Levofloxacin

Levofloxacin

Clinical data
Other names	(3S)-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 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

'Levofloxacin', sold under the brand names Iquix, Levaquin, Oftaquix, Quixin and Tavanic, is a synthetic chemotherapeutic agent used to treat severe and life threatening bacterial infections. Levofloxacin is commonly referred to as a fluoroquinolone (or quinolone) drug and is a member of the fluoroquinolone class of antibacterials. Levofloxacin is a “mirror image” or enantiomer of Ofloxacin. Ofloxacin is a racemic mixture of which levofloxacin is the active component. The biologically active enantiomer is sold separately under the chemical name of levofloxacin.

Levofloxacin interacts 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.

Levofloxacin is associated with a significant number of serious and life threatening adverse reactions as well as spontaneous tendon ruptures and irreversible peripheral neuropathy. Hepatoxicity has also been reported with the use of levofloxacin. Such reactions may manifest long after therapy had been completed and in severe cases may result in life long disabilities.

History

Levofloxacin is considered by some to be a third-generation fluoroquinolone antibiotic, marketed by Ortho-McNeil in the United States under the trade names Iquix, Levaquin, Quixin and in Canada under the trade name Levaquin. (Synonyms: L-Ofloxacin ).

Other manufacturers include Novell Pharmaceutical Laboratories (Levores). Levofloxacin was first patented in 1987 (Levofloxacin European Patent Daiichi) and was approved by the U.S. Food and Drug Administration on December 20, 1996 for use in the United States to treat severe and life threatening bacterial infections. Daiichi Sankyo had granted an exclusive license to Sanofi-Aventis to make, use and sell pharmaceutical preparations containing levofloxacin in the UK. Sanofi-Aventis markets levofloxacin products in the UK under the trade name Tavanic.

For all practical purposes Ofloxacin and Levofloxacin should be considered one and the same, with the exception of the potentcy shown in vitro against rnycobacteria. In vitro, it is generally twice as potent as ofloxacin while d-ofloxacin is less active against rnycobacteria. Levofloxacin has moderate activity against anaerobes, and is about twice as potent as ofloxacin against mycobacterium tuberculosis and other rnycobacteria including mycobactev-ium avium complex. Levofloxacin is currently the only respiratory quinolone approved by the FDA for the treatment of nosocomial pneumonia in adult patients.

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 dollars.

Levofloxacin is marketed worldwide under a significant number of different brand names. This causes a lot of confusion which makes post marketing survelliance extremely difficult.

Additionally 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 have filed numerous patent lawsuits to prevent such generic equivalents from being marketed, claiming that their patent does not expire until June 23, 2009. see Generic Equivalents

Licensed Uses

The licensed uses for levofloxacin in the United States are as follows:

Fluoroquinolones are not licensed by the FDA for use in children due to the risk of fatalities as well as permanent injury to the multiskeletal system, with two exceptions. Ciprofloxacin has been approved to treat Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli as well as Inhalational Anthrax (post-exposure) and recently levofloxacin received approval to treat Anthrax (post-exposure). Although alleged to be effective, levofloxacin is not to be considered a first line agent for inhalation anthrax in the pediatric population due to severe adverse reactions involving the multiskeletal system and other serious adverse reactions, including fatalities.

The CDC revoked it's recommendation regarding the use of fluoroquinolones (ciprofloxacin) as a first line agent in treating anthrax due to the unacceptable risk documented within the Antimicrobial Postexposure Prophylaxis for Anthrax study (aka Cipro 60 day study). However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK. Prescribing a fluoroquinolone to treat an unapproved use within the pediatric (as well as the adult population) exposes the treating physician to the risk of being sued for malpractice should the treating physician fail to both warn the patient of this fact, as well as the risks of any adverse drug reactions the patient may experience.

In the adult population levofloxacin is limited to the treatment of proven serious and life threatening bacterial infections such as:

• Nosocomial Pneumonia
• Community-acquired pneumonia
• Acute Bacterial Sinusitis
• Acute Bacterial Exacerbation of Chronic Bronchitis
• Skin and Skin Structure Infections
• Chronic Bacterial Prostatitis
• Urinary Tract Infections
• Acute Pyelonephritis
• Inhalational Anthrax (Post-Exposure)

In the pediatric population levofloxacin is limited to the treatment of only one proven serious and life threatening bacterial infection:

• Inhalational Anthrax (Post-Exposure)

NOTE: Levofloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.

Availability

Levofloxacin is available as:

• Tablet; Oral Multiple Strengths Prescription
• Injectable; Injection Multiple Strengths Prescription
• Solution; Oral 250MG/10ML Prescription
• Also used in eye and ear drops. Prescription

See the latest package insert for Levofloxacin (Levaquin) for additional details.

Activity

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 (Hussy et al.).

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

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

Contraindications

Use against chlamydia and mycoplasma infections is now contraindicated; levofloxacin appears to be ineffective against these organisms, merely stopping their growth (and allowing them to resume growth after the antibiotic is withdrawn) rather than eradicating the infections. Levofloxacin is also contraindicated for the treatment of sexually transmitted diseases.

Medications or supplements containing metals, such as aluminium, magnesium, calcium, ferrous sulfate, iron, and zinc, are believed to form chelation complexes with fluoroquinolone antibiotics and thereby prevent the drugs from being properly absorbed during therapy. Because of this patients are advised within the package insert to avoid taking levofloxacin with antacids which contain aluminium, magnesium or calcium while undergoing fluoroquinolone therapy.

Exercise while undergoing fluoroquinolone therapy is to be discouraged, as spontaneous tendon ruptures as well as torn muscles and cartilage have been reported in patients taking levofloxacin. The risk of spontaneous tendon ruptures due to levofloxacin has recently been highlighted within the package inserts via a BLACK BOX WARNING. (November 2008). Fluoroquinolones are increasingly contraindicated for patients who have been to southeast Asia due to the growing prevalence of antibiotic resistance to the class of antibiotics in that region.

Caution in patients with liver disease.

Levofloxacin is also contraindicated within the pediatric population (except for the one indication outlined under licensed use above), pregnancy, nursing mothers, and 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 who take levofloxacin may expose their infants to severe adverse reactions and pregnant women are at risk of killing or damaging their unborn child. For this reason the prescribing of levofloxacin is contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. Other flouroquinolones have also been reported as being present in the mother’s milk and are passed on to the nursing child, which may increases the risk of the child suffering from this syndrome as well, even though the child had never been prescribed or taken any of the drugs found within this class.

• Pediatric Use

Fluoroquinolones are not licensed by the FDA for use in children due to the risk of permanent injury to the multiskeletal system, with two exceptions. Ciprofloxacin is only licensed for the treatment of Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli and Inhalational Anthrax (post-exposure). Within the studies submitted in response to a Pediatric Written Request (Ciprofloxacin, circa 2004) the rate of athropy was reported to be 9.3%. Levofloxacin was recently licensed for the treatment of Inhalational Anthrax (post-exposure). However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

Levofloxacin is not licensed for use in the pediatric population, except as noted above, due to the risk of serious, life threating 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 multiskeletal 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 and ADR rate in excess of 40%, as well as a number of reported fatalities. Within the first study it is stated that “Of the 712 subjects evaluable for safety, 275 (52%) levofloxacin-treated subjects experienced one or more adverse event... Serious adverse events were reported in 33 (6%) levofloxacin-treated subjects... Two serious adverse events in levofloxacin-treated subjects resulted in fatal outcomes.” Within the second study it is stated that “Of the 204 subjects evaluable for safety, 122 experienced one or more adverse events...Twelve subjects (6%) discontinued study drug due to an adverse event...Seven subjects (3%) experienced 8 serious adverse events.” (circa 2007)

As such the current ban on the use of levofloxacin and other fluoroquinolones in the pediatric population appears to be both reasonable and supported by various clinical studies. The risk of permanent injury may outweigh the potential benefits. Within the United States the FDA has stated that it is their intention to pursue the licensing of the fluoroquinolones for pediatric use. in spite of the evidence presented at that 62 Meeting of the Anti-Infective Drugs Advisory Committee that the fluoroquinolones cause irreversible joint damage in the pediatric population.

Adverse effects

See also: Adverse effects of fluoroquinolones

Fluoroquinolones are generally well tolerated with most side effects being mild and serious adverse effects being rare. Some of the serious adverse effects which occur more commonly with fluoroquinolones than with other antibiotic drug classes include CNS and tendon toxicity. The currently marketed quinolones have safety profiles similar to that of other antimicrobial classes.

The serious events may occur with therapeutic or with acute overdose. At therapeutic doses they include: central nervous system toxicity, cardiovascular toxicity, tendon / articular toxicity, and rarely hepatic toxicity. Events that may occur in acute overdose are rare and include: renal failure and seizure. Seizures have however, been reported to occur at therapeutic dosage. Toxic epidermal necrolysis, coagulation abnormalities and pancytopenia are other rare but possible adverse effect of levofloxacin. Children and the elderly are at greater risk. Adverse reactions may manifest during, as well as after fluoroquinolone therapy.

The most widely used fluoroquinolones include ciprofloxacin, levofloxacin and moxifloxacin. Many others have been removed from the market due to adverse drug events including: gatifloxacin.

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 these groups as well as action by the consumer advocate group Public Citizen. Partly as a result of the efforts of Public Citizen the FDA ordered a black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.

Liver damage and dysglycemia has been associated with levofloxacina rare adverse reaction. A very rare but serious adverse effect is autoimmune hemolytic anemia.

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.

Significant Drug Interactions

Levofloxacin interacts 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. [7]

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 contra-indicated due to the risk of severe CNS adverse reactions, including but not limited to seizure disorders. Fluoroquinolones with an unsubstituted piperazinyl moiety at position 7 have the potential to interact with NSAIDs and/or their metabolites, resulting in antagonism of GABA neurotransmission. Whether or not such reactions occur after completion of therapy is a matter of considerable debate. Patients have reported reactions to NSAIDS long after completion of fluoroquinolone therapy, but there does not appear to be any research that would either confirm or deny this association other than these anecdotal reports.

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

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

Current or past treatment with oral corticosteroids is associated with an increased risk of Achilles tendon rupture, especially in elderly patients who are also taking the fluoroquinolones. This effect seems to be restricted to people aged 60 or over, and within this group concomitant use of corticosteroids increases this risk substantially. Though technically not to be considered a drug interaction, mention of this is made here due to fact that the etiology of such ruptures remains elusive and further research may confirm such a drug interaction may play a role in this particular reaction. However, at the moment, this is to be considered speculatory in nature and additional research to confirm or deny is required.

Overdose

In the event of 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. See the latest package insert for levofloxacin (Levaquin) for additional details.

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). See the latest package insert for levofloxacin (Levaquin) for additional details.

Pharmacokinetics

Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens. Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hours after oral dosing. Levofloxacin is excreted largely as unchanged drug in the urine. 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 either.

See the latest package insert for levofloxacin (Levaquin) for additional details.

Dosing

Levofloxacin should only be administered as described within the Dosage Guidelines table found within the most current package insert. The status of the patient’s renal function and hepatic function must also be taken into consideration to avoid an accumulation that may lead to a fatal drug overdose. 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.) However, since the drug is known to be substantially excreted by the kidneys, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. The duration of treatment depends upon the severity of infection and the usual duration is 7 to 14 days.

NOTE: The patient’s serum levels should be monitored during therapy to avoid a drug overdose. See the most current Package Insert for proper dosing guidelines and relevant warnings/precautions.

Current Litigation

There are a significant number of cases currently pending before the United States District Court, District of Minnesota, involving Levaquin. On June 13th, 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 aggressively seeking additional plaintiffs who may have been damaged by this class.

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.

Regulatory History United States

Levofloxacin was first patented in 1987 (Levofloxacin European Patent Daiichi), later approved for use in Japan October 1st, 1993; Korea April 4th, 1994; Hong Kong October 3rd, 1994 and China, May 3rd, 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.

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).

• 12/17/1998

Treatment of uncomplicated urinary tract infections (uti) was licensed. Addition of the warnings concerning spontaneous tendon ruptures.

• 2/2/2000

Treatment of community-acquired pneumonia was licensed.

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).

• 9/8/2000

The treatment of complicated skin and skin structure infections was licensed.

• 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.

• 10/30/2002

The treatment of nosocomial pneumonia was licensed.

The FDA gave notice to the manufacturers of Levofloxacin that a recent court ruling did NOT prevent the manufacturers from conducting pediatric studies, and that such studies may result in additional marketing exclusivity for Levofloxacin. The FDA stated that: “On October 17, 2002, the court ruled that FDA did not have the authority to issue the Pediatric Rule and has barred FDA from enforcing it... The pediatric exclusivity provisions of FDAMA as re-authorized by the Best Pharmaceuticals for Children Act are not affected by the court's ruling. Pediatric studies conducted under the terms of section 505A of the Federal Food, Drug, and Cosmetic Act may result in additional marketing exclusivity for certain products (pediatric exclusivity).”

Note: In 1994 FDA issued a regulation requiring manufacturers of marketed drugs to survey existing data and to determine whether the data were sufficient to support additional pediatric use information in the drug's labeling. If the data existed, manufacturers were encouraged to submit a supplemental NDA seeking a labeling change, thereby allowing the use of the drug in the pediatric population. If the information was insufficient, the rule required the labeling of the drug to state that "...safety and effectiveness in pediatric patients have not been established." In 2003 Congress overruled the courts by passing legislation granting the FDA authority to issue and enforce this Pediatric Rule.

• 05/23/2003

Addition of the license to treat chronic bacterial prostatitis.

• 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

Tendon warning changed to reflect the fact that tendons other than the Achilles may rupture and that tendon rupture can occur during or after therapy.

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.

The following were added to the Post-Marketing Adverse Reactions section: Peripheral neuropathy; Rhabdomyolysis; Stevens-Johnson Syndrome

• 11/4/2004

Warnings given regarding Levofloxacin being associated with persistent lesions of the cartilage.

• 11/24/2004

The treatment of inhalational anthrax (post-exposure) in adults was licensed. No licensed issued for pediatric use at this time.

• 8/4/2005

Licensed approved for the five-day treatment of acute bacterial sinusitis.

• 6/23/2006

The Indications and Usage section of the package insert was revised to include the following licensed uses:

Acute bacterial sinusitis

Acute bacterial exacerbation of chronic bronchitis

Nosocomial pneumonia

Community-acquired pneumonia

Complicated skin and skin structure infections

Uncomplicated skin and skin structure infections

Chronic bacterial prostatitis

Complicated urinary tract infections

Acute pyelonephritis

Uncomplicated urinary tract infections

Inhalational anthrax (post-exposure): Adult population only. No license granted at that time to treat within the pediatric population.

• 5/10/2007

Warnings regarding fatal Clostridium difficile associated diarrhea (CDAD) and that this (CDAD) has been reported to occur over two months after the administration of antibacterial agents.

• 5/31/2007

Warnings given that the following have been associated with Levofloxacin: Acute Renal Failure; Aplastic Anemia; Angioneurotic Edema; Anosmia; Ageusia; Blurred Vision; Dysphonia; Electrocardiogram QT Prolonged; Eosinophilia; Hepatitis; Hemolytic Anemia; Hypoacusis; Interstitial Nephritis; Leukocytoclastic Vasculitis; Leukopenia; Muscle Injury (including rupture); Pancytopenia; Peripheral Neuropathy; Photosensitivity Reaction; Psychosis; Paranoia; Pseudomembraneous (C. difficile colitis; Rhabdomyolysis; Suicide Attempts or Suicidal Ideation; Scotomata; Stevens-Johnson Syndrome; Serum Sickness; Toxic Epidermal Necrolysis (TEN); Tendon rupture; Torsades de Pointes; Vasodilation; Vision Disturbances (including diplopia); Visual Acuity Reduced

• 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.

• 9/11/2007

Provided for the addition of pediatric safety information to the package insert.

• 9/14/2007

Licensed approved that provided for the treatment of complicated urinary tract infection and acute pyelonephritis with Levaquin 750 mg once daily for five days.

• 11/15/2007

Removal of the false and misleading information found within the clinical trials referred to within the Use in Specific Populations/ Geriatric Use section. No Dear Doctor Letter was sent concerning this change.

• 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

Licensed approved for the treating of inhalational anthrax (post-exposure) in the pediatric population. 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.

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 generic versions of the fluoroquinolones have not been updated to include this Black Box Warning as of February 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 manufactures 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.

Scripting Abuse and Bacterial Resistance

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 over in Europe, has been implicated.

The ever increasing bacterial resistance to levofloxacin, (which is a major concern) together with an unacceptable safety profile, may very well threaten its future viability to treat serious and life threatening bacterial infections. Years ago the FDA had added warnings regarding the proper use of these drugs within the package inserts to combat such scripting 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. Though considered to be a very important and necessary drug required to treat severe and life threatening bacterial infections, the associated scripting 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 which 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.

Within a recent study concerning the proper use of this class in the emergency room it was revealed that 99% of these prescriptions were in error. Out of the one hundred total patients studied, eighty one received a fluoroquinolone for an inappropriate indication. Out of these cases, forty three (53%) were judged to be inappropriate because another agent was considered first line, twenty seven (33%) because there was no evidence of a bacterial infection to begin with (based on the documented evaluation), and eleven (14%) because of the need for such therapy was questionable. Out of the nineteen patients who received a fluoroquinolone for an appropriate indication, only one patient out of one hundred received both the correct dose and duration of therapy.

Fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002. Nearly half (42%) of these prescriptions were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study that was supported in part by the Agency for Healthcare Research and Quality.. Additionally they are commonly prescribed for medical conditions that are not even bacterial to begin, with such as viral infections, or those to which no proven benefit exist.

There are three known mechanisms of resistance. Some types of efflux pumps can act to decrease intracellular quinolone concentration. In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or Topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug's effectiveness. Levaquin, in the same manner as Ciprofloxacin, 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 Johnsons total revenue generating 1.6 billion dollars, which was 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

Any number of adverse drug reaction forums related to Levaquin, as well as the fluoroquinolone class, may be found on the Internet. The various manufacturers and the members of the medical community’s reaction to these forums have been one of disbelief and denial. Claiming that “Some of the personal stories {of these members} on the Internet are truly wacky...”

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.”

• 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 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 were disastrous, and 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 multiskeletal 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 and ADR rate in excess of 40%, as well as a number of reported fatalities. Within the first study it is stated that “Of the 712 subjects evaluable for safety, 275 (52%) levofloxacin-treated subjects experienced one or more adverse event... Serious adverse events were reported in 33 (6%) levofloxacin-treated subjects... Two serious adverse events in levofloxacin-treated subjects resulted in fatal outcomes.” Within the second study it is stated that “Of the 204 subjects evaluable for safety, 122 experienced one or more adverse events...Twelve subjects (6%) discontinued study drug due to an adverse event...Seven subjects (3%) experienced 8 serious adverse events.” (circa 2007)

• 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. 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.

• Economic impact: adverse reactions:

The adverse drug reaction profile of levofloxacin and other fluoroquinolone drugs has spawned a grass root movement of those so effected to lobby for Black Box Warnings and Dear Doctor Letters as well as the petitioning of the FDA for the removal of some fluoroquinolone drugs from clinical practice.

A number of class action lawsuits as well as malpractice litigation has been spawned by this unacceptable safety profile. The various manufacturers have countered these allegations stating that they believe that these drugs are both safe and effective antibiotics, well tolerated with a minimum of side effects, such reactions are “rare” (contrary to the literature) and the benefits of such therapy outweigh the perceived risks.

Risk/Benefit Assessment

The benefits of 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. 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 to be considered unnecessary and as such exposes the patient to an unacceptable risk of suffering a severe adverse reaction. Antibiotics' futility against bronchitis had been confirmed in 2002.

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.

• Chronic Bacterial Prostatitis

Prostatitis has been termed "the waste basket of clinical ignorance" by prominent Stanford University Urologist Dr. Thomas Stamey. Campbell's Urology, the urologist's most authoritative reference text, identifies only about 5% of all patients with prostatitis as having bacterial prostatitis which can be "cured" at least in the short term by antibiotics. In other words, 95% of men with prostatitis have little hope for a cure with antibiotics alone since they don't actually have any identifiable bacterial infection. Within a 2003 study involving the use of fluoroquinolones to treat Chronic Bacterial Prostatitis it was found that the level of improvement was no different from that associated with placebo. Within a 2003 randomized, double-blind trial involving levofloxacin specifically, it was found that “...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 of 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 for levofloxacin have shown either lack of reasonable efficacy within some independent studies, or has 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 assesment should be performed prior to implementing fluoroquinolone therapy, and the patient fully advised concerning possible adverse reactions beforehand.

See Also

• Fluoroquinolone toxicity
• Fluoroquinolone
• Quinolone

Package Insert Links

• Levaquin Package Insert
• Floxin (Ofloxacin -- Floxacin) Package Insert
• Iquix Package Insert
• Quixin Package Insert

External Links

• Levaquin information from RxList