levofloxacin - wikipedia, the free encyclopedia

19
6/10/13 Levofloxacin - Wikipedia, the free encyclopedia en.wikipedia.org/wiki/Levofloxacin 1/19 Levofloxacin Systematic (IUPAC) name (S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methylpiperazin-1- yl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid Clinical data Trade names EVO (Beximco, Bangladesh),Levaquin, Quixin AHFS/Drugs.com monograph MedlinePlus a697040 Licence data US FDA:link Pregnancy cat. C (US) Legal status Prescription only Routes Oral, IV, ophthalmic Pharmacokinetic data Bioavailability 99% Protein binding 24 to 38% Metabolism Renal Half-life 6 to 8 hours Excretion Urinary Identifiers CAS number 100986-85-4 ATC code J01MA12 S01AE05 PubChem CID 149096 DrugBank DB01137 ChemSpider 131410 UNII RIX4E89Y14 KEGG D08120 ChEMBL CHEMBL33 NIAID ChemDB 002307 Synonyms (S)-9-fluoro-3-methyl-10-(4- Levofloxacin From Wikipedia, the free encyclopedia Levofloxacin (Levaquin (U.S.), Tavanic (E.U.), and others) is a broad spectrum antibiotic of the fluoroquinolone drug class. [1][2] Its spectrum of activity includes most strains of bacterial pathogens responsible for respiratory, urinary tract, gastrointestinal, and abdominal infections, including Gram-(-) (Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis, and Pseudomonas aeruginosa), Gram-(+) (methicillin-sensitive but not methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, Staphylococcus epidermidis, Enterococcus faecalis, and Streptococcus pyogenes), and atypical bacterial pathogens (Chlamydophila pneumoniae and Mycoplasma pneumoniae). Levofloxacin and other fluoroquinolones are valued for this broad spectrum of activity, excellent tissue penetration, and for their availability in both oral and intravenous formulations. [3] (Many antibacterials used in serious infections must be dosed intravenously.) Levaquin is used alone or in combination with other antibacterial drugs to treat certain bacterial infections including pneumonia, [4] urinary tract infections, [5][6] and abdominal infections. [7] Levofloxacin is a chiral fluorinated carboxyquinolone. Investigation of ofloxacin, an older drug that is the racemic mixture, found that the (–)-(S) enantiomer (also known as the S isomer) [8] is more active. This specific component is levofloxacin. [9][10] Levofloxacin and other fluoroquinolones are generally well tolerated, but in rare instances have produced serious and life-threatening adverse reactions as well as spontaneous tendon ruptures and irreversible peripheral neuropathy. Tendon damage may manifest months after therapy had been completed and in severe cases may result in lifelong disabilities. Other controversies associated with this drug include increasing resistance due to their overuse. This overuse includes situations in which antibiotic therapy is unnecessary, and others in which the use of a less broad spectrum agent would produce equivalent results. As of 2011, the U.S. Food and Drug Administration (FDA) has added two Black box warnings 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-

Upload: ankan-pal

Post on 22-Jan-2016

166 views

Category:

Documents


0 download

DESCRIPTION

medicine

TRANSCRIPT

Page 1: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 1/19

Levofloxacin

Systematic (IUPAC) name

(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methylpiperazin-1-

yl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic

acid

Clinical data

Trade names EVO (Beximco,

Bangladesh),Levaquin, Quixin

AHFS/Drugs.com monograph

MedlinePlus a697040

Licence data US FDA:link

Pregnancy cat. C (US)

Legal status ℞ Prescription only

Routes Oral, IV, ophthalmic

Pharmacokinetic data

Bioavailability 99%

Protein binding 24 to 38%

Metabolism Renal

Half-life 6 to 8 hours

Excretion Urinary

Identifiers

CAS number 100986-85-4

ATC code J01MA12 S01AE05

PubChem CID 149096

DrugBank DB01137

ChemSpider 131410

UNII RIX4E89Y14

KEGG D08120

ChEMBL CHEMBL33

NIAID ChemDB 002307

Synonyms (S)-9-fluoro-3-methyl-10-(4-

LevofloxacinFrom Wikipedia, the free encyclopedia

Levofloxacin (Levaquin (U.S.), Tavanic (E.U.), andothers) is a broad spectrum antibiotic of the

fluoroquinolone drug class.[1][2] Its spectrum of activityincludes most strains of bacterial pathogens responsiblefor respiratory, urinary tract, gastrointestinal, andabdominal infections, including Gram-(-) (Escherichia coli,Haemophilus influenzae, Klebsiella pneumoniae,Legionella pneumophila, Moraxella catarrhalis, Proteusmirabilis, and Pseudomonas aeruginosa), Gram-(+)(methicillin-sensitive but not methicillin-resistantStaphylococcus aureus, Streptococcus pneumoniae,Staphylococcus epidermidis, Enterococcus faecalis, andStreptococcus pyogenes), and atypical bacterialpathogens (Chlamydophila pneumoniae and Mycoplasmapneumoniae). Levofloxacin and other fluoroquinolones arevalued for this broad spectrum of activity, excellent tissuepenetration, and for their availability in both oral and

intravenous formulations.[3] (Many antibacterials used inserious infections must be dosed intravenously.) Levaquinis used alone or in combination with other antibacterialdrugs to treat certain bacterial infections including

pneumonia,[4] urinary tract infections,[5][6] and abdominal

infections.[7]

Levofloxacin is a chiral fluorinated carboxyquinolone.Investigation of ofloxacin, an older drug that is the racemicmixture, found that the (–)-(S) enantiomer (also known as

the S isomer)[8] is more active. This specific component is

levofloxacin.[9][10] Levofloxacin and otherfluoroquinolones are generally well tolerated, but in rareinstances have produced serious and life-threateningadverse reactions as well as spontaneous tendon rupturesand irreversible peripheral neuropathy. Tendon damagemay manifest months after therapy had been completedand in severe cases may result in lifelong disabilities. Othercontroversies associated with this drug include increasingresistance due to their overuse. This overuse includessituations in which antibiotic therapy is unnecessary, andothers in which the use of a less broad spectrum agentwould produce equivalent results.

As of 2011, the U.S. Food and Drug Administration(FDA) has added two Black box warnings for this drug inreference to spontaneous tendon ruptures and the fact thatlevofloxacin may cause worsening of myasthenia gravissymptoms, including muscle weakness and breathingproblems. Such an adverse reaction is a potentially life-

Page 2: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 2/19

methylpiperazin-1-yl) -7-oxo-2,3-

dihydro-7H-[1,4]oxazino[2,3,4-ij]

quinoline-6-carboxylic acid

Chemical data

Formula C18H20FN3O4

Mol. mass 361.368 g/mol

(what is this?) (verify)

threatening event and may require ventilatory support.[11]

Contents

1 Medical uses

1.1 Availability

2 Contraindications

3 Special precautions

4 Adverse effects

5 Overdose

6 Pharmacology

7 Pharmacokinetics

8 Mechanism of action

9 Interactions9.1 Significant drug interactions

10 History10.1 Regulatory history in the United

States11 Antibiotic abuse and bacterial resistance12 Social and economic impact

12.1 Patent extensions12.2 Generic equivalents

13 Current litigation14 References

15 External links

Medical uses

Levofloxacin is used to treat infections including: respiratory tract infections, cellulitis, urinary tract infections,prostatitis, anthrax, endocarditis, meningitis, pelvic inflammatory disease, traveler's diarrhea, tuberculosis and

plague.[12]

In the adult population oral and I.V. levofloxacin is used for the treatment of bacterial infections such as:

Urinary Tract Infections Added 17 December 1998[13]

Community-acquired pneumonia Added 2 February 2000[14]

Skin and Skin Structure Infections Added 9/8/2000[15]

Nosocomial Pneumonia Added 30 October 2002[16]

Chronic bacterial prostatitis Added 23 May 2003[17] Recommended as first line therapy.[18][19]

Inhalational Anthrax (Post-Exposure)Added 24 November 2004[20]

SMILES

InChI

Page 3: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 3/19

Levofloxacin 750mg IV

Acute Bacterial Sinusitis Added 8/4/2005[21] Revised 23 June 2006[22]

Acute Bacterial Exacerbation of Chronic Bronchitis Added 23 June 2006[22]

Acute Pyelonephritis Added 23 June 2006[22]

Pneumonic plague and septicemic plague (Yersinia pestis) and prophylaxis in adults and pediatric

patients, 6 months of age and older.[23]

Within the pediatric population Oral and I.V. levofloxacin is limited to:

Inhalational Anthrax (Post-Exposure) Added 5 May 2008[24]

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.[25]

Oral and I.V. Levaquin are not licensed by the FDA for use in children other than the exception (inhalational

anthrax),[26] due to the risk of injury to the musculoskeletal system.[27] Levofloxacin is not to be considered afirst line agent for inhalational anthrax in the pediatric population due to severe adverse reactions involving the

musculoskeletal system and other serious adverse reactions.[27][28][29]

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.[9] In India it is marketed by Intas under the trade name 'Flolev'.

Contraindications

There is one contraindication now found within the 2008 packageinsert for Levaquin, namely that Levaquin is to be avoided in patientswith a known hypersensitivity to levofloxacin or other quinolone

drugs.[9]

Caution should be exercised in prescribing to patients with liver

disease.[30]

Levofloxacin is also considered to be contraindicated in patients with

epilepsy or other seizure disorders.[citation needed]

Pregnancy

Page 4: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 4/19

According to the FDA approved Prescribing Information(http://www.fda.gov/downloads/Drugs/EmergencyPreparedness/BioterrorismandDrugPreparedness/UCM133684.pdf), levofloxacin is Pregnancy Category C. This designation indicates that animal reproduction studies haveshown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans but thepotential benefit to the mother may in some cases outweigh the risk to the fetus. Other flouroquinolones have

also been reported as being present in the mother's milk and are passed on to the nursing child.[31][32]

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 injury to the pediatric patient. In one study,[33][34] 1534 juvenile patients (age 6 months to 16 years)treated with levofloxacin as part of three efficacy trials were followed up to assess all musculoskeletal eventsoccurring up to 12 months post-treatment. At 12 months follow-up the cumulative incidence of musculoskeletaladverse events was 3.4%, compared to 1.8% among 893 patients treated with other antibiotics. In thelevafloxacin-treated group, approximately two-thirds of these musculoskeletal AEs occurred in the first 60 days,86% were mild, 17% were moderate, and all resolved without long-term sequelae.

In a study comparing the safety and efficacy of levofloxacin to that of azithromycin or the ceftriaxone in 712children with community-acquired pneumonia, serious adverse events were experienced by 6% of those treatedwith levofloxacin and 4% of those treated with comparator antibiotics. Most of these were considered by thetreating physician to be unrelated or doubtfully related to the study drug. Two deaths were observed in thelevofloxacin group, neither of which was thought to be treatment-related. Spontaneous reports to the FDAAdverse Effects Reporting System at the time of the 20 September 2011 FDA Pediatric Drugs AdvisoryCommittee include musculoskeletal events (39, including 5 cases of tendon rupture) and CNS events (19,including 5 cases of seizures) as the most common spontaneous reports between April 2005 and March 2008.An estimated 130,000 pediatric prescriptions for levofloxacin were filled on behalf of 112,000 pediatric patients

during that period.[35]

Special precautions

Levofloxacin should be administered only as described within the Dosage Guidelines table found within the mostcurrent package insert. The status of the patient's renal function and hepatic function must also be taken intoconsideration to avoid an accumulation that may lead to a fatal drug overdose. Levofloxacin is eliminatedprimarily by renal excretion. However, the drug is also metabolized and partially cleared through the liver andthe intestine. Modification of the dosage is recommended using the table found within the package insert forthose with impaired liver or kidney function (particularly for patients with severe renal dysfunction). Withinthe 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."[9] The duration of treatment

depends upon the severity of infection, in the range of 3 days to 60 days.[9]

Adverse effects

See also: Adverse effects of fluoroquinolones

Most adverse reactions are mild to moderate; however, on occasion, serious adverse effects occur.[36][37][38]

additional warnings and safety information added to the package inserts, which includes Black Box Warnings[39]

together with the issuance of "Dear Doctor Letters" concerning the recent addition of the Black Box Warnings.

Page 5: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 5/19

In 2004, the FDA requested new warning labels to be added to all of the Fluoroquinolones, including

levofloxacin, regarding peripheral neuropathy (irreversible nerve damage),[40][41] tendon damage,[42][43] heart

problems (prolonged QT Interval / Torsades de pointes),[14][40] Pseudomembranous colitis, Rhabdomyolysis

(muscle wasting),[44][45][46] Stevens-Johnson Syndrome,[47] as well as concurrent usage of NSAIDs

contributing to the severity of these reactions.[40]

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

levofloxacin."[48][49]

The serious adverse effects that may occur as a result of levofloxacin therapy include irreversible peripheral

neuropathy,[41][50] spontaneous tendon rupture and tendonitis,[51][52][53][54][55] QTc prolongation/torsades de

pointes,[51] toxic epidermal necrolysis (TEN)[51] and Stevens-Johnson syndrome, erythema multiforme,[56]

severe central nervous system disorders (CNS), including seizures[57] and clostridium difficile associated disease

(CDAD: Pseudomembranous colitis)[58][59][60][61] photosensitivity/phototoxicity reactions,[56][62] fatal

hypoglycemia, kidney damage, rhabdomyolysis (muscle wasting),[44][45][46] as well as anaphylactoid

reactions[63][64] and myasthenia crisis.[65]

Additional serious adverse reactions include acute pancreatitis,[66][67] temporary as well as permanent loss of

vision, irreversible double vision,[68] impaired color vision, exanthema, abdominal pain, malaise, drug fever,[69]

dysaesthesia and eosinophilia. Pseudotumor cerebri, commonly known as idiopathic intracranial hypertension

(IIH), (also referred to as increased intracranial pressure),[70] has been reported to occur as a serious adverse

reaction to levofloxacin. Another serious adverse effect is autoimmune hemolytic anemia.[71]

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.[9] Patientswith known prolongation, those with hypokalemia, or being treated with other drugs that prolong the QT intervalshould avoid the use of Levaquin. Hematologic reactions (including agranulocytosis, thrombocytopenia), and

renal toxicities may occur after multiple doses.[9][52]

Children and the elderly are at a much greater risk of experiencing such adverse reactions.[72][73] Such reactions

may manifest during, as well as long after fluoroquinolone therapy had been discontinued.[74]

Serious visual complications have also been reported to occur with ophthalmic fluoroquinolone therapy, whichmay also occur with levofloxacin eye drops, especially corneal perforation, but also evisceration andenucleation. This increased incidents of corneal perforation may be due to fluoroquinolones causing alterations in

stromal collagen, leading to a reduction in tectonic strength.[75][76] As noted previously permanent double vision

(diplopia) has also been reported.[68]

Some groups refer to these adverse events as "fluoroquinolone toxicity". These groups of people claim to havesuffered serious long term harm to their health from using fluoroquinolones. This has led to a class action lawsuitby people harmed by the use of fluoroquinolones as well as legal action by the consumer advocate group Public

Citizen.[77] Partly as a result of the efforts of The State of Illinois and Public Citizen the FDA ordered a blackbox warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on

tendons.[78]

Overdose

Page 6: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 6/19

In the event of an acute overdosage, the stomach should be emptied. The patient should be observed andappropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal

dialysis.[9]

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 substanceofloxacin. 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.[9]

Some of the endogenous compounds that are affected by the levofloxacin include GABA receptors (inhibitor),

OCTN2 (inhibitor),[79] blood glucose (alteration) potassium channels (in myocardial cells – inhibitor),[80]

pancreatic β-cell potassium channels (inhibitor)[81] and glutathione (depletor). Levofloxacin can be usedeffectively as a positive control in thorough QT/QTc studies in healthy volunteers and can fulfil the criteria for apositive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTcstudy. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more

rigorous QT/QTc studies.[82]

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 plasmaconcentrations are usually attained one to two hours after oral dosing. The plasma concentration profile oflevofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed forLEVAQUIN Tablets when equal doses (mg/mg) are administered. Levofloxacin is excreted largely asunchanged 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.[9][83]

Glucuronidation and hydroxylation have been cited as one of the major metabolic pathways for levofloxacin

hydrochloride.[84] However the drug card for levofloxacin (DB01137

(http://www.drugbank.ca/drugs/DB01137)) states that the biotransformation information is not available.[83]

Specific information regarding biotransformation does not appear to be readily available within the packageinserts.

Mechanism 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,[85] which is anenzyme necessary to separate replicated DNA, thereby inhibiting cell division. This can also affect mammaliancell replication. In particular, some congeners of this drug family display activity not only against bacterialtopoisomerases but also against eukaryotic topoisomerases, and are toxic to cultured mammalian cells and invivo tumor models.

Interactions

Page 7: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 7/19

Levofloxacin interacts with other drugs, as well as herbal and natural supplements. Such interactions increase therisk of cardiotoxicity and arrhythmias, anticoagulation, the formation of non-absorbable complexes, as well as

increasing the risk of toxicity.[83]

The toxicity of drugs that are metabolised by the cytochrome P450 system is enhanced by concomitant use ofsome quinolones. Coadministration may dangerously increase warfarin (Coumadin) activity; INR should bemonitored 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.[86] Quercetin, a flavonol, a kind offlavonoid, occasionally used as a dietary supplement, may interact with fluoroquinolones, as quercetincompetitively 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.[87]

Specific drug interaction studies have not been conducted with levofloxacin. However, the systemicadministration of some quinolones has been shown to interfere with the metabolism of caffeine, elevate plasmaconcentrations 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.[83]

Significant drug interactions

Levofloxacin has been reported to interact with other drugs, as well as herbal and natural supplements. Suchinteractions 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, specificallyinteractions involving NSAIDS and theophylline. Ciprofloxacin has been shown to interact with thyroid

medications (levothyroxine) resulting in unexplained hypothyroidism.[88] As such it is possible that levofloxacinmay interact with thyroid medications as well.

The use of NSAIDs (Non-Steroid Anti-Inflammatory Drugs) while undergoing fluoroquinolone therapy iscontraindicated 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.[89] Whether or not suchreactions occur after completion of therapy is unclear. Patients have reported reactions to NSAIDS long aftercompletion of fluoroquinolone therapy, but there does not appear to be any research that would either confirmor deny this association other than these anecdotal reports.

Some quinolones exert an inhibitory effect on the cytochrome P-450 system, thereby reducing theophyllineclearance and increasing theophylline blood levels. Coadministration of certain fluoroquinolones and other drugsprimarily metabolized by CYP1A2 (e.g., theophylline, methylxanthines, tizanidine) results in increased plasmaconcentrations and could lead to clinically significant side-effects of the coadministered drug. In addition, otherfluoroquinolones, especially enoxacin, and to a lesser extent ciprofloxacin and pefloxacin, also inhibit the

metabolic clearance of theophylline.[90]

Such drug interactions appear to be related to the structural changes of the quinolone ring and the inhibitoryeffect on the cytochrome P-450 system. As such, these drug interactions involving the fluoroquinolones appearto be drug-specific rather than a class effect.

Current or past treatment with oral corticosteroids is associated with an increased risk of Achilles tendonrupture, especially in elderly patients also taking the fluoroquinolones. This effect seems to be restricted topeople aged 60 or over and within this group concomitant use of corticosteroids increases this risk

substantially.[42][91]

Page 8: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 8/19

Fluoroquinolones are associated with false-positive results for opiates on urine opiate screening drug test. Of thefluoroquinolones, Ofloxacin and Levofloxacin are most likely to cause false positive results. Most levels detectedare below (2000 ng/mL). A false-positive result may be ruled out by using a more specific test, usually gaschromatography/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.[92]

Cardiac antidysrhythmics that prolong the QT interval should not be used in combination with levofloxacin dueto 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 aswell.

History

Levofloxacin is a fluoroquinolone antibiotic, marketed by Sanofi-Aventis under the tradename "Tavanic".[93]

Levaquin is also marketed worldwide for oral and IV use, as well as used in ophthalmic solutions. DaiichiSankyo had granted an exclusive license to Sanofi-Aventis to make, use and sell pharmaceutical preparations

containing levofloxacin in the UK and Mexico.[94] Other manufacturers include Novell PharmaceuticalLaboratories (Levores).

Levaquin has proven to be a blockbuster drug for Johnson and Johnson / Ortho McNeil, generating billions ofdollars 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.[95] Ranking 37th within the top 200prescribed 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.[96] Levaquin was the most prescribed fluoroquinolone drug in the world for

2007.[97]

Levofloxacin was first patented in 1987 (Levofloxacin European patent – Daiichi Pharmaceutical Co., Ltd.) andwas approved by the United States Food and Drug Administration on 20 December 1996 for use in the UnitedStates to treat bacterial sinusitus, bacterial exacerbations of bronchitis, community-acquired pneumonia,

uncomplicated skin infections, complicated urinary tract infections, and acute pyelonephritis.[98] Levofloxacin is

described in some publications as a second generation fluoroquinolone.[99][100][101] Other publications

describe it as a third-generation fluoroquinolone.[102][103]

Levofloxacin is considered to be same as Ofloxacin by the U.S. Food and Drug Administration (FDA), with theexception 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.[104][105]

The current United States patent is held by Ortho-McNeil-Janssen.[96] Ranked 19th in world sales in 2007,

sales for Levaquin exceeded $1.4 billion.[96] Levaquin was the most prescribed fluoroquinolone drug in the

world for 2007.[106]

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 pronouncedwith the long-e from the Latin prefix "levo-" (meaning left).

Levofloxacin is marketed worldwide under many brand names, making post-marketing surveillance

difficult.[107][108]

Page 9: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 9/19

In addition, generic versions of levofloxacin had been available since 2004 and marketed as a generic drugunder a variety of different brand names. However, Daiichi Sankyo-Johnson and Johnson-Ortho McNeil filednumerous patent lawsuits to prevent such generic equivalents from being marketed, claiming that their patent did

not expire until 23 June 2009.[109] see Generic equivalents

Regulatory history in the United States

Levofloxacin was first patented in 1987, and was subsequently approved for use in Japan (1 October 1993),Korea (4 April 1994), Hong Kong (3 October 1994), and China (3 May 1995). Levofloxacin received FDAapproval in the United States 20 December 1996. Floxin (ofloxacin – floxacin) was patented in 1982 (Europeanpatent Daiichi) and received FDA approval 28 December 1990. The U.S. patent is owned by Daiichi Sankyo

and exclusively licensed to Ortho-McNeil.[98][110]

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. Whenlevofloxacin disks were not available in early clinical trials, a 5-pg Floxin (ofloxacin –floxacin) disk wassubstituted. The FDA medical reviewers considered the two drugs to be one and the same and hence

interchangeable.[98]

12 March 2009[111]

The FDA requested updating the carton and container labels to include a statement to let dispensers know that aMedication Guide must be dispensed with the product, in compliance with the Medication Guide Regulations asspecified in 21 CFR 208.24 (d).

27 April 2009[112]

Issuance of a Medication Guide and revisions to include new safety information. The FDA has determined thatlevofloxacin 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.[113]

25 February 2011[114]

Additional Black Box warning added to all the drugs within this class, including levofloxacin, stating that thefluoroquinolone class may cause worsening of myasthenia gravis symptoms, including muscle weakness andbreathing problems. Such an adverse reaction is a potentially life-threatening event and may require ventilatorysupport.

Note: Although the FDA had requested that the revised labeling (which were to include the Black Box

Warnings)[115] accompany the package inserts for any newly shipped products (effective January 2009) thereare continuing reports that as of July 2009, that the products continue to contain the older labels, and not therevised labels, and that the Medication Guides (absent of the Black Box Warnings) were not made available fordistribution.

See also the Black Box Warnings section of the Quinolones article for a discussion of the history of thesewarnings and the role of public advocacy groups in their inclusion in the product label.

Antibiotic abuse and bacterial resistance

See also: Antibiotic abuse and Antibiotic resistance

Page 10: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 10/19

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.[116] There are three known mechanisms of resistance. Some types of efflux pumpscan act to decrease intracellular quinolone concentration. In gram-negative bacteria, plasmid-mediatedresistance 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.[117]

Years ago, the FDA had added warnings regarding the proper use of Levaquin within the package inserts tocombat 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...."[49]

Though considered to be a very important and necessary drug required to treat severe and life-threateningbacterial infections, the associated prescription abuse of levofloxacin remains unchecked, which has contributedto 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.[118]

Fluoroquinolones, including levofloxacin, had become the most commonly prescribed class of antibiotics toadults in 2002. Nearly half (42%) of these prescriptions were for conditions not approved by the FDA, such asacute 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.[119][120] In addition, they are commonlyprescribed for medical conditions that are not even bacterial to begin, with such as viral infections, or those towhich no proven benefit exists.

Social and economic impact

See also: Quinolone#Social and economic impact

Patent extensions

From 2001–2008, patent extension legislation was signed into law that allowed a six-month patent extension fortesting their products for safety in children, an under-represented category in clinical trials. The FDA grantedJohnson and Johnson–Ortho McNeil pediatric exclusivity for Levaquin. This extended their patent until the endof 2010.

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 17 October 2006, Daiichi Sankyo also won apatent infringement lawsuit in Canada involving the generic version of Levaquin. The Canadian Federal AppealsCourt upheld a lower court's ruling handed down last October, which accepted the validity of Daiichi Sankyo'spatent until 23 June 2009. Daiichi Sankyo and Janssen-Ortho Inc., a Johnson & Johnson subsidiary, filed alawsuit with a federal court in Toronto after Teva Novopharm Ltd., started selling the generic version oflevofloxacin 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.[109]

On 7 June 2007, the Canadian Federal Appeal Court dismissed this appeal. Novopharm was prevented frommaking, using, offering to sell, or selling a generic version of levofloxacin tablets in the Canadian market until theexpiration of patent on 23 June 2009. Novopharm's generic version of Levaquin, had been sold in Canada since2004.

Page 11: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 11/19

Current litigation

An official complaint has been filed by The US Justice Department with a Federal Court in Boston (January2010) accusing Johnson and Johnson of illegally paying millions of dollars in kickbacks to Omnicare, one of thenation's largest pharmacies specializing in nursing home patients. In return, Omnicare nearly tripled its annualpurchase of Johnson and Johnson's products; including Levaquin.

There are also cases currently pending before the United States District Court, District of Minnesota, involvingLevaquin. On 13 June 2008, a Judicial Panel On Multidistrict Litigation (MDL) granted the Plaintiffs' motion tocentralize individual and class action lawsuits involving Levaquin in the District of Minnesota over objection of

Defendants, Johnson and Johnson / Ortho McNeil.[121] On 6 July 2009, The New Jersey Supreme Court hadalso 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.[122][123]

Additional lawsuits have also been recently filed in the Illinois State Court. Of a total of about 3400 cases, 845were recently settled out of court after Johnson and Johnson prevailed in three of the first four cases to go to

trial[124][125]

On 8 April 2010 in the Beaumont Division of the Eastern District of Texas, a class action lawsuit was filed byLisa Presley on behalf of herself and others similar situated against Johnson and Johnson, Ortho-McNeilPharmaceuticals Inc. and Johnson and Johnson Pharmaceutical Research and Development LLC. (Case No

1:10cv00200.)[126]

The various manufacturers have countered these allegations stating that they believe that these drugs are bothsafe and effective antibiotics, well tolerated with a minimum of side-effects, that such reactions are rare and thebenefits of such therapy outweigh the perceived risks.

References

1. ^ Nelson, JM.; Chiller, TM.; Powers, JH.; Angulo, FJ. (Apr 2007). "Fluoroquinolone-resistant Campylobacterspecies and the withdrawal of fluoroquinolones from use in poultry: a public health success story.". Clin Infect

Dis 44 (7): 977–80. doi:10.1086/512369 (http://dx.doi.org/10.1086%2F512369). PMID 17342653(//www.ncbi.nlm.nih.gov/pubmed/17342653).

2. ^ Kawahara, S. (Dec 1998). "[Chemotherapeutic agents under study]". Nippon Rinsho 56 (12): 3096–9.PMID 9883617 (//www.ncbi.nlm.nih.gov/pubmed/9883617).

3. ^ Laurence Brunton; John Lazo; Keith Parker (23 August 2005). Goodman & Gilman's The PharmacologicalBasis of Therapeutics (http://books.google.com/books?id=PtWdBgnQdjMC). McGraw-Hill Prof Med/Tech.ISBN 978-0-07-142280-2. Retrieved 30 October 2012.

4. ^ Mandell LA, Wunderink RG, Anzueto A, et al. (March 2007). "Infectious Diseases Society ofAmerica/American Thoracic Society consensus guidelines on the management of community-acquiredpneumonia in adults". Clin. Infect. Dis. 44 Suppl 2: S27–72. doi:10.1086/511159(http://dx.doi.org/10.1086%2F511159). PMID 17278083 (//www.ncbi.nlm.nih.gov/pubmed/17278083).

5. ^ "www.uroweb.org" (http://www.uroweb.org/gls/pdf/Urological%20Infections%202010.pdf).

6. ^ "National Guideline Clearinghouse | Treatment of urinary tract infections in nonpregnant women."(http://guidelines.gov/content.aspx?id=12628#Section420).

7. ^ Solomkin JS, Mazuski JE, Bradley JS, et al. (January 2010). "Diagnosis and management of complicatedintra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious

Diseases Society of America". Clin. Infect. Dis. 50 (2): 133–64. doi:10.1086/649554(http://dx.doi.org/10.1086%2F649554). PMID 20034345 (//www.ncbi.nlm.nih.gov/pubmed/20034345).

8. ^ Morrissey I, Hoshino K, Sato K, Yoshida A, Hayakawa I, Bures MG, Shen LL.,Mechanism of differentialactivities of ofloxacin enantiomers, in Antimicrob Agents Chemother. 1996 Aug;40(8):1775-84

9. ̂a b c d e f g h i j Janssen Pharmaceutica (September 2008). "Highlights of Prescribing Information"(http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021721s020_020635s57_020634s52_lbl.pdf).

Page 12: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 12/19

(http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021721s020_020635s57_020634s52_lbl.pdf).U.S. Food and Drug Administration (FDA).

10. ^ Morrissey, I.; Hoshino, K.; Sato, K.; Yoshida, A.; Hayakawa, I.; Bures, MG.; Shen, LL. (August 1996)."Mechanism of differential activities of ofloxacin enantiomers" (http://aac.asm.org/cgi/reprint/40/8/1775.pdf)

(PDF). Antimicrob Agents Chemother 40 (8): 1775–84. PMC 163416(//www.ncbi.nlm.nih.gov/pmc/articles/PMC163416). PMID 8843280(//www.ncbi.nlm.nih.gov/pubmed/8843280).

11. ^ label(http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020634s058,020635s064,021721s025lbl.pdf)

12. ^ "Levofloxacin" (http://www.drugs.com/monograph/levofloxacin.html). The American Society of Health-System Pharmacists. Retrieved 3 April 2011.

13. ^ Mark J. Goldberger (17 December 1998). "Center for drug evaluation and research"(http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020634s04_appltr.pdf). U.S. Food and DrugAdministration (FDA).

14. ̂a b Mark J. Goldberger. "NDA 20-634/S-008, S-009, NDA 20-635/S-007, S-008"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2000/20635S7,8LTR.PDF). U.S. Food and DrugAdministration (FDA).

15. ^ Renata Albrecht,. "NDA 20-634/S-013, NDA 20-635/S-010"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2000/20635S10ltr.pdf). U.S. Food and DrugAdministration (FDA).

16. ^ Renata Albrecht. "NDA 20-634/S-025, NDA 20-635/S-022"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/20634se1-025,20635se1-022ltr.pdf). U.S.Food and Drug Administration (FDA).

17. ^ Renata Albrecht (23 May 2003). "NDA 20-634/S-027, NDA 20-635/S-026"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2003/20634se1-027,20635se1-026ltr.pdf). U.S.Food and Drug Administration (FDA).

18. ^ "www.uroweb.org" (http://www.uroweb.org/gls/pdf/15_Urological_Infections.pdf).

19. ^ Schaeffer AJ (September 2004). "NIDDK-sponsored chronic prostatitis collaborative research network(CPCRN) 5-year data and treatment guidelines for bacterial prostatitis". Int. J. Antimicrob. Agents. 24 Suppl 1:S49–52. doi:10.1016/j.ijantimicag.2004.02.009 (http://dx.doi.org/10.1016%2Fj.ijantimicag.2004.02.009).PMID 15364307 (//www.ncbi.nlm.nih.gov/pubmed/15364307).

20. ^ Renata Albrecht (24 November 2004). "NDA 20-634/S-035, NDA 20-635/S-035, NDA 21-721/S-003"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/20634s035,20635s035,21721s003ltr.pdf).U.S. Food and Drug Administration (FDA).

21. ^ Renata Albrecht (8 April 2005). "NDA 20-634/S-037, NDA 20-635/S-038, NDA 21-721/S-002"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/020634s037,020635s038,021721s002ltr.pdf).U.S. Food and Drug Administration (FDA).

22. ̂a b c Renata Albrecht (23 June 2006). "NDA 20-634/S-040, NDA 20-635/S-043, NDA 21-721/S-007"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/020634s040,020635s043,021721s007LTR.pdf). U.S. Food and Drug Administration (FDA).

23. ^ "FDA OKs Levaquin To Treat Plague" (http://www.rttnews.com/1871281/fda-ok-s-levaquin-to-treat-plague.aspx). RTTNews. 29 April 2012.

24. ^ Renata Albrecht (5 May 2008). "NDA 20-634/S-047, NDA 20-635/S-051, NDA 21-721/S-015"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/020634se5-047020635se5-051021721se5-015ltr.pdf). U.S. Food and Drug Administration (FDA).

25. ^ John A. Bosso (1998). "New and Emerging Quinolone Antibiotics"

(http://bubl.ac.uk/archive/journals/jidp/v02n0498.htm#6new). Journal of Infectious Disease Pharmacotherapy 2(4): 61–76. doi:10.1300/J100v02n04_06 (http://dx.doi.org/10.1300%2FJ100v02n04_06). ISSN 1068-7777(//www.worldcat.org/issn/1068-7777).

26. ^ "SYNOPSIS" (http://download.veritasmedicine.com/PDF/CR002392_CSR.pdf) (PDF). veritasmedicine.com.6 September 2005.

27. ̂a b Dolui SK, Das M, Hazra A (2007). "Ofloxacin-induced reversible arthropathy in a child". Journal of

Postgraduate Medicine 53 (2): 144–5. doi:10.4103/0022-3859.32220 (http://dx.doi.org/10.4103%2F0022-3859.32220). PMID 17495385 (//www.ncbi.nlm.nih.gov/pubmed/17495385).

28. ^ Division of Special Pathogen and Immunologic Drug Products Summary of Clinical Review of StudiesSubmitted in Response to a Pediatric Written Request

29. ^ Chalumeau M, Tonnelier S, D'Athis P (June 2003). "Fluoroquinolone safety in pediatric patients: a

Page 13: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 13/19

29. ^ Chalumeau M, Tonnelier S, D'Athis P (June 2003). "Fluoroquinolone safety in pediatric patients: aprospective, multicenter, comparative cohort study in France"

(http://pediatrics.aappublications.org/cgi/content/full/111/6/e714). Pediatrics 111 (6 Pt 1): e714–9.doi:10.1542/peds.111.6.e714 (http://dx.doi.org/10.1542%2Fpeds.111.6.e714). PMID 12777590(//www.ncbi.nlm.nih.gov/pubmed/12777590). Retrieved 29 June 2009.

30. ^ Coban S, Ceydilek B, Ekiz F, Erden E, Soykan I (October 2005). "Levofloxacin-induced acute fulminant

hepatic failure in a patient with chronic hepatitis B infection". Ann Pharmacother 39 (10): 1737–40.doi:10.1345/aph.1G111 (http://dx.doi.org/10.1345%2Faph.1G111). PMID 16105873(//www.ncbi.nlm.nih.gov/pubmed/16105873).

31. ^ Shin HC, Kim JC, Chung MK (September 2003). "Fetal and maternal tissue distribution of the new

fluoroquinolone DW-116 in pregnant rats". Comp. Biochem. Physiol. C Toxicol. Pharmacol. 136 (1): 95–102.doi:10.1016/j.cca.2003.08.004 (http://dx.doi.org/10.1016%2Fj.cca.2003.08.004). PMID 14522602(//www.ncbi.nlm.nih.gov/pubmed/14522602).

32. ^ Dan M, Weidekamm E, Sagiv R, Portmann R, Zakut H (February 1993). "Penetration of fleroxacin intobreast milk and pharmacokinetics in lactating women"

(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC187655). Antimicrob. Agents Chemother. 37 (2): 293–6.doi:10.1128/AAC.37.2.293 (http://dx.doi.org/10.1128%2FAAC.37.2.293). PMC 187655(//www.ncbi.nlm.nih.gov/pmc/articles/PMC187655). PMID 8452360(//www.ncbi.nlm.nih.gov/pubmed/8452360).

33. ^ "www.accessdata.fda.gov"(http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020634s061,020635s067,021721s028lbl.pdf).

34. ^ Noel GJ, Bradley JS, Kauffman RE (October 2007). "Comparative safety profile of levofloxacin in 2523

children with a focus on four specific musculoskeletal disorders". Pediatr. Infect. Dis. J. 26 (10): 879–91.doi:10.1097/INF.0b013e3180cbd382 (http://dx.doi.org/10.1097%2FINF.0b013e3180cbd382). PMID 17901792(//www.ncbi.nlm.nih.gov/pubmed/17901792).

35. ^ "www.fda.gov" (http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4399s1-06%20%28Levofloxacin%29.pdf).

36. ^ Owens Rc, Jr; Ambrose, PG (July 2005). "Antimicrobial safety: focus on fluoroquinolones". ClinicalInfectious Diseases. 41 Suppl 2: S144–57. doi:10.1086/428055 (http://dx.doi.org/10.1086%2F428055).ISSN 1058-4838 (//www.worldcat.org/issn/1058-4838). PMID 15942881(//www.ncbi.nlm.nih.gov/pubmed/15942881).

37. ^ U S Food and Drug Administration (8 July 2008). "FDA Requests Boxed Warnings on FluoroquinoloneAntimicrobial Drugs"(http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116919.htm). U.S. Food andDrug Administration (FDA). Retrieved 5 September 2009.

38. ^ US Food and Drug Administration (2008). "Fluoroquinolone Antimicrobial Drugs [ciprofloxacin (marketed asCipro and generic ciprofloxacin), ciprofloxacin extended-release (marketed as Cipro XR and Proquin XR),gemifloxacin (marketed as Factive), levofloxacin (marketed as Levaquin), moxifloxacin (marketed as Avelox),norfloxacin (marketed as Noroxin), and ofloxacin (marketed as Floxin and generic ofloxacin)]"(http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm084316.htm). USA. Retrieved 5 September 2009.

39. ^ US Food and Drug Administration. "Drugs at FDA: FDA Approved Drug Products"(http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist). USA: U.S. Food and Drug Administration (FDA).Retrieved 5 September 2009.

40. ̂a b c Renata Albrecht (14 September 2004). "NDA 20-634/S-033, S-034, NDA 20-635/S-033, S-034"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/20634s033,034,20635s033,034ltr.pdf). U.S.Food and Drug Administration (FDA).

41. ̂a b Renata Albrecht (14 July 2004). "NDA 19-537/S-053, S-054, NDA 20-780/S-017, S-018"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19537s053,054,20780s017,018ltr.pdf). U.S.Food and Drug Administration (FDA). Retrieved 5 September 2009.

42. ̂a b Renata Albrecht (18 December 2001). "NDA 20-634/S-015, S-021, S-022, NDA 20-635/S-012, S-019, S-020" (http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2001/20634s15s21s22ltr.pdf). U.S. Food andDrug Administration (FDA).

43. ^ Renata Albrecht (4 November 2004). "NDA 20-634/S-036, NDA 20-635/S-037"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/20635s037,20634s036ltr.pdf). U.S. Food andDrug Administration (FDA).

44. ̂a b Petitjeans, F.; Nadaud, J.; Perez, JP.; Debien, B.; Olive, F.; Villevieille, T.; Pats, B. (December 2003). "A

Page 14: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 14/19

44. ̂a b Petitjeans, F.; Nadaud, J.; Perez, JP.; Debien, B.; Olive, F.; Villevieille, T.; Pats, B. (December 2003). "A

case of rhabdomyolysis with fatal outcome after a treatment with levofloxacin". Eur J Clin Pharmacol 59 (10):779–80. doi:10.1007/s00228-003-0688-x (http://dx.doi.org/10.1007%2Fs00228-003-0688-x). PMID 14576967(//www.ncbi.nlm.nih.gov/pubmed/14576967).

45. ̂a b Hsiao, SH.; Chang, CM.; Tsao, CJ.; Lee, YY.; Hsu, MY.; Wu, TJ. (January 2005). "Acute

rhabdomyolysis associated with ofloxacin/levofloxacin therapy". Ann Pharmacother 39 (1): 146–9.doi:10.1345/aph.1E285 (http://dx.doi.org/10.1345%2Faph.1E285). PMID 15562138(//www.ncbi.nlm.nih.gov/pubmed/15562138).

46. ̂a b Korzets, A.; Gafter, U.; Dicker, D.; Herman, M.; Ori, Y. (November 2006). "Levofloxacin and

rhabdomyolysis in a renal transplant patient". Nephrol Dial Transplant 21 (11): 3304–5. doi:10.1093/ndt/gfl396(http://dx.doi.org/10.1093%2Fndt%2Fgfl396). PMID 16968728 (//www.ncbi.nlm.nih.gov/pubmed/16968728).

47. ^ Renata Albrecht (31 May 2007). "NDA 20-634/S-042, NDA 20-635/S-045, NDA 21-721/S-010"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/020634s042,020635s045,021721s010ltr.pdf).U.S. Food and Drug Administration (FDA).

48. ^ Renata Albrecht (19 June 2006). "NDA 19-537/S-062, NDA 20-780/S-023, NDA 19-847/S-037, NDA 19-857/S-042, NDA 21-473/S-016"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/019537s62,020780s23,019847s37,019857s42,021473s16LTR.pdf). U.S. Food and Drug Administration (FDA). Retrieved 5 September 2009.

49. ̂a b Renata Albrecht (5 March 2004). "NDA 20-634/S-029, NDA 20-635/S-029"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/20634slr029,20635slr029ltr.pdf). U.S. Foodand Drug Administration (FDA).

50. ^ Cohen JS (December 2001). "Peripheral Neuropathy Associated with Fluoroquinolones"

(http://fqvictims.org/fqvictims/News/neuropathy/Neuropathy.pdf) (PDF). Ann Pharmacother 35 (12): 1540–7.doi:10.1345/aph.1Z429 (http://dx.doi.org/10.1345%2Faph.1Z429). PMID 11793615(//www.ncbi.nlm.nih.gov/pubmed/11793615).

51. ̂a b c Renata Albrecht (19 June 2007). "NDA 20-634/S-045, NDA 20-635/S-048, NDA 21-721/S-013"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/020634s045,%20020635s048,%20021721s013ltr.pdf) (PDF). USA: U.S. Food and Drug Administration (FDA).

52. ̂a b Renata Albrecht (16 April 2008). "NDA 20-634/S-051, NDA 20-635/S-055, NDA 21-721/S-019"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/020634s051,%20020635s055,%20021721s019ltr.pdf). U.S. Food and Drug Administration (FDA).

53. ^ Renata Albrecht (15 March 2004). "NDA 19-537/S-048, S-050, S-051 NDA 20-780/S-012, S-014, S-015"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/19537slr048,050,051,20780slr012,014,015ltr.pdf). U.S. Food and Drug Administration (FDA). Retrieved September 2009.

54. ^ Renata Albrecht (3 October 2008). "NDA 20-634/S-052, NDA 20-635/S-057, NDA 21-721/S-020"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/020634s052,%20020635s057,021721s020ltr%20.pdf). U.S. Food and Drug Administration (FDA).

55. ^ Renata Albrecht (3 October 2008). "NDA 19-537/S-068, NDA 19-847/S-042, NDA 19-857/S-049, NDA 20-780/S-026, NDA 21-473/S-024"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/019537s068,019847s042ltr.pdf). U.S. Foodand Drug Administration (FDA). Retrieved 5 September 2009.

56. ̂a b Renata Albrecht (13 December 2007). "NDA 20-634/S-050, NDA 20-635/S-054, NDA 21-721/S-018"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/020634s050,%20020635s054,%20021721s018ltr.pdf). U.S. Food and Drug Administration (FDA).

57. ^ Kushner, JM.; Peckman, HJ.; Snyder, CR. (October 2001). "Seizures associated with fluoroquinolones". Ann

Pharmacother 35 (10): 1194–8. doi:10.1345/aph.10359 (http://dx.doi.org/10.1345%2Faph.10359).PMID 11675843 (//www.ncbi.nlm.nih.gov/pubmed/11675843).

58. ^ Ozawa, TT.; Valadez, T. (March 2002). "Clostridium difficile infection associated with levofloxacin

treatment". Tenn Med 95 (3): 113–5. PMID 11898264 (//www.ncbi.nlm.nih.gov/pubmed/11898264).

59. ^ Gopal Rao, G.; Mahankali Rao, CS.; Starke, I. (March 2003). "Clostridium difficile-associated diarrhoea inpatients with community-acquired lower respiratory infection being treated with levofloxacin compared with

beta-lactam-based therapy". J Antimicrob Chemother 51 (3): 697–701. doi:10.1093/jac/dkg115(http://dx.doi.org/10.1093%2Fjac%2Fdkg115). PMID 12615873 (//www.ncbi.nlm.nih.gov/pubmed/12615873).

60. ^ Muto CA, Pokrywka M, Shutt K (March 2005). "A large outbreak of Clostridium difficile-associated diseasewith an unexpected proportion of deaths and colectomies at a teaching hospital following increasedfluoroquinolone use" (http://www.journals.uchicago.edu/doi/pdf/10.1086/502539). Infect Control Hosp

Epidemiol 26 (3): 273–80. doi:10.1086/502539 (http://dx.doi.org/10.1086%2F502539). PMID 15796280

Page 15: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 15/19

Epidemiol 26 (3): 273–80. doi:10.1086/502539 (http://dx.doi.org/10.1086%2F502539). PMID 15796280(//www.ncbi.nlm.nih.gov/pubmed/15796280).

61. ^ Deshpande, A.; Pant, C.; Jain, A.; Fraser, TG.; Rolston, DD. (February 2008). "Do fluoroquinolonespredispose patients to Clostridium difficile associated disease? A review of the evidence". Curr Med Res Opin

24 (2): 329–33. doi:10.1185/030079908X253735 (http://dx.doi.org/10.1185%2F030079908X253735).PMID 18067688 (//www.ncbi.nlm.nih.gov/pubmed/18067688).

62. ^ Cho, S.; Breedlove, JJ.; Gunning, ST. (January 2008). "Radiation recall reaction induced by levofloxacin". J

Drugs Dermatol 7 (1): 64–7. PMID 18246700 (//www.ncbi.nlm.nih.gov/pubmed/18246700).

63. ^ Smythe, MA.; Cappelletty, DM. (December 2000). "Anaphylactoid reaction to levofloxacin".

Pharmacotherapy 20 (12): 1520–3. doi:10.1592/phco.20.19.1520.34868(http://dx.doi.org/10.1592%2Fphco.20.19.1520.34868). PMID 11130225(//www.ncbi.nlm.nih.gov/pubmed/11130225).

64. ^ Takahama, H.; Tsutsumi, Y.; Kubota, Y. (September 2005). "Anaphylaxis due to levofloxacin". Int J

Dermatol 44 (9): 789–90. doi:10.1111/j.1365-4632.2004.02325.x (http://dx.doi.org/10.1111%2Fj.1365-4632.2004.02325.x). PMID 16135155 (//www.ncbi.nlm.nih.gov/pubmed/16135155).

65. ^ Gunduz, A.; Turedi, S.; Kalkan, A.; Nuhoglu, I. (August 2006). "Levofloxacin induced myasthenia crisis"

(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564188). Emerg Med J 23 (8): 662.doi:10.1136/emj.2006.038091 (http://dx.doi.org/10.1136%2Femj.2006.038091). PMC 2564188(//www.ncbi.nlm.nih.gov/pmc/articles/PMC2564188). PMID 16858118(//www.ncbi.nlm.nih.gov/pubmed/16858118).

66. ^ Mennecier, D.; Thiolet, C.; Bredin, C.; Potier, V.; Vergeau, B.; Farret, O. (October 2001). "[Acute

pancreatitis after treatment by levofloxacin and methylprednisolone]". Gastroenterol Clin Biol 25 (10): 921–2.PMID 11852403 (//www.ncbi.nlm.nih.gov/pubmed/11852403).

67. ^ Domínguez Jiménez, JL.; Bernal Blanco, E.; Marín Moreno, MA.; Puente Gutiérrez, JJ. (April 2009). "[Acutepancreatitis associated with levofloxacin]" (http://www.elsevier.es/revistas/ctl_servlet?

_f=7064&ip=94.7.35.23&articuloid=13136637&revistaid=14). Gastroenterol Hepatol (in Spanish) 32 (4): 323–4. doi:10.1016/j.gastrohep.2008.09.027 (http://dx.doi.org/10.1016%2Fj.gastrohep.2008.09.027).PMID 19371975 (//www.ncbi.nlm.nih.gov/pubmed/19371975).

68. ̂a b Fraunfelder, FW.; Fraunfelder, FT. (September 2009). "Diplopia and fluoroquinolones". Ophthalmology

116 (9): 1814–7. doi:10.1016/j.ophtha.2009.06.027 (http://dx.doi.org/10.1016%2Fj.ophtha.2009.06.027).PMID 19643481 (//www.ncbi.nlm.nih.gov/pubmed/19643481).

69. ^ Grépinet, C.; Guillocheau, E.; Berteloot, A.; Vachée, A.; Herbin, O.; Gautier, S.; l'association des centresrégionaux de pharmacovigilance (2008). "[Drug-induced fever during treatment with levofloxacin: a case-

report]". Therapie 63 (4): 341–3. PMID 19043827 (//www.ncbi.nlm.nih.gov/pubmed/19043827).

70. ^ Lardizabal, DV. (February 2009). "Intracranial hypertension and levofloxacin: a case report". Headache 49(2): 300–1. doi:10.1111/j.1526-4610.2008.01212.x (http://dx.doi.org/10.1111%2Fj.1526-4610.2008.01212.x).PMID 18647180 (//www.ncbi.nlm.nih.gov/pubmed/18647180).

71. ^ Oh YR, Carr-Lopez SM, Probasco JM, Crawley PG (2003). "Levofloxacin-induced autoimmune hemolytic

anemia". Ann Pharmacother 37 (7–8): 1010–3. doi:10.1345/aph.1C525(http://dx.doi.org/10.1345%2Faph.1C525). PMID 12841809 (//www.ncbi.nlm.nih.gov/pubmed/12841809).

72. ^ Iannini, PB. (June 2007). "The safety profile of moxifloxacin and other fluoroquinolones in special patient

populations". Curr Med Res Opin 23 (6): 1403–13. doi:10.1185/030079907X188099(http://dx.doi.org/10.1185%2F030079907X188099). PMID 17559736(//www.ncbi.nlm.nih.gov/pubmed/17559736).

73. ^ Owens, RC.; Ambrose, PG. (July 2005). "Antimicrobial safety: focus on fluoroquinolones". Clin Infect Dis.41 Suppl 2: S144–57. doi:10.1086/428055 (http://dx.doi.org/10.1086%2F428055). PMID 15942881(//www.ncbi.nlm.nih.gov/pubmed/15942881).

74. ^ Saint, F.; Gueguen, G.; Biserte, J.; Fontaine, C.; Mazeman, E. (September 2000). "[Rupture of the patellar

ligament one month after treatment with fluoroquinolone]". Rev Chir Orthop Reparatrice Appar Mot 86 (5):495–7. PMID 10970974 (//www.ncbi.nlm.nih.gov/pubmed/10970974).

75. ^ Gangopadhyay, N.; Daniell, M.; Weih, L.; Taylor, HR. (April 2000). "Fluoroquinolone and fortified antibioticsfor treating bacterial corneal ulcers" (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1723447). Br J

Ophthalmol 84 (4): 378–84. doi:10.1136/bjo.84.4.378 (http://dx.doi.org/10.1136%2Fbjo.84.4.378).PMC 1723447 (//www.ncbi.nlm.nih.gov/pmc/articles/PMC1723447). PMID 10729294(//www.ncbi.nlm.nih.gov/pubmed/10729294).

76. ^ Walter, K.; Tyler, ME. (August 2006). "Severe corneal toxicity after topical fluoroquinolone therapy: report

Page 16: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 16/19

76. ^ Walter, K.; Tyler, ME. (August 2006). "Severe corneal toxicity after topical fluoroquinolone therapy: report

of two cases". Cornea 25 (7): 855–7. doi:10.1097/01.ico.0000224642.43601.14(http://dx.doi.org/10.1097%2F01.ico.0000224642.43601.14). PMID 17068466(//www.ncbi.nlm.nih.gov/pubmed/17068466).

77. ^ "Public Citizen Warns of Cipro Dangers"(http://www.consumeraffairs.com/news04/2006/08/pubcit_cipro.html). USA: Consumer affairs. 30 August2006. Retrieved 7 September 2009.

78. ^ "FDA orders 'black box' label on some antibiotics"(http://www.cnn.com/2008/HEALTH/07/08/antibiotics.risk/index.html). CNN. 8 July 2008. Retrieved 8 July2008.

79. ^ Hirano T, Yasuda S, Osaka Y (March 2008). "The inhibitory effects of fluoroquinolones on L-carnitine

transport in placental cell line BeWo". International Journal of Pharmaceutics 351 (1–2): 113–8.doi:10.1016/j.ijpharm.2007.09.022 (http://dx.doi.org/10.1016%2Fj.ijpharm.2007.09.022). PMID 17977676(//www.ncbi.nlm.nih.gov/pubmed/17977676).

80. ^ Friedrich, LV.; Dougherty, R. (December 2004). "Fatal hypoglycemia associated with levofloxacin"

(http://www.medscape.com/viewarticle/496197). Pharmacotherapy 24 (12): 1807–12.doi:10.1592/phco.24.17.1807.52348 (http://dx.doi.org/10.1592%2Fphco.24.17.1807.52348). PMID 15585448(//www.ncbi.nlm.nih.gov/pubmed/15585448).

81. ^ Melissa Hunt (January 2007). "Levofloxacin: dysglycemia and liver disorders" (http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/carn-bcei_v17n1-eng.pdf) (PDF). Canadian adverse reaction

newsletter (Canada: Health Canada Newsletter) 17 (1).

82. ^ Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers(http://www.richmondpharmacology.com/downloads/Publications/bcp_3595_rpl.pdf)Taubel, Jorg; Naseem,A., Harada, T., Wang, D., Arezina, R., Lorch, U. and Camm, A. J. (2010) (November 2009). "Levofloxacincan be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers"

(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848412). British Journal of Clinical Pharmacology 69 (4):391–400. doi:10.1111/j.1365-2125.2009.03595.x (http://dx.doi.org/10.1111%2Fj.1365-2125.2009.03595.x).PMC 2848412 (//www.ncbi.nlm.nih.gov/pmc/articles/PMC2848412). PMID 20406223(//www.ncbi.nlm.nih.gov/pubmed/20406223).

83. ̂a b c d DrugBank (19 February 2009). "Showing drug card for Levofloxacin (DB01137)"(http://www.drugbank.ca/drugs/DB01137). Canada.

84. ^ "Showing drug card for Rimantadine (DB00478)" (http://www.drugbank.ca/drugs/DB00478). Canada. 23June 2009.

85. ^ Drlica K, Zhao X (1 September 1997). "DNA gyrase, topoisomerase IV, and the 4-quinolones"

(http://mmbr.asm.org/cgi/pmidlookup?view=long&pmid=9293187). Microbiol Mol Biol Rev. 61 (3): 377–92.PMC 232616 (//www.ncbi.nlm.nih.gov/pmc/articles/PMC232616). PMID 9293187(//www.ncbi.nlm.nih.gov/pubmed/9293187).

86. ^ Brouwers JR (1992). "Drug interactions with quinolone antibacterials". Drug Saf 7 (4): 268–81.doi:10.2165/00002018-199207040-00003 (http://dx.doi.org/10.2165%2F00002018-199207040-00003).PMID 1524699 (//www.ncbi.nlm.nih.gov/pubmed/1524699).

87. ^ Hilliard JJ, Krause HM, Bernstein JI (1995). "A comparison of active site binding of 4-quinolones and novel

flavone gyrase inhibitors to DNA gyrase". Adv Exp Med Biol. 390: 59–69. PMID 8718602(//www.ncbi.nlm.nih.gov/pubmed/8718602).

88. ^ Cooper JG, Harboe K, Frost SK, Skadberg Ø (April 2005). "Ciprofloxacin interacts with thyroid replacement

therapy" (http://www.bmj.com/cgi/content/full/330/7498/1002). BMJ 330 (7498): 1002.doi:10.1136/bmj.330.7498.1002 (http://dx.doi.org/10.1136%2Fbmj.330.7498.1002). PMC 557149(//www.ncbi.nlm.nih.gov/pmc/articles/PMC557149). PMID 15860826(//www.ncbi.nlm.nih.gov/pubmed/15860826).

89. ^ Domagala JM (April 1994). "Structure-activity and structure-side-effect relationships for the quinolone

antibacterials" (http://jac.oxfordjournals.org/cgi/reprint/33/4/685). J. Antimicrob. Chemother. 33 (4): 685–706.doi:10.1093/jac/33.4.685 (http://dx.doi.org/10.1093%2Fjac%2F33.4.685). PMID 8056688(//www.ncbi.nlm.nih.gov/pubmed/8056688).

90. ^ Janknegt R (November 1990). "Drug interactions with quinolones". J. Antimicrob. Chemother. 26 Suppl D:7–29. PMID 2286594 (//www.ncbi.nlm.nih.gov/pubmed/2286594).

91. ^ van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH (2003)."Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking

oral corticosteroids" (http://archinte.ama-assn.org/cgi/content/full/163/15/1801). Arch. Intern. Med. 163 (15):

Page 17: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 17/19

1801–7. doi:10.1001/archinte.163.15.1801 (http://dx.doi.org/10.1001%2Farchinte.163.15.1801).PMID 12912715 (//www.ncbi.nlm.nih.gov/pubmed/12912715).

92. ^ Zacher, JL; Givone, DM (2004). "False-positive urine opiate screening associated with fluoroquinolone use".Ann Pharmacother (38): 1525–1528.

93. ^ University of Maryland Medical Center. "Levofloxacin" (http://www.umm.edu/altmed/drugs/levofloxacin-075755.htm#U.S.%20Brand%20Names). USA: University of Maryland.

94. ^ Takashi Shoda (23 October 2008). "UK Levofloxacin SPC and Underlying Patent Upheld by High CourtPatent Court" (http://www.daiichisankyo.com/news/yymmdd_nn.html?b_newsrelease_n1_eng.detail%5Bid%5D=682.3&b_newsrelease_n1_eng.year_selector%5Bid%5D=682.3&b_newsrelease_n1_eng.category_selector%5Bid%5D=682.3). USA: Daiichi Sankyo, Limited.

95. ^ Johnson & Johnson (2009). "Analysis of Sales by Business Segments"(http://files.shareholder.com/downloads/JNJ/0x0x171267/057640f8-b2c0-4b0f-9f54-7a24a553c3ce/2007AR.pdf) (PDF). Shareholder. p. 27.

96. ̂a b c "LEVAQUIN" (http://www.drugpatentwatch.com/premium/preview/detail/index.php?searchtype=alpha&category=Tradename&searchstring=LEVAQUIN). USA: drugpatentwatch.com.

97. ^ "drugtopics.modernmedicine.com" (http://drugtopics.modernmedicine.com/drugtopics/article/articleList.jsp?sort=null&pageNo=2&start=9&categoryId=7604).

98. ̂a b c "www.accessdata.fda.gov" (http://www.accessdata.fda.gov/drugsatfda_docs/nda/96/020634-1.pdf).

99. ^ "Levofloxacin". Tuberculosis (Edinb) 88 (2): 119–21. March 2008. doi:10.1016/S1472-9792(08)70013-1(http://dx.doi.org/10.1016%2FS1472-9792%2808%2970013-1). PMID 18486047(//www.ncbi.nlm.nih.gov/pubmed/18486047).

100. ^ North DS, Fish DN, Redington JJ (1998). "Levofloxacin, a second-generation fluoroquinolone".

Pharmacotherapy 18 (5): 915–35. PMID 9758306 (//www.ncbi.nlm.nih.gov/pubmed/9758306).

101. ^ edited by Thomas L. Lemke, David A. Williams ; assistant editors, Victoria F. Roche, S. William Zito ...,Thomas L.; Williams, David A. (1 October 2007). Foye's Principles of Medicinal Chemistry(http://books.google.com/?id=NHQQBMM-qMEC&pg=PP1) (6 ed.). USA: Lippincott Williams & Wilkins.ISBN 978-0-7817-6879-5. More than one of |last1= and |author= specified (help)

102. ^ "Levaquin Information" (http://www.medications.com/drugs/levaquin). USA: Medications.com.

103. ^ King DE, Malone R, Lilley SH (May 2000). "New classification and update on the quinolone antibiotics"

(http://www.aafp.org/afp/20000501/2741.html). American Family Physician 61 (9): 2741–8. PMID 10821154(//www.ncbi.nlm.nih.gov/pubmed/10821154). Retrieved 30 June 2009.

104. ^ Davis R, Bryson HM (April 1994). "Levofloxacin. A review of its antibacterial activity, pharmacokinetics and

therapeutic efficacy". Drugs 47 (4): 677–700. doi:10.2165/00003495-199447040-00008(http://dx.doi.org/10.2165%2F00003495-199447040-00008). PMID 7516863(//www.ncbi.nlm.nih.gov/pubmed/7516863).

105. ^ "STATISTICAL REVIEW AND EVALUATION"(http://www.accessdata.fda.gov/drugsatfda_docs/nda/96/020634-4.pdf) (PDF). USA: U.S. Food and DrugAdministration (FDA). 21 November 1996.

106. ^ Ed Lamb (1 May 2008). "Top 200 Prescription Drugs of 2007"(http://www.pharmacytimes.com/issues/articles/2008-05_003.asp). Pharmacy Times. Retrieved 21 July 2009.

107. ^ Cravit, Cravit Ophthalmic, Elequine, Floxel, Iquix, Leroxacin, Lesacin, Levaquin, Levokacin, Levox,Levoxacin, Mosardal, Nofaxin, Quixin, Reskuin, Tavanic, Volequin http://www.drugbank.ca/drugs/DB01137

108. ^ Cravox, Floxlevo, Levoxacine, Levoxetina, Nislev, Oftaquix, Prixar, Reskuin, Tavanic source:http://www.umm.edu/altmed/drugs/levofloxacin-075755.htm#International%20Brand%20Names

109. ̂a b "Novopharm Limited" (http://investing.businessweek.com/research/stocks/private/snapshot.asp?privcapId=4240255). USA. 3 November 2009.

110. ^ JOHNSON & JOHNSON (28 March 2004). "UNITED STATES SECURITIES AND EXCHANGECOMMISSION" (http://apps.shareholder.com/sec/viewerContent.aspx?companyid=JNJ&docid=2940855).USA: shareholder.com. pp. 28–29.

111. ^ "NDA 20-634/S-054, NDA 20-635/S-059, NDA 21-721/S-022"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/020634s054,020635s059,021721s022ltr.pdf).U.S. Food and Drug Administration (FDA). 12 March 2009.

112. ^ Ozlem Belen (27 March 2009). "NDA 20-634/S-053, NDA 20-635/S-058, NDA 21-721/S-021"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/020634s053,020635s058,021721s021lt.pdf).U.S. Food and Drug Administration (FDA).

113. ^ Ortho-McNeil-Janssen Pharmaceuticals, Inc. (October 2008). "FDA-Approved Medication Guide"

Page 18: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 18/19

(http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020634s053,020635s058,%20021721s021lbl.pdf).U.S. Food and Drug Administration (FDA).

114. ^ Levaquin (Levofloxacin)(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/020634s058,020635s064,021721s025ltr.pdf)

115. ^ Renata Albrecht (3 October 2008). "NDA 19-735/S-059"(http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/019735s059ltr.pdf). U.S. Food and DrugAdministration (FDA).

116. ^ M Jacobs, Worldwide Overview of Antimicrobial Resistance. International Symposium on AntimicrobialAgents and Resistance 2005.

117. ^ Robicsek A, Jacoby GA, Hooper DC (October 2006). "The worldwide emergence of plasmid-mediated

quinolone resistance". The Lancet Infectious Diseases 6 (10): 629–40. doi:10.1016/S1473-3099(06)70599-0(http://dx.doi.org/10.1016%2FS1473-3099%2806%2970599-0). PMID 17008172(//www.ncbi.nlm.nih.gov/pubmed/17008172).

118. ^ Froom J, Culpepper L, Jacobs M (July 1997). "Antimicrobials for acute otitis media? A review from theInternational Primary Care Network" (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2127061). BMJ (Clinical

Research Ed.) 315 (7100): 98–102. doi:10.1136/bmj.315.7100.98(http://dx.doi.org/10.1136%2Fbmj.315.7100.98). PMC 2127061(//www.ncbi.nlm.nih.gov/pmc/articles/PMC2127061). PMID 9240050(//www.ncbi.nlm.nih.gov/pubmed/9240050).

119. ^ Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS (March 2005). "Fluoroquinolone prescribing in

the United States: 1995 to 2002". The American Journal of Medicine 118 (3): 259–68.doi:10.1016/j.amjmed.2004.09.015 (http://dx.doi.org/10.1016%2Fj.amjmed.2004.09.015). PMID 15745724(//www.ncbi.nlm.nih.gov/pubmed/15745724).

120. ^ K08 HS14563 and HS11313

121. ^ "Levaquin MDL | 08-MD-1943" (http://www.mnd.uscourts.gov/MDL-Levaquin/index.shtml). USA: USDistrict Court District of Minnesota. Retrieved 7 September 2009.

122. ^ Charles Toutant (6 July 2009). "Litigation Over Johnson & Johnson Antibiotic Levaquin Designated N.J.Mass Tort" (http://www.law.com/jsp/article.jsp?id=1202431984309). New Jersey Law Journal.

123. ^ Reed Abelson; Natasha Singer (14 October 2011). "Johnson & Johnson Wins Suit Over Antibiotic's SideEffects" (http://www.nytimes.com/2011/10/15/business/johnson-johnson-wins-suit-over-levaquins-side-effects.html). The New York Times.

124. ^ "Levaquin MDL | United States District Court – District of Minnesota, United States District Court – Districtof Minnesota" (http://www.mnd.uscourts.gov/MDL-Levaquin/current-developments.shtml).

125. ^ "Johnson & Johnson Settles 845 Levaquin Lawsuits – Businessweek"(http://www.businessweek.com/news/2012-11-01/johnson-and-johnson-reaches-settlement-in-845-levaquin-cases).

126. ^ The Southeast Texas Record. 17 April 2010 S.E. Texas' Legal Journal Class action alleges antibiotic causestendon damage 15 April 2010 8:21 am By Michelle Massey, East Texas Bureauhttp://www.setexasrecord.com/news/226050-class-action-alleges-antibiotic-causes-tendon-damage

External links

Levofloxacin (http://www.dmoz.org/Society/Issues/Health/Drugs/Medical/) at the Open Directory ProjectU.S. National Library of Medicine: Drug Information Portal – Levofloxacin

(http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Levofloxacin)Levaquin Package Insert

(http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021721s020_020635s57_020634s52_lbl.pdf)

Iquix Package Insert (http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21571_iquix_lbl.pdf)Quixin Package Insert(http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021199s004,005lbl.pdf)

Page 19: Levofloxacin - Wikipedia, The Free Encyclopedia

6/10/13 Levofloxacin - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Levofloxacin 19/19

Retrieved from "http://en.wikipedia.org/w/index.php?title=Levofloxacin&oldid=558000578"Categories: Enantiopure drugs Fluoroquinolone antibiotics Nitrogen heterocycles Oxygen heterocycles

Piperazines Quinolone antibiotics

This page was last modified on 2 June 2013 at 17:30.

Text is available under the Creative Commons Attribution-ShareAlike License; additional terms mayapply. By using this site, you agree to the Terms of Use and Privacy Policy. Wikipedia® is a registered trademark of the Wikimedia Foundation, Inc., a non-profit organization.