Moxifloxacin
Encyclopedia
Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent developed by Bayer AG (initially called BAY 12-8039). It is marketed worldwide (as the hydrochloride) under the brand names Avelox, Avalox, and Avelon for oral treatment. In most countries, the drug is also available in parenteral form for intravenous infusion. Moxifloxacin is also sold in an ophthalmic solution (eye drops) under the brand names Vigamox, Moxeza for the treatment of conjunctivitis (pink eye).
A United States patent application was submitted on June 30, 1989 for Avelox (moxifloxacin hydrochloride), but it was not until 1999 (ten years later) that Avelox was approved by the U.S. Food and Drug Administration (FDA) for use in the United States to treat severe and life threatening bacterial infections.
The licensed uses for moxifloxacin are quite limited as moxifloxacin is to be considered a drug of last resort when all other antibiotics have failed. There are currently only six approved uses in the adult population (three of which are restricted) and Vigamox (ophthalmic) is the only one used for children. Moxifloxacin interacts with a number of other drugs, as well as a number of herbal and natural supplements.
Avelox (moxifloxacin) was launched in the United States in 1999 and is currently marketed in more than 80 countries worldwide. In the United States, Avelox is marketed by Bayer's partner Merck. Within the past year (2008–2009) Bayer has issued three Dear Doctor Letters concerning severe adverse reactions associated with the use of moxifloxacin, as well as giving notice regarding restrictions in its use. First marketed in 1999, moxifloxacin is Bayer's heir apparent to ciprofloxacin.
As of 2011 the FDA has added two boxed warnings for this drug in reference to spontaneous tendon ruptures and the fact that moxifloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Such an adverse reaction is a potentially life-threatening event and may require ventilatory support.
, anthrax
, intraabdominal infections, endocarditis
, meningitis
, and tuberculosis
.
In the adult population its oral and intravenous is limited to the treatment of proven serious and life-threatening bacterial infections. The initial approval by the FDA (December 1999) encompassed the following indications:
Additional indications were approved by the FDA as follows:
The licensed uses noted as restricted use requires that moxifloxacin only be prescribed when other antibiotics that have been initially recommended for treatment cannot be used or have failed.
At the current time, there are no approved uses within the pediatric population for Oral and I.V. moxifloxacin. A significant number of drugs found within this class, including moxifloxacin, 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.
Prescribing moxifloxacin to treat an unapproved use (other than those listed above) within the pediatric, as well as the adult population, does however take place rather frequently.
In ophthalmology
, moxifloxacin licensed use is limited to the treatment of conjunctiva
l infections caused by susceptible bacteria.
Note: Moxifloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.
, pseudomembranous colitis
, psychotic reactions and Stevens–Johnson syndrome have also been associated with moxifloxacin therapy.
There has been a number of regulatory actions taken as a result of such adverse reactions, which include published warnings, the issuance of numerous "Dear Doctor Letters", the restrictions regarding the use of moxifloxacin instituted by the European agency's Committee for Medicinal Products for Human Use (CHMP), as well as the recent addition of Black Box Warnings. On March 22, 2010 Health Canada issued a notice to health care professionals and Canadians regarding the recent changes to the labeling information for Avelox (moxifloxacin). The 2010 Canadian updated labeling now includes information regarding the risk of severe liver injury during moxifloxacin therapy.
These serious events may occur with therapeutic or with acute overdose. Such adverse reactions may manifest during, as well as after moxifloxacin therapy.
Most recently, the German regulatory authorities placed additional restrictions on the use of oral moxifloxacin in patients with acute bacterial sinusitis (ABS), acute exacerbation of chronic bronchitis (AECB), and community-acquired pneumonia (CAP) stating that in case of these diseases moxifloxacin should only be prescribed when other antibiotics that have been initially recommended for treatment cannot be used or have failed. Additional notice was given that rhabdomyolysis, the exacerbation of symptoms of myasthenia gravis and the risk of cardiac arrhythmia in women and older patients, was associated with moxifloxacin.
Currently the German regulatory authorities are investigating the association of severe and life threatening QTc prolongation/torsades de pointes with moxifloxacin therapy, which the FDA had raised serious concerns about during the initial drug approval process back in 1999.
Serious visual complications have also been reported to occur with ophthalmic
fluoroquinolone therapy, which may also occur with Vigamox, especially corneal perforation, but also evisceration
and enucleation
. Corneal perforation occurred most commonly in elderly patients with deep ulcers. These increased incidents of corneal perforation may be due to fluoroquinolones' causing alterations in stromal collagen, leading to a reduction in tectonic strength.
Due to growing prevalence of antibiotic resistance to the fluoroquinolones in southeast Asia, the use of the drugs found within the fluoroquinolone class (which would include moxifloxacin) in patients having been to southeast Asia is increasingly being contraindicated.
There are only two listed contraindications found within the 2008 package insert:
Though not stated as such within the package insert, ziprasidone is also considered to be contraindicated, as it may have the potential to prolong QT interval. Moxifloxacin should also be avoided in patients with uncorrected hypokalemia, or concurrent administration of other medications known to prolong the QT interval (antipsychotics and tricyclic antidepressants).
Moxifloxacin should be used with caution in patients suffering from diabetes, as glucose regulation may be significantly altered.
Moxifloxacin is also considered to be contraindicated within the pediatric population, pregnancy
, nursing mothers, patients with a history of tendon disorder, patients with documented QT prolongation, and patients with epilepsy
or other seizure disorders. Coadministration of moxifloxacin with other drugs that also prolong the QT interval or induce bradycardia (e.g., beta-blockers, amiodarone) should be avoided. Careful consideration should be given in the use of moxifloxacin in patients with cardiovascular disease, including those with conduction abnormalities.
Recently (2008), Bayer issued a Europrean Dear Doctor Letter concerning moxifloxacin-associated liver damage, and, as such, the use of moxifloxacin would now be considered contraindicated in patients with impaired liver function.
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's 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 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. It does not appear that there have been any pediatric trials involving oral or IV moxifloxacin to date. But the fluoroquinolones that have been involved in pediatric clinical trials reveal the following:
Within one study it was stated that the pediatric patient has a 3.8% chance of experiencing a serious musculoskeletal 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. This 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 consistent 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.
or magnesium
ion
s inhibit the absorption of moxifloxacin. Drugs that prolong the QT interval
(e.g., pimozide
) may have an additive effect on QT prolongation and lead to increased risk of ventricular arrhythmias. The INR (International Normalised Ratio
) may be increased or decreased in patients treated with warfarin
. Moxifloxacin has been shown in a number of case reports to interact with warfarin. The exact mechanism for the warfarin-quinolone drug interaction is unknown. A precautionary measure would be to monitor the INR more closely and, if necessary, adjust the anticoagulant dose as necessary. Moxifloxacin does not appear to inhibit theophylline metabolism. However, caution may be warranted when using theophylline with all of the fluoroquinolones, including moxifloxacin. Drug Interaction Facts notes that some fluoroquinolones, especially ciprofloxacin, enoxacin, and norfloxacin, interact with theophylline.
A potentially serious drug interaction is the combination of corticosteroids and moxifloxacin, as this combination increases tendon toxicity, which has potential to result in tendonitis
and disability.
that is active against both
Gram-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 replication.
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, including moxifloxacin, 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 adverse reactions experienced by some patients following fluoroquinolone therapy.
There are a number of endogenous compounds that have been reported to be affected by moxifloxacin as inhibitors, alteraters, and depletors. See the latest package insert for Ciprofloxacin for additional details.
In vitro studies with cytochrome (CYP) P450 enzymes indicate that moxifloxacin does not inhibit 80 CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2, suggesting that moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.
The pharmacokinetics of moxifloxacin in pediatric subjects have not been studied.
The half-life of moxifloxacin is 11.5-15.6 hours (single-dose, oral). Approximately 45% of an oral or intravenous dose of moxifloxacin is excreted as unchanged drug (~20% in urine and ~25% in feces). A total of 96% ± 4% of an oral dose is excreted as either unchanged drug or known metabolites. The mean (± SD) apparent total body clearance and renal clearance are 12 ± 2 L/hr and 2.6 ± 0.5 L/hr, respectively. The CSF penetration of moxifloxacin is 70% to 80% in patients with meningitis.
, has proven to be a blockbuster drug for Bayer A. G., generating billions of dollars in additional revenue. In 2007 alone, Avelox generated sales of $697.3 million dollars worldwide.
However, there were serious questions raised within the NDA (New Drug Application, 1999) regarding the safety and efficacy of moxifloxacin, which now appears to threaten its continuing viability. Of particular concern is moxifloxacin-induced cardiac arrhythmias. The Medical Review Officer stated that "Moxifloxacin clearly prolongs QTc intervals
in a concentration-related manner and, as a result, puts patients at risk for developing malignant arrhythmias. The data provided by the sponsor did not include all patients treated, about 90% were excluded, and ECG were obtained as late as 6 hours after the drug intake (peak concentration is about 2 hours). So the sponsor's argument that moxifloxacin is safe because it causes only a small increase in QTc is flawed. What was shown in the database is that there are examples of patients on moxifloxacin with changes in QTc intervals greater than 80 msec over baseline with resulting QTc intervals above 500 msec.... Moxifloxacin raises the QTc interval in a concentration-related manner and, therefore, has the potential to cause malignant ventricular arrhythmias, including torsade de pointes, and death.... In summary, it is hard to justify approving this agent as a first-line therapy for non-life-threatening infections in which there are a plethora of treatment choices.(sic)"
The FDA approved moxifloxacin over the objections of the members of the FDA advisory committee, as well as the medical review officer (noted above), even though the studies submitted with the NDA failed to show any advantage over the comprators presented in a number of instances.
Since the approval of moxifloxacin in 1999, there has been numerous upgrades to the warnings sections of the package inserts, as well as three Dear Doctor Letters issued by the manufacturer over the past year. The latest involving the very issues raised with the NDA, ten years ago. Within the 2009 "Rote-Hand-Brief" German officials warned German physicians of the associated risk of cardiac arrhythmia in women and older patients. At its July 2008 meeting, the agency's Committee for Medicinal Products for Human Use (CHMP) recommended restricting the use of moxifloxacin due to safety concerns, mainly related to an increased risk of adverse hepatic reactions.
Nevertheless, moxifloxacin continues to be aggressively marketed by Bayer. Bayer makes about $500 million a year from moxifloxacin, which it sells in the United States as Avelox and elsewhere as Avalox, Avelon, Megaxin, Actira, and Izilox.
Moxifloxacin was subsequently (ten years later) approved by the U.S. Food and Drug Administration (FDA) for use in the United States in 1999. There have been at least four additional United States patents filed regarding moxifloxacin hydrochloride since the 1989 United States application, as well as patents outside of the USA.
6/26/2003 New Zealand Pharmacovigilance warns of moxifloxacin induced respiratory insufficiency.
10/6/2003 Changes made to minimize the impact of post marketing reports as well as the risk of tendon injuries.
12/29/2008 Addition of numerous adverse reactions associated with the use of moxifloxacin.
04/27/2009
Issuance of a Medication Guide and revisions to include new safety information including the addition of the Black Box Warning to the Medication Guide. The FDA had determined that Moxifloxacin poses a serious and significant public health concern, requiring the distribution of a Medication Guide.
06/24/2009 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.(emphasis added)
. 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 Boxed 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 Boxed 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 Cipro (ciprofloxacin
), Avelox (moxifloxacin), Proquin XR, Factive (gemifloxacin
), Floxin (ofloxacin
), Noroxin (norfloxacin
) and Levaquin (levofloxacin
) were amended on September 8, 2008 to include these new warnings. 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 Boxed Warning as of February 2009. And there are numerous reports that this information has not been disseminated 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 pharmacist or physician for distribution.
December 15, 1999 Lack of fair balance and presentation of misleading safety information, promotion of unapproved uses, unsubstantiated superiority claims.
June 21, 2001 Promotion of unapproved uses.
to moxifloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogen
s, including Staphylococcus aureus
, enterococci, and Streptococcus pyogenes
now exhibit resistance worldwide. Widespread veterinary usage of the fluoroquinolones, in particular in Europe, has been implicated.
The ever-increasing bacterial resistance to moxifloxacin, (which is a major concern) together with an unacceptable safety profile, may very well threaten its future viability to treat serious and life-threatening bacterial infections. Years ago, the FDA had added warnings regarding the proper use of these drugs within the package inserts to combat such antibiotic abuse. Advising physicians that moxifloxacin: "...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)
Under normal circumstances, moxifloxacin and other fluoroquinolone drugs would be used only in patients having failed at least one prior therapy, reserved for the use in patients seriously ill and soon requiring 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 moxifloxacin 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 that are resistant to antibiotics entirely.
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.
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. In addition, 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.
Resistance to moxifloxacin arises in Mycobacterium tuberculosis if moxifloxacin is used alone instead of in combination with other anti-TB drugs, which appears to be the explanation for the appearance of moxifloxacin resistance in newly diagnosed TB patients in Baltimore and in Taiwan. Of concern is that the development of resistance can appear in as short a time as seven days. This calls into question the first-line use of moxifloxacin and other respiratory quinolones as first-line therapy for the treatment of community-acquired pneumonia in populations where TB is still endemic.
In 2007, the U.S. District Court for the District of Delaware held that two Bayer patents on Avelox (moxifloxacin hydrochloride) are valid and enforceable, and infringed by Dr. Reddy's ANDA for a generic version of Avelox. The district court sided with Bayer, citing the Federal Circuit's prior decision in Takeda v. Alphapharm as "affirming the district court's finding that defendant failed to prove a prima facie case of obviousness where the prior art disclosed a broad selection of compounds, any one of which could have been selected as a lead compound for further investigation, and defendant did not prove that the prior art would have led to the selection of the particular compound singled out by defendant." According to Bayer's press release announcing the court's decision, it was noted that Teva had also challenged the validity of the same Bayer patents at issue in the Dr. Reddy's case. Within Bayer's first quarter 2008 stockholder's newsletter Bayer stated that they had reached an agreement with Teva Pharmaceuticals USA, Inc., the adverse party, to settle their patent litigation with regard to the two Bayer patents. Under the settlement terms agreed upon, Teva would obtain a license to sell its generic moxifloxacin tablet product in the U.S. shortly before the second of the two Bayer patents expires in March 2014.
The adverse drug reaction profile of moxifloxacin and other fluoroquinolone drugs has spawned a grass-roots movement of those so affected 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 United States patent application was submitted on June 30, 1989 for Avelox (moxifloxacin hydrochloride), but it was not until 1999 (ten years later) that Avelox was approved by the U.S. Food and Drug Administration (FDA) for use in the United States to treat severe and life threatening bacterial infections.
The licensed uses for moxifloxacin are quite limited as moxifloxacin is to be considered a drug of last resort when all other antibiotics have failed. There are currently only six approved uses in the adult population (three of which are restricted) and Vigamox (ophthalmic) is the only one used for children. Moxifloxacin interacts with a number of other drugs, as well as a number of herbal and natural supplements.
Avelox (moxifloxacin) was launched in the United States in 1999 and is currently marketed in more than 80 countries worldwide. In the United States, Avelox is marketed by Bayer's partner Merck. Within the past year (2008–2009) Bayer has issued three Dear Doctor Letters concerning severe adverse reactions associated with the use of moxifloxacin, as well as giving notice regarding restrictions in its use. First marketed in 1999, moxifloxacin is Bayer's heir apparent to ciprofloxacin.
As of 2011 the FDA has added two boxed warnings for this drug in reference to spontaneous tendon ruptures and the fact that moxifloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Such an adverse reaction is a potentially life-threatening event and may require ventilatory support.
Medical uses
Moxifloxacin is used to treat a number of infections including: respiratory tract infections, cellulitisCellulitis
Cellulitis is a diffuse inflammation of connective tissue with severe inflammation of dermal and subcutaneous layers of the skin. Cellulitis can be caused by normal skin flora or by exogenous bacteria, and often occurs where the skin has previously been broken: cracks in the skin, cuts, blisters,...
, anthrax
Anthrax
Anthrax is an acute disease caused by the bacterium Bacillus anthracis. Most forms of the disease are lethal, and it affects both humans and other animals...
, intraabdominal infections, endocarditis
Endocarditis
Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves . Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or even on intracardiac devices...
, meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
, and tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
.
In the adult population its oral and intravenous is limited to the treatment of proven serious and life-threatening bacterial infections. The initial approval by the FDA (December 1999) encompassed the following indications:
- Acute Exacerbations of Chronic Bronchitis (AECB) (restricted use)
- Acute Bacterial Sinusitis (ABS) (restricted use)
- Community Acquired Pneumonia (CAP)(restricted use)
Additional indications were approved by the FDA as follows:
- April, 2001: Uncomplicated Skin and Skin Structure Infections (uSSSI)
- May, 2004: Community Acquired Pneumonia caused by multi-drug resistant Streptococcus pneumoniae.
- June, 2005: Complicated Skin and Skin Structure Infections (cSSSI)
- November, 2005: Complicated Intra-Abdominal Infections (cIAI).
The licensed uses noted as restricted use requires that moxifloxacin only be prescribed when other antibiotics that have been initially recommended for treatment cannot be used or have failed.
At the current time, there are no approved uses within the pediatric population for Oral and I.V. moxifloxacin. A significant number of drugs found within this class, including moxifloxacin, 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.
Prescribing moxifloxacin to treat an unapproved use (other than those listed above) within the pediatric, as well as the adult population, does however take place rather frequently.
In ophthalmology
Ophthalmology
Ophthalmology is the branch of medicine that deals with the anatomy, physiology and diseases of the eye. An ophthalmologist is a specialist in medical and surgical eye problems...
, moxifloxacin licensed use is limited to the treatment of conjunctiva
Conjunctiva
The conjunctiva covers the sclera and lines the inside of the eyelids. It is composed of rare stratified columnar epithelium.-Function:...
l infections caused by susceptible bacteria.
Note: Moxifloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.
Adverse effects
The serious adverse effects that may occur as a result of moxifloxacin therapy include irreversible peripheral neuropathy, spontaneous tendon rupture and tendonitis, acute liver failure or serious liver injury, QTc prolongation/torsades de pointes, toxic epidermal necrolysis (TEN), and clostridium difficile-associated disease (CDAD), as well as photosensitivity/phototoxicity reactions. HepatitisHepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
, pseudomembranous colitis
Pseudomembranous colitis
Pseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...
, psychotic reactions and Stevens–Johnson syndrome have also been associated with moxifloxacin therapy.
There has been a number of regulatory actions taken as a result of such adverse reactions, which include published warnings, the issuance of numerous "Dear Doctor Letters", the restrictions regarding the use of moxifloxacin instituted by the European agency's Committee for Medicinal Products for Human Use (CHMP), as well as the recent addition of Black Box Warnings. On March 22, 2010 Health Canada issued a notice to health care professionals and Canadians regarding the recent changes to the labeling information for Avelox (moxifloxacin). The 2010 Canadian updated labeling now includes information regarding the risk of severe liver injury during moxifloxacin therapy.
These serious events may occur with therapeutic or with acute overdose. Such adverse reactions may manifest during, as well as after moxifloxacin therapy.
Most recently, the German regulatory authorities placed additional restrictions on the use of oral moxifloxacin in patients with acute bacterial sinusitis (ABS), acute exacerbation of chronic bronchitis (AECB), and community-acquired pneumonia (CAP) stating that in case of these diseases moxifloxacin should only be prescribed when other antibiotics that have been initially recommended for treatment cannot be used or have failed. Additional notice was given that rhabdomyolysis, the exacerbation of symptoms of myasthenia gravis and the risk of cardiac arrhythmia in women and older patients, was associated with moxifloxacin.
Currently the German regulatory authorities are investigating the association of severe and life threatening QTc prolongation/torsades de pointes with moxifloxacin therapy, which the FDA had raised serious concerns about during the initial drug approval process back in 1999.
Serious visual complications have also been reported to occur with ophthalmic
Eye drop
Eye drops are saline-containing drops used as a route to administer medication in the eye. Depending on the condition being treated, they may contain steroids, antihistamines, sympathomimetics, beta receptor blockers, parasympathomimetics, parasympatholytics, prostaglandins, non-steroidal...
fluoroquinolone therapy, which may also occur with Vigamox, especially corneal perforation, but also evisceration
Evisceration
An evisceration is the removal of the eye's contents, leaving the scleral shell and extraocular muscles intact. The procedure is usually performed to reduce pain or improve cosmesis in a blind eye, as in cases of endophthalmitis unresponsive to antibiotics...
and enucleation
Enucleation
Enucleation is removal of the eye, leaving the eye muscles and remaining orbital contents intact. This type of ocular surgery is indicated for a number of different ocular tumors, in eyes that have suffered severe trauma, and in eyes that are blind and painful owing to other...
. Corneal perforation occurred most commonly in elderly patients with deep ulcers. These increased incidents of corneal perforation may be due to fluoroquinolones' causing alterations in stromal collagen, leading to a reduction in tectonic strength.
Contraindications
The fluoroquinolone class is now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.Due to growing prevalence of antibiotic resistance to the fluoroquinolones in southeast Asia, the use of the drugs found within the fluoroquinolone class (which would include moxifloxacin) in patients having been to southeast Asia is increasingly being contraindicated.
There are only two listed contraindications found within the 2008 package insert:
- "Nonsteroidal anti-inflammatory drugsNon-steroidal anti-inflammatory drugNonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
(NSAIDs): Although not observed with moxifloxacin in preclinical and clinical trials, the concomitant administration of a nonsteroidal anti-inflammatory drug with a fluoroquinolone may increase the risks of CNSCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
stimulation and convulsions."
- "Moxifloxacin is contraindicated in persons with a history of hypersensitivity to moxifloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components."
Though not stated as such within the package insert, ziprasidone is also considered to be contraindicated, as it may have the potential to prolong QT interval. Moxifloxacin should also be avoided in patients with uncorrected hypokalemia, or concurrent administration of other medications known to prolong the QT interval (antipsychotics and tricyclic antidepressants).
Moxifloxacin should be used with caution in patients suffering from diabetes, as glucose regulation may be significantly altered.
Moxifloxacin is also considered to be contraindicated within the pediatric population, pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
, nursing mothers, patients with a history of tendon disorder, patients with documented QT prolongation, and patients with epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
or other seizure disorders. Coadministration of moxifloxacin with other drugs that also prolong the QT interval or induce bradycardia (e.g., beta-blockers, amiodarone) should be avoided. Careful consideration should be given in the use of moxifloxacin in patients with cardiovascular disease, including those with conduction abnormalities.
Recently (2008), Bayer issued a Europrean Dear Doctor Letter concerning moxifloxacin-associated liver damage, and, as such, the use of moxifloxacin would now be considered contraindicated in patients with impaired liver function.
- Pregnancy
The fluoroquinolones rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. For this reason, the fluroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The flouroquinolones have also been reported as being present in the mother's milk and are passed on to the nursing child, which may increases the risk of the child's 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. It does not appear that there have been any pediatric trials involving oral or IV moxifloxacin to date. But the fluoroquinolones that have been involved in pediatric clinical trials reveal the following:
Within one study it was stated that the pediatric patient has a 3.8% chance of experiencing a serious musculoskeletal 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. This 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 consistent 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.
Interactions
Antacids containing aluminiumAluminium
Aluminium or aluminum is a silvery white member of the boron group of chemical elements. It has the symbol Al, and its atomic number is 13. It is not soluble in water under normal circumstances....
or magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s inhibit the absorption of moxifloxacin. Drugs that prolong the QT interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
(e.g., pimozide
Pimozide
Pimozide is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine . On a weight basis it is even more potent than haloperidol. It also has special neurologic indications for Tourette syndrome...
) may have an additive effect on QT prolongation and lead to increased risk of ventricular arrhythmias. The INR (International Normalised Ratio
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...
) may be increased or decreased in patients treated with warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
. Moxifloxacin has been shown in a number of case reports to interact with warfarin. The exact mechanism for the warfarin-quinolone drug interaction is unknown. A precautionary measure would be to monitor the INR more closely and, if necessary, adjust the anticoagulant dose as necessary. Moxifloxacin does not appear to inhibit theophylline metabolism. However, caution may be warranted when using theophylline with all of the fluoroquinolones, including moxifloxacin. Drug Interaction Facts notes that some fluoroquinolones, especially ciprofloxacin, enoxacin, and norfloxacin, interact with theophylline.
Significant interactions
Moxifloxacin is not believed to be associated with clinically significant drug interactions due to inhibition or stimulation of hepatic metabolism. Thus, it should not, for the most part, require special clinical or laboratory monitoring to ensure its safety. However, there is an additive effect of moxifloxacin and drugs that prolong the QT interval, such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. Therefore, moxifloxacin should be used with caution when given concurrently with such drugs. Moxifloxacin also has a potential for a serious drug interaction with NSAIDS. In addition, the package insert cautions that prothrombin time should be closely monitored if moxifloxacin is concomitantly administered with warfarin.A potentially serious drug interaction is the combination of corticosteroids and moxifloxacin, as this combination increases tendon toxicity, which has potential to result in tendonitis
Tendonitis
Tendinitis , meaning inflammation of a tendon , is a type of tendinopathy often confused with the more common tendinosis, which has similar symptoms but requires different treatment...
and disability.
Overdose
"In the event of acute overdose, the stomach should be emptied and adequate hydration maintained. ECG monitoring is recommended due to the possibility of QT interval prolongation. The patient should be carefully observed and given supportive treatment. The administration of activated charcoal as soon as possible after oral overdose may prevent excessive increase of systemic moxifloxacin exposure. About 3% and 9% of the dose of moxifloxacin, as well as about 2% and 4.5% of its glucuronide metabolite are removed by continuous ambulatory peritoneal dialysis and hemodialysis, respectively."(sic) Quoting from the 12/29/2008 package insert for AveloxMechanism of action
Moxifloxacin is a broad-spectrum antibioticBroad-spectrum antibiotic
The term broad-spectrum antibiotic refers to an antibiotic that acts against a wide range of disease-causing bacteria. A broad-spectrum antibiotic acts against both Gram-positive and Gram-negative bacteria, in contrast to a narrow-spectrum antibiotic, which is effective against specific families of...
that is active against both
Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
and Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria. It functions by inhibiting DNA gyrase
DNA gyrase
DNA gyrase, often referred to simply as gyrase, is an enzyme that relieves strain while double-stranded DNA is being unwound by helicase. This causes negative supercoiling of the DNA...
, a type II topoisomerase
Topoisomerase
Topoisomerases are enzymes that regulate the overwinding or underwinding of DNA. The winding problem of DNA arises due to the intertwined nature of its double helical structure. For example, during DNA replication, DNA becomes overwound ahead of a replication fork...
, and topoisomerase IV, enzymes necessary to separate bacterial DNA, thereby inhibiting cell replication.
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, including moxifloxacin, 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 adverse reactions experienced by some patients following fluoroquinolone therapy.
Pharmacology
"Moxifloxacin, a fluoroquinolone, is available as the monohydrochloride salt of 13 1-cyclopropyl-7-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3 14 quinoline carboxylic acid. It is a slightly yellow to yellow crystalline substance with a molecular 15 weight of 437.9. Its empirical formula is C21H24FN3O4 *HCl." Quoting from the 12/29/2008 package insert for AveloxThere are a number of endogenous compounds that have been reported to be affected by moxifloxacin as inhibitors, alteraters, and depletors. See the latest package insert for Ciprofloxacin for additional details.
Pharmacokinetics
Approximately 52% of an oral or intravenous dose of moxifloxacin is metabolized via glucuronide and sulfate conjugation. The cytochrome P450 system is not involved in moxifloxacin metabolism, and is not affected by moxifloxacin. The sulfate conjugate (M1) accounts for approximately 38% of the dose, and is eliminated primarily in the feces. Approximately 14% of an oral or intravenous dose is converted to a glucuronide conjugate (M2), which is excreted exclusively in the urine. Peak plasma concentrations of M2 are approximately 40% those of the parent drug, while plasma concentrations of M1 are, in general, less than 10% those of moxifloxacin.In vitro studies with cytochrome (CYP) P450 enzymes indicate that moxifloxacin does not inhibit 80 CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2, suggesting that moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.
The pharmacokinetics of moxifloxacin in pediatric subjects have not been studied.
The half-life of moxifloxacin is 11.5-15.6 hours (single-dose, oral). Approximately 45% of an oral or intravenous dose of moxifloxacin is excreted as unchanged drug (~20% in urine and ~25% in feces). A total of 96% ± 4% of an oral dose is excreted as either unchanged drug or known metabolites. The mean (± SD) apparent total body clearance and renal clearance are 12 ± 2 L/hr and 2.6 ± 0.5 L/hr, respectively. The CSF penetration of moxifloxacin is 70% to 80% in patients with meningitis.
Susceptible bacteria
A broad spectrum of bacteria is susceptible including, but not limited to:- Staphylococcus aureusStaphylococcus aureusStaphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
- Staphylococcus epidermidisStaphylococcus epidermidisStaphylococcus epidermidis is one of thirty-three known species belonging to the genus Staphylococcus. It is part of human skin flora, and consequently part of human flora. It can also be found in the mucous membranes and in animals. Due to contamination, it is probably the most common species...
- Streptococcus pneumoniaeStreptococcus pneumoniaeStreptococcus pneumoniae, or pneumococcus, is Gram-positive, alpha-hemolytic, aerotolerant anaerobic member of the genus Streptococcus. A significant human pathogenic bacterium, S...
- Haemophilus influenzaeHaemophilus influenzaeHaemophilus influenzae, formerly called Pfeiffer's bacillus or Bacillus influenzae, Gram-negative, rod-shaped bacterium first described in 1892 by Richard Pfeiffer during an influenza pandemic. A member of the Pasteurellaceae family, it is generally aerobic, but can grow as a facultative anaerobe. H...
- Klebsiella spp.KlebsiellaKlebsiella is a genus of non-motile, Gram-negative, oxidase-negative, rod-shaped bacteria with a prominent polysaccharide-based capsule. It is named after the German microbiologist Edwin Klebs...
- Moraxella catarrhalisMoraxella catarrhalisMoraxella catarrhalis is a fastidious, nonmotile, Gram-negative, aerobic, oxidase-positive diplococcus that can cause infections of the respiratory system, middle ear, eye, central nervous system and joints of humans.-History:...
- Enterobacter spp.EnterobacterEnterobacter is a genus of common Gram-negative, facultatively-anaerobic, rod-shaped bacteria of the family Enterobacteriaceae. Several strains of the these bacteria are pathogenic and cause opportunistic infections in immunocompromised hosts and in those who are on mechanical ventilation...
- Mycobacterium spp.MycobacteriumMycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy...
- Bacillus anthracisBacillus anthracisBacillus anthracis is the pathogen of the Anthrax acute disease. It is a Gram-positive, spore-forming, rod-shaped bacterium, with a width of 1-1.2µm and a length of 3-5µm. It can be grown in an ordinary nutrient medium under aerobic or anaerobic conditions.It is one of few bacteria known to...
History
Moxifloxacin was first patented (United States patent) in 1991 by Bayer A.G., and again in 1997. Avelox was subsequently approved by the U.S. Food and Drug Administration (FDA) for use in the United States in 1999 to treat specific bacterial infections. Ranking 140th within the top 200 prescribed drugs in the United States for 2007 moxifloxacin, in the same manner as ciprofloxacinCiprofloxacin
Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
, has proven to be a blockbuster drug for Bayer A. G., generating billions of dollars in additional revenue. In 2007 alone, Avelox generated sales of $697.3 million dollars worldwide.
However, there were serious questions raised within the NDA (New Drug Application, 1999) regarding the safety and efficacy of moxifloxacin, which now appears to threaten its continuing viability. Of particular concern is moxifloxacin-induced cardiac arrhythmias. The Medical Review Officer stated that "Moxifloxacin clearly prolongs QTc intervals
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
in a concentration-related manner and, as a result, puts patients at risk for developing malignant arrhythmias. The data provided by the sponsor did not include all patients treated, about 90% were excluded, and ECG were obtained as late as 6 hours after the drug intake (peak concentration is about 2 hours). So the sponsor's argument that moxifloxacin is safe because it causes only a small increase in QTc is flawed. What was shown in the database is that there are examples of patients on moxifloxacin with changes in QTc intervals greater than 80 msec over baseline with resulting QTc intervals above 500 msec.... Moxifloxacin raises the QTc interval in a concentration-related manner and, therefore, has the potential to cause malignant ventricular arrhythmias, including torsade de pointes, and death.... In summary, it is hard to justify approving this agent as a first-line therapy for non-life-threatening infections in which there are a plethora of treatment choices.(sic)"
The FDA approved moxifloxacin over the objections of the members of the FDA advisory committee, as well as the medical review officer (noted above), even though the studies submitted with the NDA failed to show any advantage over the comprators presented in a number of instances.
Since the approval of moxifloxacin in 1999, there has been numerous upgrades to the warnings sections of the package inserts, as well as three Dear Doctor Letters issued by the manufacturer over the past year. The latest involving the very issues raised with the NDA, ten years ago. Within the 2009 "Rote-Hand-Brief" German officials warned German physicians of the associated risk of cardiac arrhythmia in women and older patients. At its July 2008 meeting, the agency's Committee for Medicinal Products for Human Use (CHMP) recommended restricting the use of moxifloxacin due to safety concerns, mainly related to an increased risk of adverse hepatic reactions.
Nevertheless, moxifloxacin continues to be aggressively marketed by Bayer. Bayer makes about $500 million a year from moxifloxacin, which it sells in the United States as Avelox and elsewhere as Avalox, Avelon, Megaxin, Actira, and Izilox.
Patent
A United States patent application was made on June 30, 1989 for Avelox (moxifloxacin hydrochloride), (Bayer A.G. being the assignee), which was subsequently approved on February 5, 1991. This patent was scheduled to expire on June 30, 2009. However, this patent was extended for an additional two and one half years on September 16, 2004, and as such is not expected to expire until 2012.Moxifloxacin was subsequently (ten years later) approved by the U.S. Food and Drug Administration (FDA) for use in the United States in 1999. There have been at least four additional United States patents filed regarding moxifloxacin hydrochloride since the 1989 United States application, as well as patents outside of the USA.
Additional regulatory history
6/12/2002 Changes made to minimize the impact of warnings concerning adverse reactions.6/26/2003 New Zealand Pharmacovigilance warns of moxifloxacin induced respiratory insufficiency.
10/6/2003 Changes made to minimize the impact of post marketing reports as well as the risk of tendon injuries.
12/29/2008 Addition of numerous adverse reactions associated with the use of moxifloxacin.
04/27/2009
Issuance of a Medication Guide and revisions to include new safety information including the addition of the Black Box Warning to the Medication Guide. The FDA had determined that Moxifloxacin poses a serious and significant public health concern, requiring the distribution of a Medication Guide.
06/24/2009 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.(emphasis added)
History of the boxed warnings
Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic acidNalidixic acid
Nalidixic acid is the first of the synthetic quinolone antibiotics...
. Rheumatic disease after use of a fluoroquinolone (norfloxacin
Norfloxacin
Norfloxacin is a synthetic chemotherapeutic antibacterial agent occasionally used to treat common as well as complicated urinary tract infections. It is sold under various brand names with the most common being Noroxin. In form of ophthalmic solutions it is known as Chibroxin...
) was first reported eleven years later. In a 1995 letter published in the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
, 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
Public Citizen
Public Citizen is a non-profit, consumer rights advocacy group based in Washington, D.C., United States, with a branch in Austin, Texas. Public Citizen was founded by Ralph Nader in 1971, headed for 26 years by Joan Claybrook, and is now headed by Robert Weissman.-Lobbying Efforts: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
Illinois Attorney General
The Illinois Attorney General is the highest legal officer of the state of Illinois in the United States. Originally an appointed office, it is now an office filled by election through universal suffrage...
filed a petition with the FDA seeking Boxed 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 Boxed 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 Cipro (ciprofloxacin
Ciprofloxacin
Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
), Avelox (moxifloxacin), Proquin XR, Factive (gemifloxacin
Gemifloxacin
Gemifloxacin mesylate is an oral broad-spectrum quinolone antibacterial agent used in the treatment of acute bacterial exacerbation of chronic bronchitis and mild-to-moderate pneumonia....
), Floxin (ofloxacin
Ofloxacin
Ofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class considered to be a second-generation fluoroquinolone. The original brand, Floxin, has been discontinued by the manufacturer in the United States on 18 June 2009, though generic equivalents continue to be...
), Noroxin (norfloxacin
Norfloxacin
Norfloxacin is a synthetic chemotherapeutic antibacterial agent occasionally used to treat common as well as complicated urinary tract infections. It is sold under various brand names with the most common being Noroxin. In form of ophthalmic solutions it is known as Chibroxin...
) and Levaquin (levofloxacin
Levofloxacin
Levofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class and is used to treat severe or life-threatening bacterial infections or bacterial infections that have failed to respond to other antibiotic classes. It is sold under various brand names, such as Levaquin and...
) were amended on September 8, 2008 to include these new warnings. Bayer
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...
, 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 Boxed Warning as of February 2009. And there are numerous reports that this information has not been disseminated 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 pharmacist or physician for distribution.
FDA warning letters
The manufacturers of Avelox (moxiflocaxin – Bayer A. G.) have received warning letters from the FDA regarding false advertising, promotion of unapproved uses, and failure to provide adequate warnings within their promotional materials:December 15, 1999 Lack of fair balance and presentation of misleading safety information, promotion of unapproved uses, unsubstantiated superiority claims.
June 21, 2001 Promotion of unapproved uses.
Antibiotic misuse and bacterial resistance
ResistanceAntibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
to moxifloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s, including Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
, enterococci, and Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...
now exhibit resistance worldwide. Widespread veterinary usage of the fluoroquinolones, in particular in Europe, has been implicated.
The ever-increasing bacterial resistance to moxifloxacin, (which is a major concern) together with an unacceptable safety profile, may very well threaten its future viability to treat serious and life-threatening bacterial infections. Years ago, the FDA had added warnings regarding the proper use of these drugs within the package inserts to combat such antibiotic abuse. Advising physicians that moxifloxacin: "...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)
Under normal circumstances, moxifloxacin and other fluoroquinolone drugs would be used only in patients having failed at least one prior therapy, reserved for the use in patients seriously ill and soon requiring 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 moxifloxacin remains unchecked, which has contributed to the problem of bacterial resistance. The overuse of antibiotics, such as happens with children suffering from otitis media
Otitis media
Otitis media is inflammation of the middle ear, or a middle ear infection.It occurs in the area between the tympanic membrane and the inner ear, including a duct known as the eustachian tube. It is one of the two categories of ear inflammation that can underlie what is commonly called an earache,...
, has given rise to a breed of super-bacteria that are resistant to antibiotics entirely.
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.
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
Otitis media
Otitis media is inflammation of the middle ear, or a middle ear infection.It occurs in the area between the tympanic membrane and the inner ear, including a duct known as the eustachian tube. It is one of the two categories of ear inflammation that can underlie what is commonly called an earache,...
, and acute upper respiratory tract infection
Upper respiratory tract infection
Upper respiratory tract infections are the illnesses caused by an acute infection which involves the upper respiratory tract: nose, sinuses, pharynx or larynx...
, according to a study that was supported in part by the Agency for Healthcare Research and Quality. In addition, 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.
Resistance to moxifloxacin arises in Mycobacterium tuberculosis if moxifloxacin is used alone instead of in combination with other anti-TB drugs, which appears to be the explanation for the appearance of moxifloxacin resistance in newly diagnosed TB patients in Baltimore and in Taiwan. Of concern is that the development of resistance can appear in as short a time as seven days. This calls into question the first-line use of moxifloxacin and other respiratory quinolones as first-line therapy for the treatment of community-acquired pneumonia in populations where TB is still endemic.
Social and economic impact
- Generic equivalents
In 2007, the U.S. District Court for the District of Delaware held that two Bayer patents on Avelox (moxifloxacin hydrochloride) are valid and enforceable, and infringed by Dr. Reddy's ANDA for a generic version of Avelox. The district court sided with Bayer, citing the Federal Circuit's prior decision in Takeda v. Alphapharm as "affirming the district court's finding that defendant failed to prove a prima facie case of obviousness where the prior art disclosed a broad selection of compounds, any one of which could have been selected as a lead compound for further investigation, and defendant did not prove that the prior art would have led to the selection of the particular compound singled out by defendant." According to Bayer's press release announcing the court's decision, it was noted that Teva had also challenged the validity of the same Bayer patents at issue in the Dr. Reddy's case. Within Bayer's first quarter 2008 stockholder's newsletter Bayer stated that they had reached an agreement with Teva Pharmaceuticals USA, Inc., the adverse party, to settle their patent litigation with regard to the two Bayer patents. Under the settlement terms agreed upon, Teva would obtain a license to sell its generic moxifloxacin tablet product in the U.S. shortly before the second of the two Bayer patents expires in March 2014.
- Economic impact: adverse reactions:
The adverse drug reaction profile of moxifloxacin and other fluoroquinolone drugs has spawned a grass-roots movement of those so affected 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.