric patent extension. The legislation that was signed by President Bush, granting Bayer and other drug manufacturers a six month extension on their patents (to conduct pediatric testing), was drafted after extensive lobbying of numerous members of Congress by Bayer A.G. and others. One of the four sponsors of this legislation was Chris Dodd (D-CT), who at the time, ranked as one of the top three beneficiaries of campaign contributions by drug companies. Sen. Edward Kennedy (D-Mass.), who chaired the committee with jurisdiction over the bill, refused to fight over the language that (if it had been included) would have reduced the drug company's profits due to these patent extensions. The reasons for Sen. Edward Kennedy's decision not to fight for the inclusion of this language were not made known.
The results of these pediatric trials were disastrous. Arthropathy occurred more frequently in patients who received ciprofloxacin within these studies. The affected joints included the knees, elbows, ankles, hips, wrists, and shoulders of the pediatric patients. In one study at six weeks arthropathy was seen in 9.3% of ciprofloxacin patients. These rates increased significantly after one year to 13.7% of the ciprofloxacin patients. Such arthropathy occurred more frequently in patients treated with ciprofloxacin than any other control drug, regardless of whether they received IV ciprofloxacin or the oral version of the drug. Ciprofloxacin patients reported more than one event and on more than one occasion when compared to the control patients. The overall incidence of adverse events at six weeks was 41% in those patients being treated with ciprofloxacin. Serious adverse events were seen in 7.5% of these patients and 3% of the patients discontined the drug due to adverse events. In spite of this unacceptable safety profile the FDA stated that “The data support updating the package insert to include safety; and treatment recommendations for pediatric patients between 1 and 17 years of age with complicated urinary tract infection or pyelonephritis.”
Within a 2005 memo the FDA reviewed seventeen unique pediatric cases reported to the FDA during the thirteen month period after the pediatric exclusivity for ciprofloxacin had been granted. During this period there was one death, two reports of disability and four of hospitalization. The disabilities involved the inability to walk (in a 12-year female patient) and the inability to run (in a 12-year old male patient). The hospital admissions were for pseudomembranous colitis, pancytopenia, tendonitis and Stevens Johnson Syndrome. The female patient received 5 weeks of ciprofloxacin oral therapy at the recommended doses. Even though ciprofloxacin was discontinued, she could not stand or ambulate and required a wheelchair one month later. These seventeen unique pediatric cases showed mostly hematological, musculoskeletal, allergic/hypersensitivity, and CNS adverse events. It does not appear that this executive summary was ever released to the medical community.
- Economic impact: adverse reactions:
The adverse drug reaction profile of ciprofloxacin and other fluoroquinolone drugs has spawned a grass root movement of those so effected to lobby for Black Box Warnings and Dear Doctor Letters as well as the petitioning of the FDA for the removal of some fluoroquinolone drugs from clinical practice.
A number of class action lawsuits as well as malpractice litigation has been spawned by this unacceptable safety profile. The various manufacturers have countered these allegations stating that they believe that these drugs are both safe and effective antibiotics, well tolerated with a minimum of side effects, such reactions are “rare” (contrary to the literature) and the benefits of such therapy outweigh the perceived risks.
Risk/benefit assessment
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.
In a 1986 issue of the Journal of Antimicrobial Chemotherapy, a leading article on quinolones in chest infections concludes that there is little reason for optimism about the role of quinolones in chest infections mainly because of problems with resistance, recurrence, and reinfection with Pseudomonas aeruginosa and S pneumoniae. Bantz et al (Some of Bantz's colleagues were employed by Bayer at that time) were cited in one of Bayer's promotional leaflets for Ciproxin; they mentioned a >95% resolution rate but compared only doxycycline with ciprofloxacin and made no reference to what bacterial pathogens were being treated. In the same supplement to the American Journal of Medicine, however, other papers gave less than favorable reviews. For example one paper stated that, "the activity of ciprofloxacin against Streptococci and Enterococci is marginal, at best." Which is diametrically opposed to the views expressed by Bantz et al. In spite of this dismal track record 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.
Antibiotics do not improve sinusitis symptoms a number of studies have shown. Primary care physicians (family doctors) commonly prescribe ciprofloxacin to treat acute maxillary sinusitis (inflamed membranes of the sinuses), although there is no evidence that this approach is effective. A report in the British medical Journal the Lancet found that antibiotics did nothing more than the placebos used as the control.
Only about 5-10% of bronchitis cases are caused by a bacterial infection. Most cases of bronchitis are caused by a viral infection and are "self-limited" and resolve themselves in a few weeks.
- Chronic bacterial prostatitis:
Prostatitis has been termed "the waste basket of clinical ignorance" by prominent Stanford University Urologist Dr. Thomas Stamey. Campbell's Urology, the urologist's most authoritative reference text, identifies only about 5% of all patients with prostatitis as having bacterial prostatitis which can be "cured" at least in the short term by antibiotics. In other words, 95% of men with prostatitis have little hope for a cure with antibiotics alone since they don't actually have any identifiable bacterial infection. Within a 2003 study involving the use of fluoroquinolones to treat Chronic Bacterial Prostatitis it was found that the level of improvement was no different from that associated with placebo. Within a 2004 randomized, double-blind trial involving ciprofloxacin specifically, it was found that ciprofloxacin “did not substantially reduce symptoms in men with long-standing CP/CPPS who had at least moderate symptoms.”
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, we see a 65% adverse drug reaction rate 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...”
A Clostridium difficile infection is the principal cause of ciprofloxacin-associated diarrhea and pseudomembranous colitis. In June of 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.As such the efficacy of ciprofloxacin to treat infectious diarrhea would be called into question.
- Uncomplicated cervical and urethra gonorrhea:
As previously stated the use of ciprofloxacin to treat this disease has been severely compromised by bacterial resistance.
As such most of the approved uses for ciprofloxacin have shown either lack of reasonal efficacy within a number of independent studies, or has been severely compromised by growing bacterial resistance. Applying a reasonable risk/benefit assessment to the use of ciprofloxacin there would be very few cases where the use of a fluoroquinolone drug, such as ciprofloxacin, should be considered by the treating physician to be a first line agent. Ciprofloxacin has been associated with significant collateral system toxicity during therapy; as such the potential for benefit may not outweigh the proven risk when there is a safer alternative available to the treating physician.
See Also
- Fluoroquinolone toxicity
- Fluoroquinolone
- Quinolone
Package insert links
External links
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