Pharmacotherapeutic Group: Corticosteroids and anti-infectives in combination. ATC Code: S01CA01.
Pharmacology: Pharmacodynamics: Dexamethasone is one of the most potent corticosteroids with a relative anti-inflammatory potency greater than prednisolone or hydrocortisone.
Mechanism of Action: Dexamethasone/Moxifloxacin is an isotonic and sterile ophthalmic solution combining moxifloxacin hydrochloride and dexamethasone disodium phosphate. Subjects who may benefit from the topical combined therapy with an antibacterial agent and an anti-inflammatory agent are those who have undergone ocular surgery, such as cataract extraction and refractive surgery. Instillation of 1 steroid and 1 associated antibiotic is beneficial in these subjects in the following manner: the steroid suppresses inflammation, while the antibiotic controls the proliferation of potentially pathogenic susceptible bacteria, and also works in a prophylactic way. Many bacterial species found in post-surgical endophthalmitis are the same species generally found in the periocular flora.
Moxifloxacin, a fourth-generation fluoroquinolone, inhibits the DNA gyrase and topoisomerase IV required for bacterial DNA replication, repair, and recombination. Dexamethasone is a moderately powerful corticosteroid having good penetration in ocular tissue. Corticosteroids have an anti-inflammatory as well as a vasoconstrictive effect. They suppress the inflammatory response and symptoms in various disorders without basically curing these disorders.
The exact mechanism of anti-inflammatory action of dexamethasone is unknown. It inhibits multiple inflammatory cytokines and produces multiple glucocorticoid and mineralocorticoid effects.
Clinical Studies: Clinical efficacy and safety: The efficacy and safety of Moxifloxacin/ Dexamethasone Eye Drops were supported by four clinical studies (C-05-12, BRA-05-01, BRA-05-02, BRA-07-02).
In a 8-day, controlled clinical study (C-05-12) in patients of at least 1 year of age (N=227 patients), of any race or sex with a diagnosis of bacterial blepharitis, Moxifloxacin/ Dexamethasone Eye Drops demonstrated a similar mean clinical score to Moxifloxacin 0.5% Ophthalmic Solution. The mean clinical score (sum of the 4 cardinal ocular signs of bacterial blepharitis: scaling/crusting of lid/lash margins, eyelid erythema, eyelid swelling, and bulbar conjunctival injection) for Moxifloxacin/ Dexamethasone Eye Drops was 3.2 at the Exit Visit compared to 3.8 for Moxifloxacin 0.5%.
In a 15-day, controlled clinical study (BRA-05-01) in patients, who were at least 18 years of age (N=139 patients), following cataract surgery, Moxifloxacin/ Dexamethasone Eye Drops was non inferior to Moxifloxacin 0.5% Ophthalmic Solution + Dexamethasone Phosphate 0.1% Ophthalmic Solution in the percentage of patients with score of zero for presence of cells (between 0 and 4 cells) in the anterior chamber measured at the slit-lamp.
In a 15-day, controlled clinical study (BRA-05-02) in patients between 18 and 50 years of age (N=128 patients), following LASIK (laser in-situ keratomileusis) procedure, Moxifloxacin/ Dexamethasone Eye Drops was non inferior to Moxifloxacin 0.5% Ophthalmic Solution + Dexamethasone Phosphate 0.1% Ophthalmic Solution in the percentage of patients with score of zero for presence of cells (between 0 and 4 cells) in the anterior chamber.
In a 8-day, controlled clinical study (BRA-07-02) in patients who were at least 18 years of age (N=102 patients), with bacterial ocular inflammation and infection (blepharitis and/or keratitis and/or conjunctivitis), Moxifloxacin/ Dexamethasone Eye Drops has demonstrated similar efficacy to Moxifloxacin 0.5% Ophthalmic Solution + Dexamethasone Phosphate 0.1% Ophthalmic Solution in the clinical cure (sum of scores = 0) for the 5 cardinal ocular signs.
Pharmacokinetics: The systemic pharmacokinetics of moxifloxacin and dexamethasone has not been studied in humans following topical ocular dosing of Moxifloxacin Ophthalmic Solution, 0.5% or Gel. However, the pharmacokinetics of moxifloxacin and dexamethasone in humans has been well characterized following oral, intravenous and topical ocular administration.
Absorption: Moxifloxacin: The corneal penetration of moxifloxacin was evaluated in adult cataract surgery patients after topical ocular administration of Moxifloxacin Ophthalmic Solution, 0.5%. Moxifloxacin readily penetrated the cornea and was well absorbed, achieving a mean maximum concentration (Cmax) of 1.61 ± 1.26 μg/mL in the aqueous humor within 2 hours post-dose following a 2 day QID dosing regimen (1 drop for 4 doses on the day prior to surgery and on the day of surgery) and a Cmax of 1.55 ± 0.71 μg/mL within 30 minutes postdose following a 1 day dosing regimen (1 drop every 15 minutes for 4 doses on the day of surgery). The plasma concentrations of moxifloxacin were measured in healthy subjects who received bilateral topical ocular doses of moxifloxacin ophthalmic solution 0.5% 3 times per day. The Cmax values at steady state (2.70 ± 1.29 ng/mL) and the estimated area under the curve (AUC0-∞;41.9 ± 15.6 ng•h/mL) were approximately 1600 and 1000 times smaller than the mean Cmax and AUC obtained following oral therapeutic doses of 400 mg of moxifloxacin. The plasma half-life of moxifloxacin was estimated to be approximately 13 hours. In a clinical pharmacokinetics study reported in the literature, oral absorption of moxifloxacin of healthy volunteers is rapid and the bioavailability is almost complete at 86%.
Dexamethasone: After topical ocular administration of dexamethasone 0.1% ophthalmic solution to patients undergoing cataract surgery, dexamethasone is detectable after 30 minutes in the aqueous humor and peaks at 90 to 120 minutes with a mean concentration of 31 ng/mL. Low but detectable concentrations are observed in the aqueous humor after 12 hours. Oral bioavailability of dexamethasone ranges from 70-80% in normal subjects and patients.
Distribution: Moxifloxacin: In humans, the volume of distribution at steady-state was approximately 2.0 L/kg at a mean terminal half-life of elimination at approximately 15 hours. Moxifloxacin is approximately 48% bound to plasma proteins. The degree of protein binding was consistent across the range of concentrations in plasma tested (0.05 to 4.7 mg/L).
Dexamethasone: The volume of distribution in humans at steady state was 0.58 L/kg. In vitro, no change in human plasma protein binding was observed with dexamethasone concentrations from 0.04 to 4 μg/mL, with a mean plasma protein binding of 77.4%.
Biotransformation/metabolism: Moxifloxacin: In humans, the metabolism of moxifloxacin is characterized by Phase II metabolic routes leading to sulfate conjugation of the secondary amine (M1) and glucuronidation of the carboxyl group (M2).
Dexamethasone: After oral administration, 6β-hydroxydexamethasone and 6β-hydroxy-20- dihydrodexamethasone have been identified as the 2 major metabolites.
Elimination: Moxifloxacin: After both iv or oral routes of administration, the terminal half-lives of elimination are similar at approximately 12 hours. The total body clearance is slow at approximately 12 L/hr. About 20% of the dose is excreted unchanged in the urine and the renal clearance was 43 mL/min. M1 is primarily excreted in the feces (34% of the dose) with little found in urine (3%). M2 is only excreted in the urine (14%).
Dexamethasone: After intravenous administration of dexamethasone, the systemic clearance was 0.125 L/hr/kg. After iv bolus administration, 2.6% of the unchanged parent drug was recovered in the urine, while up to 70% of the dose was recovered as identified metabolites. After systemic dosing, the half-life has been reported as 3-4 hours but was found to be slightly longer in males. This observed difference was not attributed to changes in systemic clearance but to differences in volume of distribution and body weight.
Linearity/non-linearity: Moxifloxacin: The pharmacokinetics of moxifloxacin was linear in the range of 50 to 800 mg following the administration of a single oral dose. The plasma concentration time curves followed very similar patterns for all doses, and no significant dose dependency was detectable.
Dexamethasone: Linear pharmacokinetics was observed after oral administration with doses between 0.5 to 1.5 mg where the AUC was less than proportional to the oral dose.
Pharmacokinetic/pharmacodynamic relationship(s): A pharmacodynamic/pharmacokinetic relationship after topical ocular administration has not been established.
Special populations: Moxifloxacin: Moxifloxacin does not exhibit age- or gender-dependent pharmacokinetics comparing young and elderly healthy volunteers.
Pediatric patients (below 18 years): Moxifloxacin: No pediatric pharmacokinetic results have been published.
Dexamethasone: Pediatric pharmacokinetics varied between age groups but wide interpatient variabilities were observed.
Renal impairment: Moxifloxacin: Dose adjustment of moxifloxacin does not appear to be necessary in those with renal dysfunction.
Dexamethasone: Pharmacokinetics of systemic dexamethasone did not significantly differ in renal-impaired patients when compared to normal subjects.
Hepatic impairment: Moxifloxacin: Dose adjustment of moxifloxacin does not appear to be necessary in those with mild to moderate hepatic impairment. The pharmacokinetics of moxifloxacin has not been studied in patients with severe hepatic insufficiency.
Toxicology: Non-clinical safety data: Effects in non-clinical studies were observed only at moxifloxacin exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Non-clinical data reveal no special hazard for humans, at the recommended clinical dose of topical ocular dexamethasone, based on repeated dose toxicity, genotoxicity or carcinogenic studies.
Reproductive toxicity: See Use in Pregnancy & Lactation.
In rats, male and female fertility was not impaired at 500 mg/kg/d doses of moxifloxacin, however alterations in sperm morphology and estrous cycle were observed. NOAEL for fertility and early embryonic development was determined to be 100 mg/kg/d. No developmental toxicity (fertility) studies have been conducted with Dexamethasone. In a non-standard study, dexamethasone enhanced fertility in primed, immature rats.
Juvenile animal studies: In an oral juvenile toxicity study in dogs with moxifloxacin, chondropathy was noted at doses of 30 mg/kg/d and above. The NOAEL was determined to be 10 mg/kg/d. No studies have been conducted to specifically address risks related to administration of dexamethasone to juvenile animals.
Microbiology: Mechanisms of Resistance: Resistance to fluoroquinolones, including moxifloxacin, occurs generally by chromosomal mutations in genes encoding DNA gyrase and topoisomerase IV. In Gram-negative bacteria, moxifloxacin resistance can be due to mutations in the multiple antibiotic resistance and quinolone resistance gene systems. Cross-resistance with beta-lactams, macrolides and aminoglycosides is not expected due to differences in mode of action.
Breakpoints: The minimal inhibitory concentration (MIC) breakpoints (mg/L) established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows (where S = susceptibility and R = resistance): Staphylococcus species S ≤ 0.5, R > 1; Streptococcus A,B,C,G S ≤ 0.5, R > 1; Streptococcus pneumoniae S ≤ 0.5, R > 0.5; Haemophilus influenzae S ≤ 0.5, R > 0.5; Moraxella catarrhalis S ≤ 0.5, R > 0.5; Enterobacteriaceae S ≤ 0.5, R > 1; Not species-related S ≤ 0.5, R > 1.
The in vitro breakpoints have been useful in predicting clinical efficacy of moxifloxacin when administered systemically. These breakpoints might not be applicable on topical ocular use of the medicinal product as higher concentrations are obtained in the eye and the local physical/chemical circumstances can influence the activity of the product on the site of administration.
Susceptibility: The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of moxifloxacin in at least some types of infections is questionable.
COMMONLY SUSCEPTIBLE SPECIES: Aerobic Gram positive micro organisms: Corynebacterium species including Corynebacterium diphtheriae, Staphylococcus aureus methicillin susceptible, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans Group.
Aerobic Gram negative micro organisms: Enterobacter cloacae, Haemophilus influenzae, Klebsiella oxytoca, Moraxella catarrhalis, Serratia marcescens.
Anaerobic micro organisms: Proprionibacterium acnes.
Other micro organisms: Chlamydia trachomatis.
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM: Aerobic Gram positive micro organisms: Staphylococcus aureus methicillin resistant, Staphylococcus coagulase negative species methicillin resistant.
Aerobic Gram negative micro organisms: Neisseria gonorrhoeae.
Other micro organisms: None.
INHERENTLY RESISTANT ORGANISMS: Aerobic Gram negative micro organisms: Pseudomonas aeruginosa.
Other micro organisms: None.
Pediatric Use: The safety and efficacy of dexamethasone/moxifloxacin have not been studied in children. For information concerning posology, precautions, and warnings for pediatric subjects see Dosage & Administration and Precautions.