Moxifloxacin

Moxifloxacin

Systematic (IUPAC) name
1-cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo [4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo- quinoline-3-carboxylic acid
Clinical data
Trade names	Avelox
AHFS/Drugs.com	monograph
MedlinePlus	a600002
Licence data	US FDA:link
Pregnancy cat.	B3 (AU) C (US)
Legal status	℞-only (US)
Routes	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
Half-life	12 hours
Excretion	hepatic
Identifiers
CAS number	354812-41-2 Y
ATC code	J01MA14 S01AE07
PubChem	CID 152946
DrugBank	DB00218
ChemSpider	134802 Y
UNII	U188XYD42P N
ChEMBL	CHEMBL32 Y
NIAID ChemDB	070017
Chemical data
Formula	C21H24FN3O4
Mol. 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
N (what is this?)  (verify)

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, Moxeza for the treatment of conjunctivitis (pink eye).

A United States patent application was submitted on 30 June 1989, for Avelox (moxifloxacin hydrochloride).^[1] In 1999 Avelox was approved by the U.S. Food and Drug Administration (FDA) for use in the United States.^[2]

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.^[3] 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.^[4] 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 currently 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 boxed 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.^[5]

Medical uses

Moxifloxacin is used to treat a number of infections including: respiratory tract infections, cellulitis, anthrax, intraabdominal infections, endocarditis, meningitis, and tuberculosis.^[6]

The initial approval by the FDA (December 1999)^[7] encompassed the following indications:

• Acute Exacerbations of Chronic Bronchitis (AECB)

• Acute Bacterial Sinusitis (ABS)

• Community Acquired Pneumonia (CAP)

Additional indications were approved by the FDA as follows:

• April 2001: Uncomplicated Skin and Skin Structure Infections (uSSSI)^[8]

• May 2004: Community Acquired Pneumonia caused by multi-drug resistant Streptococcus pneumoniae.^[9]

• June 2005: Complicated Skin and Skin Structure Infections (cSSSI)^[10]

• November 2005: Complicated Intra-Abdominal Infections (cIAI).^[11]

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.^[12][13]

At the current time, there are no approved uses within the pediatric population for Oral and I.V. moxifloxacin. 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.^[14][15][16]

In ophthalmology, moxifloxacin is approved for the treatment of conjunctival infections caused by susceptible bacteria.^[17]

Note: Moxifloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.^{[citation needed]}

Availability

Moxifloxacin is available as tablet, intravenous solution, and eye drop. Moziflozacin is available in tablet, & infusion form eg ( Mozibact tablet & Moxibact Infusion)

Adverse effects

The serious adverse effects that may occur as a result of moxifloxacin therapy include irreversible peripheral neuropathy,SIADH,^[18] spontaneous tendon rupture and tendonitis,^[19] acute liver failure or serious liver injury, QTc prolongation/torsades de pointes, toxic epidermal necrolysis (TEN), and clostridium difficile-associated disease (CDAD),^[20] as well as photosensitivity/phototoxicity reactions.^[21] Hepatitis, pseudomembranous colitis, psychotic reactions and Stevens–Johnson syndrome have also been associated with moxifloxacin therapy.^[22]

There have been a number of regulatory actions taken as a result of such adverse reactions, which include published warnings,^[23] the issuance of numerous "Dear Doctor Letters", ^[24][25] the restrictions regarding the use of moxifloxacin instituted by the European agency's Committee for Medicinal Products for Human Use (CHMP),^[26] as well as the recent addition of Black Box Warnings.^[27] On 22 March 2010, Health Canada issued a notice to health care professionals and Canadians regarding the recent changes to the labeling information for Avelox (moxifloxacin). The 2010 Canadian updated labeling includes information regarding the risk of severe liver injury during moxifloxacin therapy.^[28]

These serious events may occur with therapeutic or with acute overdose. Tendonitis or tendon rupture may occur during, as well as after moxifloxacin therapy.^[29]

Most recently, the German regulatory authorities placed additional restrictions on the use of oral moxifloxacin in patients with acute bacterial sinusitis (ABS), acute exacerbation of chronic bronchitis (AECB), and community-acquired pneumonia (CAP) stating that in case of these diseases moxifloxacin should only be prescribed when other antibiotics that have been initially recommended for treatment cannot be used or have failed. Additional notice was given that rhabdomyolysis, the exacerbation of symptoms of myasthenia gravis and the risk of cardiac arrhythmia in women and older patients, was associated with moxifloxacin.^[30] QT prolongations induced by moxifloxacin were discussed extensively at the pre-approval FDA Advisory Committee meeting, but the meeting adjourned with a majority vote in favor of approval. The official US prescribing information notes that no increase in cardiovascular mortality or morbidity was seen among approximately 15,500 patients enrolled in pre-approval clinical trials, nor in 18,000 additional patients in a post-approval study. The Prescribing Information notes that caution should be exercised in using the drug in patients who are at high risk of arrhythmia to to pre-existing conditions or concomitant treatment with other drugs that prolong the QT interval.^[3]

Contraindications

There are only two listed contraindications 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."^[31]

• "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."^[31]

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).^[32]

Moxifloxacin should be used with caution in patients suffering from diabetes, as glucose regulation may be significantly altered.^[32]

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,^[33] 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.^[32]

• Pregnancy

The fluoroquinolones rapidly cross the blood-placenta and blood-milk barrier, and are extensively distributed into the fetal tissues. For this reason, the fluoroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The fluoroquinolones 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's suffering from this syndrome as well, even though the child had never been prescribed or taken any of the drugs found within this class.^[34][35]

• Pediatric population

With limited exceptions, fluoroquinolones are not licensed by the FDA due to the risk injury to the musculoskeletal system. Ciprofloxacin is being licensed for the treatment of Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli and Inhalational Anthrax (post-exposure), and 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. It does not appear that there have been any pediatric trials involving oral or IV moxifloxacin to date.

Within one study it was stated that the pediatric patient has a 3.4% chance of experiencing a serious musculoskeletal adverse event compared to 1.8% for a control group treated with other antibiotics.^[36] Within the studies submitted in response to a Pediatric Written Request (Ciprofloxacin, circa 2004) the rate of athropy was reported to be 9.3% compared to 6.0% in a control group treated with other antibiotics.^[37] Within the BPCA Pediatric Studies Summary for ciprofloxacin,^[37] it was stated that the overall incidence of adverse events at six weeks was 41%, compared to 31% in subjects treated with other antibiotics.

Interactions

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 INR (International Normalised Ratio) may be increased or decreased in patients treated with warfarin. Moxifloxacin has been shown in a number of case reports to interact with warfarin.^[38] The exact mechanism for the warfarin-quinolone drug interaction is unknown.^[39] A precautionary measure would be to monitor the INR more closely and, if necessary, adjust the anticoagulant dose as necessary. Moxifloxacin does not appear to inhibit theophylline metabolism.^[40] However, caution may be warranted when using theophylline with all of the fluoroquinolones, including moxifloxacin. Drug Interaction Facts notes that some fluoroquinolones, especially ciprofloxacin, enoxacin, and norfloxacin, interact with theophylline.^[39]

Significant 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.^[41] However, there is an additive effect of moxifloxacin and drugs that prolong the QT interval, such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. Therefore, moxifloxacin should be used with caution when given concurrently with such drugs. Moxifloxacin also has a potential for a serious drug interaction with NSAIDS. In addition, the package insert cautions that prothrombin time should be closely monitored if moxifloxacin is concomitantly administered with warfarin.^[42]

A potentially serious drug interaction is the combination of corticosteroids and moxifloxacin, as this combination increases tendon toxicity, which has potential to result in tendonitis and disability.^[43]

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."(sic) Quoting from the 29 December 2008 package insert for Avelox.^[31]

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,^[44] enzymes necessary to separate bacterial DNA, thereby inhibiting cell replication.

Pharmacology

"Moxifloxacin, a fluoroquinolone, is available as the monohydrochloride salt of 13 1-cyclopropyl-7-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3 14 quinoline carboxylic acid. It is a slightly yellow to yellow crystalline substance with a molecular 15 weight of 437.9. Its empirical formula is C21H24FN3O4 *HCl." Quoting from the 29 December 2008 package insert for Avelox.^[31]

There are a number of endogenous compounds that have been reported to be affected by moxifloxacin as inhibitors, alteraters, and depletors. See the latest package insert for Ciprofloxacin for additional details.

Pharmacokinetics

Approximately 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 approximately 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 approximately 40% those of the parent drug, while plasma concentrations of M1 are, in general, less than 10% those of moxifloxacin.^[31]

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.^[31]

The pharmacokinetics of moxifloxacin in pediatric subjects have not been studied.^[31]

The half-life of moxifloxacin is 11.5-15.6 hours (single-dose, oral).^[45] Approximately 45% of an oral or intravenous dose of moxifloxacin is excreted as unchanged drug (~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.^[45] The CSF penetration of moxifloxacin is 70% to 80% in patients with meningitis.^[46]

Susceptible bacteria

A broad spectrum of bacteria is susceptible including, but not limited to:

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

History

Moxifloxacin was first patented (United States patent) in 1991 by Bayer A.G., and again in 1997.^[47] 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.^[2] Ranking 140th within the top 200 prescribed drugs in the United States for 2007^[48] moxifloxacin, in the same manner as ciprofloxacin, has proven to be a blockbuster drug for Bayer A. G., generating billions of dollars in additional revenue. In 2007 alone, Avelox generated sales of $697.3 million dollars worldwide.^[26]

Moxifloxacin is also manufactured by Alcon as Vigamox.^{[citation needed]}

Patent

A United States patent application was made on 30 June 1989, for Avelox (moxifloxacin hydrochloride),(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 is not expected to expire until 2012.^[49] Moxifloxacin was subsequently (ten years later) approved by the U.S. Food and Drug Administration (FDA) for use in the United States in 1999. There have been at least four additional United States patents filed regarding moxifloxacin hydrochloride since the 1989 United States application,^[47][50] as well as patents outside of the USA.

Additional regulatory history

6/12/2002 Changes made to minimize the impact of warnings concerning adverse reactions.^[51]

26 June 2003 New Zealand Pharmacovigilance warns of moxifloxacin induced respiratory insufficiency.^[52]

10/6/2003 Changes made to minimize the impact of post marketing reports as well as the risk of tendon injuries.^[53]

29 December 2008 Addition of numerous adverse reactions associated with the use of moxifloxacin.^[54]

27 April 2009 Issuance of a Medication Guide and revisions to include new safety information including the addition of the Black Box Warning to the Medication Guide. The FDA had determined that Moxifloxacin poses a serious and significant public health concern, requiring the distribution of a Medication Guide.^[55]

24 June 2009 Updating of the carton and container labels to include a statement to let dispensers know that a Medication Guide must be dispensed with the product.(emphasis added)^[56]

History of the boxed 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.^[57] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.^[58] 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."^[59]

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.^[60] 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.^[61]

In 2005, the Illinois Attorney General filed a petition with the FDA seeking Boxed 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.^[62] In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for a Boxed Warning.^[62][63] In January 2008, Public Citizen filed suit to compel the FDA to respond to their 2006 petition.^[64][65] On 7 July, 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.^[66] The package inserts for Cipro (ciprofloxacin), Avelox (moxifloxacin), Proquin XR, Factive (gemifloxacin), Floxin (ofloxacin), Noroxin (norfloxacin) and Levaquin (levofloxacin) were amended on 8 September 2008 to include these new warnings.^[67][68] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on 22 October concerning these changes.^[69] 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.

Social and economic impact

• Generic equivalents

In 2007, the U.S. District Court for the District of Delaware held that two Bayer patents on Avelox (moxifloxacin hydrochloride) are valid and enforceable, and infringed by Dr. Reddy's ANDA for a generic version of Avelox.^[70][71] The district court sided with Bayer, citing the Federal Circuit's prior decision in Takeda v. Alphapharm^[72] 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^[70] 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^[73] 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.

• Economic impact: adverse reactions:

The advocacy group Public Citizen has lobbied for increasing safety warnings and for the removal of some fluoroquinolone drugs from clinical practice.^{[74][75][76][77][78][79][80][81]}

References

v t e Antibacterials: nucleic acid inhibitors (J01E, J01M) Antifolates (inhibits purine metabolism, thereby inhibiting DNA and RNA synthesis) DHFR inhibitor 2,4-Diaminopyrimidine Trimethoprim# Brodimoprim Tetroxoprim Iclaprim† Sulfonamides (DHPS inhibitor) Short- acting Sulfaisodimidine Sulfamethizole Sulfadimidine Sulfapyridine Sulfafurazole Sulfanilamide Prontosil Sulfathiazole Sulfathiourea Intermediate- acting Sulfamethoxazole Sulfadiazine# Sulfamoxole Long- acting Sulfadimethoxine Sulfadoxine Sulfalene Sulfametomidine Sulfametoxydiazine Sulfamethoxypyridazine Sulfaperin Sulfamerazine Sulfaphenazole Sulfamazone Other/ungrouped Sulfacetamide Sulfadicramide Sulfametrole Combinations Trimethoprim/sulfamethoxazole# Topoisomerase inhibitors/ quinolones/ (inhibits DNA replication) 1st g. Cinoxacin‡ Flumequine Nalidixic acid Oxolinic acid Pipemidic acid Piromidic acid Rosoxacin Fluoro- quinolones 2nd g. Ciprofloxacin# Enoxacin‡ Fleroxacin‡ Lomefloxacin Nadifloxacin Ofloxacin Norfloxacin Pefloxacin Rufloxacin 3rd g. Balofloxacin Grepafloxacin‡ Levofloxacin Pazufloxacin Sparfloxacin‡ Temafloxacin‡ Tosufloxacin 4th g. Besifloxacin Clinafloxacin† Garenoxacin Gemifloxacin Moxifloxacin Gatifloxacin‡ Sitafloxacin Trovafloxacin‡/Alatrofloxacin‡ Prulifloxacin Vet. Danofloxacin Difloxacin Enrofloxacin Ibafloxacin Marbofloxacin Orbifloxacin Pradofloxacin Sarafloxacin Related (DG) Aminocoumarins: Novobiocin Anaerobic DNA inhibitors Nitro- imidazole derivatives Metronidazole# Tinidazole Ornidazole Nitrofuran derivatives Nitrofurantoin# Furazolidone‡ Nifurtoinol RNA synthesis Rifamycins/ RNA polymerase Rifampicin# Rifabutin Rifapentine Rifaximin #WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III M: BAC bact (clas) gr+f/gr+a (t)/gr-p (c)/gr-o drug (J1p, w, n, m, vacc)