Levofloxacin

Levofloxacin

Clinical data
Other names	(S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl) -7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij] quinoline-6-carboxylic acid
Pregnancy category	C (United States)
Routes of administration	Oral, IV, ophthalmic
ATC code	J01MA12 (WHO) S01AX19 (WHO)
Legal status
Legal status	US: WARNING Prescription Only
Pharmacokinetic data
Bioavailability	99%
Protein binding	24 to 38%
Metabolism	Renal
Elimination half-life	6 to 8 hours
Excretion	Urinary
Identifiers
IUPAC name (S)-7-fluoro-6-(4-methylpiperazin-1-yl) -10-oxo-4-thia-1-azatricyclo[7.3.1.05,13] trideca-5(13),6,8,11-tetraene-11-carboxylic acid
CAS Number	100986-85-4
PubChem CID	149096
DrugBank	APRD00477
ChemSpider	131410
CompTox Dashboard (EPA)	DTXSID0041060
ECHA InfoCard	100.115.581
Chemical and physical data
Formula	C18H20FN3O4
Molar mass	361.368 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES CN1CCN(CC1)c1c(F)cc2c3c1OCC(C)n3cc(C(=O)O)c2=O
(verify)

Levofloxacin is a synthetic chemotherapeutic agent used to treat severe or life-threatening bacterial infections. 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 belongs to the class of fluoroquinolone (or quinolone) antiinfectives.

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.

History

Levofloxacin is a fluoroquinolone antibiotic, marketed by Ortho-McNeil in the United States and Canada under various trade names. 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).

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 was 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 rnycobacteria. Within the New Drug Application (NDA) for levofloxacin it was stated that:

“...pre- NDA discussions with the applicant suggested quite strongly that levofloxacin is conceptually identical to ofloxacin. For ofloxacin, the dominant active drug substance is its 1- isomer, which is levofloxacin. Conceptually, this premise should lead to microbiological labeling essentially identical to ofloxacin... the applicant provided various basic studies in support of levofloxacin that had been actually performed using ofloxacin instead of levofloxacin. Particularly, some of the studies on mechanisms of action and the related resistance mechanisms were recapitulated from ofloxacin data rather than being generated anew for levofloxacin...."

Levofloxacin has moderate activity against anaerobes, and is about twice as potent as ofloxacin against mycobacterium tuberculosis and other mycobacteria, including mycobacterium avium complex.

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.

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

Licensed uses

The licensed uses for Oral and I.V. levofloxacin in the United States are as follows:

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 pneumonia Added 2/2/2000

• Skin and Skin Structure Infections Added 9/8/2000

• Nosocomial Pneumonia Added 10/30/2002

• Chronic Bacterial Prostatitis Added 05/23/2003

• 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

Prescribing Levaquin to treat an unapproved use (other than those listed above) within the pediatric, as well as the adult population, does take place rather frequently. Even though within the pediatric population Oral and I.V. levofloxacin is limited to the treatment of inhalational anthrax (post-exposure) as noted above.

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 by prescription in tablet form (oral multiple strengths), injection (multiple strengths), solution (oral 250 mg/10ml) as well as used in prescription eye and ear drops.

Mode of action

Levofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase iv, which is an enzyme necessary to separate replicated DNA, thereby inhibiting cell division.

The fluoroquinolones interfere with DNA replication by inhibiting an enzyme complex called DNA gyrase. This can also affect mammalian cell replication. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases but also against eukaryotic topoisomerases, and are toxic to cultured mammalian cells and in vivo tumor models. Although the quinolone is highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone-induced DNA damage was first reported in 1986.

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

There continues to be considerable debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe and non-abating adverse reactions experienced by some patients following fluoroquinolone therapy.

Contraindications

As noted above, under licensed use, 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.

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 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.

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 such 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.

Adverse effects

See also: Adverse effects of fluoroquinolones

Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes. In most adverse reactions are mild to moderate however, occasionally serious adverse effects occur. There has been a number of regulatory actions taken as a result of such adverse reactions, which included published warnings, additional warnings and safety information added to the package inserts together with the issuance of "Dear Doctor Letters" concerning the recent addition of Black Box Warnings.

In 2004 the FDA requested new warning labels to be added to all of the Fluoroquinolones, including levofloxacin, regarding Peripheral Neuropathy (irreversible nerve damage), Tendon Damage, Heart Problems (prolonged QT Interval / Torsades de pointes), Pseudomembranous colitis, Rhabdomyolysis (muscle wasting), Steven Johnson Syndrome, as well as concurrent usage of NSAIDs contributing to the severity of these reactions.

Subsequent to this, on June 25, 2007, the FDA required the manufacturer to add an additional warning to the package inserts that stated that “Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including levofloxacin.”

The serious adverse effects that may occur as a result of levofloxacin therapy include irreversible peripheral neuropathy, spontaneous tendon rupture and tendonitis, acute liver failure or serious liver injury (Hepatitis), QTc prolongation/torsades de pointes, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome, severe central nervous system disorders (CNS), and clostridium difficile associated disease (CDAD: Pseudomembranous colitis) 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.

Interactions

The toxicity of drugs that are metabolised by the cytochrome P450 system is enhanced by concomitant use of some quinolones. Coadministration may dangerously increase coumadin warfarin activity; INR should be monitored closely. They may also interact with the GABA A receptor and cause neurological symptoms; this effect is augmented by certain non-steroidal anti-inflammatory drugs. Quercetin, a flavonoid occasionally used as a dietary supplement, may interact with fluoroquinolones, as quercetin competitively binds to bacterial DNA gyrase. Some foods such as garlic and apples contain high levels of quercetin; whether this inhibits or enhances the effect of fluoroquinolones is not entirely clear.

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. 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. Though technically not to be considered a drug interaction, mention of this is made here due to fact that the etiology of such ruptures remains elusive and further research may confirm such a drug interaction may play a role in this particular reaction.

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. Chemically, 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) as well glutathione (depletor).

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. Half life is 6–8 hours.

Dosing

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.

Susceptible bacteria

Aerobic Gram-Positive Microorganisms

• Enterococcus faecalis (many strains are only moderately susceptible)
• Staphylococcus aureus (methicillin-susceptible strains)
• Staphylococcus epidermidis (methicillin-susceptible strains)
• Staphylococcus saprophyticus
• Streptococcus pneumoniae (including multi-drug resistant strains). MDRSP (Multi-drug-resistant Streptococcus pneumoniae) isolates are strains resistant to two or more of the following antibiotics: penicillin (MIC ≥2 mcg/mL), second-generation cephalosporins, e.g., cefuroxime; macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
• Streptococcus pyogenes

Aerobic gram-negative microorganisms

• Enterobacter cloacae
• Escherichia coli
• Haemophilus influenzae
• Haemophilus parainfluenzae
• Klebsiella pneumoniae
• Legionella pneumophila
• Moraxella catarrhalis
• Proteus mirabilis
• Pseudomonas aeruginosa
• Serratia marcescens

As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with levofloxacin.

Other microorganisms

• Chlamydophila pneumoniae
• Mycoplasma pneumoniae
• Levofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of plasma levels as a surrogate marker in a rhesus monkey model for anthrax (post-exposure).

Current litigation

There are 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. As a result of this order, product liability attorneys are currently seeking additional plaintiffs who may have been injured by this drug. 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.

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” (contrary to the literature) and the benefits of such therapy outweigh the perceived risks.

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.

Additional 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. As such, the regulatory history concerning Floxin (ofloxacin – floxacin) should be consulted as well when reviewing the following regulatory history. Though levofloxacin had been in use in Europe and Asia for almost a decade prior to the FDA's 1996 approval, nothing regarding the European or Asian prior histories (or safety profiles) was submitted to the FDA within the NDA.

Levofloxacin:

• 12/20/1996 The approval of the new drug application (NDA for levofloxacin).

• 2/2/2000

A warning regarding Torsades de pointes was added excluding the fact that elderly patients may be more sensitive to drug-associated effects on the QT interval. This additional warning was not added to Floxin until four years later (09/15/2004).

• 12/18/2001

Warning added regarding tendon ruptures may be increased in patients receiving concomitant corticosteroids, especially in the elderly. This warning was not added to Floxin until September 2004.

• 3/5/2004

Changes made to the package insert for levofloxacin to state that levofloxacin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.... Prescribing levofloxacin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient.

• 9/14/2004

A peripheral neuropathy subsection was added to warn the physician and patient that irreversible peripheral neuropathy was associated with levofloxacin.

Revision to the warning regarding Torsades de pointes; adding that elderly patients may be more susceptible to drug-associated effects on the QT interval. This was excluded from the original warning added back in February 2000.

• 6/19/2007

Revisions to the package insert to communicate the risks of fatal or acute liver failure and acute severe liver injury, QTc prolongation/torsades de pointes, tendon rupture, and toxic epidermal necrolysis (TEN). However, none of these risks received a Black Box Warning, nor was any Dear Doctor Letters sent concerning them.

• 12/13/2007

Warnings regarding severe photosensitivity/phototoxicity reactions were revised. Warning added regarding: Stevens-Johnson Syndrome; Toxic Epidermal Necrolysis; Erythema Multiforme

• 4/16/2008

Additional warnings were added regarding the fact that hematological (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses. Severe, and sometimes fatal, hepatotoxicity has been associated with levofloxacin (Most cases were not associated with hypersensitivity) and should be discontinue immediately if signs and symptoms of hepatitis occur. No Dear Doctor Letter has been sent regarding these potentially fatal adverse reactions.

• 5/5/2008

Additional pediatric warnings added regarding the fact that musculoskeletal disorders (arthralgia, arthritis, tendonopathy, and gait abnormality) were seen in more levofloxacin treated patients than in the comparators.

• 10-3-2008

Addition of Black Box Warning concerning spontaneous tendon ruptures.

• 3/12/2009

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).

• 4/27/2009

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.

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 acid. Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later. In a 1995 letter published in the New England Journal of Medicine, representatives of the U.S. Food and Drug Administration (FDA) stated that the agency would "update the labeling [package insert] for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture."

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

In 2005, the Illinois Attorney General filed a petition with the FDA seeking black box warnings and "Dear Doctor" letters emphasizing the risk of tendon rupture; the FDA responded that it had not yet been able to reach a decision on the matter. In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for a black box warning. In January 2008, Public Citizen filed suit to compel the FDA to respond to their 2006 petition. On July 7, the FDA ordered the makers of systemic-use fluoroquinolones to add a boxed warning regarding tendon rupture, and to develop a Medication Guide for patients. The package inserts for 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.

FDA warning letters

The manufacturers of Floxin (oflocaxin – floxacin—R.W. Johnson) received warning letters from the FDA regarding false advertising and failure to provide adequate warnings within their promotional materials.

Antibiotic abuse and bacterial resistance

See also: Antibiotic abuse

Resistance to levofloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, and Streptococcus pyogenes now exhibit resistance worldwide. Widespread veterinary usage of the fluoroquinolones, in particular in Europe, has been implicated. 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.

The ever increasing bacterial resistance to levofloxacin, (which is a major concern) together with the proven risks of such therapy, 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 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...."( See the monographs for this class)

"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 perscription 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.

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, 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.

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.

Social and economic impact

Spontaneous reports of adverse drug reactions associated with Levaquin, as well as other drugs found within the fluoroquinolone class, are repeatedly made on many Internet forums and medication feedback sites related to prescription drugs worldwide. These adverse drug reactions are easily and likely often misdiagnosed as seizure disorder or regular CNS or psychiatric symptoms and the diagnosis of quinolone toxicity or adverse reaction missed. Research conducted in Italy has shown that quinolones such as levofloxacin are one of the top causes of CNS disturbances in general practice.

Increased hospitalizations attributed to adverse drug reactions alone account for billions of dollars each year within the US healthcare system. Severe reactions do occur with the fluoroquinolone class and can add significantly to the cost of care. Antibacterial adverse effects account for nearly 25% of all adverse drug reactions amongst hospitalized patients. “Indirect costs as a result of reduced quality of life or loss of productivity are certainly not reflected in the acquisition costs of antimicrobials.”

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

Under the Bush administration (2001–2008), patent extension legislation was signed into law that allowed Johnson and Johnson–Ortho McNeil, as well as other drug companies, a six-month patent extension for testing their products for safety in children. Johnson and Johnson–Ortho McNeil will earn hundreds of millions of dollars due to the FDA's recently granting pediatric exclusivity for Levaquin, as this extends their patent monopoly till the end of 2010. The legislation that was signed by President Bush, granting Johnson and Johnson–Ortho McNeil and other drug manufacturers a six-month extension on their patents (to conduct pediatric testing), was drafted after extensive lobbying of numerous members of Congress by Bayer A.G., 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-Mass.), who chaired the committee with jurisdiction over the bill, refused to fight over the language that (if it had been included) would have reduced the drug company's profits due to these patent extensions. The reasons for Sen. Edward Kennedy's decision not to fight for the inclusion of this language were not made known.

The results of these pediatric trials 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, 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%, 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)

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 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.

Risk/benefit ratio

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

Respiratory infections

In a 1986 issue of the Journal of Antimicrobial Chemotherapy, a leading article on quinolones in chest infections concludes that there is little reason for optimism about the role of quinolones in chest infections mainly because of problems with resistance, recurrence, and reinfection with Pseudomonas aeruginosa and S pneumoniae. Melinda et al., in 2003, confirmed the validity of the concerns raised within 1986 issue of the Journal of Antimicrobial Chemotherapy (referenced to previously), concerning the use of the fluoroquinolones to treat acute respiratory infections. Stating that: “Overuse of these antibiotics will eventually render them useless for treating antibiotic-resistant infections, for which broad-spectrum antibiotics are supposed to be reserved.”

Antibiotics do not improve sinusitis symptoms, a number of studies have shown. Primary-care physicians (family doctors) commonly prescribe levofloxacin to treat acute maxillary sinusitis (inflamed membranes of the sinuses), although there is no evidence that this approach is effective. A report in the British medical Journal the Lancet found that antibiotics did nothing more than the placebos used as the control. Only about 5-10% of bronchitis cases are caused by a bacterial infection. Most cases of bronchitis are caused by a viral infection and are "self-limited" and resolve themselves in a few weeks. The use of antibiotics such as levofloxacin to treat bronchitis is considered by some experts and researchers to be unnecessary, and, as such, exposes the patient to an unacceptable risk of suffering a severe adverse reaction.

When prescribed for Community Acquired Pneumonia, Chronic Bronchitis, and Acute Bacterial Sinusitis, the use of the fluoroquinolone class offers no compelling advantages over established treatment. Nor does antibiotic treatment help sore throats. Additionally levofloxacin and other fluoroquinolones have no effect upon viral infections such as the common head cold. Nevertheless, for severe forms of community-acquired pneumonia the fluoroquinolones seem to be associated with improved treatment rates, but with no differences found in mortality between antibiotic regimens.

Chronic bacterial prostatitis

Campbell's Urology, the urologist's most authoritative reference text, identifies only about 5% of all patients with prostatitis as having bacterial prostatitis that can be "cured," at least in the short term, by antibiotics. In other words, 95% of men with prostatitis do not actually have any identifiable bacterial infection that would respond to antibiotic therapy.

Within a 2003 study involving the use of fluoroquinolones (levofloxacin specifically) to treat CP/CPPS (also known as "chronic nonbacterial prostatitis"), it was found that “...6 weeks of levofloxacin therapy in men diagnosed with CP/CPPS resulted in symptom improvement that was not significantly different from that with placebo”.

Infectious diarrhea

A Clostridium difficile infection is the principal cause of levofloxacin-associated diarrhea and pseudomembranous colitis. In May 2007 the FDA changed the package insert for levofloxacin to include the warning that that Clostridium difficile associated diarrhea (CDAD) is associated with the use of levofloxacin. As such the efficacy of levofloxacin to treat infectious diarrhea would be called into question.

Uncomplicated cervical and urethra gonorrhea

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

Most of the approved uses of levofloxacin either have shown lack of reasonable efficacy within some independent studies or have been severely compromised by growing bacterial resistance. Applying a reasonable risk/benefit assessment to the use of levofloxacin, there should be very few cases where the use of a fluoroquinolone drug, such as levofloxacin, would be considered by the treating physician to be a first-line agent. Levofloxacin has been associated with significant adverse reactions during therapy; as such, the potential for benefit may not outweigh the proven risk when there is a safer alternative available to the treating physician. A complete risk/benefit assessment should be performed prior to implementing fluoroquinolone therapy, and the patient fully advised concerning possible adverse reactions beforehand.

Package insert links

• Levaquin Package Insert
• Iquix Package Insert
• Quixin Package Insert

See also

• Fluoroquinolone toxicity
• Fluoroquinolone
• Quinolone

External links

• Template:DMOZ