Moxifloxacin

Moxifloxacin

File:Moxifloxacin Structural Formulae V.1.svg
File:Moxifloxacin-cation-from-xtal-3D-balls.png
Systematic (IUPAC) name
1-Cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid
Clinical data
Trade names	Avelox Vigamox, Moxeza (eye drops)
AHFS/Drugs.com	monograph
MedlinePlus	a600002
Licence data	US FDA:link
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Oral, IV, local (eyedrops)
Pharmacokinetic data
Bioavailability	86 to 92%
Protein binding	30 to 50%
Metabolism	Glucuronide and sulfate conjugation Cytochrome P450 system not involved
Biological half-life	12 hours
Excretion	hepatic
Identifiers
CAS Number	354812-41-2 Y
ATC code	J01MA14 (WHO) S01AE07
PubChem	CID: 152946
DrugBank	DB00218 Y
ChemSpider	134802 Y
UNII	U188XYD42P Y
ChEMBL	CHEMBL32 Y
NIAID ChemDB	070017
Chemical data
Formula	C21H24FN3O4
Molecular mass	401.431 g/mol
SMILES COc1c2c(cc(c1N3C[C@@H]4CCCN[C@@H]4C3)F)c(=O)c(cn2C5CC5)C(=O)O
InChI InChI=1S/C21H24FN3O4/c1-29-20-17-13(19(26)14(21(27)28)9-25(17)12-4-5-12)7-15(22)18(20)24-8-11-3-2-6-23-16(11)10-24/h7,9,11-12,16,23H,2-6,8,10H2,1H3,(H,27,28)/t11-,16+/m0/s1 Y Key:FABPRXSRWADJSP-MEDUHNTESA-N Y
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Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent developed by Bayer AG (initially called BAY 12-8039). It is marketed worldwide (as the hydrochloride) under the brand names Avelox, Avalox, and Avelon for oral treatment. In most countries, the drug is also available in parenteral form for intravenous infusion. Moxifloxacin is also sold in an ophthalmic solution (eye drops) under the brand names Vigamox, and Moxeza for the treatment of conjunctivitis (pink eye). Its antibacterial spectrum includes enteric Gram-(−) rods (Escherichia coli, Proteus species, Klebsiella species), Haemophilus influenzae, atypical bacteria (Mycoplasma, Chlamydia, Legionella), and Streptococcus pneumoniae, and anaerobic bacteria. It differs from earlier antibacterials of the fluoroquinolone class such as levofloxacin and ciprofloxacin in having greater activity against Gram-positive bacteria and anaerobes. Because of its potent activity against the common respiratory pathogen Streptococcus pneumoniae, it is considered a "respiratory quinolone."

A United States patent application was submitted on 30 June 1989, for Avelox (moxifloxacin hydrochloride). In 1999 Avelox was approved by the U.S. Food and Drug Administration (FDA) for use in the United States.

In the United States, moxifloxacin is licensed for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, community acquired pneumonia, complicated and uncomplicated skin and skin structure infections, and complicated intra-abdominal infections. In the European Union, it is licensed for acute bacterial exacerbations of chronic bronchitis, non-severe community-acquired pneumonia, and acute bacterial sinusitis. Based on its investigation into reports of rare but severe cases of liver toxicity and skin reactions, the European Medicines Agency recommended in 2008 that the use of the oral (but not the IV) form of moxifloxacin be restricted to infections in which other antibacterial agents cannot be used or have failed. In the US, the marketing approval does not contain these restrictions, though the label contains prominent warnings against skin reactions.

Avelox (moxifloxacin) was launched in the United States in 1999 and is marketed in more than 80 countries worldwide. In the United States, Avelox is marketed by Bayer's partner Merck.

In 2011, the FDA added two box warnings for this drug in reference to spontaneous tendon ruptures and the fact that moxifloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and life-threatening breathing problems.

Medical uses

Moxifloxacin is used to treat a number of infections, including: respiratory tract infections, cellulitis, anthrax, intraabdominal infections, endocarditis, meningitis, and tuberculosis.

The initial approval by the FDA (December 1999) encompassed these indications:

• Acute exacerbations of chronic bronchitis
• Acute bacterial sinusitis
• Community acquired pneumonia

Additional indications were approved by the FDA are:

• April 2001: Uncomplicated skin and skin structure infections
• May 2004: Community acquired pneumonia caused by multidrug resistant Streptococcus pneumoniae
• June 2005: Complicated skin and skin structure infections
• November 2005: Complicated intra-abdominal infections

The European Union requires that moxifloxacin only be prescribed when other antibiotics that have been initially recommended for treatment cannot be used or have failed.

No uses within the pediatric population for oral and intravenous moxifloxacin have been approved. A significant number of drugs found within this class, including moxifloxacin, are not licensed by the FDA for use in children due to the risk of permanent injury to the musculoskeletal system.

In ophthalmology, moxifloxacin is approved for the treatment of conjunctival infections caused by susceptible bacteria.

Adverse effects

See also: Adverse effects of fluoroquinolones

Rare but serious adverse effects that may occur as a result of moxifloxacin therapy include irreversible peripheral neuropathy, spontaneous tendon rupture and tendonitis, hepatitis, psychiatric effects (hallucinations, depression), torsades de pointes, Stevens-Johnson syndrome and Clostridium difficile-associated disease, and photosensitivity/phototoxicity reactions.

Several reports suggest the use of moxifloxacin may lead to uveitis.

Contraindications

Only two listed contraindications are found within the 2008 package insert:

• "Nonsteroidal anti-inflammatory drugs (NSAIDs): Although not observed with moxifloxacin in preclinical and clinical trials, the concomitant administration of a nonsteroidal anti-inflammatory drug with a fluoroquinolone may increase the risks of CNS stimulation and convulsions."

• "Moxifloxacin is contraindicated in persons with a history of hypersensitivity to moxifloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components."

Though not stated as such within the package insert, ziprasidone is also considered to be contraindicated, as it may have the potential to prolong QT interval. Moxifloxacin should also be avoided in patients with uncorrected hypokalemia, or concurrent administration of other medications known to prolong the QT interval (antipsychotics and tricyclic antidepressants).

Moxifloxacin should be used with caution in patients suffering from diabetes, as glucose regulation may be significantly altered.

Moxifloxacin is also considered to be contraindicated within the pediatric population, pregnancy, nursing mothers, patients with a history of tendon disorder, patients with documented QT prolongation, and patients with epilepsy or other seizure disorders. Coadministration of moxifloxacin with other drugs that also prolong the QT interval or induce bradycardia (e.g., beta-blockers, amiodarone) should be avoided. Careful consideration should be given in the use of moxifloxacin in patients with cardiovascular disease, including those with conduction abnormalities.

Pregnancy

Well-controlled studies of the safety of moxifloxacin in pregnancy or lactating mothers have not been performed. Animal studies suggest the potential for harm to the fetus in pregnancy, and suggest that moxifloxacin may be excreted into the milk of lactating mothers. Decisions as to whether to continue therapy during pregnancy or while breast feeding should take the potential risk of harm to the fetus or child into account, as well as the importance of the drug to the well being of the mother.

Pediatric population

The safety of moxifloxacin in children under age 18 has not been established. Animal studies suggest the potential for musculoskeletal harm in juveniles.

Interactions

Moxifloxacin is not believed to be associated with clinically significant drug interactions due to inhibition or stimulation of hepatic metabolism. Thus, it should not, for the most part, require special clinical or laboratory monitoring to ensure its safety. Moxifloxacin has a potential for a serious drug interaction with NSAIDS.

The combination of corticosteroids and moxifloxacin has increased potential to result in tendonitis and disability.

Antacids containing aluminium or magnesium ions inhibit the absorption of moxifloxacin. Drugs that prolong the QT interval (e.g., pimozide) may have an additive effect on QT prolongation and lead to increased risk of ventricular arrhythmias. The international normalised ratio may be increased or decreased in patients treated with warfarin.

Overdose

"In the event of acute overdose, the stomach should be emptied and adequate hydration maintained. ECG monitoring is recommended due to the possibility of QT interval prolongation. The patient should be carefully observed and given supportive treatment. The administration of activated charcoal as soon as possible after oral overdose may prevent excessive increase of systemic moxifloxacin exposure. About 3% and 9% of the dose of moxifloxacin, as well as about 2% and 4.5% of its glucuronide metabolite are removed by continuous ambulatory peritoneal dialysis and hemodialysis, respectively." (Quoting from the 29 December 2008 package insert for Avelox)

Mechanism of action

Moxifloxacin 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, enzymes necessary to separate bacterial DNA, thereby inhibiting cell replication.

Pharmacokinetics

About 52% of an oral or intravenous dose of moxifloxacin is metabolized via glucuronide and sulfate conjugation. The cytochrome P450 system is not involved in moxifloxacin metabolism, and is not affected by moxifloxacin. The sulfate conjugate (M1) accounts for around 38% of the dose, and is eliminated primarily in the feces. Approximately 14% of an oral or intravenous dose is converted to a glucuronide conjugate (M2), which is excreted exclusively in the urine. Peak plasma concentrations of M2 are about 40% those of the parent drug, while plasma concentrations of M1 are, in general, less than 10% those of moxifloxacin.

In vitro studies with cytochrome (CYP) P450 enzymes indicate that moxifloxacin does not inhibit 80 CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2, suggesting that moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.

The pharmacokinetics of moxifloxacin in pediatric subjects have not been studied.

The half-life of moxifloxacin is 11.5-15.6 hours (single-dose, oral). About 45% of an oral or intravenous dose of moxifloxacin is excreted as unchanged drug (about 20% in urine and 25% in feces). A total of 96 ± 4% of an oral dose is excreted as either unchanged drug or known metabolites. The mean (± SD) apparent total body clearance and renal clearance are 12 ± 2 L/h and 2.6 ± 0.5 L/h, respectively. The CSF penetration of moxifloxacin is 70% to 80% in patients with meningitis.

Susceptible bacteria

A broad spectrum of bacteria is susceptible, including:

• Staphylococcus aureus
• Staphylococcus epidermidis
• Streptococcus pneumoniae
• Haemophilus influenzae
• Klebsiella spp.
• Moraxella catarrhalis
• Enterobacter spp.
• Mycobacterium spp.
• Bacillus anthracis

Chemistry

Moxifloxacin monohydrochloride is a slightly yellow to yellow crystalline substance. It is synthesized in several steps, the first involving the preparation of racemic 2,8-diazabicyclo[4.3.0]nonane which is then resolved using tartaric acid. A suitably derivatised quinolinecarboxylic acid is then introduced, in the presence of DABCO, followed by acidification to form moxifloxacin hydrochloride.

History

Moxifloxacin was first patented (United States patent) in 1991 by Bayer A.G., and again in 1997. Avelox was subsequently approved by the U.S. Food and Drug Administration (FDA) for use in the United States in 1999 to treat specific bacterial infections. Ranking 140th within the top 200 prescribed drugs in the United States for 2007, Avelox generated sales of $697.3 million worldwide.

Moxifloxacin is also manufactured by Alcon as Vigamox.

Patent

A United States patent application was made on 30 June 1989, for Avelox, Bayer A.G. being the assignee, which was subsequently approved on 5 February 1991. This patent was scheduled to expire on 30 June 2009. However, this patent was extended for an additional two and one half years on 16 September 2004, and as such was not expected to expire until 2012. Moxifloxacin was subsequently (ten years later) approved by the FDA for use in the United States in 1999. At least four additional United States patents have been filed regarding moxifloxacin hydrochloride since the 1989 United States application, as well as patents outside of the USA.

Society and culture

Regulatory actions

Regulatory agencies have taken actions to address certain rare but serious adverse events associated with moxifloxacin therapy.

Based on its investigation into reports of rare but severe cases of liver toxicity and skin reactions, the European Medicines Agency recommended in 2008 that the use of the oral (but not the IV) form of moxifloxacin be restricted to infections in which other antibacterial agents cannot be used or have failed. Similarly, the Canadian label includes a warning of the risk of liver injury.

The U.S. label does not contain restrictions similar to the European label, but a carries a "black box" warning of the risk of tendon damage and/or rupture and warnings regarding the risk of irreversible peripheral neuropathy.

Generic equivalents

In 2007, the U.S. District Court for the District of Delaware held that two Bayer patents on Avelox are valid and enforceable, and infringed by Dr. Reddy's ANDA for a generic version of Avelox. The district court sided with Bayer, citing the Federal Circuit's prior decision in Takeda v. Alphapharm as "affirming the district court's finding that defendant failed to prove a prima facie case of obviousness where the prior art disclosed a broad selection of compounds, any one of which could have been selected as a lead compound for further investigation, and defendant did not prove that the prior art would have led to the selection of the particular compound singled out by defendant." According to Bayer's press release announcing the court's decision, it was noted that Teva had also challenged the validity of the same Bayer patents at issue in the Dr. Reddy's case. Within Bayer's first-quarter 2008 stockholder's newsletter Bayer stated that they had reached an agreement with Teva Pharmaceuticals USA, Inc., the adverse party, to settle their patent litigation with regard to the two Bayer patents. Under the settlement terms agreed upon, Teva would obtain a license to sell its generic moxifloxacin tablet product in the U.S. shortly before the second of the two Bayer patents expires in March 2014. In Bangladesh, it is available with brand name of Optimox.