Levofloxacin
Encyclopedia
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 Tavanic, the most common. In form of ophthalmic solutions it is known as Oftaquix, Quixin and Iquix.
Levofloxacin is a chiral
fluorinated carboxyquinolone. Investigation of ofloxacin
, an older drug that is the racemic
mixture, found that the l form [the (–)-(S) enantiomer
] is more active. This specific component is levofloxacin.
Levofloxacin interacts with a number of other drugs, as well as a number of herbal and natural supplements. Such interactions increase the risk of cardiotoxicity
and arrhythmias, anticoagulation, the formation of non-absorbable complexes, as well as increasing the risk of toxicity.
Levofloxacin is associated with a number of serious and life-threatening adverse reactions as well as spontaneous tendon ruptures and irreversible peripheral neuropathy
. Such reactions may manifest long after therapy had been completed and in severe cases may result in life-long disabilities. Hepatoxicity has also been reported with the use of levofloxacin.
, the U.S. Food and Drug Administration (FDA) has added two Black box warning
s for this drug in reference to spontaneous tendon ruptures and the fact that levofloxacin 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.
, urinary tract infections, prostatitis
, anthrax
, endocarditis
, meningitis
, pelvic inflammatory disease
, and traveler's diarrhea
.
In the adult population Oral and I.V. levofloxacin is limited to the treatment of proven serious and life-threatening bacterial infections such as:
Within the pediatric population Oral and I.V. levofloxacin is limited to:
Note: Levofloxacin has shown moderate activity against anaerobes, and is about twice as potent as ofloxacin against mycobacterium tuberculosis and other mycobacteria, including mycobacterium avium complex.
Oral and I.V. Levaquin are not licensed by the FDA for use in children other than the exception (inhalational anthrax), due to the risk of reversible or irreversible injury to the musculoskeletal system. Although claimed to be effective, levofloxacin is not to be considered a first line agent for inhalational anthrax in the pediatric population due to severe adverse reactions involving the musculoskeletal system and other serious adverse reactions, including fatalities.
The CDC revoked its recommendation regarding the use of fluoroquinolones (ciprofloxacin) as a first-line agent in treating anthrax (in part) due to the risk of adverse reactions 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.
Note: levofloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.
There is one contraindication now found within the 2008 package insert for Levaquin, namely that Levaquin is to be avoided in patients with a known hypersensitivity to levofloxacin or other quinolone drugs.
Due to growing prevalence of antibiotic resistance to the fluoroquinolones in Southeast Asia, the use of levofloxacin in patients that have been to Southeast Asia is increasingly being contraindicated.
Caution should be exercised in prescribing to patients with liver disease
.
Levofloxacin is also considered to be contraindicated in patients with epilepsy
or other seizure disorders.
Pregnancy
Research indicates that the fluoroquinolones can rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. Peak concentration in human breast milk is similar to concentration levels attained in plasma. Breast-feeding mothers that take levofloxacin may expose their infants to severe adverse reactions, and pregnant women are at risk of spontaneous abortions and birth defects.
For this reason the prescribing of levofloxacin is contraindicated during pregnancy. Other flouroquinolones have also been reported as being present in the mother's milk and are passed on to the nursing child.
Pediatric use
Oral and I.V. Levofloxacin is not licensed for use in the pediatric population, except as noted above, due to the risk of serious, life-threatening and permanent injury to the pediatric patient. Within one study, it was stated that the pediatric patient has a 3.8% chance of experiencing a serious musculoskeletal adverse event.
Adverse effects that have been associated with levofloxacin use in children include musculoskeletal disorders such as arthralgia, arthritis, tendonopathy, and gait abnormality The studies found within the new drug application (NDA) for levofloxacin showed an adverse drug reaction (ADR) rate in excess of 40%, as well as a number of reported fatalities. However, the two most 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. Within the first pediatric 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 pediatric 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)
The current ban on the use of Oral and I.V. levofloxacin and other fluoroquinolones in the pediatric population has been supported by a number of clinical studies. The evidence presented at that 62 Meeting of the Anti-Infective Drugs Advisory Committee showed that the fluoroquinolones cause irreversible joint damage in the pediatric population. The conclusion reached by this Advisory Committee was that the risk of permanent injury may outweigh the potential benefits. Subsequent to this meeting, which took place in 1997, the Food and Drug Administration (FDA) has stated that it is their intention to continue to pursue the licensing of the fluoroquinolones for pediatric use in the United States, in spite of these findings.
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.
In 2004, the FDA requested new warning labels to be added to all of the Fluoroquinolones, including levofloxacin, regarding peripheral neuropathy
(irreversible nerve damage), tendon
damage, Heart Problems (prolonged QT Interval / Torsades de pointes
), Pseudomembranous colitis, Rhabdomyolysis
(muscle wasting), Stevens-Johnson Syndrome, as well as concurrent usage of NSAIDs contributing to the severity of these reactions.
Subsequent to this, on June 25, 2007, the FDA required the manufacturer to add an additional warning to the package inserts that stated that "Other serious and sometimes fatal events, some due to hypersensitivity
, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including levofloxacin."
The serious adverse effects that may occur as a result of levofloxacin therapy include irreversible peripheral neuropathy, spontaneous tendon rupture and tendonitis, QTc prolongation/torsades de pointes, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome, erythema multiforme
, severe central nervous system disorders (CNS), including seizures and clostridium difficile associated disease (CDAD: Pseudomembranous colitis) photosensitivity/phototoxicity reactions, fatal hypoglycemia, kidney damage,
rhabdomyolysis (muscle wasting), as well as anaphylactoid reactions and myasthenia crisis.
Additional serious adverse reactions include acute pancreatitis, temporary as well as permanent loss of vision, irreversible double vision,
impaired color vision, exanthema, abdominal pain, malaise, drug fever, dysaesthesia and eosinophilia. Pseudotumor cerebri, commonly known as idiopathic intracranial hypertension (IIH), (also referred to as increased intracranial pressure), has been reported to occur as a serious adverse reaction to levofloxacin. Another serious adverse effect is autoimmune hemolytic anemia
.
Older patients may have an increased risk of tendinopathy (including rupture), especially with concomitant corticosteroid use, and such patients may also be more susceptible to prolongation of the QT interval. Patients with known prolongation, those with hypokalemia, or being treated with other drugs that prolong the QT interval should avoid the use of Levaquin. Hematologic reactions (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses.
Children and the elderly are at a much greater risk of experiencing such adverse reactions. Such reactions may manifest during, as well as long after fluoroquinolone therapy had been discontinued.
Serious visual complications have also been reported to occur with ophthalmic fluoroquinolone therapy, which may also occur with levofloxacin eye drops, especially corneal perforation, but also evisceration and enucleation. This increased incidents of corneal perforation may be due to fluoroquinolones causing alterations in stromal collagen, leading to a reduction in tectonic strength. As noted previously permanent double vision (diplopia) has also been reported.
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.
In chemical terms, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure
(-)-(S)-enantiomer of the racemic drug substance ofloxacin. The chemical name is (-)-(S)-9fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4benzoxazine-6-carboxylic acid hemihydrate. The empirical formula is C18H20FN3O4 • ½ H2O, and the molecular weight is 370.38. Levofloxacin is a light-yellowish-white to yellow-white crystal or crystalline powder.
Some of the endogenous compounds that are affected by the levofloxacin include GABA receptors (inhibitor), OCTN2 (inhibitor), blood glucose (alteration) potassium channels (in myocardial cells - inhibitor), pancreatic β-cell potassium channels (inhibitor) and glutathione (depletor).
Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers and can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies.
Glucuronidation and hydroxylation have been cited as one of the major metabolic pathways for levofloxacin hydrochloride. However the drug card for levofloxacin (DB01137) states that the biotransformation information is not available. Specific information regarding biotransformation does not appear to be readily available within the package inserts.
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.
Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.
As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.
There continues to be debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe and non-abating adverse reactions experienced by some patients following fluoroquinolone therapy.
(Coumadin) 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 drug
s. Quercetin
, a flavonol, a kind of 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 apple
s contain high levels of quercetin
; whether this inhibits or enhances the effect of fluoroquinolones is not entirely clear.
Specific drug interaction studies have not been conducted with levofloxacin. However, the systemic administration of some quinolones has been shown to interfere with the metabolism of caffeine, elevate plasma concentrations of theophylline, and enhance the effects of the warfarin and its derivatives. In patients receiving systemic cyclosporine concomitantly, transient elevations in serum creatinine has been noted.
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
. As such it is possible that levofloxacin may interact with thyroid medications as well.
The use of NSAIDs (Non-Steroid Anti-Inflammatory Drugs) while undergoing fluoroquinolone therapy is contraindicated 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 unclear. 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. In addition, 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.
Current or past treatment with oral corticosteroids is associated with an increased risk of Achilles tendon
rupture, especially in elderly patients 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.
Fluoroquinolones are associated with false-positive results for opiates on urine opiate screening drug test. Of the fluoroquinolones, Ofloxacin and Levofloxacin are most likely to cause false positive results. Most levels detected are below (2000 ng/mL). A false-positive result may be ruled out by using a more specific test, usually gas chromatography/mass spectrometry (GC-MS). Therefore, any patient who screens positive for opiates but denies taking them and has recently taken a Fluoroquinolone should be offered more specific testing.
Concommitant use with cardiac antidysrhythmics that prolong the QT interval should not be used in combination with levofloxacin due to the risk of torsades and R on T syndrome. Common medications still in use today include amiodarone, tykosin, and propafenone. Older medication such as ethmozine, quinidine, and mexilitine should be avoided as well.
, marketed by Sanofi-Aventis
under the tradename "Tavanic". Levaquin is also marketed worldwide for oral and IV use, as well as used in ophthalmic solutions.
Daiichi Sankyo had granted an exclusive license to Sanofi-Aventis to make, use and sell pharmaceutical preparations containing levofloxacin in the UK and Mexico. Other manufacturers include Novell Pharmaceutical Laboratories (Levores).
Levaquin has proven to be a blockbuster drug for Johnson and Johnson / Ortho McNeil, generating billions of dollars in additional revenue. In 2007 alone, Levaquin accounted for 6.5% of Johnson and Johnson's total revenue, generating $1.6 billion, an 8% increase over the previous year. Ranking 37th within the top 200 prescribed drugs in the United States for 2007, and ranked 19th in world sales in 2007, total sales for Levaquin were in excess of 1.6 billion dollars.
Levaquin was the most prescribed fluoroquinolone drug in the world for 2007.
Levofloxacin was first patented in 1987 (Levofloxacin European patent – Daiichi Pharmaceutical Co., Ltd.) and was approved by the United States Food and Drug Administration on December 20, 1996 for use in the United States to treat severe and life-threatening bacterial infections.
Within a significant number of medical publications and books levofloxacin is described as a second generation fluoroquinolone. Where as within a number of medical web sites it has been described as a third-generation fluoroquinolone.
Levofloxacin is considered to be same as Ofloxacin by the U.S. Food and Drug Administration (FDA), with the exception of the potency shown in vitro against mycobacteria. In vitro, it is, in general, twice as potent as ofloxacin, whereas d-ofloxacin is less active against mycobacteria.
During the 2008 Johnson & Johnson shareholder's meetings, the safety of both ofloxacin and levafloxacin were called into question. Paul Cahan, a shareholder who had suffered severe and continuing adverse reactions to ofloxacin, publicly challenged Johnson and Johnson's CEO, William Weldon, to adhere to the company's credo. This credo states in part "to put the needs and well-being of the people we serve first". Mr. Cahan requested additional warnings be added to the package inserts for both ofloxacin and levofloxacin. His request had not been acted upon to date.
During the 2009 meeting, yet another shareholder who alleges to have been crippled by these drugs, raised these same issues having seen no significant changes in the warnings (regarding the issues raised during the 2008 meeting). Once again a public request for stronger warnings for both ofloxacin and levofloxacin was made. Though the FDA requested additional Black Box Warnings concerning the tendon issues in 2008, these warnings were still not present in the inserts for ofloxacin or levofloxacin that are being dispensed by pharmacists in 2009, prompting this second request by a shareholder for stronger warnings and Dear Doctor Letters. Again this second request for additional warnings had not been acted upon to date.
The current United States patent is held by Ortho-McNeil-Janssen.
Ranked 19th in world sales in 2007, sales for Levaquin exceeded $1.4 billion. Levaquin was the most prescribed fluoroquinolone drug in the world for 2007.
Levaquin sample boxes showed a macron
over the letter "e," indicating pronunciation with a long-"e" sound, although Merriam-Webster indicates a short-"e" pronunciation. Levofloxacin would typically be pronounced with the long-e from the Latin prefix "levo-" (meaning left).
Levofloxacin is marketed worldwide under a significant number of different brand names, making post-marketing surveillance difficult.
In addition, generic versions of levofloxacin had been available since 2004 and marketed as a generic drug under a variety of different brand names. However, Daiichi Sankyo-Johnson and Johnson-Ortho McNeil filed numerous patent lawsuits to prevent such generic equivalents from being marketed, claiming that their patent did not expire until June 23, 2009. see Generic equivalents
Many of the clinical isolates that were initially tested within the NDA for levofloxacin against Floxin (ofloxacin –floxacin) disks instead of levofloxacin disks but reported as susceptible or resistant to levofloxacin. When levofloxacin disks were not available in early clinical trials, a 5-pg Floxin (ofloxacin –floxacin) disk was substituted. The FDA medical reviewers considered the two drugs to be one and the same and hence interchangeable.
The FDA requested updating the carton and container labels to include a statement to let dispensers know that a Medication Guide must be dispensed with the product, in compliance with the Medication Guide Regulations as specified in 21 CFR 208.24 (d).
Issuance of a Medication Guide and revisions to include new safety information. The FDA has determined that levofloxacin poses a serious and significant public health concern, requiring the distribution of a Medication Guide. However the Medication Guide does not include any Black Box Warnings.
Additional Black Box warning added to all the drugs within this class, including levofloxacin, stating that the fluoroquinolone class 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.
Note: Although the FDA had requested that the revised labeling (which were to include the Black Box Warnings) accompany the package inserts for any newly shipped products (effective January 2009) there are continuing reports that as of July 2009, that the products continue to contain the older labels, and not the revised labels, and that the Medication Guides (absent of the Black Box Warnings) were not made available for distribution.
. 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 warning
s 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 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 majority of the generic versions of the fluoroquinolones have not been updated to include this Black Box Warning as of July 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.
to levofloxacin 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. 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.
Years ago, the FDA had added warnings regarding the proper use of Levaquin within the package inserts to combat such prescription abuse. Advising physicians that levofloxacin: "...should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria...."
"Normally levofloxacin 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."(sic) Though considered to be a very important and necessary drug required to treat severe and life-threatening bacterial infections, the associated prescription abuse of levofloxacin 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.
Fluoroquinolones, including levofloxacin, 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 exists.
The results of these pediatric trials involving levofloxacin included two reported pediatric fatalities that the investigators determined were not related to the drug. Within one study it was stated that the pediatric patient has a 3.8% chance of experiencing a serious musculoskeletal adverse event. However, the two most 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 (serious or minor), which would be consistent with the studies found within the NDA (new drug application) for levofloxacin, which showed an ADR rate in excess of 40%. 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)
There is also a significant number of cases currently pending before the United States District Court
, District of Minnesota, involving Levaquin. On June 13, 2008, a Judicial Panel On Multidistrict Litigation (MDL) granted the Plaintiffs' motion to centralize individual and class action lawsuits involving Levaquin in the District of Minnesota over objection of Defendants, Johnson and Johnson / Ortho McNeil.
On July 6, 2009, The New Jersey Supreme Court
had also designated litigation over Levaquin as a mass tort and has assigned it to an Atlantic County, N.J., judge. The suits charge that the drug has caused achilles tendon
ruptures and other permanent damage. Additional lawsuits have also been recently filed in the Illinois State Court (September 2009) by a national law firm based in St. Louis currently investigating over 1,200 potential claims alleging that Johnson & Johnson and Ortho-McNeil Pharmaceutical Inc. tried to thwart early efforts to warn patients of the risks by manipulating study data and that they downplayed the risks to physicians.
On April 8, 2010 in the Beaumont Division of the Eastern District of Texas, a class action lawsuit was filed by Lisa Presley on behalf of herself and others similar situated against Johnson and Johnson, Ortho-McNeil Pharmaceuticals Inc. and Johnson and Johnson Pharmaceutical Research and Development LLC. (Case No 1:10cv00200.) This class action lawsuit was filed in regards to the severe and permanent adverse reactions associated with levaquin therapy.
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, that such reactions are "rare" and the benefits of such therapy outweigh the perceived risks.
On December 8, 2010 Johnson & Johnson was ordered to pay plaintiff John Schedin $1.1 million in punitive damages, as well as compensatory damages in the amount of $700,000, in the first Levaquin MDL case to go to trial. The federal court jury in Minneapolis found that Johnson & Johnson together with its Ortho-McNeil-Janssen Pharmaceuticals unit had failed to properly warn of the risks of taking levaquin. This failure to warn resulted in a combined verdict of $1,800.000.00 for the plaintiff.
Several class action lawsuits had been filed in regards to the adverse reactions suffered by those exposed to ciprofloxacin during the anthrax scare of 2001, as well.
Levofloxacin is a chiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
fluorinated carboxyquinolone. Investigation of 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...
, an older drug that is the racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
mixture, found that the l form [the (–)-(S) enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
] is more active. This specific component is levofloxacin.
Levofloxacin interacts with a number of other drugs, as well as a number of herbal and natural supplements. Such interactions increase the risk of cardiotoxicity
Cardiotoxicity
Cardiotoxicity is the occurrence of heart electrophysiology dysfunction or/and muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood...
and arrhythmias, anticoagulation, the formation of non-absorbable complexes, as well as increasing the risk of toxicity.
Levofloxacin is associated with a number of serious and life-threatening adverse reactions as well as spontaneous tendon ruptures and irreversible peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
. Such reactions may manifest long after therapy had been completed and in severe cases may result in life-long disabilities. Hepatoxicity has also been reported with the use of levofloxacin.
, the U.S. Food and Drug Administration (FDA) has added two Black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
s for this drug in reference to spontaneous tendon ruptures and the fact that levofloxacin 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
Levofloxacin 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,...
, urinary tract infections, prostatitis
Prostatitis
Prostatitis is an inflammation of the prostate gland, in men. A prostatitis diagnosis is assigned at 8% of all urologist and 1% of all primary care physician visits in the United States.-Classification:...
, 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...
, 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...
, pelvic inflammatory disease
Pelvic inflammatory disease
Pelvic inflammatory disease is a generic term for inflammation of the uterus, fallopian tubes, and/or ovaries as it progresses to scar formation with adhesions to nearby tissues and organs. This may lead to infections. PID is a vague term and can refer to viral, fungal, parasitic, though most...
, and traveler's diarrhea
Traveler's diarrhea
Traveler's diarrhea , is the most common illness affecting travelers. An estimated 10 million people—20% to 50% of international travelers—develop it annually. TD is defined as three or more unformed stools in 24 hours passed by a traveler, commonly accompanied by abdominal cramps, nausea, and...
.
In the adult population Oral and I.V. levofloxacin is limited to the treatment of proven serious and life-threatening bacterial infections such as:
- Urinary Tract Infections Added 12/17/1998
- Community-acquired pneumoniaCommunity-acquired pneumoniaCommunity-acquired pneumonia is a term used to describe one of several diseases in which individuals who have not recently been hospitalized develop an infection of the lungs . CAP is a common illness and can affect people of all ages. CAP often causes problems like difficulty in breathing, fever,...
Added 2/2/2000
- Skin and Skin Structure Infections Added 9/8/2000
- Nosocomial PneumoniaHospital-acquired pneumoniaHospital-acquired pneumonia or nosocomial pneumonia refers to any pneumonia contracted by a patient in a hospital at least 48–72 hours after being admitted. It is usually caused by a bacterial infection, rather than a virus....
Added 10/30/2002
- Chronic bacterial prostatitisChronic bacterial prostatitisChronic bacterial prostatitis is a bacterial infection of the prostate gland. It should be distinguished from other forms of prostatitis such as acute bacterial prostatitis and chronic pelvic pain syndrome .-Signs and symptoms:...
Added 05/23/2003 Not generally recommended due to lack of superiority to placebo.
- Inhalational Anthrax (Post-Exposure)Added 11/24/2004
- Acute Bacterial Sinusitis Added 8/4/2005 Revised 6/23/2006
- Acute Bacterial Exacerbation of Chronic Bronchitis Added 6/23/2006
- Acute Pyelonephritis Added 6/23/2006
Within the pediatric population Oral and I.V. levofloxacin is limited to:
- Inhalational Anthrax (Post-Exposure) Added 5/5/2008
Note: Levofloxacin has shown moderate activity against anaerobes, and is about twice as potent as ofloxacin against mycobacterium tuberculosis and other mycobacteria, including mycobacterium avium complex.
Oral and I.V. Levaquin are not licensed by the FDA for use in children other than the exception (inhalational anthrax), due to the risk of reversible or irreversible injury to the musculoskeletal system. Although claimed to be effective, levofloxacin is not to be considered a first line agent for inhalational anthrax in the pediatric population due to severe adverse reactions involving the musculoskeletal system and other serious adverse reactions, including fatalities.
The CDC revoked its recommendation regarding the use of fluoroquinolones (ciprofloxacin) as a first-line agent in treating anthrax (in part) due to the risk of adverse reactions 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.
Note: levofloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.
Availability
Levofloxacin is available in tablet form, injection, oral solution, as well as used in prescription eye and ear drops.Contraindications
As noted above, under licensed use, levofloxacin is now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.There is one contraindication now found within the 2008 package insert for Levaquin, namely that Levaquin is to be avoided in patients with a known hypersensitivity to levofloxacin or other quinolone drugs.
Due to growing prevalence of antibiotic resistance to the fluoroquinolones in Southeast Asia, the use of levofloxacin in patients that have been to Southeast Asia is increasingly being contraindicated.
Caution should be exercised in prescribing to patients with liver disease
Liver disease
Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...
.
Levofloxacin is also considered to be contraindicated in 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.
Pregnancy
Research indicates that the fluoroquinolones can rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. Peak concentration in human breast milk is similar to concentration levels attained in plasma. Breast-feeding mothers that take levofloxacin may expose their infants to severe adverse reactions, and pregnant women are at risk of spontaneous abortions and birth defects.
For this reason the prescribing of levofloxacin is contraindicated during pregnancy. Other flouroquinolones have also been reported as being present in the mother's milk and are passed on to the nursing child.
Pediatric use
Oral and I.V. Levofloxacin is not licensed for use in the pediatric population, except as noted above, due to the risk of serious, life-threatening and permanent injury to the pediatric patient. Within one study, it was stated that the pediatric patient has a 3.8% chance of experiencing a serious musculoskeletal adverse event.
Adverse effects that have been associated with levofloxacin use in children include musculoskeletal disorders such as arthralgia, arthritis, tendonopathy, and gait abnormality The studies found within the new drug application (NDA) for levofloxacin showed an adverse drug reaction (ADR) rate in excess of 40%, as well as a number of reported fatalities. However, the two most 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. Within the first pediatric 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 pediatric 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)
The current ban on the use of Oral and I.V. levofloxacin and other fluoroquinolones in the pediatric population has been supported by a number of clinical studies. The evidence presented at that 62 Meeting of the Anti-Infective Drugs Advisory Committee showed that the fluoroquinolones cause irreversible joint damage in the pediatric population. The conclusion reached by this Advisory Committee was that the risk of permanent injury may outweigh the potential benefits. Subsequent to this meeting, which took place in 1997, the Food and Drug Administration (FDA) has stated that it is their intention to continue to pursue the licensing of the fluoroquinolones for pediatric use in the United States, in spite of these findings.
Special precautions
Levofloxacin should be administered only 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. Levofloxacin 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). Within the package insert, it is stated "...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 duration varies anywheres from 3 days to 60 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.
Adverse effects
Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes. In most adverse reactions are mild to moderate; however, on occasion, serious adverse effects occur. There have been a number of regulatory actions taken as a result of such adverse reactions, which included published warnings, additional warnings and safety information added to the package inserts, which includes Black Box Warnings together with the issuance of "Dear Doctor Letters" concerning the recent addition of the Black Box Warnings.In 2004, the FDA requested new warning labels to be added to all of the Fluoroquinolones, including levofloxacin, regarding peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
(irreversible nerve damage), tendon
Tendon
A tendon is a tough band of fibrous connective tissue that usually connects muscle to bone and is capable of withstanding tension. Tendons are similar to ligaments and fasciae as they are all made of collagen except that ligaments join one bone to another bone, and fasciae connect muscles to other...
damage, Heart Problems (prolonged QT Interval / Torsades de pointes
Torsades de pointes
Torsades de pointes, or simply torsades, is a French term that literally means "twisting of the points". It was first described by Dessertenne in 1966 and refers to a specific, rare variety of ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram .- Presentation...
), Pseudomembranous colitis, Rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
(muscle wasting), Stevens-Johnson Syndrome, as well as concurrent usage of NSAIDs contributing to the severity of these reactions.
Subsequent to this, on June 25, 2007, the FDA required the manufacturer to add an additional warning to the package inserts that stated that "Other serious and sometimes fatal events, some due to hypersensitivity
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including levofloxacin."
The serious adverse effects that may occur as a result of levofloxacin therapy include irreversible peripheral neuropathy, spontaneous tendon rupture and tendonitis, QTc prolongation/torsades de pointes, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome, erythema multiforme
Erythema multiforme
Erythema multiforme is a skin condition of unknown cause, possibly mediated by deposition of immune complex in the superficial microvasculature of the skin and oral mucous membrane that usually follows an infection or drug exposure...
, severe central nervous system disorders (CNS), including seizures and clostridium difficile associated disease (CDAD: Pseudomembranous colitis) photosensitivity/phototoxicity reactions, fatal hypoglycemia, kidney damage,
rhabdomyolysis (muscle wasting), as well as anaphylactoid reactions and myasthenia crisis.
Additional serious adverse reactions include acute pancreatitis, temporary as well as permanent loss of vision, irreversible double vision,
impaired color vision, exanthema, abdominal pain, malaise, drug fever, dysaesthesia and eosinophilia. Pseudotumor cerebri, commonly known as idiopathic intracranial hypertension (IIH), (also referred to as increased intracranial pressure), has been reported to occur as a serious adverse reaction to levofloxacin. Another serious adverse effect is autoimmune hemolytic anemia
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia occurs when antibodies directed against the person's own red blood cells cause the RBCs to burst , leading to insufficient plasma concentration. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases...
.
Older patients may have an increased risk of tendinopathy (including rupture), especially with concomitant corticosteroid use, and such patients may also be more susceptible to prolongation of the QT interval. Patients with known prolongation, those with hypokalemia, or being treated with other drugs that prolong the QT interval should avoid the use of Levaquin. Hematologic reactions (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses.
Children and the elderly are at a much greater risk of experiencing such adverse reactions. Such reactions may manifest during, as well as long after fluoroquinolone therapy had been discontinued.
Serious visual complications have also been reported to occur with ophthalmic fluoroquinolone therapy, which may also occur with levofloxacin eye drops, especially corneal perforation, but also evisceration and enucleation. This increased incidents of corneal perforation may be due to fluoroquinolones causing alterations in stromal collagen, leading to a reduction in tectonic strength. As noted previously permanent double vision (diplopia) has also been reported.
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.
Overdose
In the event of an acute overdosage, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.Pharmacology
Levofloxacin is the L-isomer of the racemate ofloxacin, a quinolone antimicrobial agent.In chemical terms, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure
(-)-(S)-enantiomer of the racemic drug substance ofloxacin. The chemical name is (-)-(S)-9fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4benzoxazine-6-carboxylic acid hemihydrate. The empirical formula is C18H20FN3O4 • ½ H2O, and the molecular weight is 370.38. Levofloxacin is a light-yellowish-white to yellow-white crystal or crystalline powder.
Some of the endogenous compounds that are affected by the levofloxacin include GABA receptors (inhibitor), OCTN2 (inhibitor), blood glucose (alteration) potassium channels (in myocardial cells - inhibitor), pancreatic β-cell potassium channels (inhibitor) and glutathione (depletor).
Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers and can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies.
Pharmacokinetics
Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens. Levofloxacin is rapidly and, in essence, completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hours after oral dosing. The plasma concentration profile of levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed for LEVAQUIN Tablets when equal doses (mg/mg) are administered. Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously.Glucuronidation and hydroxylation have been cited as one of the major metabolic pathways for levofloxacin hydrochloride. However the drug card for levofloxacin (DB01137) states that the biotransformation information is not available. Specific information regarding biotransformation does not appear to be readily available within the package inserts.
Mechanism of action
Levofloxacin 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, 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.
Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.
As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.
There continues to be debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe and non-abating adverse reactions experienced by some patients following fluoroquinolone therapy.
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 warfarinWarfarin
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...
(Coumadin) activity; INR should be monitored closely. They may also interact with the GABA A receptor
GABA A receptor
The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
and cause neurological symptoms; this effect is augmented by certain non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal 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...
s. Quercetin
Quercetin
Quercetin , a flavonol, is a plant-derived flavonoid found in fruits, vegetables, leaves and grains. It also may be used as an ingredient in supplements, beverages or foods.-Occurrence:...
, a flavonol, a kind of flavonoid, occasionally used as a dietary supplement
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
, may interact with fluoroquinolones, as quercetin competitively binds to bacterial DNA gyrase. Some foods such as garlic
Garlic
Allium sativum, commonly known as garlic, is a species in the onion genus, Allium. Its close relatives include the onion, shallot, leek, chive, and rakkyo. Dating back over 6,000 years, garlic is native to central Asia, and has long been a staple in the Mediterranean region, as well as a frequent...
and apple
Apple
The apple is the pomaceous fruit of the apple tree, species Malus domestica in the rose family . It is one of the most widely cultivated tree fruits, and the most widely known of the many members of genus Malus that are used by humans. Apple grow on small, deciduous trees that blossom in the spring...
s contain high levels of quercetin
Quercetin
Quercetin , a flavonol, is a plant-derived flavonoid found in fruits, vegetables, leaves and grains. It also may be used as an ingredient in supplements, beverages or foods.-Occurrence:...
; whether this inhibits or enhances the effect of fluoroquinolones is not entirely clear.
Specific drug interaction studies have not been conducted with levofloxacin. However, the systemic administration of some quinolones has been shown to interfere with the metabolism of caffeine, elevate plasma concentrations of theophylline, and enhance the effects of the warfarin and its derivatives. In patients receiving systemic cyclosporine concomitantly, transient elevations in serum creatinine has been noted.
Significant drug interactions
Levofloxacin has been reported to interact with a significant number of other drugs, as well as a number of herbal and natural supplements. Such interactions increased the risk of cardiotoxicity and arrhythmias, anticoagulant effects, the formation of non-absorbable complexes, as well as increasing the risk of toxicity.Some drug interactions are associated with molecular structural modifications of the quinolone ring, specifically interactions involving NSAIDS and theophylline
Theophylline
Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
. The fluoroquinolones have also been shown to interfere with the metabolism of caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
and the absorption of levothyroxine
Levothyroxine
Levothyroxine, also L-thyroxine, synthetic T4, or 3,5,3',5'-tetraiodo-L-thyronine, is a synthetic form of thyroxine , used as a hormone replacement for patients with thyroid problems. The natural hormone is chemically in the chiral L-form, as is the pharmaceutical agent...
. 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
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
. As such it is possible that levofloxacin may interact with thyroid medications as well.
The use of NSAIDs (Non-Steroid Anti-Inflammatory Drugs) while undergoing fluoroquinolone therapy is contraindicated 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
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
neurotransmission. Whether or not such reactions occur after completion of therapy is unclear. 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
CYP1A2
Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
(e.g., theophylline, methylxanthines, tizanidine
Tizanidine
Tizanidine is a drug that is used as a muscle relaxant. It is a centrally acting α2 adrenergic agonist. It is used to treat the spasms, cramping, and tightness of muscles caused by medical problems such as multiple sclerosis, spastic diplegia, back pain, or certain other injuries to the spine or...
) results in increased plasma concentrations and could lead to clinically significant side-effects of the coadministered drug. In addition, other fluoroquinolones, especially enoxacin
Enoxacin
Enoxacin is an oral broad-spectrum fluoroquinolone antibacterial agent used in the treatment of urinary tract infections and gonorrhea...
, and to a lesser extent ciprofloxacin and pefloxacin
Pefloxacin
Pefloxacin is a synthetic chemotherapeutic agent used to treat severe and life threatening bacterial infections. Pefloxacin is commonly referred to as a fluoroquinolone drug and is a member of the fluoroquinolone class of antibacterials. It is an analog of norfloxacin. It is a synthetic...
, 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.
Current or past treatment with oral corticosteroids is associated with an increased risk of Achilles tendon
Achilles tendon
The Achilles tendon , also known as the calcaneal tendon or the tendo calcaneus, is a tendon of the posterior leg. It serves to attach the plantaris, gastrocnemius and soleus muscles to the calcaneus bone.- Anatomy :The Achilles is the tendonous extension of 3 muscles in the lower leg:...
rupture, especially in elderly patients 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.
Fluoroquinolones are associated with false-positive results for opiates on urine opiate screening drug test. Of the fluoroquinolones, Ofloxacin and Levofloxacin are most likely to cause false positive results. Most levels detected are below (2000 ng/mL). A false-positive result may be ruled out by using a more specific test, usually gas chromatography/mass spectrometry (GC-MS). Therefore, any patient who screens positive for opiates but denies taking them and has recently taken a Fluoroquinolone should be offered more specific testing.
Concommitant use with cardiac antidysrhythmics that prolong the QT interval should not be used in combination with levofloxacin due to the risk of torsades and R on T syndrome. Common medications still in use today include amiodarone, tykosin, and propafenone. Older medication such as ethmozine, quinidine, and mexilitine should be avoided as well.
History
Levofloxacin is a fluoroquinolone antibioticAntibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
, marketed by Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
under the tradename "Tavanic". Levaquin is also marketed worldwide for oral and IV use, as well as used in ophthalmic solutions.
Daiichi Sankyo had granted an exclusive license to Sanofi-Aventis to make, use and sell pharmaceutical preparations containing levofloxacin in the UK and Mexico. Other manufacturers include Novell Pharmaceutical Laboratories (Levores).
Levaquin has proven to be a blockbuster drug for Johnson and Johnson / Ortho McNeil, generating billions of dollars in additional revenue. In 2007 alone, Levaquin accounted for 6.5% of Johnson and Johnson's total revenue, generating $1.6 billion, an 8% increase over the previous year. Ranking 37th within the top 200 prescribed drugs in the United States for 2007, and ranked 19th in world sales in 2007, total sales for Levaquin were in excess of 1.6 billion dollars.
Levaquin was the most prescribed fluoroquinolone drug in the world for 2007.
Levofloxacin was first patented in 1987 (Levofloxacin European patent – Daiichi Pharmaceutical Co., Ltd.) and was approved by the United States Food and Drug Administration on December 20, 1996 for use in the United States to treat severe and life-threatening bacterial infections.
Within a significant number of medical publications and books levofloxacin is described as a second generation fluoroquinolone. Where as within a number of medical web sites it has been described as a third-generation fluoroquinolone.
Levofloxacin is considered to be same as Ofloxacin by the U.S. Food and Drug Administration (FDA), with the exception of the potency shown in vitro against mycobacteria. In vitro, it is, in general, twice as potent as ofloxacin, whereas d-ofloxacin is less active against mycobacteria.
During the 2008 Johnson & Johnson shareholder's meetings, the safety of both ofloxacin and levafloxacin were called into question. Paul Cahan, a shareholder who had suffered severe and continuing adverse reactions to ofloxacin, publicly challenged Johnson and Johnson's CEO, William Weldon, to adhere to the company's credo. This credo states in part "to put the needs and well-being of the people we serve first". Mr. Cahan requested additional warnings be added to the package inserts for both ofloxacin and levofloxacin. His request had not been acted upon to date.
During the 2009 meeting, yet another shareholder who alleges to have been crippled by these drugs, raised these same issues having seen no significant changes in the warnings (regarding the issues raised during the 2008 meeting). Once again a public request for stronger warnings for both ofloxacin and levofloxacin was made. Though the FDA requested additional Black Box Warnings concerning the tendon issues in 2008, these warnings were still not present in the inserts for ofloxacin or levofloxacin that are being dispensed by pharmacists in 2009, prompting this second request by a shareholder for stronger warnings and Dear Doctor Letters. Again this second request for additional warnings had not been acted upon to date.
The current United States patent is held by Ortho-McNeil-Janssen.
Ranked 19th in world sales in 2007, sales for Levaquin exceeded $1.4 billion. Levaquin was the most prescribed fluoroquinolone drug in the world for 2007.
Levaquin sample boxes showed a macron
Macron
A macron, from the Greek , meaning "long", is a diacritic placed above a vowel . It was originally used to mark a long or heavy syllable in Greco-Roman metrics, but now marks a long vowel...
over the letter "e," indicating pronunciation with a long-"e" sound, although Merriam-Webster indicates a short-"e" pronunciation. Levofloxacin would typically be pronounced with the long-e from the Latin prefix "levo-" (meaning left).
Levofloxacin is marketed worldwide under a significant number of different brand names, making post-marketing surveillance difficult.
In addition, generic versions of levofloxacin had been available since 2004 and marketed as a generic drug under a variety of different brand names. However, Daiichi Sankyo-Johnson and Johnson-Ortho McNeil filed numerous patent lawsuits to prevent such generic equivalents from being marketed, claiming that their patent did not expire until June 23, 2009. see Generic equivalents
Regulatory history in the United States
Levofloxacin was first patented in 1987, and was subsequently approved for use in Japan (October 1, 1993), Korea (April 4, 1994), Hong Kong (October 3, 1994), and China (May 3, 1995). Levofloxacin received FDA approval in the United States December 20, 1996. Floxin (ofloxacin – floxacin) was patented in 1982 (European patent Daiichi) and received FDA approval December 28, 1990. The U.S. patent is owned by Daiichi Sankyo and exclusively licensed to Ortho-McNeil.Many of the clinical isolates that were initially tested within the NDA for levofloxacin against Floxin (ofloxacin –floxacin) disks instead of levofloxacin disks but reported as susceptible or resistant to levofloxacin. When levofloxacin disks were not available in early clinical trials, a 5-pg Floxin (ofloxacin –floxacin) disk was substituted. The FDA medical reviewers considered the two drugs to be one and the same and hence interchangeable.
- March 12, 2009
The FDA requested updating the carton and container labels to include a statement to let dispensers know that a Medication Guide must be dispensed with the product, in compliance with the Medication Guide Regulations as specified in 21 CFR 208.24 (d).
- April 27, 2009
Issuance of a Medication Guide and revisions to include new safety information. The FDA has determined that levofloxacin poses a serious and significant public health concern, requiring the distribution of a Medication Guide. However the Medication Guide does not include any Black Box Warnings.
- February 25, 2011
Additional Black Box warning added to all the drugs within this class, including levofloxacin, stating that the fluoroquinolone class 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.
Note: Although the FDA had requested that the revised labeling (which were to include the Black Box Warnings) accompany the package inserts for any newly shipped products (effective January 2009) there are continuing reports that as of July 2009, that the products continue to contain the older labels, and not the revised labels, and that the Medication Guides (absent of the Black Box Warnings) were not made available for distribution.
History of the black box warnings
Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic 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 black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
s 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 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
Moxifloxacin
Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent developed by Bayer AG . It is marketed worldwide 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...
), 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) 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 majority of the generic versions of the fluoroquinolones have not been updated to include this Black Box Warning as of July 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.
Antibiotic abuse 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 levofloxacin 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. 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
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...
, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or Topoisomerase IV
Topoisomerase IV
Topoisomerase IV is one of two type-II topoisomerases in bacteria, the other being DNA gyrase. Like gyrase, topoisomerase IV is able to pass one double-strand of DNA through another double-strand of DNA, thereby changing the linking number of DNA by two in each enzymatic...
can decrease their binding affinity to quinolones, decreasing the drug's effectiveness.
Years ago, the FDA had added warnings regarding the proper use of Levaquin within the package inserts to combat such prescription abuse. Advising physicians that levofloxacin: "...should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria...."
"Normally levofloxacin 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."(sic) Though considered to be a very important and necessary drug required to treat severe and life-threatening bacterial infections, the associated prescription abuse of levofloxacin 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.
Fluoroquinolones, including levofloxacin, 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 exists.
Social and economic impact
The adverse drug reaction profile of levofloxacin and other fluoroquinolone drugs has spawned a grass root 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.Patent extensions
From 2001–2008, patent extension legislation was signed into law that allowed a six-month patent extension for testing their products for safety in children, an under-represented category in clinical trials. The FDA granted Johnson and Johnson–Ortho McNeil pediatric exclusivity for Levaquin. This extended their patent until the end of 2010. The legislation was drafted after extensive lobbying of numerous members of Congress by Bayer A.G., Johnson and Johnson–Ortho McNeil, 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-Massachusetts), 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 involving levofloxacin included two reported pediatric fatalities that the investigators determined were not related to the drug. Within one study it was stated that the pediatric patient has a 3.8% chance of experiencing a serious musculoskeletal adverse event. However, the two most 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 (serious or minor), which would be consistent with the studies found within the NDA (new drug application) for levofloxacin, which showed an ADR rate in excess of 40%. 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)
Generic equivalents
In 2005, the US Court of Appeals for the Federal Circuit had affirmed the validity of US patent (No. 5,053,407) on levofloxacin, held by Daiichi Sankyo Co., Ltd. On October 17, 2006, Daiichi Sankyo also won a patent infringement lawsuit in Canada involving the generic version of Levaquin. The Canadian Federal Appeals Court upheld a lower court's ruling handed down last October, which accepted the validity of Daiichi Sankyo's patent until June 23, 2009. Daiichi Sankyo and Janssen-Ortho Inc., a Johnson & Johnson subsidiary, filed a lawsuit with a federal court in Toronto after Teva Novopharm Ltd., started selling the generic version of levofloxacin in December 2004. The Canadian Federal Court in Toronto ordered Novopharm to suspend selling the generic version of the drug. Unsatisfied with the ruling, Novopharm appealed to the higher court. On June 7, 2007, the Canadian Federal Appeal Court dismissed this appeal. Novopharm was prevented from making, using, offering to sell, or selling a generic version of levofloxacin tablets in the Canadian market until the expiration of patent on June 23, 2009. Novopharm's generic version of Levaquin, had been sold in Canada since 2004.Current litigation
An official complaint has been filed by The US Justice Department with a Federal Court in Boston (January 2010) accusing Johnson and Johnson of illegally paying millions of dollars in kickbacks to Omnicare, one of the nation's largest pharmacies specializing in nursing home patients. In return, Omnicare nearly tripled its annual purchase of Johnson and Johnson's products; including Levaquin. The sales of Levaquin overtook other leading medications like Ciprofloxacin over a five year period between 1999 and 2004. These sales increased dramatically despite the growing reports concerning the severe adverse reactions associated with such therapy in the elderly.There is also a significant number of cases currently pending before the United States District Court
United States district court
The United States district courts are the general trial courts of the United States federal court system. Both civil and criminal cases are filed in the district court, which is a court of law, equity, and admiralty. There is a United States bankruptcy court associated with each United States...
, District of Minnesota, involving Levaquin. On June 13, 2008, a Judicial Panel On Multidistrict Litigation (MDL) granted the Plaintiffs' motion to centralize individual and class action lawsuits involving Levaquin in the District of Minnesota over objection of Defendants, Johnson and Johnson / Ortho McNeil.
On July 6, 2009, The New Jersey Supreme Court
New Jersey Supreme Court
The New Jersey Supreme Court is the highest court in the U.S. state of New Jersey. It has existed in three different forms under the three different state constitutions since the independence of the state in 1776...
had also designated litigation over Levaquin as a mass tort and has assigned it to an Atlantic County, N.J., judge. The suits charge that the drug has caused achilles tendon
Achilles tendon
The Achilles tendon , also known as the calcaneal tendon or the tendo calcaneus, is a tendon of the posterior leg. It serves to attach the plantaris, gastrocnemius and soleus muscles to the calcaneus bone.- Anatomy :The Achilles is the tendonous extension of 3 muscles in the lower leg:...
ruptures and other permanent damage. Additional lawsuits have also been recently filed in the Illinois State Court (September 2009) by a national law firm based in St. Louis currently investigating over 1,200 potential claims alleging that Johnson & Johnson and Ortho-McNeil Pharmaceutical Inc. tried to thwart early efforts to warn patients of the risks by manipulating study data and that they downplayed the risks to physicians.
On April 8, 2010 in the Beaumont Division of the Eastern District of Texas, a class action lawsuit was filed by Lisa Presley on behalf of herself and others similar situated against Johnson and Johnson, Ortho-McNeil Pharmaceuticals Inc. and Johnson and Johnson Pharmaceutical Research and Development LLC. (Case No 1:10cv00200.) This class action lawsuit was filed in regards to the severe and permanent adverse reactions associated with levaquin therapy.
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, that such reactions are "rare" and the benefits of such therapy outweigh the perceived risks.
On December 8, 2010 Johnson & Johnson was ordered to pay plaintiff John Schedin $1.1 million in punitive damages, as well as compensatory damages in the amount of $700,000, in the first Levaquin MDL case to go to trial. The federal court jury in Minneapolis found that Johnson & Johnson together with its Ortho-McNeil-Janssen Pharmaceuticals unit had failed to properly warn of the risks of taking levaquin. This failure to warn resulted in a combined verdict of $1,800.000.00 for the plaintiff.
Several class action lawsuits had been filed in regards to the adverse reactions suffered by those exposed to ciprofloxacin during the anthrax scare of 2001, as well.