Moxifloxacin (Page 2 of 2)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Moxifloxacin is a member of the fluoroquinolone class of anti-infective drugs [see Microbiology (12.4)].

12.3 Pharmacokinetics

Plasma concentrations of moxifloxacin were measured in healthy adult male and female subjects who received bilateral topical ocular doses of moxifloxacin ophthalmic solution 3 times a day. The mean steady-state Cmax (2.7 ng/mL) and AUC0-∞ (41.9 ng●hr/mL) values were 1,600 and 1,100 times lower than the mean Cmax and AUC reported after therapeutic 400 mg doses of moxifloxacin. The plasma half-life of moxifloxacin was estimated to be 13 hours.

12.4 Microbiology

The antibacterial action of moxifloxacin results from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division.

The mechanism of action for quinolones, including moxifloxacin, is different from that of macrolides, aminoglycosides, or tetracyclines. Therefore, moxifloxacin may be active against pathogens that are resistant to these antibiotics and these antibiotics may be active against pathogens that are resistant to moxifloxacin. There is no cross-resistance between moxifloxacin and the aforementioned classes of antibiotics. Cross-resistance has been observed between systemic moxifloxacin and some other quinolones.

In vitro resistance to moxifloxacin develops via multiple-step mutations. Resistance to moxifloxacin occurs in vitro at a general frequency of between 1.8 x 10-9 to less than 1 x 10-11 for gram-positive bacteria.

Moxifloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the Indication and Usage section:

Aerobic Gram-Positive Microorganisms

Corynebacterium species*

Micrococcus luteus*

Staphylococcus aureus

Staphylococcus epidermidis

Staphylococcus haemolyticus

Staphylococcus hominis

Staphylococcus warneri*

Streptococcus pneumoniae

Streptococcus viridans group

Aerobic Gram-Negative Microorganisms

Acinetobacter lwoffii*

Haemophilus influenzae

Haemophilus parainfluenzae*

Other Microorganisms

Chlamydia trachomatis

*Efficacy for this organism was studied in fewer than 10 infections.

The following in vitro data are also available, but their clinical significance in ophthalmic infections is unknown. The safety and effectiveness of moxifloxacin ophthalmic solution in treating ophthalmological infections due to these microorganisms have not been established in adequate and well-controlled trials.

The following organisms are considered susceptible when evaluated using systemic breakpoints. However, a correlation between the in vitro systemic breakpoint and ophthalmological efficacy has not been established. The list of organisms is provided as guidance only in assessing the potential treatment of conjunctival infections. Moxifloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 2 mcg/mL or less (systemic susceptible breakpoint) against most (greater than or equal to 90%) strains of the following ocular pathogens.

Aerobic Gram-Positive Microorganisms

Listeria monocytogenes

Staphylococcus saprophyticus

Streptococcus agalactiae

Streptococcus mitis

Streptococcus pyogenes

Streptococcus Group C, G and F

Aerobic Gram-Negative Microorganisms

Acinetobacter baumannii

Acinetobacter calcoaceticus

Citrobacter freundii

Citrobacter koseri

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumoniae

Moraxella catarrhalis

Morganella morganii

Neisseria gonorrhoeae

Proteus mirabilis

Proteus vulgaris

Pseudomonas stutzeri

Anaerobic Microorganisms

Clostridium perfringens

Fusobacterium species

Prevotella species

Propionibacterium acnes

Other Microorganisms

Chlamydia pneumoniae

Legionella pneumophila

Mycobacterium avium

Mycobacterium marinum

Mycoplasma pneumoniae

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to determine the carcinogenic potential of moxifloxacin have not been performed. However, in an accelerated study with initiators and promoters, moxifloxacin was not carcinogenic in rats following up to 38 weeks of oral dosing at 500 mg/kg/day (3224 times the highest recommended total daily human ophthalmic dose for a 60 kg person, based on body surface area).

Mutagenesis

Moxifloxacin was not mutagenic in four bacterial strains used in the Ames Salmonella reversion assay. As with other quinolones, the positive response observed with moxifloxacin in strain TA 102 using the same assay may be due to the inhibition of DNA gyrase. Moxifloxacin was not mutagenic in the CHO/HGPRT mammalian cell gene mutation assay. An equivocal result was obtained in the same assay when V79 cells were used. Moxifloxacin was clastogenic in the V79 chromosome aberration assay, but it did not induce unscheduled DNA synthesis in cultured rat hepatocytes. There was no evidence of genotoxicity in vivo in a micronucleus test or a dominant lethal test in mice.

Impairment of Fertility

Moxifloxacin had no effect on fertility in male and female rats at oral doses as high as 500 mg/kg/day, approximately 3,224 times the highest recommended total daily human ophthalmic dose, based on body surface area. At 500 mg/kg/day orally there were slight effects on sperm morphology (head-tail separation) in male rats and on the estrous cycle in female rats.

14 CLINICAL STUDIES

In two randomized, double-masked, multicenter, controlled clinical trials in which patients were dosed 3 times a day for 4 days, moxifloxacin ophthalmic solution produced clinical cures on Day 5 to 6 in 66% to 69% of patients treated for bacterial conjunctivitis. Microbiological success rates for the eradication of baseline pathogens ranged from 84% to 94%.

In a randomized, double-masked, multicenter, parallel-group clinical trial of pediatric patients with bacterial conjunctivitis between birth and 31 days of age, patients were dosed with moxifloxacin ophthalmic solution or another anti-infective agent. Clinical outcomes for the trial demonstrated a clinical cure rate of 80% at Day 9 and a microbiological eradication success rate of 92% at Day 9.

Please note that microbiologic eradication does not always correlate with clinical outcome in anti-infective trials.

16 HOW SUPPLIED/STORAGE AND HANDLING

Moxifloxacin Ophthalmic Solution, USP 0.5% is supplied as a sterile ophthalmic solution in a dispensing system consisting of a natural low density polyethylene bottle and dispensing plug and tan polypropylene closure. Tamper evidence is provided with a shrink band around the closure and neck area of the package.

NDC 17478-519-19 3 mL in 5 mL bottle

Storage: Store at 2° to 25°C (36° to 77°F).

17 PATIENT COUNSELING INFORMATION

Avoid Contamination of the Product

Advise patients not to touch the dropper tip to any surface to avoid contaminating the contents.

Avoid Contact Lens Wear

Advise patients not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis [see Warnings and Precautions (5.3)].

Hypersensitivity Reactions

Systemically administered quinolones including moxifloxacin have been associated with hypersensitivity reactions, even following a single dose. Instruct patients to discontinue use immediately and contact their physician at the first sign of a rash or allergic reaction [see Warnings and Precautions (5.1)].

AKRON
Manufactured by:
Akorn Operating Company LLC
Lake Forest, IL 60045

MX00N Rev. 11/21

Principal Display Panel Text for Container Label:

NDC 17478-519-19

Moxifloxacin

Ophthalmic

Solution, USP

0.5%

FOR USE IN THE EYES ONLY

Principal Display Panel Text for Container Label
(click image for full-size original)

Principal Display Panel Text for Carton Label:

NDC 17478-519-19

Moxifloxacin

Ophthalmic

Solution, USP

0.5%

FOR USE IN THE EYES ONLY

Sterile

3 mL

Rx only Akorn Logo

Principal Display Panel Text for Carton Label
(click image for full-size original)
MOXIFLOXACIN
moxifloxacin solution/ drops
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17478-519
Route of Administration OPHTHALMIC DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Moxifloxacin Hydrochloride (Moxifloxacin) Moxifloxacin 5 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
Boric Acid
Sodium Chloride
Water
Hydrochloric Acid
Sodium Hydroxide
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:17478-519-19 1 BOTTLE, DROPPER in 1 CARTON contains a BOTTLE, DROPPER
1 3 mL in 1 BOTTLE, DROPPER This package is contained within the CARTON (17478-519-19)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA202916 11/09/2017
Labeler — Akorn (117696770)
Registrant — Akorn Operating Company LLC (117693100)
Establishment
Name Address ID/FEI Operations
Akorn 117696840 MANUFACTURE (17478-519), ANALYSIS (17478-519), LABEL (17478-519), PACK (17478-519), STERILIZE (17478-519)

Revised: 11/2021 Akorn

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